**3. Clinical manifestation and classification**

SMA is manifested by various clinical features that cause a variety of debilitating symptoms. Muscle weakness is a hallmark feature of SMA and patients with SMA are among the weakest and most hypotonic seen in any muscle clinic.13 Clinically, the disease is characterized by progressive symmetrical muscle weakness, which starts proximally and moves distally, with the proximal muscles being more affected than the distal muscles.5 Muscle weakness is associated with muscle atrophy, hypotonia, absence or marked decrease of deep tendon reflexes, fasciculation of the tongue, and tremors of the hand.5,20 Patients with SMA have normal intellectual function. Contractures and spinal deformity have been reported to be common impairments. Pulmonary infections and restrictive lung disease are

Spinal Muscular Atrophy 223

years is typical, weakness in other mild cases may not be noticeable until late childhood. Patients are able to achieve independent walking and whilst some children may lose this ability in childhood, others maintain walking until adolescence or adulthood.30 Early motor milestones are often normal, including ability to walk, which is achieved at the normal age or slightly late. Although they are able to ambulate, they may show difficulty with walking at some point in their clinical course secondary to proximal muscle weakness. Walking is characterized by lack of balance, falls, increased lumbar lordosis, hyperextended knees or genu recurvatum, and excessive waddling. Muscle weakness mainly affects proximal muscles of the lower extremities and is less severe than types I and II SMA. Proximal muscle weakness often results in difficulty in stairs climbing, hopping, running and jumping. Gower's' maneuver may be present when getting up off the floor. Scoliosis and pulmonary complications are common in patients with type III SMA but less frequent and not severe as in patients with type II SMA. The incidence and severity of complications including scoliosis and pulmonary complications are related to the degree of muscle weakness and the functional status. Many patients with type III lose the ability to functionally ambulate as they get weaker during adulthood. Individuals with type III SMA usually have normal life

Adult-onset SMA is a rare type. The onset of the disease is in the adulthood, typically in the third or fourth decades. The signs and symptoms are similar to those of type III SMA but the

There are other very rare types of SMA disorders with similar symptoms but they are caused by different genes other than SMN1 and genetic mutation. Other forms of SMA include *distal spinal muscular atrophy*, characterized by distal muscle weakness; *X-linked spinal and bulbar muscular atrophy (Kennedy disease*), an X-linked adult onset form of SMA; *childhood bulbar SMA (Fazio-londe disease), a progressive bulbar palsy; Hexosaminidase a deficiency,* with variable neurologic findings, including progressive dystonia, spinocerebellar degeneration, and lower motor neuron disease; and *Monomelic muscular atrophy,* a cervical

Diagnosis of SMA is suspected on the bases of the clinical picture, muscle biopsy and electromyography. Genetic testing is the only definitive diagnostic test for patients with SMA. With the use of genetic testing, the role of EMG and muscle biopsy in confirming the diagnosis of SMA is limited. They can be used for the diagnosis of patients with SMA who present without homozygous deletion of the SMN gene.32 Genetic testing of SMA shows a deletion of the SMN gene on the fifth chromosome. EMG findings usually show a pattern of denervation including fibrillation potentials, positive sharp waves, and large amplitude, short duration actions potentials. Sensory nerve conduction velocities are normal with no marked decrease of motor nerve conduction velocities. Muscle biopsy provides evidence of muscle denervation with groups of small atrophic fibers with large hypertrophic fibers.

impairments and degree of disability are often mild. Life expectancy is normal.

expectancy.

**3.4 SMA type IV (Adult-onset form)** 

**3.5 Other forms of SMA** 

form of spinal muscular atrophy.24

**4. Diagnosis** 

the most serious complications in SMA.12 In general, the clinical course of SMA is highly variable, and it is more of a continuous spectrum with the age of onset from birth to adulthood, and the age of death from infancy to normal life expectancy. The severity of the diseases and clinical manifestations show a continuous range from the very severe to very mild forms of the disease.20 With age, muscle weakness increases, and the symptoms progress and patients lose their functions over time.25 The progression of the disease process varies both between and within types.21 Current evidence suggests that maximum function achieved is more closely related to life expectancy than age at onset.24 Based on the age at onset, clinical presentation, and the maximum functional level achieved, SMA is usually classified into the following broad types.

#### **3.1 Type I SMA (Werdnig-Hoffmann disease)**

Type I SMA is the most severe form of SMA, it is also known as Werdnig-Hoffman disease. The age of onset is typically from birth or in the first 6 months of life and the child never developing independent sitting. Werdnig-Hoffmann disease is characterized by severe generalized muscle weakness and hypotonia.20 Infants typically have significant wasting, and weakness in the limbs and trunk and present with decreased movements, especially against gravity. Most infants present with lack of head control and are never able to roll from supine or to pull to sitting.13 Significant oral motor weakness results in difficulties in sucking and swallowing and makes feeding progressively more difficult. Weakness of the intercostal muscles results in limited respiratory function, and breathing is usually entirely diaphragmatic resulting in development of abnormal breathing patterns and respiratory complications. The severity of respiratory complications is generally proportional to the weakness.24 Early morbidity and mortality are commonly associated with pulmonary complications,30 and death occurs during the first 2 to 3 years of life.

#### **3.2 Type II SMA (Intermediate form)**

Children with the intermediate form have an onset between 6 and 18 months of age.17 They are able to sit and may develop ability to stand but they are unable to walk independently.21,30 Some of the less involved children are able to walk with braces or assistive devices at some point of their life.8 Children with type II exhibit symptoms of weakness similar to type I SMA but with much less severe degree. Distal muscle weakness is less severe than proximal muscle weakness and starts later in the course of the disease. There is a delay in the acquisition of motor skills, with the majority of those children sit at the age of 12 months of age. As the disease progresses, children exhibit more weakness and regressed gross motor development. Feeding and swallowing are not difficult. Contractures are common including scoliosis or kyphoscoliosis. Early onset and rapidly progressing scoliosis is uniformly present; severity of scoliosis increases as the disease progresses and may require bracing and/or spinal fusion. Pulmonary complications are pervasive especially with scoliosis and as the disease progresses. Ventilatory assistance is common in later stages of the disease.

#### **3.3 Type III SMA (Kugelberg-Welander disease)**

Type III SMA, often referred to as Kugelberg-Welander disease or Juvenile-onset SMA, is the mild form of the disease. Children with type III SMA have an onset age typically after 18 months. This form is more variable in age of onset, although most diagnosis prior to age 3

the most serious complications in SMA.12 In general, the clinical course of SMA is highly variable, and it is more of a continuous spectrum with the age of onset from birth to adulthood, and the age of death from infancy to normal life expectancy. The severity of the diseases and clinical manifestations show a continuous range from the very severe to very mild forms of the disease.20 With age, muscle weakness increases, and the symptoms progress and patients lose their functions over time.25 The progression of the disease process varies both between and within types.21 Current evidence suggests that maximum function achieved is more closely related to life expectancy than age at onset.24 Based on the age at onset, clinical presentation, and the maximum functional level achieved, SMA is usually

Type I SMA is the most severe form of SMA, it is also known as Werdnig-Hoffman disease. The age of onset is typically from birth or in the first 6 months of life and the child never developing independent sitting. Werdnig-Hoffmann disease is characterized by severe generalized muscle weakness and hypotonia.20 Infants typically have significant wasting, and weakness in the limbs and trunk and present with decreased movements, especially against gravity. Most infants present with lack of head control and are never able to roll from supine or to pull to sitting.13 Significant oral motor weakness results in difficulties in sucking and swallowing and makes feeding progressively more difficult. Weakness of the intercostal muscles results in limited respiratory function, and breathing is usually entirely diaphragmatic resulting in development of abnormal breathing patterns and respiratory complications. The severity of respiratory complications is generally proportional to the weakness.24 Early morbidity and mortality are commonly associated with pulmonary

Children with the intermediate form have an onset between 6 and 18 months of age.17 They are able to sit and may develop ability to stand but they are unable to walk independently.21,30 Some of the less involved children are able to walk with braces or assistive devices at some point of their life.8 Children with type II exhibit symptoms of weakness similar to type I SMA but with much less severe degree. Distal muscle weakness is less severe than proximal muscle weakness and starts later in the course of the disease. There is a delay in the acquisition of motor skills, with the majority of those children sit at the age of 12 months of age. As the disease progresses, children exhibit more weakness and regressed gross motor development. Feeding and swallowing are not difficult. Contractures are common including scoliosis or kyphoscoliosis. Early onset and rapidly progressing scoliosis is uniformly present; severity of scoliosis increases as the disease progresses and may require bracing and/or spinal fusion. Pulmonary complications are pervasive especially with scoliosis and as the disease progresses. Ventilatory assistance is common in later stages of the disease.

Type III SMA, often referred to as Kugelberg-Welander disease or Juvenile-onset SMA, is the mild form of the disease. Children with type III SMA have an onset age typically after 18 months. This form is more variable in age of onset, although most diagnosis prior to age 3

classified into the following broad types.

**3.2 Type II SMA (Intermediate form)** 

**3.3 Type III SMA (Kugelberg-Welander disease)** 

**3.1 Type I SMA (Werdnig-Hoffmann disease)** 

complications,30 and death occurs during the first 2 to 3 years of life.

years is typical, weakness in other mild cases may not be noticeable until late childhood. Patients are able to achieve independent walking and whilst some children may lose this ability in childhood, others maintain walking until adolescence or adulthood.30 Early motor milestones are often normal, including ability to walk, which is achieved at the normal age

or slightly late. Although they are able to ambulate, they may show difficulty with walking at some point in their clinical course secondary to proximal muscle weakness. Walking is characterized by lack of balance, falls, increased lumbar lordosis, hyperextended knees or genu recurvatum, and excessive waddling. Muscle weakness mainly affects proximal muscles of the lower extremities and is less severe than types I and II SMA. Proximal muscle weakness often results in difficulty in stairs climbing, hopping, running and jumping. Gower's' maneuver may be present when getting up off the floor. Scoliosis and pulmonary complications are common in patients with type III SMA but less frequent and not severe as in patients with type II SMA. The incidence and severity of complications including scoliosis and pulmonary complications are related to the degree of muscle weakness and the functional status. Many patients with type III lose the ability to functionally ambulate as they get weaker during adulthood. Individuals with type III SMA usually have normal life expectancy.

### **3.4 SMA type IV (Adult-onset form)**

Adult-onset SMA is a rare type. The onset of the disease is in the adulthood, typically in the third or fourth decades. The signs and symptoms are similar to those of type III SMA but the impairments and degree of disability are often mild. Life expectancy is normal.

#### **3.5 Other forms of SMA**

There are other very rare types of SMA disorders with similar symptoms but they are caused by different genes other than SMN1 and genetic mutation. Other forms of SMA include *distal spinal muscular atrophy*, characterized by distal muscle weakness; *X-linked spinal and bulbar muscular atrophy (Kennedy disease*), an X-linked adult onset form of SMA; *childhood bulbar SMA (Fazio-londe disease), a progressive bulbar palsy; Hexosaminidase a deficiency,* with variable neurologic findings, including progressive dystonia, spinocerebellar degeneration, and lower motor neuron disease; and *Monomelic muscular atrophy,* a cervical form of spinal muscular atrophy.24
