**Alström Syndrome**

Cristina Maria Mihai1, Jan D. Marshall2 and Ramona Mihaela Stoicescu3

*1"Ovidius" University, Faculty of Medicine, Constanta, 2The Jackson Laboratory, Bar Harbor, ME, 3"Ovidius" University, Faculty of Pharmacy, Constanta 1,3Romania 2USA* 

#### **1. Introduction**

204 Advances in the Study of Genetic Disorders

Zammit, VA., & Moir, AM. (1994). Monitoring the partitioning of hepatic fatty acids in vivo:

Zschocke, J., Penzien, JM., Bielen, R., Casals, N., Aledo, R., Pié, J., Hoffmann, GF., Hegardt,

*Journal*, Vol. 198, No. 1 (July 1981), pp. 75-83 ISSN 7326003

pp.313-317, ISSN 7940674

12072887

esters in livers of fed or starved pregnant, lactating and weaned rats. *Biochemical* 

keeping track of control. *Trends of Biochemistry Science*, Vol. 19, No.8, (August 1994),

FG., & Mayatepek, E. (2002). The diganosis of mitochondrial HMG-CoA synthase deficiency. *The Journal of Pediatrics,* Vol. 6, No. 140, (June 2002); pp.778-780, ISSN

> Recent advancements in genetic research that have elucidated the function of some of the rare disease-causing genes have suggested that a large number of genetic disorders with widely divergent phenotypes, that were not previously identified as related, may be, in fact, highly related in cellular function or common pathways. A classic example of this is the recent category of disorders called ciliopathies. Cilia and flagella are ancient, evolutionarily conserved organelles that project from cell surfaces to perform diverse biological roles, including whole-cell locomotion; movement of fluid; chemo-, mechano-, and photosensation; and sexual reproduction. Over the past ten years, several studies demonstrated the connections between cilia, basal bodies and human diseases with a wide phenotypic spectrum, including randomization of body symmetry, obesity, cystic kidney diseases and retinal degeneration. Defects in ciliary structure or function can lead to a broader set of developmental and adult phenotypes, with mutations in ciliary proteins now associated with nephronophthisis, Joubert Syndrome, Meckel-Gruber Syndrome, Bardet-Biedl Syndrome, and Alström Syndrome (ALMS), [Badano et al., 2006]. Further study of these diverse ciliopathies could lead to an understanding of the phenotypic patterns that could potentially have predictive and therapeutic value. Alström Syndrome (ALMS; MIM #203800), first described by Carl-Henry Alström, in 1959 [Alström et al., 1959], is a rare condition that affects many body systems. ALMS is characterized by a constelation of serious or life-threatening medical problems including sensory deficits, obesity, type 2 diabetes mellitus, and multiple organ failure. The signs and symptoms of ALMS vary in severity, and not all affected individuals have all of the characteristic features of the disorder, making the diagnosis more difficult. Additionally, many of the signs and symptoms of this condition begin in infancy or early childhood, although some appear later in life. The major phenotypes usually observed in children with ALMS include cone–rod retinal dystrophy beginning in infancy and leading to juvenile blindness, sensorineural hearing impairment, insulin resistance, and obesity, and congestive heart failure (CHF) due to dilated cardiomyopathy (DCM). As patients reach adolescence, more of the major phenotypes develop, including type 2 diabetes mellitus, hypertriglyceridemia, hypothyroidism, and short adult stature. Males and females have hypogonadism and are infertile. Pulmonary, hepatic, and renal phenotypes are progressive [Marshall et al. 1997,

Alström Syndrome 207

2007a]. There is evidence that vestibular function is abnormal in some patients. [Möller, 2005]. Because hearing loss develops gradually and the onset is post-lingual, children typically do not experience the speech problems often associated with deafness. These early changes in neurosensory capabilities can have tremendous impact not only on the social development of the child but also on his/her adaptation to the external environment [Joyet

Obesity in Alström Syndrome is an early and consistent feature observed in nearly all affected children [Marshall et al., 2005, 2007a]. Body Mass Index (kg/m2) is typically greater than 25 or >95th centile, with the distribution of adipose tissue predominantly viscerally and subcutaneously [Paisey et al., 2008]. Birth weight is normal, but rapid weight gain usually begins at approximately 6 months to 1 year of age. In some individuals body weight tends to normalize, decreasing into the high-normal to normal range after adolescence. The moderation of weight does not seem to be correlated with the onset of other serious complications such as CHF, T2DM, or renal failure [Minton et al., 2006]. Wide shoulders, a barrel chest, a 'stocky' build, and truncal obesity are typical [Marshall et al., 2007a]. However, both waist circumference and body fat percentage (as measured using dualenergy X-ray absorptiometry) negatively correlated with age, and was independent of Body Mass Index, indicating the possible recruitment of more metabolically active fat stores [Minton et al., 2006]. The presence of hyperphagia has been controversial, although both hyperphagia and food obsession are common anecdotal complaints [Marshall et al., 1997,

Children grow rapidly and are initially tall for their age with a height >50th centile, with 2–3 years advanced bone age prior to puberty. However, early closure of the growth plates results in height below the 50th centile by age 14–16 years [Michaud et al., 1996]. Thoracic and lumbar scoliosis and kyphosis commonly develop in the early teenage years and can progress rapidly. Many patients have a 'buffalo hump' of increased fatty tissue above the shoulders [Marshall et al., 2005, 2007a]. Abnormalities of the insulin-like growth factor system (IGFs) of affected patients have been demonstrated [Maffei et al., 2007, Mihai et al.,

DCM can occur at any age, but is seen most typically during infancy. Onset, progression, and clinical outcome of the DCM vary, even within families [Hoffman et al., 2005, Makaryus et al., 2003]. Approximately 40% of affected infants have a transient but severe DCM with onset between age three weeks and four months [Marshall et al., 2005, Worthley & Zeitz, 2001]. Most of these children survive and make an apparently full recovery in infancy. The proportion of those with ALMS who develop infantile-onset DCM may be underestimated because some infants who succumb early may have undiagnosed Alström syndrome. A subset of 10-15% of patients does not experience infantile DCM, but develop cardiomyopathy for the first time as adolescents or adults. These patients present with a progressive restrictive cardiomyopathy [Worthley & Zeitz, 2001], identified between the teens to late 30s. Although DCM is the most common underlying cause of death in the infantile period, survival for children with infantile-onset tends to be better than that for

2008, 2009]. Yet, the exact reasons for short stature remain to be determined.

al., 2007, Van den Abeele et al., 2001].

**Obesity** 

2005].

**Growth and development** 

**Dilated cardiomyopathy** 

2005]. The primary cause of mortality among young affected patients is cardiac involvement from dilated cardiomyopathy whereas renal failure is the major cause of death among the older subgroup [Marshall et al., 1997]. Systemic fibrosis is commonly observed [Marshall et al., 2005]. About 700 affected individuals have been identified worldwide. The estimated prevalence is of <1: 5,000,000 [JD.Marshall, Personal communication]. Ethnically or geographically isolated populations have a higher-than-average frequency of Alström syndrome [Deeble et al., 2000 & Ozgül et al., 2007].

### **2. Diagnosis**

### **2.1 Clinical diagnosis**

The diagnosis of ALMS is usually established by clinical findings. Diagnosis may be delayed because some features begin at birth and others emerge as the child develops. Diagnosis can also be difficult due to variable expression of the severity of the clinical features both within and among families. It is important to note that, although some of the features are seen frequently, affected individuals may not have all of the symptoms discussed below.

### **2.1.1 Major features**

**Cone-rod dystrophy**. The first symptoms are pendular or searching nystagmus and extreme photodysphoria or light sensitivity. The retinal dystrophy in ALMS often develops within a few weeks after birth and virtually all children exhibit low vision within the first year of life [Malm et al., 2008; Russell-Eggitt et al., 1998]. Fundus examination in the first decade may be normal or may show a pale optic disc and narrowing of the retinal vessels. Electroretinography (ERG), required to establish the diagnosis of cone-rod dystrophy, is abnormal from birth, eventually with impairment of both cone and rod function. Rod function is preserved initially but deteriorates as the individual ages. By 9 – 10 years of age, visual acuity is severely impaired. There is increasing constriction of visual fields, leading to total blindness with no light perception by age 16- 20 years [Marshall et al., 2007a, Michaud et al., 1996]. The severity and age of onset of the retinal degeneration vary among ALMS patients [Malm et al., 2008]. Retinal changes include attenuated vessels, pale optic discs, and partial atrophy of the retinal pigment epithelium. Pathological studies show a reduction of cell layers in the posterior retina and depletion of peripheral cells, the outer nuclear layer, and photoreceptors [Sebag et al., 1984, Vingolo et al., 2010]. Exudative retinopathy was described in Alström Syndrome [Gogi et al., 2007]. Vision may be aided in the first few years if the child is given prescription dark, red-tinted glasses. Cataract is a common finding and some patients might transiently benefit from its treatment/removal [Marshall et al., 2005, 2007, Satman et al., 2002].

### **Progressive bilateral sensorineural hearing impairment**

Most patients develop mild-to-moderate bilateral sensorineural hearing loss in early childhood (<10 years) that is slowly progressive, particularly in the high-frequency range [Van den Abeele et al., 2001; Welsh 2007]. There is a high incidence of otitis media and fluid retention along with a high susceptibility to glue ear, which compounds the existing sensorineural impairment [Marshall et al. 2005, Michaud et al., 1997]. Hearing loss may be detected as early as age one year in some patients, although wide differences in acuity exist. Although bilateral hearing aids generally benefit most children, about 10% progress to profound deafness and must rely on tactile signing for communication [Marshall et al.,

2005]. The primary cause of mortality among young affected patients is cardiac involvement from dilated cardiomyopathy whereas renal failure is the major cause of death among the older subgroup [Marshall et al., 1997]. Systemic fibrosis is commonly observed [Marshall et al., 2005]. About 700 affected individuals have been identified worldwide. The estimated prevalence is of <1: 5,000,000 [JD.Marshall, Personal communication]. Ethnically or geographically isolated populations have a higher-than-average frequency of Alström

The diagnosis of ALMS is usually established by clinical findings. Diagnosis may be delayed because some features begin at birth and others emerge as the child develops. Diagnosis can also be difficult due to variable expression of the severity of the clinical features both within and among families. It is important to note that, although some of the features are seen

**Cone-rod dystrophy**. The first symptoms are pendular or searching nystagmus and extreme photodysphoria or light sensitivity. The retinal dystrophy in ALMS often develops within a few weeks after birth and virtually all children exhibit low vision within the first year of life [Malm et al., 2008; Russell-Eggitt et al., 1998]. Fundus examination in the first decade may be normal or may show a pale optic disc and narrowing of the retinal vessels. Electroretinography (ERG), required to establish the diagnosis of cone-rod dystrophy, is abnormal from birth, eventually with impairment of both cone and rod function. Rod function is preserved initially but deteriorates as the individual ages. By 9 – 10 years of age, visual acuity is severely impaired. There is increasing constriction of visual fields, leading to total blindness with no light perception by age 16- 20 years [Marshall et al., 2007a, Michaud et al., 1996]. The severity and age of onset of the retinal degeneration vary among ALMS patients [Malm et al., 2008]. Retinal changes include attenuated vessels, pale optic discs, and partial atrophy of the retinal pigment epithelium. Pathological studies show a reduction of cell layers in the posterior retina and depletion of peripheral cells, the outer nuclear layer, and photoreceptors [Sebag et al., 1984, Vingolo et al., 2010]. Exudative retinopathy was described in Alström Syndrome [Gogi et al., 2007]. Vision may be aided in the first few years if the child is given prescription dark, red-tinted glasses. Cataract is a common finding and some patients might transiently benefit from its treatment/removal [Marshall et al., 2005,

Most patients develop mild-to-moderate bilateral sensorineural hearing loss in early childhood (<10 years) that is slowly progressive, particularly in the high-frequency range [Van den Abeele et al., 2001; Welsh 2007]. There is a high incidence of otitis media and fluid retention along with a high susceptibility to glue ear, which compounds the existing sensorineural impairment [Marshall et al. 2005, Michaud et al., 1997]. Hearing loss may be detected as early as age one year in some patients, although wide differences in acuity exist. Although bilateral hearing aids generally benefit most children, about 10% progress to profound deafness and must rely on tactile signing for communication [Marshall et al.,

frequently, affected individuals may not have all of the symptoms discussed below.

syndrome [Deeble et al., 2000 & Ozgül et al., 2007].

**2. Diagnosis** 

**2.1 Clinical diagnosis** 

**2.1.1 Major features** 

2007, Satman et al., 2002].

**Progressive bilateral sensorineural hearing impairment** 

2007a]. There is evidence that vestibular function is abnormal in some patients. [Möller, 2005]. Because hearing loss develops gradually and the onset is post-lingual, children typically do not experience the speech problems often associated with deafness. These early changes in neurosensory capabilities can have tremendous impact not only on the social development of the child but also on his/her adaptation to the external environment [Joyet al., 2007, Van den Abeele et al., 2001].

#### **Obesity**

Obesity in Alström Syndrome is an early and consistent feature observed in nearly all affected children [Marshall et al., 2005, 2007a]. Body Mass Index (kg/m2) is typically greater than 25 or >95th centile, with the distribution of adipose tissue predominantly viscerally and subcutaneously [Paisey et al., 2008]. Birth weight is normal, but rapid weight gain usually begins at approximately 6 months to 1 year of age. In some individuals body weight tends to normalize, decreasing into the high-normal to normal range after adolescence. The moderation of weight does not seem to be correlated with the onset of other serious complications such as CHF, T2DM, or renal failure [Minton et al., 2006]. Wide shoulders, a barrel chest, a 'stocky' build, and truncal obesity are typical [Marshall et al., 2007a]. However, both waist circumference and body fat percentage (as measured using dualenergy X-ray absorptiometry) negatively correlated with age, and was independent of Body Mass Index, indicating the possible recruitment of more metabolically active fat stores [Minton et al., 2006]. The presence of hyperphagia has been controversial, although both hyperphagia and food obsession are common anecdotal complaints [Marshall et al., 1997, 2005].

#### **Growth and development**

Children grow rapidly and are initially tall for their age with a height >50th centile, with 2–3 years advanced bone age prior to puberty. However, early closure of the growth plates results in height below the 50th centile by age 14–16 years [Michaud et al., 1996]. Thoracic and lumbar scoliosis and kyphosis commonly develop in the early teenage years and can progress rapidly. Many patients have a 'buffalo hump' of increased fatty tissue above the shoulders [Marshall et al., 2005, 2007a]. Abnormalities of the insulin-like growth factor system (IGFs) of affected patients have been demonstrated [Maffei et al., 2007, Mihai et al., 2008, 2009]. Yet, the exact reasons for short stature remain to be determined.

#### **Dilated cardiomyopathy**

DCM can occur at any age, but is seen most typically during infancy. Onset, progression, and clinical outcome of the DCM vary, even within families [Hoffman et al., 2005, Makaryus et al., 2003]. Approximately 40% of affected infants have a transient but severe DCM with onset between age three weeks and four months [Marshall et al., 2005, Worthley & Zeitz, 2001]. Most of these children survive and make an apparently full recovery in infancy. The proportion of those with ALMS who develop infantile-onset DCM may be underestimated because some infants who succumb early may have undiagnosed Alström syndrome.

A subset of 10-15% of patients does not experience infantile DCM, but develop cardiomyopathy for the first time as adolescents or adults. These patients present with a progressive restrictive cardiomyopathy [Worthley & Zeitz, 2001], identified between the teens to late 30s. Although DCM is the most common underlying cause of death in the infantile period, survival for children with infantile-onset tends to be better than that for

Alström Syndrome 209

steatosis, steatohepatitis, and enlarged liver and spleen, which can progress in ALMS patients as they grow older. In some individuals, hepatic inflammation and fibrosis develops, with a highly variable age of onset, clinical course, and prognosis. As the disease progresses, liver function tests are further disturbed with altered prothrombin values or elevated International normalized ratio (INR) and ammonia. Progression to hepatic failure can occur in childhood [Quiros-Tejeira et al., 2001], but usually worsens in the second to third decades. Portal hypertension, hepatosplenomegaly, cirrhosis, esophageal varices, ascites, and liver failure are among the late clinical signs and the upper gastro-intestinal hemorrhage due to portal hypertension is a cause of death in some patients [Marshall et al., 2005, 2007a]. It is not yet known why the hepatic function becomes serious in some children, while others remain stable [Awazu et al., 1995, 1997, Connolly et al., 1991 & Marshall et al.,

Liver biopsies and postmortem examination have revealed varying degrees of steatohepatitis, hepatic fibrosis, cirrhosis, chronic nonspecific active hepatitis with lymphocytic infiltration, patchy necrosis, [Marshall et al., 2005, Quiros-Tejeira et al., 2001]. Macrovesicular steatosis can be present or absent [Marshall et al., 2005]. Other gastrointestinal manifestations include upper gastrointestinal pain, chronic diarrhea, constipation, cecal volvulus, and gastroesophageal reflux [Marshall et al., 2005; Khoo et al.,

The age of onset, progression rate, and severity of renal involvement are variable in ALMS, but most often becomes serious in adolescents or adults. Slowly progressive nephropathy, progressive glomerulofibrosis, and a gradual destruction of the kidneys are a major feature in adult patients with ALMS. Whether hypertension is a consequence of or contributes to renal dysfunction is uncertain, but it is present in ~30% of individuals [Marshall et al., 2005]. Patients may have symptoms ranging from chronic, mild kidney dysfunction to end-stage renal failure. Histopathologic changes include hyalinization of tubules and interstitial fibrosis [Goldstein and Fialkow, 1973, Marshall et al., 2005, 2007a]. There is evidence suggesting that the position of the alteration in *ALMS1* may play a r*o*le in the severity of the

Male hypogonadotropic hypogonadism results in low plasma testosterone secondary to low plasma gonadotropin concentration. Males often have a small penis and testes, usually with gynecomastia in adolescence. Atrophic fibrotic seminiferous tubules are described [Marshall et al., 2007a]. Secondary sexual characteristics such as axillary and pubic hair are normal in both males and females. In female adolescents, sexual development usually progresses normally and menarche is not delayed (average age 12 years). In a few patients, precocious puberty has occurred (age 6–10) and breast development has been delayed. The external genitalia, uterus, and fallopian tubes are normal, but menstruation is often scant, sporadic, or irregular, sometimes accompanied by endometriosis. There can be reduced plasma gonadotropin concentrations. Baseline FSH and LH in female adolescents are usually in the normal range; however, some evidence of primary hypogonadism has been reported [Quiros-Tejeira et al., 2001]. Increased androgen production and hirsuitism are common [Kocova et al., 2010]. A relatively high frequency (>20% of female patients) of ovarian cysts is reported, which may be associated with obesity and hyperinsulinemia. No ALMS patients

2005].

2009].

**Renal disease** 

renal disease [Marshall et al., 2007b]. **Hypogonadotropic hypogonadism** 

adult-onset. Marshall et al showed that while one-third of adult-onset DCM patients died, ~74% of infantile-onset DCM patients survived [Marshall et al., 2005]. As these children grow older, their cardiac function tends to be low-normal, and they remain at risk for a recurrence of CHF as adolescents or adults, with a poor prognosis. Postmortem myocardial fibrosis has been described [Minton et al., 2006]. Cardiac magnetic resonance imaging suggests myocardial fibrosis may be present both in clinically affected and asymptomatic individuals [Loudon et al., 2009].

Augmented aortic systolic pressure may also contribute to heart failure [Smith et al., 2007]. DCM in infants in the presence of nystagmus and photophobia should be a strong indicator of a diagnosis of ALMS.

#### **Pulmonary disease**

Chronic respiratory illness is one of the most frequent complaints and ranges in severity from frequent bronchial infections to chronic asthma, sinusitis/bronchitis, alveolar hypoventilation, and frequent episodes of pneumonia. The chronically inflamed airways are hyper-reactive and highly sensitive to triggering or irritating factors. In some patients, as inflammation continues, the lungs are infiltrated by fibrotic lesions and moderate to severe interstitial fibrosis has been reported [Marshall et al., 2005]. Pulmonary disease can be quite severe and include chronic obstructive pulmonary disease and pulmonary hypertension, secondary to pulmonary fibrosis. Respiratory infections with sudden reduced blood oxygen saturation have triggered sudden death. Acute hypoxia and acute respiratory distress syndrome in some older patients probably results from a combination of pulmonary fibrosis and severe scoliosis [Khoo et al., 2009; Florentzson et al., 2010].

#### **Insulin resistance/type 2 diabetes mellitus**

Two of the earliest metabolic changes in ALMS, insulin resistance and hyperinsulinemia, have been observed in patients as young as 1 year of age, sometimes before the onset of obesity [Marshall et al., 2005, 2007a]. Most children will eventually develop T2DM, some as early as age 4, but there is wide variability in the age of onset. The median age of onset is 16 years. T2DM in Alström syndrome is the result of tissue resistance to the actions of insulin, as demonstrated by an elevated plasma insulin concentration and glucose intolerance that usually present in childhood [Marshall et al., 2005, 2007a]. *Acanthosis nigricans,* a common feature in ALMS, consistent with severe insulin resistance, obesity, hyperinsulinemia, is described in about one-third of patients, whether or not they have diabetes [Marshall et al., 2005, 2007a]. However, in a small study of 12 unrelated individuals with ALMS, severe childhood obesity, BMI and waist circumference decreased with age, whereas insulin resistance increased [Minton et al., 2006]. Interestingly, ALMS patients with T2DM do not appear to develop typical peripheral sensory neuropathy symptoms and maintain good protective sensation despite comparable hyperglycemia and dyslipidemia seen in other types of diabetes. This suggests the *ALMS1* mutations might in some way protect against hyperglycemia-induced sensory neuropathy [Paisey et al., 2009]. However, studies of nerve conduction in these patients are needed to confirm these findings.

#### **Hepatic disease**

 Nearly all patients with ALMS may have some degree of liver involvement that first presents with fatty liver. Initially, overt clinical manifestations are absent, but transaminases and gamma-glutamyl transpeptidase could be elevated. Ultrasound may show evidence of

adult-onset. Marshall et al showed that while one-third of adult-onset DCM patients died, ~74% of infantile-onset DCM patients survived [Marshall et al., 2005]. As these children grow older, their cardiac function tends to be low-normal, and they remain at risk for a recurrence of CHF as adolescents or adults, with a poor prognosis. Postmortem myocardial fibrosis has been described [Minton et al., 2006]. Cardiac magnetic resonance imaging suggests myocardial fibrosis may be present both in clinically affected and asymptomatic

Augmented aortic systolic pressure may also contribute to heart failure [Smith et al., 2007]. DCM in infants in the presence of nystagmus and photophobia should be a strong indicator

Chronic respiratory illness is one of the most frequent complaints and ranges in severity from frequent bronchial infections to chronic asthma, sinusitis/bronchitis, alveolar hypoventilation, and frequent episodes of pneumonia. The chronically inflamed airways are hyper-reactive and highly sensitive to triggering or irritating factors. In some patients, as inflammation continues, the lungs are infiltrated by fibrotic lesions and moderate to severe interstitial fibrosis has been reported [Marshall et al., 2005]. Pulmonary disease can be quite severe and include chronic obstructive pulmonary disease and pulmonary hypertension, secondary to pulmonary fibrosis. Respiratory infections with sudden reduced blood oxygen saturation have triggered sudden death. Acute hypoxia and acute respiratory distress syndrome in some older patients probably results from a combination of pulmonary fibrosis

Two of the earliest metabolic changes in ALMS, insulin resistance and hyperinsulinemia, have been observed in patients as young as 1 year of age, sometimes before the onset of obesity [Marshall et al., 2005, 2007a]. Most children will eventually develop T2DM, some as early as age 4, but there is wide variability in the age of onset. The median age of onset is 16 years. T2DM in Alström syndrome is the result of tissue resistance to the actions of insulin, as demonstrated by an elevated plasma insulin concentration and glucose intolerance that usually present in childhood [Marshall et al., 2005, 2007a]. *Acanthosis nigricans,* a common feature in ALMS, consistent with severe insulin resistance, obesity, hyperinsulinemia, is described in about one-third of patients, whether or not they have diabetes [Marshall et al., 2005, 2007a]. However, in a small study of 12 unrelated individuals with ALMS, severe childhood obesity, BMI and waist circumference decreased with age, whereas insulin resistance increased [Minton et al., 2006]. Interestingly, ALMS patients with T2DM do not appear to develop typical peripheral sensory neuropathy symptoms and maintain good protective sensation despite comparable hyperglycemia and dyslipidemia seen in other types of diabetes. This suggests the *ALMS1* mutations might in some way protect against hyperglycemia-induced sensory neuropathy [Paisey et al., 2009]. However, studies of nerve

 Nearly all patients with ALMS may have some degree of liver involvement that first presents with fatty liver. Initially, overt clinical manifestations are absent, but transaminases and gamma-glutamyl transpeptidase could be elevated. Ultrasound may show evidence of

and severe scoliosis [Khoo et al., 2009; Florentzson et al., 2010].

conduction in these patients are needed to confirm these findings.

**Insulin resistance/type 2 diabetes mellitus** 

individuals [Loudon et al., 2009].

of a diagnosis of ALMS. **Pulmonary disease** 

**Hepatic disease** 

steatosis, steatohepatitis, and enlarged liver and spleen, which can progress in ALMS patients as they grow older. In some individuals, hepatic inflammation and fibrosis develops, with a highly variable age of onset, clinical course, and prognosis. As the disease progresses, liver function tests are further disturbed with altered prothrombin values or elevated International normalized ratio (INR) and ammonia. Progression to hepatic failure can occur in childhood [Quiros-Tejeira et al., 2001], but usually worsens in the second to third decades. Portal hypertension, hepatosplenomegaly, cirrhosis, esophageal varices, ascites, and liver failure are among the late clinical signs and the upper gastro-intestinal hemorrhage due to portal hypertension is a cause of death in some patients [Marshall et al., 2005, 2007a]. It is not yet known why the hepatic function becomes serious in some children, while others remain stable [Awazu et al., 1995, 1997, Connolly et al., 1991 & Marshall et al., 2005].

Liver biopsies and postmortem examination have revealed varying degrees of steatohepatitis, hepatic fibrosis, cirrhosis, chronic nonspecific active hepatitis with lymphocytic infiltration, patchy necrosis, [Marshall et al., 2005, Quiros-Tejeira et al., 2001]. Macrovesicular steatosis can be present or absent [Marshall et al., 2005]. Other gastrointestinal manifestations include upper gastrointestinal pain, chronic diarrhea, constipation, cecal volvulus, and gastroesophageal reflux [Marshall et al., 2005; Khoo et al., 2009].

#### **Renal disease**

The age of onset, progression rate, and severity of renal involvement are variable in ALMS, but most often becomes serious in adolescents or adults. Slowly progressive nephropathy, progressive glomerulofibrosis, and a gradual destruction of the kidneys are a major feature in adult patients with ALMS. Whether hypertension is a consequence of or contributes to renal dysfunction is uncertain, but it is present in ~30% of individuals [Marshall et al., 2005]. Patients may have symptoms ranging from chronic, mild kidney dysfunction to end-stage renal failure. Histopathologic changes include hyalinization of tubules and interstitial fibrosis [Goldstein and Fialkow, 1973, Marshall et al., 2005, 2007a]. There is evidence suggesting that the position of the alteration in *ALMS1* may play a r*o*le in the severity of the renal disease [Marshall et al., 2007b].

#### **Hypogonadotropic hypogonadism**

Male hypogonadotropic hypogonadism results in low plasma testosterone secondary to low plasma gonadotropin concentration. Males often have a small penis and testes, usually with gynecomastia in adolescence. Atrophic fibrotic seminiferous tubules are described [Marshall et al., 2007a]. Secondary sexual characteristics such as axillary and pubic hair are normal in both males and females. In female adolescents, sexual development usually progresses normally and menarche is not delayed (average age 12 years). In a few patients, precocious puberty has occurred (age 6–10) and breast development has been delayed. The external genitalia, uterus, and fallopian tubes are normal, but menstruation is often scant, sporadic, or irregular, sometimes accompanied by endometriosis. There can be reduced plasma gonadotropin concentrations. Baseline FSH and LH in female adolescents are usually in the normal range; however, some evidence of primary hypogonadism has been reported [Quiros-Tejeira et al., 2001]. Increased androgen production and hirsuitism are common [Kocova et al., 2010]. A relatively high frequency (>20% of female patients) of ovarian cysts is reported, which may be associated with obesity and hyperinsulinemia. No ALMS patients

Alström Syndrome 211

probably contribute to the early developmental, expressive and receptive language, and learning delays seen in many young children with ALMS. Children with a receptive language deficit also tend to have an expressive language delay. Intellectual delays and behavioral issues in rare cases have resulted in a diagnosis of mental retardation. A range of autism-spectrum behavior has been observed in a subset of patients [Marshall et al., 2005,

Other neurologic manifestations may include absence seizures and general sleep disturbances [Marshall et al., 2005, 2007a]. The frequency of mood and psychiatric disorders

The combined effect of hearing loss and an accompanying multiple disabilities present a unique and complex problem to professionals and parents, different from the problems usually associated with any disability alone. A review of the literature yields surprisingly little specific information on educational programs for such children. The fact that there are many differences among children with multiple disabilities adds to the difficulties of

A major problem in arriving at a diagnosis of ALMS is the high phenotypic heterogeneity that can occur even within the same affected family [Ozgül et al., 2007, Hoffman et al., 2005 & Titomanilo et al., 2004]. Marshall and co-workers [Marshall et al., 2007a] provided a comprehensive guidance for diagnostic criteria in their 2007 publication, as summarized

Major criteria: 1) *ALMS1* mutation in 1 allele and/or family history of Alström

2) Vision pathology (nystagmus, photophobia).

Recurrent pulmonary infections, normal digits, delayed

If old enough for testing: cone dystrophy by ERG.

2) Vision pathology (nystagmus, photophobia, diminished acuity).

in ALMS-affected individuals has not been determined [Joy et al., 2007].

Birth – 2 years: Diagnosis requires 2 major or 1 major and 2 minor criteria

2) DCM with CHF.

developmental milestones.

3–14 years of age: diagnosis requires 2 major criteria or 1 major and 3 minor criteria Major criteria: 1) *ALMS1* mutation in 1 allele and/or family history of Alström

Minor criteria: 1) Obesity and/or insulin resistance and/or T2DM 2) History of DCM with CHF

4) Hepatic dysfunction

3) Hearing loss

5) Renal failure 6) Advanced bone age

Syndrome

Syndrome

2007a].

below:

Other variable supportive evidence

providing appropriate programs.

**2.2 Diagnostic criteria in Alström Syndrome** 

Minor criteria: 1) Obesity

have been known to reproduce – the few cases where this is "reported" are in patients without a confirmed molecular diagnosis [Boor et al., 1993].

### **Hypertriglyceridemia**

Hyperlipidemia, particularly hypertriglyceridemia, can be present from early childhood. In some patients, a sudden, rapid rise in triglycerides places them at risk for pancreatitis [Paisey et al., 2009, Wu et al., 2002]. Other features in Alström Syndrome, such as hyperinsulinemia, may also contribute to the elevated triglycerides [Maffei et al., 2002, 2007].

### **2.1.2 Minor features**

#### **Hypothyroidism**

A hypothyroid condition, mostly primary (low free thyroxine (FT4), high thyroidstimulating hormone (TSH)), is observed in approximately 20% of patients [Michaud et al., 1996]. Subclinical hypothyroidisms in about 30% of patients and isolated incidents of hyperthyroidism have been observed [Ozgül et al., 2007]. The mechanism of the hypothyroidism remains unknown, although it could be hypothesized that fibrotic infiltrations in the thyroid gland play a role.

#### **Dental abnormalities**

Dental anomalies include discolored teeth, gingivitis, a large space between the front teeth, and extra or missing teeth [Koray et al., 2001].

#### **Hands and feet**

Most children have characteristic wide, thick, flat feet, and short stubby fingers and toes with no polydactyly or syndactyly. Rare cases of digit anomalies have been reported [Marshall et al., 2007a].

#### **Urological dysfunction**

Males and females with ALMS can experience varying degrees of urinary problems. Minor symptoms include urinary urgency, difficulty initiating or poor flow, long intervals between voiding, incomplete voiding (urinary retention) or abdominal pain before or during urination [Marshall et al., 2005]. There can be an unusual changing presentation, switching from retention to increased frequency, and incontinence. Recurrent urinary tract infections or cystitis are common in both males and females. Urethral strictures have also been described and fibrotic infiltrations have been noted histopathologically. A subset of patients have developed more severe complications such as marked frequency and urgency, incontinence, and significant perineal or abdominal pain requiring surgical intervention [Charles et al., 1990, Marshall et al., 2005, 2007a]. Anatomical abnormalities can also occur in ALMS, including calyceal deformities, narrowed ureteropelvic angles, dilated ureters, and misalignment of the kidneys [Ozgül et al., 2007].

#### **Developmental delay**

Although delay of cognitive impairment is not a common feature of ALMS, delay in early developmental milestones is seen in ~45% of affected children. Motor milestones, in particular sitting, standing, and walking, are typically delayed by 1–2 years and there may be deficits in coordination, balance, and fine motor skills. Hearing and vision deficits

have been known to reproduce – the few cases where this is "reported" are in patients

Hyperlipidemia, particularly hypertriglyceridemia, can be present from early childhood. In some patients, a sudden, rapid rise in triglycerides places them at risk for pancreatitis [Paisey et al., 2009, Wu et al., 2002]. Other features in Alström Syndrome, such as hyperinsulinemia, may also contribute to the elevated triglycerides [Maffei et al., 2002,

A hypothyroid condition, mostly primary (low free thyroxine (FT4), high thyroidstimulating hormone (TSH)), is observed in approximately 20% of patients [Michaud et al., 1996]. Subclinical hypothyroidisms in about 30% of patients and isolated incidents of hyperthyroidism have been observed [Ozgül et al., 2007]. The mechanism of the hypothyroidism remains unknown, although it could be hypothesized that fibrotic

Dental anomalies include discolored teeth, gingivitis, a large space between the front teeth,

Most children have characteristic wide, thick, flat feet, and short stubby fingers and toes with no polydactyly or syndactyly. Rare cases of digit anomalies have been reported

Males and females with ALMS can experience varying degrees of urinary problems. Minor symptoms include urinary urgency, difficulty initiating or poor flow, long intervals between voiding, incomplete voiding (urinary retention) or abdominal pain before or during urination [Marshall et al., 2005]. There can be an unusual changing presentation, switching from retention to increased frequency, and incontinence. Recurrent urinary tract infections or cystitis are common in both males and females. Urethral strictures have also been described and fibrotic infiltrations have been noted histopathologically. A subset of patients have developed more severe complications such as marked frequency and urgency, incontinence, and significant perineal or abdominal pain requiring surgical intervention [Charles et al., 1990, Marshall et al., 2005, 2007a]. Anatomical abnormalities can also occur in ALMS, including calyceal deformities, narrowed ureteropelvic angles, dilated ureters, and

Although delay of cognitive impairment is not a common feature of ALMS, delay in early developmental milestones is seen in ~45% of affected children. Motor milestones, in particular sitting, standing, and walking, are typically delayed by 1–2 years and there may be deficits in coordination, balance, and fine motor skills. Hearing and vision deficits

without a confirmed molecular diagnosis [Boor et al., 1993].

**Hypertriglyceridemia** 

**2.1.2 Minor features Hypothyroidism** 

**Dental abnormalities** 

[Marshall et al., 2007a]. **Urological dysfunction** 

**Developmental delay** 

**Hands and feet** 

infiltrations in the thyroid gland play a role.

and extra or missing teeth [Koray et al., 2001].

misalignment of the kidneys [Ozgül et al., 2007].

2007].

probably contribute to the early developmental, expressive and receptive language, and learning delays seen in many young children with ALMS. Children with a receptive language deficit also tend to have an expressive language delay. Intellectual delays and behavioral issues in rare cases have resulted in a diagnosis of mental retardation. A range of autism-spectrum behavior has been observed in a subset of patients [Marshall et al., 2005, 2007a].

Other neurologic manifestations may include absence seizures and general sleep disturbances [Marshall et al., 2005, 2007a]. The frequency of mood and psychiatric disorders in ALMS-affected individuals has not been determined [Joy et al., 2007].

The combined effect of hearing loss and an accompanying multiple disabilities present a unique and complex problem to professionals and parents, different from the problems usually associated with any disability alone. A review of the literature yields surprisingly little specific information on educational programs for such children. The fact that there are many differences among children with multiple disabilities adds to the difficulties of providing appropriate programs.

#### **2.2 Diagnostic criteria in Alström Syndrome**

A major problem in arriving at a diagnosis of ALMS is the high phenotypic heterogeneity that can occur even within the same affected family [Ozgül et al., 2007, Hoffman et al., 2005 & Titomanilo et al., 2004]. Marshall and co-workers [Marshall et al., 2007a] provided a comprehensive guidance for diagnostic criteria in their 2007 publication, as summarized below:


Alström Syndrome 213

patients are diagnosed with developmental delay, based on the assessment of early development milestones. Liver involvement develops variabily, between 8 and 30 years of age, in 23-98% of patients. Over 98% are diagnosed with short stature after puberty or in adulthood. Among the endocrine abnormalities, hypogonadotropic hypogonadism was

Alström Syndrome is the consequence of recessively inherited mutations in a single gene, *ALMS1,* located on the short arm of chromosome 2 [Collin et al., 2002, Hearn et al., 2002]. Parents are obligate carriers of a single copy of the altered gene and have no reported heterozygous phenotypic characteristics. Males and females are affected with equal probability (1:1 ratio). Although the incidence is greater in isolated or consanguineous communities, there is no one ethnic group more likely to carry *ALMS1* mutations [Marshall

*ALMS1* is comprised of 23 exons. The longest *ALMS1* transcript potentially encodes a 461 kDa protein of 4169 amino acids. Exon 1 contains a tract of glutamic acid residues (aa 13–29), followed by a stretch of seven alanine residues (aa 30−36) [Collin et al., 2002, Hearn et al., 2002]. Exon 8, a large 6-kb exon, contains a large tandem repeat domain encoding 34 imperfect repeats of 45–50 amino acids. This domain constitutes 40% of the protein, a short polyglutamine segment, a leucine zipper domain and a conserved motif near the C-

The *ALMS1* protein is ubiquitously expressed and at least one isoform localizes to centrosomes and basal bodies of ciliated cells, perhaps playing an important role in cilia function and intraflagellar transport [Collin et al., 2005, Hearn et al., 2005; Knorz et al., 2010]. RNA interference knockdown experiments indicate that a total lack of *ALMS1* impairs cilia

To date, the mutations reported in *ALMS1* have been nonsense and frameshift variations (insertions or deletions) and one reciprocal translocation that are predicted to cause premature protein truncation [Collin et al., 2002, Hearn et al., 2002]. Since 2002, more than 100 different mutations in *ALMS1* have been identified. The variants are primarily clustered in exons 16, 10, and 8, but less common mutations also occur in exons 12 and 18 [Marshall et al., 2007a; Joy et al., 2007; Pereiro, et al., 2010]. Founder effects are reported in families of English and Turkish descent. In addition, numerous single-nucleotide polymorphisms have been identified, the functional significance of which is unclear [Marshall et al., 2007a]. The mechanisms by which disease alleles of *ALMS1* cause the various pathologies observed in Alström Syndrome remain unknown and identification of pathogenic mutations in *ALMS1* has not led to any genotype-specific treatments [Hearn et al., 2005, Kinoshita et al., 2003, Li

*ALMS1* RNA is widely expressed by many tissues. Splice variants have been identified from human brain and testis which may suggest differing functions of theALMS1 protein

The ubiquitous expression of *ALMS1* correlates with the wide range of organ dysfunction in ALMS and suggests that the C-terminal portion of the Alms1 protein that is missing in ALMS patients plays a critical role in disease causation [Girard & Petrovsky, 2010]. Because *ALMS1* is a very large gene, complete sequencing is time consuming and expensive. Therefore, we recommend a screening strategy that targets the regions of *ALMS1* where most of the mutations are seen (exons 16, 10, part of 8). If no mutation is identified in these

diagnosed in 78% of males.

**2.4 Genetic diagnosis** 

et al, 2007a].

terminus.

formation [Li G et al., 2007].

G et al., 2007, Minton et al., 2006 & Patel et al., 2006].

between organs [Hearn et al., 2002].


Table 1.

In conclusion, ALMS is a very complex disorder, being characterized by a constellation of progressive and highly variable disease symptoms. Diagnosis is made on the basis of clinical features observed, usually without genetic confirmation. Delay of onset of some of the characteristic features (type 2 diabetes mellitus, DCM/chronic heart failure, hepatic dysfunction, pulmonary, and renal disease) makes early differential diagnosis very difficult in young children, as many of the cardinal features do not become apparent until the teenage years. As the child grows, the characteristic pattern of ALMS evolves and the clinical picture becomes clearer.

#### **2.3 Age of onset and incidence of common features of Alström Syndrome**

Marshall and co-workers [Marshall et al., 2005] described the age of onset and the incidence of common features of Alstrom syndrome. Cone-rod dystrophy was diagnosed in 100% of ALMS patients between birth and 15 months. Obesity usually begins to develop during the first year, birth weight being normal. Hearing loss is progressive and presents in 88% of cases during the first 9 years. Dilated cardiomyopathy could be diagnosed in 42% of infants under 4 months of age. In adolescents and adults the pattern is often restrictive cardiomyopathy, with an overall incidence of 18%. Insulin resistance/type 2 diabetes can be diagnosed in children as young as 4 years of age. While urologic dysfunction can be seen at any age, chronic renal failure begins in adolescents and adults. About 25-30 % of ALMS

infections, growth hormone deficiency

15 years – adulthood: 2 major and 2 minor criteria or 1 major and 4 minor criteria Major criteria: 1) ALMS1 mutation in 1 allele and/or family history of Alström

Minor criteria: 1) Obesity and/or insulin resistance and/or T2DM

4) Hepatic dysfunction

3) Hearing loss

5) Renal failure 6) Short stature

**2.3 Age of onset and incidence of common features of Alström Syndrome** 

2) History of DCM with CHF.

and/or hyperandrogenism

In conclusion, ALMS is a very complex disorder, being characterized by a constellation of progressive and highly variable disease symptoms. Diagnosis is made on the basis of clinical features observed, usually without genetic confirmation. Delay of onset of some of the characteristic features (type 2 diabetes mellitus, DCM/chronic heart failure, hepatic dysfunction, pulmonary, and renal disease) makes early differential diagnosis very difficult in young children, as many of the cardinal features do not become apparent until the teenage years. As the child grows, the characteristic pattern of ALMS evolves and the

Marshall and co-workers [Marshall et al., 2005] described the age of onset and the incidence of common features of Alstrom syndrome. Cone-rod dystrophy was diagnosed in 100% of ALMS patients between birth and 15 months. Obesity usually begins to develop during the first year, birth weight being normal. Hearing loss is progressive and presents in 88% of cases during the first 9 years. Dilated cardiomyopathy could be diagnosed in 42% of infants under 4 months of age. In adolescents and adults the pattern is often restrictive cardiomyopathy, with an overall incidence of 18%. Insulin resistance/type 2 diabetes can be diagnosed in children as young as 4 years of age. While urologic dysfunction can be seen at any age, chronic renal failure begins in adolescents and adults. About 25-30 % of ALMS

Recurrent pulmonary infections, normal digits, history of developmental delay, hyperlipidemia, scoliosis, flat wide feet,

hypothyroidism, hypertension, recurrent urinary tract infections/urinary dysfunction, growth hormone deficiency,

Syndrome

alopecia.

Recurrent pulmonary infections, normal digits, delayed developmental milestones, hyperlipidemia, scoliosis, flat wide feet, hypothyroidism, hypertension, recurrent urinary tract

2) Vision pathology (history of nystagmus in infancy/childhood,

7) Males: hypogonadism. Females: irregular menses

legal blindness, cone and rod dystrophy by ERG).

Other variable supportive evidence

Other variable supportive evidence

clinical picture becomes clearer.

Table 1.

patients are diagnosed with developmental delay, based on the assessment of early development milestones. Liver involvement develops variabily, between 8 and 30 years of age, in 23-98% of patients. Over 98% are diagnosed with short stature after puberty or in adulthood. Among the endocrine abnormalities, hypogonadotropic hypogonadism was diagnosed in 78% of males.

#### **2.4 Genetic diagnosis**

Alström Syndrome is the consequence of recessively inherited mutations in a single gene, *ALMS1,* located on the short arm of chromosome 2 [Collin et al., 2002, Hearn et al., 2002]. Parents are obligate carriers of a single copy of the altered gene and have no reported heterozygous phenotypic characteristics. Males and females are affected with equal probability (1:1 ratio). Although the incidence is greater in isolated or consanguineous communities, there is no one ethnic group more likely to carry *ALMS1* mutations [Marshall et al, 2007a].

*ALMS1* is comprised of 23 exons. The longest *ALMS1* transcript potentially encodes a 461 kDa protein of 4169 amino acids. Exon 1 contains a tract of glutamic acid residues (aa 13–29), followed by a stretch of seven alanine residues (aa 30−36) [Collin et al., 2002, Hearn et al., 2002]. Exon 8, a large 6-kb exon, contains a large tandem repeat domain encoding 34 imperfect repeats of 45–50 amino acids. This domain constitutes 40% of the protein, a short polyglutamine segment, a leucine zipper domain and a conserved motif near the Cterminus.

The *ALMS1* protein is ubiquitously expressed and at least one isoform localizes to centrosomes and basal bodies of ciliated cells, perhaps playing an important role in cilia function and intraflagellar transport [Collin et al., 2005, Hearn et al., 2005; Knorz et al., 2010]. RNA interference knockdown experiments indicate that a total lack of *ALMS1* impairs cilia formation [Li G et al., 2007].

To date, the mutations reported in *ALMS1* have been nonsense and frameshift variations (insertions or deletions) and one reciprocal translocation that are predicted to cause premature protein truncation [Collin et al., 2002, Hearn et al., 2002]. Since 2002, more than 100 different mutations in *ALMS1* have been identified. The variants are primarily clustered in exons 16, 10, and 8, but less common mutations also occur in exons 12 and 18 [Marshall et al., 2007a; Joy et al., 2007; Pereiro, et al., 2010]. Founder effects are reported in families of English and Turkish descent. In addition, numerous single-nucleotide polymorphisms have been identified, the functional significance of which is unclear [Marshall et al., 2007a]. The mechanisms by which disease alleles of *ALMS1* cause the various pathologies observed in Alström Syndrome remain unknown and identification of pathogenic mutations in *ALMS1* has not led to any genotype-specific treatments [Hearn et al., 2005, Kinoshita et al., 2003, Li G et al., 2007, Minton et al., 2006 & Patel et al., 2006].

*ALMS1* RNA is widely expressed by many tissues. Splice variants have been identified from human brain and testis which may suggest differing functions of theALMS1 protein between organs [Hearn et al., 2002].

The ubiquitous expression of *ALMS1* correlates with the wide range of organ dysfunction in ALMS and suggests that the C-terminal portion of the Alms1 protein that is missing in ALMS patients plays a critical role in disease causation [Girard & Petrovsky, 2010]. Because *ALMS1* is a very large gene, complete sequencing is time consuming and expensive. Therefore, we recommend a screening strategy that targets the regions of *ALMS1* where most of the mutations are seen (exons 16, 10, part of 8). If no mutation is identified in these

Alström Syndrome 215

*Leber congenital* 

No

No

No

No

No

No

Normal/

delayed

*amaurosis* (*LCA*)

*Wolfram*

No

Yes

Diabetic

No

n-dependent

diabetes mellitus

insuli

No

behavior problems

Normal,

Diabetes insipidus,

nephropathy

(*DIDMOAD*)

*Cohen Syndrome*

No

No

No

obesity, thin

No

No

Moderate-tosevere delay

arms and legs

Yes, abdominal

*Biemond II* 

*Syndrome*

No

No

No

Yes

No

Yes

n

Mental retardatio

Respiratory

Neurosensory

Renal

Obesity

Diabetes

Hypogonadism

Mental

development

hearing loss

*Alström* 

failure,

Pulmonary

*Syndrome*

recurrent

Yes (90%)

Glomerulosclerosis

Yes

T2DM (90%)

Yes

Normal/delayed

cough

*Bardet–Biedl* 

 *Syndrome*

No

Yes (5–20%)

Structural

renal

Yes

T2DM (5–15%)

Yes

Mental retardation

(50%)

abnormalities

(*BBS* #*1-14*)

*Congenital* 

No

No

No

No

No

No

Normal/

delayed

*achromatopsia*

areas, the remaining genomic regions can be sequenced on a research basis. The sensitivity of this approach is approximately 65%, that is, in about 42% of all patients both mutations will be detected, in about half of the patients, only one of the two mutations will be found, and in about 10% of the patients, none of the mutations will be found. The recent development of an-ALMS mutation array to detect known mutations in *ALMS1* (Asper Biotech (www.asperbio.com) can be used as an efficient and cost-effective first pass screening for known mutations *ALMS1* and 10 known Bardet-Biedl Syndrome (BBS) genes [Pereiro et al.,2010]. New technological developments including target capture and next generation sequencing will offer the possibility of efficient and cost-effective identification of novel *ALMS1* mutations and for carrier testing [Bell et al., 2011]

The possible results of genetic testing must be interpreted within the context of the clinical picture [Marshall et al., 2007a]:



### **3. Differential diagnosis of Alström Syndrome [Marshall et al., 2007a]**


#### Alström Syndrome 215

214 Advances in the Study of Genetic Disorders

areas, the remaining genomic regions can be sequenced on a research basis. The sensitivity of this approach is approximately 65%, that is, in about 42% of all patients both mutations will be detected, in about half of the patients, only one of the two mutations will be found, and in about 10% of the patients, none of the mutations will be found. The recent development of an-ALMS mutation array to detect known mutations in *ALMS1* (Asper Biotech (www.asperbio.com) can be used as an efficient and cost-effective first pass screening for known mutations *ALMS1* and 10 known Bardet-Biedl Syndrome (BBS) genes [Pereiro et al.,2010]. New technological developments including target capture and next generation sequencing will offer the possibility of efficient and cost-effective identification

The possible results of genetic testing must be interpreted within the context of the clinical

• 1 mutation in *ALMS1* together with clinical signs of Alström Syndrome. Diagnosis: very strong evidence for the confirmation of ALMS (although about 0.25% of all healthy

• No ALMS1 mutation identified. This does not exclude the diagnosis, in the presence of

*Leber* 

*congenital* 

204000

Cone dystrophy (infancy)

No

*amaurosis*

(*LCA*)

*Wolfram*

222300

Optic atrophy

No

(*DIDMOAD*)

*Cohen* 

216550

Rod–cone dystrophy >5

years myopia, bulls-eye

No

maculopathy, peripheral

vision loss

Coloboma,

*Syndrome*

*Biemond II* 

210350

microphthalmia, aniridia,

No

cataract

*Syndrome*

**3. Differential diagnosis of Alström Syndrome [Marshall et al., 2007a]** 

*achromatopsia*

*Congenital* 

216900

262300

Cone dystrophy

No

139340

of novel *ALMS1* mutations and for carrier testing [Bell et al., 2011]

• 2 mutations identified in ALMS1. Diagnosis: ALMS.

individuals could also show this result).

clinical manifestations suggestive for ALMS.

*Bardet–Biedl* 

 *Syndrome*

209900

Night blindness, rod–cone

dystrophy

Congenital heart

defects (5–10%)

(age 10–16)

(*BBS* #*1-14*)

picture [Marshall et al., 2007a]:

*Alström* 

203800

Cone dystrophy,

Yes

photophobia

*Syndrome*

OMIM

Vision

Cardiac


Table 2.

Alström Syndrome 217

There is no treatment at this time that can cure ALMS or prevent or reverse the medical

Early diagnosis is important to allow counseling of parents and institution of appropriate supportive medical treatment. In the absence of specific therapy to correct the underlying genetic defect, ALMS remains a progressive disease and regular intensive medical management is essential to track progression and to anticipate the emergence of new

Cardiac, renal and liver review should be routinely performed in all ALMS patients, even if

The main causes of death in ALMS are from cardiomyopathy, pulmonary, kidney or liver failure [Marshall et al., 2005, Benso et al., 2002]. In the end stage, multiple organs are

Vision and hearing loss can impact the social and educational success of the child, so, management of the multiple sensory deficits in young children diagnosed with ALMS and

Photophobia and nystagmus are serious problems, particularly in younger children. Regular ophthalmologic evaluations should be sought as soon as possible [Gogi et al., 2007]. Redtinted prescription glasses are helpful in alleviating the distress children experience in bright lighting. No therapy for the progressive vision loss exists, but early evaluation of visual acuity facilitates the provision of visual aids and helps prepare the child for a future with little or no sight. Educational planning should anticipate future blindness, therefore, early mobility training and Braille or other non-visual language skills is critically important for the learning environment of the child. Computing skills (including voice recognition and transcription software), and the use of large print reading materials early on while vision is

Hearing evaluation should begin early in childhood, as otoacoustic emissions and audiometry may reveal subclinical hearing loss. Conductive loss is common in children as a result of chronic otitis media. Hearing can usually be effectively managed with bilateral digital hearing aids, but should be monitored regularly. Myringotomy has been helpful in individuals with recurrent "glue ear". Cochlear implantation has benefitted some patients, but surgeons should be aware of the risk of sudden hypoxia for these patients undergoing

Candidate therapeutic intervention to treat severe insulin resistance and possibly prevent the transition from insulin resistance to overt diabetes include insulin-sensitizing drugs (metformin and thiazolidinediones) [Sinha et al., 2007 as cited in Atabek, 2007, Nag S et al.,

**4. Management** 

symptoms and disease manifestations.

**4.1 Management of sensory deficits** 

still present are crucial [Marshall et al 2010].

**4.1.2 Progressive sensorineural hearing loss** 

**4.2 Obesity. Insulin resistance/Type 2 diabetes** 

procedures requiring anesthesiology [Florentzson et al., 2010].

The major clinical treatment focus is on control of obesity and T2DM.

**4.1.1 Rod-cone dystrophy** 

compromised, and sudden multiple organ failure is common.

social support at school are crucial [Marshall et al., 2007a].

complications.

asymptomatic.

*Leber* 

*congenital* 

*amaurosis*

No

Normal

No

(*LCA*)

*Wolfram*

No

Urinary atony

Normal

No

*WFS1* (4p16)

*COH1* (8q22)

(*DIDMOAD*)

*Cohen* 

No

Narrow hands

and feet,

Characteristic

facial features

tapered fingers

Postaxial

Absent incisors,

microcephaly,

characteristic

facial features

polydactyly,

scoliosis

*Syndrome*

*Biemond II* 

*Syndrome*

No

Hepatic

Urologic

Orthopedic

Head

Genetic

Table 2.

*Alström* 

Steatosis

Varying

Short fingers,

wide flat feet,

No

*ALMS1* (2p13)

scoliosis

degrees of

urinary

problems (25%)

*Syndrome*

cirrhosis

*Bardet–Biedl* 

 *Syndrome*

Steatosis

Poly-, brachy-,

High-arched

*BBS1*, *BBS2*, *ARL6/BBS3*, *BBS4*, *BBS5*, *MKKS/BBS6*,

*BBS7*, *TTC8/BBS8*, *B1/BBS9*, *BBS10*, *TRIM32/BBS11,* 

*BBS12, MKS1/BBS13,*

*CNGA3*

*CNGB3GNAT2*

*GUCY2D* (LCA1), *RPE65* (LCA2), *SPATA7* (LCA3),

*AIPL1* (LCA4), *LCA5* (LCA5), *RPGRIP1* (LCA6), *CRX*

(LCA7), *CRB1* (LCA8), *CEP290* (LCA10), *IMPDH1*

(LCA11), *RD3* (LCA12), and *RDH12* (LCA13).

*CEP290/BBS14*.

palate,

hypodontia

and syndactyly

(*BBS* #*1-14*)

*Congenital* 

No

Normal

No

*achromatopsia*

### **4. Management**

There is no treatment at this time that can cure ALMS or prevent or reverse the medical complications.

Early diagnosis is important to allow counseling of parents and institution of appropriate supportive medical treatment. In the absence of specific therapy to correct the underlying genetic defect, ALMS remains a progressive disease and regular intensive medical management is essential to track progression and to anticipate the emergence of new symptoms and disease manifestations.

Cardiac, renal and liver review should be routinely performed in all ALMS patients, even if asymptomatic.

The main causes of death in ALMS are from cardiomyopathy, pulmonary, kidney or liver failure [Marshall et al., 2005, Benso et al., 2002]. In the end stage, multiple organs are compromised, and sudden multiple organ failure is common.

### **4.1 Management of sensory deficits**

Vision and hearing loss can impact the social and educational success of the child, so, management of the multiple sensory deficits in young children diagnosed with ALMS and social support at school are crucial [Marshall et al., 2007a].

#### **4.1.1 Rod-cone dystrophy**

Photophobia and nystagmus are serious problems, particularly in younger children. Regular ophthalmologic evaluations should be sought as soon as possible [Gogi et al., 2007]. Redtinted prescription glasses are helpful in alleviating the distress children experience in bright lighting. No therapy for the progressive vision loss exists, but early evaluation of visual acuity facilitates the provision of visual aids and helps prepare the child for a future with little or no sight. Educational planning should anticipate future blindness, therefore, early mobility training and Braille or other non-visual language skills is critically important for the learning environment of the child. Computing skills (including voice recognition and transcription software), and the use of large print reading materials early on while vision is still present are crucial [Marshall et al 2010].

### **4.1.2 Progressive sensorineural hearing loss**

Hearing evaluation should begin early in childhood, as otoacoustic emissions and audiometry may reveal subclinical hearing loss. Conductive loss is common in children as a result of chronic otitis media. Hearing can usually be effectively managed with bilateral digital hearing aids, but should be monitored regularly. Myringotomy has been helpful in individuals with recurrent "glue ear". Cochlear implantation has benefitted some patients, but surgeons should be aware of the risk of sudden hypoxia for these patients undergoing procedures requiring anesthesiology [Florentzson et al., 2010].

#### **4.2 Obesity. Insulin resistance/Type 2 diabetes**

The major clinical treatment focus is on control of obesity and T2DM.

Candidate therapeutic intervention to treat severe insulin resistance and possibly prevent the transition from insulin resistance to overt diabetes include insulin-sensitizing drugs (metformin and thiazolidinediones) [Sinha et al., 2007 as cited in Atabek, 2007, Nag S et al.,

Alström Syndrome 219

hormone deficiency condition in 15 young adults with ALMS [Maffei et al., 2000]. RhGH therapy should be considered still investigational [Marshall et al. 2007a]. Several studies are needed to prove that this therapy is cost-effective and without risk in patients with

Patients diagnosed with ALMS should be regularly monitored for cardiac function by echocardiography, even if asymptomatic [Makaryus et al., 2002, Zubrow et al., 2006]. Several authors [Loudon et al., 2009, Makaryus et al., 2007] stated the importance of serial cardiac magnetic resonance scanning in diagnosis of the underlying disease progression and responses to treatment. Long-term angiotensin-converting enzyme inhibition is indicated for the patient with cardiomyopathy. Many patients respond to other medications, which favorably affect heart function, such as diuretics, digitalis, beta-blockers, and spironolactone. Whether cardiac transplantation is a viable option is yet to be determined, due to the multisystemic involvement, particularly pulmonary, endocrine, and renal function. There has been one successful heart-lung transplantation reported in an adolescent patient with Alström Syndrome, but with no T2DM or significant renal failure [Görler et al., 2007]. A second successful heart transplant has been achieved in an infant prior to the onset of the

endocrinological and renal disturbances [JD Marshall, Personal communication].

necessary in rare patients [Marshall et al., 2007; Charles, et al. 1990].

Replacement therapy with L-thyroxin, when needed, is very effective and well-tolerated in

Thyroid function should be monitored closely in critical hospital settings [Marshall et al., 2007].

Lack of coordination between bladder and urine outflow (detrusor-urethral dyssynergia) can be helped by intermittent self-catheterization of the bladder. Ileal diversion may be

If abnormalities in pubertal development or menstrual abnormalities are present, the affected individual should be referred to an endocrinologist with expertise in sexual developmental abnormalities. Primary hypogonadism in ALMS males result in low levels of testosterone, treated with weekly or twice monthly injections of testosterone from puberty onwards. Treatment with cyclical oestrogen and progesterone is important and effective to

 Liver function parameters should be routinely monitored, beginning in childhood. Portal hypertension and varices may be aggressively treated with beta-blockers and sclerotherapy of the esophageal veins. Variceal banding could be useful to prevent upper gastro-intestinal hemorrhage. A transjugular intrahepatic portosystemic shunt (TIPS) is used to treat the complications of portal hypertension, when the patient has failed to respond to previous therapeutic measures. Patients with significant portal hypertension should be evaluated

ALMS and severe insulin resistance.

**4.5 Cardiomyopathy** 

**4.6 Thyroid** 

**4.7 Urologic** 

the majority of patients.

**4.9 Hepatic disease** 

**4.8 Hypogonadotropic hypogonadism** 

regulate menstrual cycle and development.

early for liver transplantation [Marshall et al., 2007].

2003] and beta cell-preserving drugs (incretins, thiazolidinediones) [Pagano et al., 2008, Paisey et al., 2009]. However, this requires close monitoring of liver, cardiac, and renal function. Glitazones are added to further reduce insulin resistance but must be avoided in the presence of active or treated heart failure and when the serum creatinine concentration exceeds 200 µmol/L. Exenatide, an incretin mimetic, an injectable analogue of glucagon-like peptide 1(GLP- 1) could be promising in adults with ALMS.

Weight loss exercises should play a pivotal role in weight reduction plan for ALMS patients, as in other patients diagnosed with dibetes and obesity, although could be challenging. Walking, hiking, biking, and swimming with partners and adaptations for the blind have been helpful. Peripheral sensor-motor neuropathy is a common complication of T2DM, but in a small clinical testing study in ALMS, a full preservation of protective foot sensation was demonstrated [Paisey et al., 2009]. The responsiveness to treatment of hyperglycemia is variable. Younger patients rarely require insulin, but some patients require insulin in veryhigh doses long term [Marshall et al., 2007a].

Caloric restriction helps control obesity, glucose tolerance and hyperinsulinemia [Holder et al., Lee et al., 2009 & Paisey et al. 2008], although as with children with other genetically acquired obesity syndromes, dietary compliance may be a major problem. Reducing dietary carbohydrates may prove more effective than fat restriction in control of hyperglycemia and hyperinsulinemia [Paisey et al., 2008]. No clinical experience has been reported in ALMS of use of specific appetite suppressant medication, such as duramine or sibutramine.

### **4.3 Hypertriglyceridemia**

Insulin resistance, T2DM, dyslipidaemia and associated cardiac, renal and hepatic consequences coexist from a young age with considerable morbidity and reduction in life expectancy. ALMS patients can have potentially harmfully increased lipid levels. Hypertriglyceridemia can often be normalized by diet, exercise and Metformin. Some patients with severe hypertriglyceridemia responded to a combination of low-fat diet, statins and nicotinic acid [Paisey et al., 2004], very little data existing, however, about the safety and efficacy of such treatments before puberty.

Early introduction of preventative nutrition with low-carbohydrates, exercise and drug therapies (niacin extended-release and incretins) in ALMS could be beneficial [Paisey, 2009].

Pancreatitis should be treated as in the general population, but it is a challenge to treat a patient with multiple system involvement such as ALMS patients [Marshall et al., 2010, Paisey, 2009, Wu WC et al., 2003].

#### **4.4 Impaired growth hormone (GH)-IGF1 axis function**

There is an impaired growth hormone (GH)-IGF1 axis function in ALMS (Maffei et al., 2000, 2002), therefore, therapy with recombinant human Growth Hormone (rhGH) has been attempted in a small series of patients and isolated cases and has been reported to be beneficial for some metabolic parameters. Demonstrating growth hormone deficiency in a patient with ALMS, Tai and co-workers assessed the metabolic effects of growth hormone therapy concluding that rhGH therapy might have beneficial effects on body composition, liver fat content, lipid profiles, and insulin resistance in Alström Syndrome patients, with improvement of the glucose homeostasis [Tai et al., 2003]. Also, Maffei et al. found a reduction of ALS (acid labile subunit) and the increase of IGFBP-2 as expression of growth

2003] and beta cell-preserving drugs (incretins, thiazolidinediones) [Pagano et al., 2008, Paisey et al., 2009]. However, this requires close monitoring of liver, cardiac, and renal function. Glitazones are added to further reduce insulin resistance but must be avoided in the presence of active or treated heart failure and when the serum creatinine concentration exceeds 200 µmol/L. Exenatide, an incretin mimetic, an injectable analogue of glucagon-like

Weight loss exercises should play a pivotal role in weight reduction plan for ALMS patients, as in other patients diagnosed with dibetes and obesity, although could be challenging. Walking, hiking, biking, and swimming with partners and adaptations for the blind have been helpful. Peripheral sensor-motor neuropathy is a common complication of T2DM, but in a small clinical testing study in ALMS, a full preservation of protective foot sensation was demonstrated [Paisey et al., 2009]. The responsiveness to treatment of hyperglycemia is variable. Younger patients rarely require insulin, but some patients require insulin in very-

Caloric restriction helps control obesity, glucose tolerance and hyperinsulinemia [Holder et al., Lee et al., 2009 & Paisey et al. 2008], although as with children with other genetically acquired obesity syndromes, dietary compliance may be a major problem. Reducing dietary carbohydrates may prove more effective than fat restriction in control of hyperglycemia and hyperinsulinemia [Paisey et al., 2008]. No clinical experience has been reported in ALMS of

Insulin resistance, T2DM, dyslipidaemia and associated cardiac, renal and hepatic consequences coexist from a young age with considerable morbidity and reduction in life expectancy. ALMS patients can have potentially harmfully increased lipid levels. Hypertriglyceridemia can often be normalized by diet, exercise and Metformin. Some patients with severe hypertriglyceridemia responded to a combination of low-fat diet, statins and nicotinic acid [Paisey et al., 2004], very little data existing, however, about the

Early introduction of preventative nutrition with low-carbohydrates, exercise and drug therapies (niacin extended-release and incretins) in ALMS could be beneficial [Paisey,

Pancreatitis should be treated as in the general population, but it is a challenge to treat a patient with multiple system involvement such as ALMS patients [Marshall et al., 2010,

There is an impaired growth hormone (GH)-IGF1 axis function in ALMS (Maffei et al., 2000, 2002), therefore, therapy with recombinant human Growth Hormone (rhGH) has been attempted in a small series of patients and isolated cases and has been reported to be beneficial for some metabolic parameters. Demonstrating growth hormone deficiency in a patient with ALMS, Tai and co-workers assessed the metabolic effects of growth hormone therapy concluding that rhGH therapy might have beneficial effects on body composition, liver fat content, lipid profiles, and insulin resistance in Alström Syndrome patients, with improvement of the glucose homeostasis [Tai et al., 2003]. Also, Maffei et al. found a reduction of ALS (acid labile subunit) and the increase of IGFBP-2 as expression of growth

use of specific appetite suppressant medication, such as duramine or sibutramine.

peptide 1(GLP- 1) could be promising in adults with ALMS.

high doses long term [Marshall et al., 2007a].

safety and efficacy of such treatments before puberty.

**4.4 Impaired growth hormone (GH)-IGF1 axis function** 

**4.3 Hypertriglyceridemia** 

Paisey, 2009, Wu WC et al., 2003].

2009].

hormone deficiency condition in 15 young adults with ALMS [Maffei et al., 2000]. RhGH therapy should be considered still investigational [Marshall et al. 2007a]. Several studies are needed to prove that this therapy is cost-effective and without risk in patients with ALMS and severe insulin resistance.

### **4.5 Cardiomyopathy**

Patients diagnosed with ALMS should be regularly monitored for cardiac function by echocardiography, even if asymptomatic [Makaryus et al., 2002, Zubrow et al., 2006]. Several authors [Loudon et al., 2009, Makaryus et al., 2007] stated the importance of serial cardiac magnetic resonance scanning in diagnosis of the underlying disease progression and responses to treatment. Long-term angiotensin-converting enzyme inhibition is indicated for the patient with cardiomyopathy. Many patients respond to other medications, which favorably affect heart function, such as diuretics, digitalis, beta-blockers, and spironolactone. Whether cardiac transplantation is a viable option is yet to be determined, due to the multisystemic involvement, particularly pulmonary, endocrine, and renal function. There has been one successful heart-lung transplantation reported in an adolescent patient with Alström Syndrome, but with no T2DM or significant renal failure [Görler et al., 2007]. A second successful heart transplant has been achieved in an infant prior to the onset of the endocrinological and renal disturbances [JD Marshall, Personal communication].

#### **4.6 Thyroid**

Replacement therapy with L-thyroxin, when needed, is very effective and well-tolerated in the majority of patients.

Thyroid function should be monitored closely in critical hospital settings [Marshall et al., 2007].

#### **4.7 Urologic**

Lack of coordination between bladder and urine outflow (detrusor-urethral dyssynergia) can be helped by intermittent self-catheterization of the bladder. Ileal diversion may be necessary in rare patients [Marshall et al., 2007; Charles, et al. 1990].

#### **4.8 Hypogonadotropic hypogonadism**

If abnormalities in pubertal development or menstrual abnormalities are present, the affected individual should be referred to an endocrinologist with expertise in sexual developmental abnormalities. Primary hypogonadism in ALMS males result in low levels of testosterone, treated with weekly or twice monthly injections of testosterone from puberty onwards. Treatment with cyclical oestrogen and progesterone is important and effective to regulate menstrual cycle and development.

#### **4.9 Hepatic disease**

 Liver function parameters should be routinely monitored, beginning in childhood. Portal hypertension and varices may be aggressively treated with beta-blockers and sclerotherapy of the esophageal veins. Variceal banding could be useful to prevent upper gastro-intestinal hemorrhage. A transjugular intrahepatic portosystemic shunt (TIPS) is used to treat the complications of portal hypertension, when the patient has failed to respond to previous therapeutic measures. Patients with significant portal hypertension should be evaluated early for liver transplantation [Marshall et al., 2007].

Alström Syndrome 221

the pathophysiology of *ALMS1.* By developing targeted therapies, certain debilitating aspects of ALMS could be prevented or treated earlier, improving the overall outcome in this complex disorder [Marshall et al., 2007]. Also, careful clinical and genetic studies can contribute to a better understanding of the disease evolution after different therapeutic

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**6. References** 

#### **4.10 Renal disease**

Because renal insufficiency develops slowly as the patient ages, regular testing of renal function (plasma electrolytes, blood urea nitrogen, creatinine, and urea) is important, particularly in the older patient. Baseline values should be taken in children. Management of hypertension, a low-sodium and low-protein diet, avoidance of nephrotoxic drugs are very important in the preservation of renal function, as well as angiotensin-converting enzyme inhibitors prescribed according to general guidelines. Fibrosis and glomerulosclerosis in the kidneys may lead to eventual renal failure, requiring dialysis. Renal transplantation has been successful in several patients, although can be contraindicated in the presence of other complications including morbid obesity, uncontrolled diabetes, and cardiomyopathy [Marshall et al., 2007].

### **4.11 Pulmonary disease**

Pulmonary fibrosis, dilated cardiomyopathy, and scoliosis can compromise cardiorespiratory function, particularly with concomitant respiratory infection or anesthesia in routine surgical procedures. Monitoring cardiac status and oxygenation during acute illness and postoperatively are mandatory, considering that ALMS patients can suddenly, without warning become critically hypoxic [Lynch et al., 2007, Tiwari et al., 2010]. Chronic obstructive airway disease and associated infection should be managed in line with appropriate national guidelines.

### **4.12 Other**

#### **4.12.1 Gastrointestinal**

Reflux esophagitis should be diagnosed by barium swallow or upper gastrointestinal endoscopy, in the presence of suggestive symptoms and treated accordingly to the guidelines.

#### **4.12.2 Orthopedic abnormalities**

In the presence of flat feet, scoliosis, barrel chest, kyphoscoliosis the referral to an orthopedist is appropriate. Some patients have had surgical intervention for scoliosis, but care should be taken when undertaking surgical procedures, as previously mentioned.

### **4.12.3 Neurologic manifestations**

ALMS patients should be examined for: absence seizures, autistic-spectrum behavioral abnormalities, excessive startle, unexplained joint or muscle pain, muscle dystonia, or hyporeflexia.

### **4.13 Prevention of secondary complications**

There should be routine pediatric immunizations, especially against flu and hepatitis B virus infections.

 Families should be encouraged to seek contact with good sources of support and information, such as Alström Syndrome International (www.alstrom.org) or other groups assisting families with this rare disorder.

### **5. Conclusion**

Full understanding of the phenotypic characteristics, particularly with the help of existing mouse models [Collin et al., 2005, Arsov et al., 2006a, 2006b] will lead to better insight into

Because renal insufficiency develops slowly as the patient ages, regular testing of renal function (plasma electrolytes, blood urea nitrogen, creatinine, and urea) is important, particularly in the older patient. Baseline values should be taken in children. Management of hypertension, a low-sodium and low-protein diet, avoidance of nephrotoxic drugs are very important in the preservation of renal function, as well as angiotensin-converting enzyme inhibitors prescribed according to general guidelines. Fibrosis and glomerulosclerosis in the kidneys may lead to eventual renal failure, requiring dialysis. Renal transplantation has been successful in several patients, although can be contraindicated in the presence of other complications including morbid obesity, uncontrolled diabetes, and cardiomyopathy

Pulmonary fibrosis, dilated cardiomyopathy, and scoliosis can compromise cardiorespiratory function, particularly with concomitant respiratory infection or anesthesia in routine surgical procedures. Monitoring cardiac status and oxygenation during acute illness and postoperatively are mandatory, considering that ALMS patients can suddenly, without warning become critically hypoxic [Lynch et al., 2007, Tiwari et al., 2010]. Chronic obstructive airway disease and associated infection should be managed in line with

Reflux esophagitis should be diagnosed by barium swallow or upper gastrointestinal endoscopy, in the presence of suggestive symptoms and treated accordingly to the guidelines.

In the presence of flat feet, scoliosis, barrel chest, kyphoscoliosis the referral to an orthopedist is appropriate. Some patients have had surgical intervention for scoliosis, but care should be taken when undertaking surgical procedures, as previously mentioned.

ALMS patients should be examined for: absence seizures, autistic-spectrum behavioral abnormalities, excessive startle, unexplained joint or muscle pain, muscle dystonia, or

There should be routine pediatric immunizations, especially against flu and hepatitis B virus

 Families should be encouraged to seek contact with good sources of support and information, such as Alström Syndrome International (www.alstrom.org) or other groups

Full understanding of the phenotypic characteristics, particularly with the help of existing mouse models [Collin et al., 2005, Arsov et al., 2006a, 2006b] will lead to better insight into

**4.10 Renal disease** 

[Marshall et al., 2007].

**4.11 Pulmonary disease** 

appropriate national guidelines.

**4.12.2 Orthopedic abnormalities** 

**4.12.3 Neurologic manifestations** 

**4.13 Prevention of secondary complications**

assisting families with this rare disorder.

**4.12.1 Gastrointestinal** 

**4.12 Other** 

hyporeflexia.

infections.

**5. Conclusion** 

the pathophysiology of *ALMS1.* By developing targeted therapies, certain debilitating aspects of ALMS could be prevented or treated earlier, improving the overall outcome in this complex disorder [Marshall et al., 2007]. Also, careful clinical and genetic studies can contribute to a better understanding of the disease evolution after different therapeutic attempts in Alström Syndrome.

#### **6. References**


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M.I., Hattersley, A.T., Walker, M. & Barrett, T.G. (2006). Common variations in the *ALMS1* gene do not contribute to susceptibility to type 2 diabetes in a large white

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Makaryus, A.N., Popowski, B., Kort, S., Paris, Y. & Mangion, J. (2003). A rare case of Alström

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**11** 

*U.S.A* 

**Alpha One Antitrypsin Deficiency:** 

Alpha one antitrypsin protein (A1AT), is encoded on the SERPINA1 (serpin peptidase inhibitor, claude A, member 1 gene), (OMIM 107400), located on chromosome 14q32.1 and functions as inhibitor of the enzyme neutrophil elastase. People with a low serum level of this protein are described as having the alpha-1-antrypsin deficiency (A1ATD), (OMIM #613490), one of the most common heritable disorders. Having this disorder can predispose an individual to a variety of clinical diseases, with the lungs and the liver being the two organs most commonly affected. The A1AT protein is synthesized mainly in the liver by hepatocytes, secreted into the blood stream, and acts as an inhibitor of neutrophil elastase released primarily in the lung during inflammation. The most common allele for the SERPINA1 gene is named M (Middle), which encodes a normal A1AT protein identified in the middle on an isoelectric focusing gel. Over 120 allelic variants have been discovered and are named based on their position and movement on isoelectric gels, A-L if they exhibit faster migration than M, and N-Z if the proteins migrate more slowly. Rare mutations are often named after the discoverer or location of discover (Mmalton, Lowell, etc). A patient's genotype is notated as PI\*Allele-Allele, and so patient homozygous for the wild-type A1AT

The most common allelic variation causing clinical disease is the Z protein, manifesting most often in the setting of the genotype PI\*Z-Z. This mutated protein spontaneously misfolds and then polymerizes with other misfolded A1AT proteins, becoming trapped in large quantities in the endoplasmic reticulum of liver hepatocytes. This results in liver inflammation and fibrosis, and can lead to clinically significant cholestasis and cirrhosis. Not all allelic variants of A1ATD cause liver damage, however, as some encode truncated proteins which do not misfold or polymerize. Rare null mutations have also been discovered due to point mutations that introduce a premature stop codon within the DNA sequence. Patients with the genotype PI\*Null-Null do not develop liver disease because they do not synthesize mutated protein, but are at extremely high risk for the development of lung

In the case of the Z allele, the trapped protein is ineffectively secreted into the blood stream, resulting in a low serum concentration of A1AT. The mutated protein also has a reduced functional activity, making it a less effective inhibitor of neutrophil elastase. Without an appropriate level of functional A1AT in lung tissue, neutrophil elastase is free to break down elastin, a critical component of lung structure, which is thought to be the major

**1. Introduction** 

protein is noted as being PI\*M-M.

disease because of their inability to inhibit neutrophil elastase.

**A Pulmonary Genetic Disorder** 

Michael Sjoding and D. Kyle Hogarth

*University of Chicago* 


## **Alpha One Antitrypsin Deficiency: A Pulmonary Genetic Disorder**

Michael Sjoding and D. Kyle Hogarth *University of Chicago U.S.A* 

### **1. Introduction**

226 Advances in the Study of Genetic Disorders

Satman, I., Yilmaz, M.T., Gursoy, N., Karsidag, K., Dinccag, N., Ovali, T., Karadeniz, S.,

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Smith, J.C*.*, McDonnell, B., Retallick, C., McEniery, C., Carey, C., Davies, J.S., Barrett, T.,

Tai, T.S., Lin, S.Y. & Sheu, W.H.H. (2003). Metabolic Effects of Growth Hormone Therapy in an Alström Syndrome Patient. *Hormone Research.* Vol. 60, No. 6, pp. 297-301. Titomanlio, L., De Brasi, D., Buoninconti, A., Sperandeo, M.P., Pepe, A. & Andria, G. (2004)*.* 

Tiwari, A., Awasthi, D., Tayal, S. & Ganguly, S, (2010). Alström syndrome: A rare genetic

Van den Abeele, K., Craen, M., Schuil, J. & Meire, F.M. (2001). Ophthalmologic and systemic

Vingolo, E.M., Salvatore, S., Grenga, P.L., Maffei, P., Milan, G. & Marshall J (2010). High-

*Otology, Rhinology & Laryngology.* Vol. 116, Vol. 4 (April 2007), pp. 281-285. Worthley, M.I. & Zeitz, C.J. (2001). Case of Alström syndrome with late presentation dilated

Wu, W.C., Chen, S.C., Dia, C.Y., Yu, M.L., Hsieh, M.Y., Lin, Z.Y., Wang, L.Y., Tsai, J.F. &

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*d'Ophtalmologie*. Vol. 281 (2001), pp. 67–72.

*Scientific Sessions*, Baltimore, MD, June, 2006.

Vol. 37, No. 2, (February 2007), pp. 99-105.

Uysal, V., Bugra, Z., Okten, A., & Devrim, S. (2002). Evaluation of insulin resistant diabetes mellitus in Alström syndrome: a long-term prospective follow-up of three siblings. Diabetes Research and Clinical Practice. *Vol. 56, No. 3 (June* 2002), pp. 189–

and renal ultrastructure. *British Journal of Ophthalmology* Vol. 68 No. 7, (July 1984)

& Ten, S. (2007). Effect of metformin and rosiglitazone in a prepubertal boy with Alström syndrome. *Journal of Pediatric Endocrinology & Metabolism*, Vol. 21, No. 1

Cockcroft, J.R. & Paisey, R (2007). Is arterial stiffening in Alström syndrome linked to the development of cardiomyopathy? *European Journal of Clinical Investigation.* 

Alström syndrome: intrafamilial phenotypic variability in sibs with a novel nonsense mutation of the ALMS1 gene. *Clinical Genetics 2004.* Vol. 65, No. 2

disorder and its anaesthetic significance. *Indian Journal of Anesthesiology*. Vol. 54,

features of the Alström syndrome: report of 9 cases. *Bulletin de la Société Belge* 

resolution spectral domain optical coherence tomography images of alström syndrome. *Journal pediatric ophthalmology strabismus* Vol. 47: e1-e3 (May 2010)Welsh, L. W. Alström Syndrome: Progressive Deafness and Blindness (2007). *The Annals of* 

cardiomyopathy. *Internal Medicine Journal.* Vol. 31, No. 9 (December 2001), pp. 569-

Chang, W.Y. (2002). Alström Syndrome with Acute Pancreatitis: A Case Report. *The Kaohsiung Journal of Medical Sciences.* Vol. 19, No. 7 (July 2003), pp. 358-360. Zubrow, M.E., Makaryus, A., Marshall, J.D., Horowitz, S., Gillam, L.D. & Mangion, J.R.

(2006). Echocardiographic Features of the Cardiomyopathy Associated With Alström Syndrome: A Retrospective Review. *American Society for Echocardiology*  Alpha one antitrypsin protein (A1AT), is encoded on the SERPINA1 (serpin peptidase inhibitor, claude A, member 1 gene), (OMIM 107400), located on chromosome 14q32.1 and functions as inhibitor of the enzyme neutrophil elastase. People with a low serum level of this protein are described as having the alpha-1-antrypsin deficiency (A1ATD), (OMIM #613490), one of the most common heritable disorders. Having this disorder can predispose an individual to a variety of clinical diseases, with the lungs and the liver being the two organs most commonly affected. The A1AT protein is synthesized mainly in the liver by hepatocytes, secreted into the blood stream, and acts as an inhibitor of neutrophil elastase released primarily in the lung during inflammation. The most common allele for the SERPINA1 gene is named M (Middle), which encodes a normal A1AT protein identified in the middle on an isoelectric focusing gel. Over 120 allelic variants have been discovered and are named based on their position and movement on isoelectric gels, A-L if they exhibit faster migration than M, and N-Z if the proteins migrate more slowly. Rare mutations are often named after the discoverer or location of discover (Mmalton, Lowell, etc). A patient's genotype is notated as PI\*Allele-Allele, and so patient homozygous for the wild-type A1AT protein is noted as being PI\*M-M.

The most common allelic variation causing clinical disease is the Z protein, manifesting most often in the setting of the genotype PI\*Z-Z. This mutated protein spontaneously misfolds and then polymerizes with other misfolded A1AT proteins, becoming trapped in large quantities in the endoplasmic reticulum of liver hepatocytes. This results in liver inflammation and fibrosis, and can lead to clinically significant cholestasis and cirrhosis. Not all allelic variants of A1ATD cause liver damage, however, as some encode truncated proteins which do not misfold or polymerize. Rare null mutations have also been discovered due to point mutations that introduce a premature stop codon within the DNA sequence. Patients with the genotype PI\*Null-Null do not develop liver disease because they do not synthesize mutated protein, but are at extremely high risk for the development of lung disease because of their inability to inhibit neutrophil elastase.

In the case of the Z allele, the trapped protein is ineffectively secreted into the blood stream, resulting in a low serum concentration of A1AT. The mutated protein also has a reduced functional activity, making it a less effective inhibitor of neutrophil elastase. Without an appropriate level of functional A1AT in lung tissue, neutrophil elastase is free to break down elastin, a critical component of lung structure, which is thought to be the major

Alpha One Antitrypsin Deficiency: A Pulmonary Genetic Disorder 229

homozygote have a very low serum concentration of enzyme. This pattern of enzyme levels has lead many authors to describe the inheritance pattern as autosomal co-dominant, (see DeMeo's review on the genetics of A1ATD as one example (DeMeo & Silverman, 2004)). Heterozygotes have only a small increased risk for developing clinically significant disease, while homozygotes are at a much higher risk for developing disease, leading other authors to describe the deficiency as having autosomal recessive inheritance (see Alpha-1 antitrypsin deficiency page on the National Center for Biotechnology Information website as an example). We prefer to describe the inheritance pattern as autosomal co-dominant, as this highlights the fact that heterozygotes for the deficiency are at an increased risk for clinical disease when compared with the general population, especially in the setting of external risk factors for lung disease (e.g. smoking). Another important characteristic of the deficiency is its variable clinical expressivity. Some homozygotes for the deficiency do not develop impairment in the lung function and never develop symptoms related to the disease (Seersholm & Kok-Jensen 1998). Incomplete penetrance and variable clinical phenotype (expressivity) is one of the reasons why population studies estimating the number of individuals with the deficiency are much higher than the actual number of people who have been diagnosed. For unclear reasons, A1ATD is rarely tested for despite guidelines that recommend otherwise for clear patient types. Complicating A1ATD diagnosis is the continued low rate of diagnosis and management of Chronic Obstructive Pulmonary

More than 120 mutations in the SERPINA1 gene have been identified, although many do not cause a defect in the serum protein or function or relevant clinical disease (US National Library of Medicine August 2009). The allele most common to the general population is the M allele, and the most clinically relevant variants are the S and Z alleles. People with the PI\*Z-Z genotype make up at least 95% of deficient individuals who present with clinical disease, and PI\*M-Z heterozygotes on very rare occasion have any symptoms. The Z allele is caused by a glutamic acid to lysine substitution at position 342. A more common allelic variant is the S protein, caused by a glutamic acid to valine substitution at position 264. This protein is successfully degraded before accumulating in the liver and does not cause liver disease. PI\*S-S individuals are not thought to be at risk for pulmonary disease, however the compound heterozygotes PI\*S-Z or PI\*S-null are at an increased risk for developing pulmonary symptoms. Null alleles are due to mutations that introduce an early stop codon, which prevents complete transcription of the gene. Patients who are homozygote for the null mutation (PI\*null-null), or heterozygote with Z (PI\*null-Z) are at the highest risk for

The Z allele occurs mainly within one haplotype, meaning that other genetic material surrounding the allele is similar, and suggests a single relatively recent origin in Caucasians (Cox et al., 1985). Its high frequency in southern Scandinavia and estimated origination date of approximately 2000 years ago suggests that the mutation originated in the Viking population and was spread across Europe by Viking raiders. Using the pooled epidemiological data on 75,390 individuals, researchers estimated the prevalence of both the Z and S mutation in 21 countries. With this information, they created a topographic map of the mutation prevalence, depicting how the mutation may have spread. The ZZ phenotype shows highest prevalence in the southern Scandinavian Peninsula, Latvia, and Denmark, and progressively decreases towards the South and the East of Europe. The S allele has its highest prevalence in the Iberian Peninsula, which includes modern day Portugal, and Spain, as well as Southern France and gradually decreases towards the North, South and

developing severe pulmonary symptoms (Stoller & Aboussouan, 2005).

Disease (COPD).

mechanism leading to lung damage and the development of emphysema. The lung injury is worsened in the setting of chronic tobacco use, making smoking cessation paramount in the management of people with the deficiency.

Clinical disease associated with the A1AT deficiency is highly variable, suggesting that many genetic modifiers and environmental exposures play a role in the disease expression. The typical symptoms of pulmonary disease include exertional shortness of breath, wheezing, and chronic cough. The cornerstone of disease management is ensuring total smoking abstinence in all patients, as smoking is associated with a much higher rate of decline in lung function in patients with A1AT deficiency. Replacement therapy with purified A1AT protein given intravenously has been approved in several countries as treatment of the deficiency state, and can prevent decline in lung function. Though many studies support its use and clinical benefit, true randomized placebo controlled studies have been limited in size and scope.

### **2. History of the disorder**

In 1962 at the University of Lund, Sweden, Dr. Carl-Bertil Laurell (1919-2001) was examining the serum protein electrophoresis strips of patients with chronic obstructive pulmonary disease, when he noted an absence of the alpha-one band in a small group of patients. Dr. Sten Eriksson was a resident at the University hospital at the time and assisted Laurell in the study because of his previous experience with protein chemistry. Together, they discovered five cases that formed the basis of their first report of alpha one- antitrypsin deficiency. Three of the five patients in their report developed emphysema at an early age, leading to the conclusion that there must be an association between pulmonary disease and the alpha-one band deficiency (Laurell & Eriksson 1963).

It was later discovered that the major function of the alpha 1-antitrypsin protein was to inhibit the enzyme neutrophil elastase, a protease released by neutrophils in the lungs during inflammation. Neutrophil elastase was shown to induce experimental emphysema in animals. (Senior, et al. 1977). These findings lead to the first hypothesis describing the pathogenesis of lung disease, that an imbalance of proteases and anti-proteases could result in an unregulated destruction of critical components of lung structure, namely elastin, leading to the development of clinical lung disease. This hypothesis continues to be central to the understanding of lung disease pathogenesis to this day, and helps explain why patient deficient in A1AT, which could not regulate neutrophil elastase, would be predisposed to emphysema development.

Work by Dr. H. L. Sharp described the association between alpha one antitrypsin deficiency and liver disease in 10 children in 1969 (Sharp et al., 1969). Sharp discovered intracellular inclusions in the liver hepatocytes of A1ATD individuals, and further work found these inclusions to be polymers of the mutant Z allele of the A1AT protein. Evidence for A1ATD was also supported from the results of a large epidemiologic study published in 1976 by Sveger in Sweden (Sveger, 1976). After screening 200,000 infants for A1ATD he identified 127 infants and found that 14 developed cholestatic jaundice in infancy. These studies established the role of A1AT in liver disease pathogenesis.

### **3. Genetics**

Alpha-1-antitrypsin deficiency has been described as an autosomal co-dominant disorder or as an autosomal recessive disorder. Patients who are heterozygote for the enzyme deficiency have roughly half the serum concentration of A1AT compared with normal individuals, and

mechanism leading to lung damage and the development of emphysema. The lung injury is worsened in the setting of chronic tobacco use, making smoking cessation paramount in the

Clinical disease associated with the A1AT deficiency is highly variable, suggesting that many genetic modifiers and environmental exposures play a role in the disease expression. The typical symptoms of pulmonary disease include exertional shortness of breath, wheezing, and chronic cough. The cornerstone of disease management is ensuring total smoking abstinence in all patients, as smoking is associated with a much higher rate of decline in lung function in patients with A1AT deficiency. Replacement therapy with purified A1AT protein given intravenously has been approved in several countries as treatment of the deficiency state, and can prevent decline in lung function. Though many studies support its use and clinical benefit,

In 1962 at the University of Lund, Sweden, Dr. Carl-Bertil Laurell (1919-2001) was examining the serum protein electrophoresis strips of patients with chronic obstructive pulmonary disease, when he noted an absence of the alpha-one band in a small group of patients. Dr. Sten Eriksson was a resident at the University hospital at the time and assisted Laurell in the study because of his previous experience with protein chemistry. Together, they discovered five cases that formed the basis of their first report of alpha one- antitrypsin deficiency. Three of the five patients in their report developed emphysema at an early age, leading to the conclusion that there must be an association between pulmonary disease and

It was later discovered that the major function of the alpha 1-antitrypsin protein was to inhibit the enzyme neutrophil elastase, a protease released by neutrophils in the lungs during inflammation. Neutrophil elastase was shown to induce experimental emphysema in animals. (Senior, et al. 1977). These findings lead to the first hypothesis describing the pathogenesis of lung disease, that an imbalance of proteases and anti-proteases could result in an unregulated destruction of critical components of lung structure, namely elastin, leading to the development of clinical lung disease. This hypothesis continues to be central to the understanding of lung disease pathogenesis to this day, and helps explain why patient deficient in A1AT, which could not regulate neutrophil elastase, would be

Work by Dr. H. L. Sharp described the association between alpha one antitrypsin deficiency and liver disease in 10 children in 1969 (Sharp et al., 1969). Sharp discovered intracellular inclusions in the liver hepatocytes of A1ATD individuals, and further work found these inclusions to be polymers of the mutant Z allele of the A1AT protein. Evidence for A1ATD was also supported from the results of a large epidemiologic study published in 1976 by Sveger in Sweden (Sveger, 1976). After screening 200,000 infants for A1ATD he identified 127 infants and found that 14 developed cholestatic jaundice in infancy. These studies

Alpha-1-antitrypsin deficiency has been described as an autosomal co-dominant disorder or as an autosomal recessive disorder. Patients who are heterozygote for the enzyme deficiency have roughly half the serum concentration of A1AT compared with normal individuals, and

true randomized placebo controlled studies have been limited in size and scope.

the alpha-one band deficiency (Laurell & Eriksson 1963).

established the role of A1AT in liver disease pathogenesis.

predisposed to emphysema development.

**3. Genetics** 

management of people with the deficiency.

**2. History of the disorder** 

homozygote have a very low serum concentration of enzyme. This pattern of enzyme levels has lead many authors to describe the inheritance pattern as autosomal co-dominant, (see DeMeo's review on the genetics of A1ATD as one example (DeMeo & Silverman, 2004)). Heterozygotes have only a small increased risk for developing clinically significant disease, while homozygotes are at a much higher risk for developing disease, leading other authors to describe the deficiency as having autosomal recessive inheritance (see Alpha-1 antitrypsin deficiency page on the National Center for Biotechnology Information website as an example). We prefer to describe the inheritance pattern as autosomal co-dominant, as this highlights the fact that heterozygotes for the deficiency are at an increased risk for clinical disease when compared with the general population, especially in the setting of external risk factors for lung disease (e.g. smoking). Another important characteristic of the deficiency is its variable clinical expressivity. Some homozygotes for the deficiency do not develop impairment in the lung function and never develop symptoms related to the disease (Seersholm & Kok-Jensen 1998). Incomplete penetrance and variable clinical phenotype (expressivity) is one of the reasons why population studies estimating the number of individuals with the deficiency are much higher than the actual number of people who have been diagnosed. For unclear reasons, A1ATD is rarely tested for despite guidelines that recommend otherwise for clear patient types. Complicating A1ATD diagnosis is the continued low rate of diagnosis and management of Chronic Obstructive Pulmonary Disease (COPD).

More than 120 mutations in the SERPINA1 gene have been identified, although many do not cause a defect in the serum protein or function or relevant clinical disease (US National Library of Medicine August 2009). The allele most common to the general population is the M allele, and the most clinically relevant variants are the S and Z alleles. People with the PI\*Z-Z genotype make up at least 95% of deficient individuals who present with clinical disease, and PI\*M-Z heterozygotes on very rare occasion have any symptoms. The Z allele is caused by a glutamic acid to lysine substitution at position 342. A more common allelic variant is the S protein, caused by a glutamic acid to valine substitution at position 264. This protein is successfully degraded before accumulating in the liver and does not cause liver disease. PI\*S-S individuals are not thought to be at risk for pulmonary disease, however the compound heterozygotes PI\*S-Z or PI\*S-null are at an increased risk for developing pulmonary symptoms. Null alleles are due to mutations that introduce an early stop codon, which prevents complete transcription of the gene. Patients who are homozygote for the null mutation (PI\*null-null), or heterozygote with Z (PI\*null-Z) are at the highest risk for developing severe pulmonary symptoms (Stoller & Aboussouan, 2005).

The Z allele occurs mainly within one haplotype, meaning that other genetic material surrounding the allele is similar, and suggests a single relatively recent origin in Caucasians (Cox et al., 1985). Its high frequency in southern Scandinavia and estimated origination date of approximately 2000 years ago suggests that the mutation originated in the Viking population and was spread across Europe by Viking raiders. Using the pooled epidemiological data on 75,390 individuals, researchers estimated the prevalence of both the Z and S mutation in 21 countries. With this information, they created a topographic map of the mutation prevalence, depicting how the mutation may have spread. The ZZ phenotype shows highest prevalence in the southern Scandinavian Peninsula, Latvia, and Denmark, and progressively decreases towards the South and the East of Europe. The S allele has its highest prevalence in the Iberian Peninsula, which includes modern day Portugal, and Spain, as well as Southern France and gradually decreases towards the North, South and

Alpha One Antitrypsin Deficiency: A Pulmonary Genetic Disorder 231

Ser359. The protein is primarily synthesized and secreted by hepatocytes, but also in mononuclear cells, intestinal and lung epithelial cells. A1AT is an acute phase reactant with a normal concentration in serum of 20-53 micromole/L. Alpha one antitrypsin is a member of the serpin family of protease inhibitors, which regulate important proteolytic enzyme cascades including the coagulation cascade, complement cascade, and plasmin inhibition (Crowther et al., 2004). Serpins not only inhibit proteases but cause a conformational change in their structure readying them for destruction. A1AT's mechanism of inhibition has been likened to a mouse-trap. When neutrophil elastase attacks A1AT enzyme, it binds and then cleaves its reactive center loop, which causes a spring-like movement within the A1AT molecule to fling the elastase molecule across itself, inhibiting its function and altering its

The prevailing theory describing the pathogenesis of emphysema in A1AT deficient individuals is of an imbalance in protease and anti-protease enzymes in lung tissue. Neutrophil elastase is released during inflammation and leads to an uncontrolled proteolytic attack on elastin, which is left unchecked by the low concentration of alpha one antitrypsin (Gadek et al., 1981). Furthermore, the circulating Z allele of A1AT has been shown to have a less functional active site, making the small amount of mutant protein a functionally ineffective inhibitor of neutrophil elastase (Ogushi et al., 1987). Elastin is the backbone of lung structure, and a critical component of the lungs ability to recoil. It is thought that elastin's destruction leads to lung hyperinflation and obstruction, leading to

More recently, studies have shown that the mutated protein can form polymers within the lungs, similar to the polymerization occurring in the liver, and become chemoattractants for neutrophils resulting in excessive inflammation. Polymers of the mutated A1AT protein have been identified in the bronchial alveolar lavage fluid of individuals with the PiZZ phenotype (Mulgrew et al., 2004). These findings have lead to a possible evolutionary explanation for why alpha-one anti-trypsin deficiency became so prevalent in many populations. The argument for the selective advantage of being a carrier is that a less regulated pulmonary inflammatory response to an external noxious stimulus (e.g. infection) would lead to higher chances of recovery. Prior to the discovery of antibiotics for respiratory infections, the mortality rate from these illnesses was high. A more robust and unregulated inflammatory response in the lungs could have provided a survival advantage to the carriers (Lomas, 2006). In the modern antibiotic era, and the advent of mass-produced external noxious stimuli (smoking, pollution), this mutation does not appear to have a

How cigarette smoke accelerates the decline of lung function in A1ATD has also been studied. When the methionine amino acid in the active site of A1AT protein is oxidized by cigarette smoke, the kinetics of neutrophil elastase inhibition is reduced (Ogushi et al., 1991). Newer experimental data shows A1AT may have other roles in the lung epithelium besides inhibiting neutrophil elastase. A1AT has recently been found to block the cigarette smoke mediated release of TNF-alpha and MMP-12 in alveolar macrophages (Churg at al., 2007). In cellular studies, A1AT has also been found to inhibit apoptosis through direct inhibition of activated Caspase-3 (Petrache et al., 2006). The link between A1AT and apoptosis has lead to new theories of emphysema development as both an inflammatory disorder and accelerated

structure so it can be destroyed (Huntington et al., 2000).

**5.1 Pulmonary pathophysiology** 

development of emphysema.

theoretical selective advantage anymore.

lung aging process.

East of the continent. The S mutation appears to have originated within the Portuguese population, but its date of origin is unknown. It is assumed that both mutations were introduced to North America by mass migration.


Fig. 1. Common alleles of the SERPINA1 gene (adapted from Hogarth & Rachelefsky, 2008)

### **4. Epidemiology**

There is an estimated 1.1 million people with severe A1ATD and 116 million carriers in the world (Luisetti & Seersholm, 2004). Although previously consider a disease of Caucasians, recent data shows that A1ATD exists in all racial subgroups worldwide including African blacks, Arabs and Jews in the Middle East, as well as people from central, far east and south east Asia (de Serres, 2002). Determining the number of people in the United States with emphysema primarily due to A1ATD can made by taking the estimate of the number of Americans with COPD (3.1 million), and the estimate that about 1.9% of patients with emphysema are likely due to A1ATD (Lieberman et al., 1986). This results in an estimate that at least 59000 individuals in the United States have severe symptomatic COPD due to A1ATD. Large screening studies have also been undertaken, including the classic prevalence study done by Sveger, where 200,000 neonates were screened at birth in Sweden (Sveger 1974). The results demonstrated 1 in 1575 live births were homozygous for the Z mutation (PI\*ZZ). A similar study undertaken in Oregon, USA screened 107,038 newborns and found the prevalence of the ZZ phenotype in that population to be 1 in 5097 (O'Brien et al., 1978). Among 20,000 healthy blood donors tested in St. Louis, Missouri in the United States, 1 in 2857 were homozygous for the Z mutation. With this information, the researchers estimated a total prevalence of 700 individuals in St. Louis with the deficiency, however they were only to locate 28 (4%) after contacting local doctors (Silverman, et al., 1989). Estimates from Central and Southern Africa based on limited data from screening studies estimated that 1 in 15 Africans are S carriers. Our own data on carrier rate in Americans of African Descent demonstrate 1 in 18 are S carriers. Epidemiologic data not only highlight that prevalence of the deficiency is high, but reinforce that the disease is significantly under diagnosed in most populations.

### **5. Pathophysiology**

The SERPINA1 gene, previously known as the PI (proteasome inhibitor) gene, is located between 14q31.1-32.3 on the human genome, and encodes A1AT, which is a 52-kD glycoprotein composed of 394 amino acids. The active site is a single peptide bond, Met358Ser359. The protein is primarily synthesized and secreted by hepatocytes, but also in mononuclear cells, intestinal and lung epithelial cells. A1AT is an acute phase reactant with a normal concentration in serum of 20-53 micromole/L. Alpha one antitrypsin is a member of the serpin family of protease inhibitors, which regulate important proteolytic enzyme cascades including the coagulation cascade, complement cascade, and plasmin inhibition (Crowther et al., 2004). Serpins not only inhibit proteases but cause a conformational change in their structure readying them for destruction. A1AT's mechanism of inhibition has been likened to a mouse-trap. When neutrophil elastase attacks A1AT enzyme, it binds and then cleaves its reactive center loop, which causes a spring-like movement within the A1AT molecule to fling the elastase molecule across itself, inhibiting its function and altering its structure so it can be destroyed (Huntington et al., 2000).

#### **5.1 Pulmonary pathophysiology**

230 Advances in the Study of Genetic Disorders

East of the continent. The S mutation appears to have originated within the Portuguese population, but its date of origin is unknown. It is assumed that both mutations were

Fig. 1. Common alleles of the SERPINA1 gene (adapted from Hogarth & Rachelefsky, 2008)

There is an estimated 1.1 million people with severe A1ATD and 116 million carriers in the world (Luisetti & Seersholm, 2004). Although previously consider a disease of Caucasians, recent data shows that A1ATD exists in all racial subgroups worldwide including African blacks, Arabs and Jews in the Middle East, as well as people from central, far east and south east Asia (de Serres, 2002). Determining the number of people in the United States with emphysema primarily due to A1ATD can made by taking the estimate of the number of Americans with COPD (3.1 million), and the estimate that about 1.9% of patients with emphysema are likely due to A1ATD (Lieberman et al., 1986). This results in an estimate that at least 59000 individuals in the United States have severe symptomatic COPD due to A1ATD. Large screening studies have also been undertaken, including the classic prevalence study done by Sveger, where 200,000 neonates were screened at birth in Sweden (Sveger 1974). The results demonstrated 1 in 1575 live births were homozygous for the Z mutation (PI\*ZZ). A similar study undertaken in Oregon, USA screened 107,038 newborns and found the prevalence of the ZZ phenotype in that population to be 1 in 5097 (O'Brien et al., 1978). Among 20,000 healthy blood donors tested in St. Louis, Missouri in the United States, 1 in 2857 were homozygous for the Z mutation. With this information, the researchers estimated a total prevalence of 700 individuals in St. Louis with the deficiency, however they were only to locate 28 (4%) after contacting local doctors (Silverman, et al., 1989). Estimates from Central and Southern Africa based on limited data from screening studies estimated that 1 in 15 Africans are S carriers. Our own data on carrier rate in Americans of African Descent demonstrate 1 in 18 are S carriers. Epidemiologic data not only highlight that prevalence of the deficiency is high, but reinforce that the disease is

The SERPINA1 gene, previously known as the PI (proteasome inhibitor) gene, is located between 14q31.1-32.3 on the human genome, and encodes A1AT, which is a 52-kD glycoprotein composed of 394 amino acids. The active site is a single peptide bond, Met358-

introduced to North America by mass migration.

significantly under diagnosed in most populations.

**5. Pathophysiology** 

**4. Epidemiology** 

The prevailing theory describing the pathogenesis of emphysema in A1AT deficient individuals is of an imbalance in protease and anti-protease enzymes in lung tissue. Neutrophil elastase is released during inflammation and leads to an uncontrolled proteolytic attack on elastin, which is left unchecked by the low concentration of alpha one antitrypsin (Gadek et al., 1981). Furthermore, the circulating Z allele of A1AT has been shown to have a less functional active site, making the small amount of mutant protein a functionally ineffective inhibitor of neutrophil elastase (Ogushi et al., 1987). Elastin is the backbone of lung structure, and a critical component of the lungs ability to recoil. It is thought that elastin's destruction leads to lung hyperinflation and obstruction, leading to development of emphysema.

More recently, studies have shown that the mutated protein can form polymers within the lungs, similar to the polymerization occurring in the liver, and become chemoattractants for neutrophils resulting in excessive inflammation. Polymers of the mutated A1AT protein have been identified in the bronchial alveolar lavage fluid of individuals with the PiZZ phenotype (Mulgrew et al., 2004). These findings have lead to a possible evolutionary explanation for why alpha-one anti-trypsin deficiency became so prevalent in many populations. The argument for the selective advantage of being a carrier is that a less regulated pulmonary inflammatory response to an external noxious stimulus (e.g. infection) would lead to higher chances of recovery. Prior to the discovery of antibiotics for respiratory infections, the mortality rate from these illnesses was high. A more robust and unregulated inflammatory response in the lungs could have provided a survival advantage to the carriers (Lomas, 2006). In the modern antibiotic era, and the advent of mass-produced external noxious stimuli (smoking, pollution), this mutation does not appear to have a theoretical selective advantage anymore.

How cigarette smoke accelerates the decline of lung function in A1ATD has also been studied. When the methionine amino acid in the active site of A1AT protein is oxidized by cigarette smoke, the kinetics of neutrophil elastase inhibition is reduced (Ogushi et al., 1991). Newer experimental data shows A1AT may have other roles in the lung epithelium besides inhibiting neutrophil elastase. A1AT has recently been found to block the cigarette smoke mediated release of TNF-alpha and MMP-12 in alveolar macrophages (Churg at al., 2007). In cellular studies, A1AT has also been found to inhibit apoptosis through direct inhibition of activated Caspase-3 (Petrache et al., 2006). The link between A1AT and apoptosis has lead to new theories of emphysema development as both an inflammatory disorder and accelerated lung aging process.

Alpha One Antitrypsin Deficiency: A Pulmonary Genetic Disorder 233

people were diagnosed after they were discovered to have abnormal chest radiograph findings, abnormal pulmonary function tests, liver abnormalities, or other blood testing.

The NHLBI registry data provides the best clinical picture of the typical patients diagnosed with this deficiency. 97% of them had the PI\*ZZ mutation, and most were diagnosed in the third or fourth decade of life. The most common symptom in this group was shortness of breath on exertion (83%). Other common symptoms included wheezing during an upper respiratory illness (75%), wheezing without upper respiratory illness (65%), recent lung

Pulmonary function testing of individuals in the NHLBI registry demonstrated a pattern consistent with emphysema: the median Forced Expiratory Volume in one second (FEV1) was 47% of predicted, the ratio of the FEV1/FVC (Forced Vital Capacity) was 43% of predicted, and the DLCO (which represents the amount of destruction in alveoli-capillary units) was 50% of predicted. These numbers highlight a common feature of people with A1ATD: the airflow obstruction (represented by low FEV1 and low FEV1/FVC) seen on pulmonary function testing seems to be out of proportion to the lifetime quantity of cigarettes they have smoked. Also in the NHLBI registry, 28% of people showed significant bronchodilator responsiveness (i.e., reversibility) of their airflow obstruction on pulmonary function tests during their initial visit, which is a characteristic of people with asthma (Eden et al., 2003). With these common symptoms and pulmonary function test characteristics, it is easy to see why patients with A1ATD are often misdiagnosed as having only uncomplicated

In contrast to the above registry data, a study with high level of non-index cases (e.g. siblings of affected individuals) found that far fewer of this population had typical pulmonary symptoms of A1ATD (Seersholm & Kok-Jensen, 1998). After a mean follow-up of 8 years, only 46% of the non-index case patients reported symptoms of shortness of breath, 27% reported wheezing, and 14% reported a chronic cough. Also in this group, their average FEV1 was 100% of predicted, and their FEV1/FVC = 0.79, essentially normal

Classically, severe A1ATD causes panlobar emphysema with lower lobe predominance on radiologic imagining studies (Guenter et al., 1968). However, with high-resolution chest CT scanning, bronchiectasis has also been found to be a common feature of patients with A1ATD. In a study of 74 people with the P\*ZZ phenotype, 70 subjects had bronchiectasis changes on CT scan. 27% of the study participates were felt to have clinically significant bronchiectasis, which was described as 4 or more airway segments with bronchiectasis plus symptoms of regular sputum production (the most common symptom of people with

Multiple studies have measured the rate of decline in lung function among patients with A1ATD using the forced expiratory volume in one second (FEV1) as a marker of lung disease progression. This measure is used regularly to quantify the severity and progression of patients with COPD and asthma. For non-smokers with normal levels of A1AT, the rate of FEV1 decline is around 20-30 mL/year. The decline in the FEV1 among a group of A1ATD patients who never smoked was 67 mL/year, was 54 mL/year in ex-smokers, and was 109 mL/year in current smokers (Alpha-1-antitrypsin deficiency study group, 1998). The first two numbers are not statistically significantly different, however the third is

therapy with the purified A1AT protein.

**6.1 Pulmonary clinical manifestations** 

asthma, emphysema or COPD.

pulmonary function tests.

bronchiectasis) (Parr et al., 2007).

infection (67%), and chronic productive cough (49%).

### **5.2 Liver pathophysiology**

People with the alpha one antitrypsin deficiency develop liver damage by a completely different mechanism. After being synthesized in hepatocytes, the mutated A1AT alleles bind together to form large polymers that result in inflammation and fibrosis. Liver disease caused by A1ATD has become the prototypical disease in a new category of diseases, termed the conformational diseases. Also included in this category of diseases are Alzheimer's and other forms of neurodegenerative dementias, which are caused by the aggregation of proteins in neurons (Carrell & Lomas, 2002). People with the PI\*ZZ mutation of A1AT have a high concentration of the mutated alpha-one antitrypsin allele in the endoplasmic reticulum of liver cells. The Z mutation allows the protein to undergo a spontaneous structural change, which opens up the main sheets of the molecule and bind to the reactive center in the next molecule. These interactions can result in the formation of long polymers of mutated proteins (Lomas et al., 1992). The large protein structures aggregate in liver cells, which is thought to lead to inflammation, fibrosis and cirrhosis by a still unclear mechanism. The reason why some people with ZZ allele genotype do not develop clinically relevant liver disease is also not clear.

### **6. Clinical manifestations**

A1ATD is often unrecognized despite the high prevalence of lung disease in the United States and the world. Alpha-1–related lung disease presents with common respiratory symptoms including dyspnea, decreased exercise tolerance, wheezing, cough, excess sputum production, frequent lower respiratory tract infections, and a history of suspected allergies and/or asthma (Needham & Stockley, 2004). These symptoms are often ascribed to other diseases for years prior to the correct diagnosis of alpha one antitrypsin deficiency. A 1994 mail survey found that on average it took 7.2 years after symptom onset before the diagnosis was made, and 44% of people saw three different physicians before a diagnosis was made (Stoller et al., 1994). A similar survey repeated in 2003 found the mean time to diagnosis was 5.6 years, however, the delay was more pronounced in older and female patients (Stoller et al., 2005). Since the diagnosis of A1ATD requires one simple blood test, clearly more effort needs to be made to educate both physicians and the public of the disease and the importance of a diagnosis.

There is significant variability in the age of symptom onset in people with A1ATD, and some smokers and non-smokers may never develop symptoms. This highlights the variability in disease penetrance among deficient individuals, and makes accurate descriptions of the common symptoms and other clinical characteristics of deficient individuals difficult to obtain. Most of the clinical characteristics and other features of the deficiency are obtained by studying large registries of patients with the disease. These data sets are often flawed by ascertainment bias. Most of the patients in the large A1ATD registries presented initially to a doctor with concerning pulmonary symptoms, eventually leading to a diagnosis of A1ATD. These patients are then referred to a specialist who will enroll them into the registry, and are termed index cases. Less often, asymptomatic individuals who are diagnosed after a family screening are enrolled (non-index cases). This was true of the large group of 1129 A1AT deficient individuals in the National Heart, Lung and Blood Institute Registry (McElvaney et al., 1997). 72% of the enrollees were index cases, receiving a diagnosis of the A1ATD after developing concerning pulmonary symptoms, and 20% were non-index cases, diagnosed by screening following an investigation of family members of individuals with A1ATD. In that registry, the remaining smaller percentage of people were diagnosed after they were discovered to have abnormal chest radiograph findings, abnormal pulmonary function tests, liver abnormalities, or other blood testing. therapy with the purified A1AT protein.

### **6.1 Pulmonary clinical manifestations**

232 Advances in the Study of Genetic Disorders

People with the alpha one antitrypsin deficiency develop liver damage by a completely different mechanism. After being synthesized in hepatocytes, the mutated A1AT alleles bind together to form large polymers that result in inflammation and fibrosis. Liver disease caused by A1ATD has become the prototypical disease in a new category of diseases, termed the conformational diseases. Also included in this category of diseases are Alzheimer's and other forms of neurodegenerative dementias, which are caused by the aggregation of proteins in neurons (Carrell & Lomas, 2002). People with the PI\*ZZ mutation of A1AT have a high concentration of the mutated alpha-one antitrypsin allele in the endoplasmic reticulum of liver cells. The Z mutation allows the protein to undergo a spontaneous structural change, which opens up the main sheets of the molecule and bind to the reactive center in the next molecule. These interactions can result in the formation of long polymers of mutated proteins (Lomas et al., 1992). The large protein structures aggregate in liver cells, which is thought to lead to inflammation, fibrosis and cirrhosis by a still unclear mechanism. The reason why some people with ZZ allele genotype do not

A1ATD is often unrecognized despite the high prevalence of lung disease in the United States and the world. Alpha-1–related lung disease presents with common respiratory symptoms including dyspnea, decreased exercise tolerance, wheezing, cough, excess sputum production, frequent lower respiratory tract infections, and a history of suspected allergies and/or asthma (Needham & Stockley, 2004). These symptoms are often ascribed to other diseases for years prior to the correct diagnosis of alpha one antitrypsin deficiency. A 1994 mail survey found that on average it took 7.2 years after symptom onset before the diagnosis was made, and 44% of people saw three different physicians before a diagnosis was made (Stoller et al., 1994). A similar survey repeated in 2003 found the mean time to diagnosis was 5.6 years, however, the delay was more pronounced in older and female patients (Stoller et al., 2005). Since the diagnosis of A1ATD requires one simple blood test, clearly more effort needs to be made to educate both physicians and the public of the

There is significant variability in the age of symptom onset in people with A1ATD, and some smokers and non-smokers may never develop symptoms. This highlights the variability in disease penetrance among deficient individuals, and makes accurate descriptions of the common symptoms and other clinical characteristics of deficient individuals difficult to obtain. Most of the clinical characteristics and other features of the deficiency are obtained by studying large registries of patients with the disease. These data sets are often flawed by ascertainment bias. Most of the patients in the large A1ATD registries presented initially to a doctor with concerning pulmonary symptoms, eventually leading to a diagnosis of A1ATD. These patients are then referred to a specialist who will enroll them into the registry, and are termed index cases. Less often, asymptomatic individuals who are diagnosed after a family screening are enrolled (non-index cases). This was true of the large group of 1129 A1AT deficient individuals in the National Heart, Lung and Blood Institute Registry (McElvaney et al., 1997). 72% of the enrollees were index cases, receiving a diagnosis of the A1ATD after developing concerning pulmonary symptoms, and 20% were non-index cases, diagnosed by screening following an investigation of family members of individuals with A1ATD. In that registry, the remaining smaller percentage of

**5.2 Liver pathophysiology** 

**6. Clinical manifestations** 

disease and the importance of a diagnosis.

develop clinically relevant liver disease is also not clear.

The NHLBI registry data provides the best clinical picture of the typical patients diagnosed with this deficiency. 97% of them had the PI\*ZZ mutation, and most were diagnosed in the third or fourth decade of life. The most common symptom in this group was shortness of breath on exertion (83%). Other common symptoms included wheezing during an upper respiratory illness (75%), wheezing without upper respiratory illness (65%), recent lung infection (67%), and chronic productive cough (49%).

Pulmonary function testing of individuals in the NHLBI registry demonstrated a pattern consistent with emphysema: the median Forced Expiratory Volume in one second (FEV1) was 47% of predicted, the ratio of the FEV1/FVC (Forced Vital Capacity) was 43% of predicted, and the DLCO (which represents the amount of destruction in alveoli-capillary units) was 50% of predicted. These numbers highlight a common feature of people with A1ATD: the airflow obstruction (represented by low FEV1 and low FEV1/FVC) seen on pulmonary function testing seems to be out of proportion to the lifetime quantity of cigarettes they have smoked. Also in the NHLBI registry, 28% of people showed significant bronchodilator responsiveness (i.e., reversibility) of their airflow obstruction on pulmonary function tests during their initial visit, which is a characteristic of people with asthma (Eden et al., 2003). With these common symptoms and pulmonary function test characteristics, it is easy to see why patients with A1ATD are often misdiagnosed as having only uncomplicated asthma, emphysema or COPD.

In contrast to the above registry data, a study with high level of non-index cases (e.g. siblings of affected individuals) found that far fewer of this population had typical pulmonary symptoms of A1ATD (Seersholm & Kok-Jensen, 1998). After a mean follow-up of 8 years, only 46% of the non-index case patients reported symptoms of shortness of breath, 27% reported wheezing, and 14% reported a chronic cough. Also in this group, their average FEV1 was 100% of predicted, and their FEV1/FVC = 0.79, essentially normal pulmonary function tests.

Classically, severe A1ATD causes panlobar emphysema with lower lobe predominance on radiologic imagining studies (Guenter et al., 1968). However, with high-resolution chest CT scanning, bronchiectasis has also been found to be a common feature of patients with A1ATD. In a study of 74 people with the P\*ZZ phenotype, 70 subjects had bronchiectasis changes on CT scan. 27% of the study participates were felt to have clinically significant bronchiectasis, which was described as 4 or more airway segments with bronchiectasis plus symptoms of regular sputum production (the most common symptom of people with bronchiectasis) (Parr et al., 2007).

Multiple studies have measured the rate of decline in lung function among patients with A1ATD using the forced expiratory volume in one second (FEV1) as a marker of lung disease progression. This measure is used regularly to quantify the severity and progression of patients with COPD and asthma. For non-smokers with normal levels of A1AT, the rate of FEV1 decline is around 20-30 mL/year. The decline in the FEV1 among a group of A1ATD patients who never smoked was 67 mL/year, was 54 mL/year in ex-smokers, and was 109 mL/year in current smokers (Alpha-1-antitrypsin deficiency study group, 1998). The first two numbers are not statistically significantly different, however the third is

Alpha One Antitrypsin Deficiency: A Pulmonary Genetic Disorder 235

in the following circumstances - if the prevalence of A1ATD is greater than 1 in 1500 the population, smoking is prevalent, and adequate genetics counseling services are available. Nephelometry or Rocket Immunodiffusion can measure serum levels of A1AT and is a reasonable screening test for the deficiency. However, this method is subject to errors because the protein is an acute phase reactant and rise with inflammation. The gold standard for diagnosis is "Phenotyping" of the protein is done via isoelectric focus gel analysis, which can only be performed at a few specialized laboratories within the United States. DNA Analysis of genotype is done to probe for the common S and Z genes. A1ATD testing can be done via serum and whole blood draw from the vein, but can also be done via a single finger-stick of blood placed onto a card that is mailed into a central lab for testing. A combination of measuring the serum A1AT concentration and performing a PCR based assay to identify S and Z alleles will accurately identify 96% of individuals as compared to

The corner stone of alpha one antitrypsin management is smoking cessation and smoke avoidance in all individuals with the deficiency. Guidelines for the management of the chronic airflow obstruction (COPD) have been published elsewhere (GOLD guidelines, ATS guidelines, etc.) Augmentation therapy is utilized to increase serum and lung epithelial lining fluid (ELF) levels of A1AT through the weekly intravenous infusion of purified

It is FDA approved to treat for adult patients with A1ATD (protein concentration < 11 micromoles/dL) and evidence of air flow obstruction. The treatment can be very costly because it involves life-long regular infusions of a blood product, and it is not available worldwide. The treatment was approved based on two factors, that there is biochemical equivalence between exogenous replacement protein and protein found in normal human serum, and there is normalization of serum protein levels in deficient individuals who are receiving replacement. Many non-randomized prospective studies have demonstrated the effectiveness of augmentation via reduction in the annual rate of decline of lung function. Well-designed and adequately powered randomized trials have been limited to date. A recent meta-analysis of published human studies demonstrated augmentation therapy does reduce the annual rate of lung function decline (as measured by FEV1) in A1ATD

Ongoing work in areas of inhaled therapy, longer half-life protein, recombinant forms, small molecule chaperone inhibitors to increase liver secretion and gene transfer therapy continue.

Alpha1- antitrypsin deficiency is a not uncommon disease, which is not limited to the European and Caucasian American population, but now affects all ethnic groups. Effective treatments for this disease, including smoking cessation, management of COPD/emphysema and other complications, and augmentation therapy with purified A1AT protein is well established. However, the disease remains under-diagnosed, and

These studies and fields are all in various stages of development.

the more difficult gold standard isoelectric focusing (Snyder, 2006).

human A1AT protein (Wewers et al., 1987).

individuals (Chapman et al., 2009).

**8.1 Future therapies** 

**9. Conclusion** 

**8. Treatment** 

significant, which highlights the extreme importance of smoking cessation in all people with A1ATD. The difference in the rate of decline of FEV1 between A1ATD and normal patients highlights the principle of augmentation therapy with replacement alpha-one protein.

Mortality in people with A1ATD is most frequently due to respiratory failure, followed by liver cirrhosis. The observed yearly mortality rate ranges between 1.7-3.5%. Factors associated with increased mortality include older age, lower education, lower FEV1, history of lung transplant, and people who were not receiving augmentation therapy with the purified A1AT protein (Stoller et al., 2005).

### **6.2 Liver clinical manifestations**

A1ATD has a strong association with liver disease, leading to a recommendation that all individuals of any age with unexplained liver dysfunction should undergo testing for the deficiency. In the Swedish population screening study by Sveger, of 200,000 people, 18% of the 120 people found to be homozygote for the Z mutation had some evidence of liver dysfunction (Sveger, 1974). This included obstructive jaundice in 12%, and minor abnormalities in others. Among those with liver dysfunction, the risk of developing cirrhosis is high. It is possible that younger individuals more often have liver dysfunction because their hepatocytes are less well equipped to handle the polymerized A1AT proteins. In a small autopsy series of patients with A1AT disease, cirrhosis was observed in 34% of patients, and hepatocellular carcinoma was observed in 34% of those with cirrhosis (Eriksson, 1987).

#### **6.3 Necrotizing panniculitis**

Panniculitis is an uncommon skin disorder with a strong association with A1ATD. It is characterized by painful, cutaneous nodules at the sites of trauma, often on the trunk, back and thighs. On biopsy, areas of fat necrosis are interspersed with areas of normal tissue. The skin necrosis is felt to develop because of unopposed proteolysis, and augmentation therapy has been described as causing a rapid resolution of the disease (Dowd et al., 1995).

#### **7. Testing for disease**

Guidelines published by the American Thoracic Society and European Respiratory Society in 2003 have helped clarify who should undergo testing for A1ATD (American Thoracic Society, 2003). The guidelines divided people into categories for whom testing is recommended, those for whom testing could be discussed and considered, and those for whom testing was discouraged. For the following group of people testing should be recommended. These include: adults with emphysema, chronic obstructive pulmonary disease, or asthma with incompletely reversible airflow obstruction, people of all ages with otherwise unexplained liver disease, or adults with necrotizing panniculitis. In the following group of people testing could be considered and discussed: adults with bronchiectasis without an obvious etiology, adults with anti-proteinase 3-positive vasculitis (C-ANCA [anti-neutrophil cytoplasmic antibody]-positive vasculitis, formerly known as "Wegener's Granulomatosis"), adolescents with airflow obstruction on pulmonary function tests.

When family history is considered, the following recommendations were made. There is a strong recommendation for testing all siblings of an individual with A1ATD. There is also a recommendation to consider testing in the following situations: individuals with a family history of emphysema or liver disease, or anyone with a family history of A1ATD or A1ATD heterozygote. The 2003 guidelines recommended against routine population screening except the more difficult gold standard isoelectric focusing (Snyder, 2006).

in the following circumstances - if the prevalence of A1ATD is greater than 1 in 1500 the population, smoking is prevalent, and adequate genetics counseling services are available. Nephelometry or Rocket Immunodiffusion can measure serum levels of A1AT and is a reasonable screening test for the deficiency. However, this method is subject to errors because the protein is an acute phase reactant and rise with inflammation. The gold standard for diagnosis is "Phenotyping" of the protein is done via isoelectric focus gel analysis, which can only be performed at a few specialized laboratories within the United States. DNA Analysis of genotype is done to probe for the common S and Z genes. A1ATD testing can be done via serum and whole blood draw from the vein, but can also be done via a single finger-stick of blood placed onto a card that is mailed into a central lab for testing. A combination of measuring the serum A1AT concentration and performing a PCR based assay to identify S and Z alleles will accurately identify 96% of individuals as compared to

### **8. Treatment**

234 Advances in the Study of Genetic Disorders

significant, which highlights the extreme importance of smoking cessation in all people with A1ATD. The difference in the rate of decline of FEV1 between A1ATD and normal patients highlights the principle of augmentation therapy with replacement alpha-one protein. Mortality in people with A1ATD is most frequently due to respiratory failure, followed by liver cirrhosis. The observed yearly mortality rate ranges between 1.7-3.5%. Factors associated with increased mortality include older age, lower education, lower FEV1, history of lung transplant, and people who were not receiving augmentation therapy with the

A1ATD has a strong association with liver disease, leading to a recommendation that all individuals of any age with unexplained liver dysfunction should undergo testing for the deficiency. In the Swedish population screening study by Sveger, of 200,000 people, 18% of the 120 people found to be homozygote for the Z mutation had some evidence of liver dysfunction (Sveger, 1974). This included obstructive jaundice in 12%, and minor abnormalities in others. Among those with liver dysfunction, the risk of developing cirrhosis is high. It is possible that younger individuals more often have liver dysfunction because their hepatocytes are less well equipped to handle the polymerized A1AT proteins. In a small autopsy series of patients with A1AT disease, cirrhosis was observed in 34% of patients, and

hepatocellular carcinoma was observed in 34% of those with cirrhosis (Eriksson, 1987).

has been described as causing a rapid resolution of the disease (Dowd et al., 1995).

Granulomatosis"), adolescents with airflow obstruction on pulmonary function tests.

When family history is considered, the following recommendations were made. There is a strong recommendation for testing all siblings of an individual with A1ATD. There is also a recommendation to consider testing in the following situations: individuals with a family history of emphysema or liver disease, or anyone with a family history of A1ATD or A1ATD heterozygote. The 2003 guidelines recommended against routine population screening except

Panniculitis is an uncommon skin disorder with a strong association with A1ATD. It is characterized by painful, cutaneous nodules at the sites of trauma, often on the trunk, back and thighs. On biopsy, areas of fat necrosis are interspersed with areas of normal tissue. The skin necrosis is felt to develop because of unopposed proteolysis, and augmentation therapy

Guidelines published by the American Thoracic Society and European Respiratory Society in 2003 have helped clarify who should undergo testing for A1ATD (American Thoracic Society, 2003). The guidelines divided people into categories for whom testing is recommended, those for whom testing could be discussed and considered, and those for whom testing was discouraged. For the following group of people testing should be recommended. These include: adults with emphysema, chronic obstructive pulmonary disease, or asthma with incompletely reversible airflow obstruction, people of all ages with otherwise unexplained liver disease, or adults with necrotizing panniculitis. In the following group of people testing could be considered and discussed: adults with bronchiectasis without an obvious etiology, adults with anti-proteinase 3-positive vasculitis (C-ANCA [anti-neutrophil cytoplasmic antibody]-positive vasculitis, formerly known as "Wegener's

purified A1AT protein (Stoller et al., 2005).

**6.2 Liver clinical manifestations** 

**6.3 Necrotizing panniculitis** 

**7. Testing for disease** 

The corner stone of alpha one antitrypsin management is smoking cessation and smoke avoidance in all individuals with the deficiency. Guidelines for the management of the chronic airflow obstruction (COPD) have been published elsewhere (GOLD guidelines, ATS guidelines, etc.) Augmentation therapy is utilized to increase serum and lung epithelial lining fluid (ELF) levels of A1AT through the weekly intravenous infusion of purified human A1AT protein (Wewers et al., 1987).

It is FDA approved to treat for adult patients with A1ATD (protein concentration < 11 micromoles/dL) and evidence of air flow obstruction. The treatment can be very costly because it involves life-long regular infusions of a blood product, and it is not available worldwide. The treatment was approved based on two factors, that there is biochemical equivalence between exogenous replacement protein and protein found in normal human serum, and there is normalization of serum protein levels in deficient individuals who are receiving replacement. Many non-randomized prospective studies have demonstrated the effectiveness of augmentation via reduction in the annual rate of decline of lung function. Well-designed and adequately powered randomized trials have been limited to date. A recent meta-analysis of published human studies demonstrated augmentation therapy does reduce the annual rate of lung function decline (as measured by FEV1) in A1ATD individuals (Chapman et al., 2009).

#### **8.1 Future therapies**

Ongoing work in areas of inhaled therapy, longer half-life protein, recombinant forms, small molecule chaperone inhibitors to increase liver secretion and gene transfer therapy continue. These studies and fields are all in various stages of development.

### **9. Conclusion**

Alpha1- antitrypsin deficiency is a not uncommon disease, which is not limited to the European and Caucasian American population, but now affects all ethnic groups. Effective treatments for this disease, including smoking cessation, management of COPD/emphysema and other complications, and augmentation therapy with purified A1AT protein is well established. However, the disease remains under-diagnosed, and

Alpha One Antitrypsin Deficiency: A Pulmonary Genetic Disorder 237

Gadek, JE., Fells, GA., Zimmeran, RL. Rennard, SI., & Crystal, RG. (1981). Anti-elastase of

Guenter, CA., Welch, MH., Russell TR, Hyde, RM., & Hammarsten, JF. (1968). The pattern of

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### **10. References**


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**10. References** 


**12** 

 *Japan* 

**Tangier Disease** 

*Nanakuma, Jonan-ku, Fukuoka* 

*Nanakuma, Jonan-ku, Fukuoka* 

Yoshinari Uehara1, Bo Zhang2 and Keijiro Saku1

*1Department of Cardiology, Fukuoka University Faculty of Medicine,* 

*2Department of Biochemistry, Fukuoka University Faculty of Medicine,* 

Various clinical and epidemiological studies have demonstrated an inverse association between high-density lipoprotein (HDL) cholesterol and the risk of coronary events (von Eckardstein et al., 2001). However, it remains controversial whether this relationship is causal or only an epiphenomenon of a more general atherogenic disorder. HDL exerts various potential anti-atherogenic properties. For example, HDL particles transport cholesterol from cells of the arterial wall to the liver and steroidogenic organs, in which cholesterol is used for the synthesis of bile acids, lipoproteins, vitamin D, and steroid hormones (von Eckardstein et al., 2001). In contrast, low HDL cholesterol is frequently identified as a component of metabolic syndrome in many populations, i.e., together with overweight or obesity, glucose intolerance or overt diabetes mellitus, hypertriglyceridemia, and hypertension, which by themselves contribute to the pathogenesis of atherosclerosis (Despres and Marette, 1994). The most severe form of familial HDL deficiency is Tangier

HDL, isolated by ultracentrifugation, is a lipoprotein with a density in the range 1.063–1.21 g/ml (HDL2, 1.063–1.125 g/ml; HDL3, 1.125–1.21 g/ml) (Havel et al., 1955). However, HDL constitutes a heterogeneous group of particles differing in size, density, lipid composition, apolipoprotein content, and electrophoretic mobility. HDL can be separated into two main subfractions based on electrophoretic mobility, namely the major subfraction has the same mobility as alpha HDL, whereas the other subfractions migrate similar to pre-beta HDL. Most HDL particles in human plasma are alpha HDL, and pre-beta HDL represents only 2–

HDL has a very complex metabolism associated with several HDL-related genes and is synthesized via a complex pathway. Although the underlying genetic defects in many cases of primary low HDL cholesterolemia are not clearly understood, mutations in three pivotal genes, namely apoA-I, lecithin:cholesterol acyltransferase, and ATP-binding cassette transporter A1 (ABCA1) are associated with low plasma HDL cholesterol levels (Miller et al., 2003). Some mutations of these genes are also associated with an increased risk of

14% of all apolipoprotein A-I (apoA-I) (Ishida et al., 1987; Kunitake et al., 1985).

**1. Introduction** 

disease (TD), which is caused by a genetic disorder.

**2. HDL metabolism and functions** 

premature coronary artery disease (CAD).

