**1. Introduction**

Amyotrophic Lateral Sclerosis, generally known as ALS, is a lethal neurodegenerative disease that gradually affects the motor neurons (nerve cells) which control muscle movement. The causes of the disease are as yet unknown and the substantial amount of research currently under way has found that the causes of ALS are multifactorial, such as genetic predisposition. In fact, about the involvement of genetic, ALS is a multigenic disease result from mutations in more than one gene (Table 1). The annual incidence of ALS is 0,4-1,76 per 100000 [1]. The majority of cases of ALS are sporadic (90-95%), called SALS. Around 5-10% of cases are considered to be familial (FALS), where the disease is present in both a proband and firstdegree or second-degree relative [2-3]. FALS is usually inherited in an autosomal dominant manner, though there are rare cases of autosomal recessive disease. FALS is genetically heterogeneous, including 15 mapped loci, of which the causative genes are identified for 11. Mutations in several of the known FALS genes have also been described in apparently sporadic cases of ALS at low frequencies. Genetic changes detected in sporadic cases arise both from new mutations and also lack of evidence of inheritance due to the difficulty in recognizing a genetic component to rapidly lethal late-onset disease. The systematic, detailed diagnosis of neurological disease in older people is a modern, and still incomplete, medical phenomenon. For any late-onset disorder both incomplete penetrance and premature death of earlier generations due to other causes attenuates the expression of disease within a family so that in many examples where apparently sporadic ALS is associated with genetic mutation there is limited information about the family rather than a clear demonstration of unequivocally de novo genetic change [4].

© 2013 Diamanti et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


genders. 0-5% of cases have frontotemporal dementia. Median survival time is 2,5 years

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**b.** Bulbar phenotype starts with dysarthria, dysphagia, tongue wasting, fasciculation and no peripheral spinal involvement for the first 6 months after symptomps onset; pyramidal signs aren't required to be evident in the first period but needs to be evident therafter. This subtype has the same incidence in the two genders, with peak of incidence in the eighth decade. It is the commonest phenotype associated with frontotemporal dementia (10%). Median survival time is 2 years [4]. It is now accepted that FTD and MND are part of the same clinicopathological spectrum. Frontotemporal dementia is characterised clinically by progressive behavioural changes and frontal executive deficits and/or selective language difficulties. The presence of FTD is determined using a screening test, such as FAB (frontal assessment battery), and is based on Neary criteria [7-8]. Frontotem‐ poral dementia is present in about 5-10% of patients, however many ALS patients have evidence of FTD behavioural dysfunction that may not satisfy Neary criteria for FTD. Patients often have bulbar phenotype with muscle atrophy, weakness and fasciculations

**c.** Flail arm phenotype is characterised by progressive, predominantly proximal, weakness and wasting in the upper limbs and functional involvement has to be confined in this parts for at least 12 months after symptomps onset. This phenotype is relatively rare and more common in men, often benign with a median survival time of 4 years. Frontotemporal

**d.** Flail leg begins with progressive distal onset of symptomps in lower limbs. Patients with symptomps beginning proximally in the legs without distal involvement at onset are classified as classic ALS. This type of disease has the same incidence in two genders. Mean age of onset is about 65 years and the peak of incidence rate is in the eighth decade. Median

In two last categories there are forms with pathological deep tendon reflexes or Hoffmann and

**e.** Patients with pyramidal phenotype have manifestations dominated by severe spastic para/tertaparesis associated with Babinski or Hoffmann sign, hyperactive reflexes, clonic jaw jerk, dysarthric speech and pseudobulbar affect. Spastic paresis could be present at the beginning or in the fully developed stage of the disease. These patients show at the same time clear-cut signs of lower motor neuron impairment from onset of the disease, as indicated by muscle weakness and wasting and by the presence of chronic and active denervation at the EMG examination in at least two different sites. Patients have a quite young age at onset, under 60 years. Both genders are equally represented. FTD is uncom‐

**f.** There is a particular and the rarest phenotype with respiratory impairment at onset, defined as orthopnoea or dyspnoea at rest or during exertion, with only mild spinal or bulbar signs in the fisrt 6 months after onset. These patients show signs of upper motor neuron involvement. Median survival time is 1,5 years, with the worst prognosis [4].

prominent in the tongue and also in the upper extremities.

dementia is rare in this phenotype [4].

Babinski sign but without hypertonia or clonus.

mon and median survival time is 6 years [4].

survival time is 3 years [4].

[4].

**Table 1.** Genes and loci associated with ALS.

Discoveries in the clinical genetics of ALS in particular offer opportunities to deepen under‐ standing of various disease phenotypes that appear to share aspects of pathogenesis, confirm previous hypothesis around the concept of disease spectra, in terms of linkage to a specific proteinopathy, and increase the scope of pathological studies of human motor system disease.

Genetic factors may play a role in determining the range of ALS phenotypes although to date no genes have been shown to have a definite effect on phenotype [4]. In fact the genetic alteration is not the only factor that determines the clinical course of the disease, other factors must also contribute to phenotype and it is not yet possible to predict the evolution of patients based solely on presence of the mutation or rate of progression in other family members.

The diagnosis of ALS is based on the original El Escorial diagnostic criteria, revised from 2000 [5-6].

It is a generally accepted notion that the clinical spectrum of ALS includes different phenotypes marked by a varying involvement of spinal and bulbar upper and lower motor neurons. Accordingly, eight distinctive clinical phenotypes are recognised in the literature: classic, bulbar, flail arm, flail leg, pyramidal, respiratory, pure lower motor neuron, pure upper motor neuron.

**a.** Classic ALS phenotype is characterised by onset of symptomps in the upper or lower limbs, with clear but not predominant pyramidal signs. It is the commonest phenotype in men and the second in women, with a peak of incidence rate in the seventh decade in both genders. 0-5% of cases have frontotemporal dementia. Median survival time is 2,5 years [4].

**ALS type Onset Inheritance Locus Gene Protein**

ALS2 Juvenile AR 2q33-35 ALS2 Alsin

ALS4 Juvenile AD 9q34 *SETX* Senataxin ALS5 Juvenile AR 15q15-21 *SPG11* Spatacsin ALS6 Adult AD 16p11.2 *FUS* Fused in sarcoma

ALS9 Adult AD 14q11 *ANG* Angiogenin

ALS12 Adult AR/AD 10p15p14 *OPTN* Optineurin

ALS-FTD3 Adult AD 9p21 *C9Orf72* C9Orf72

ALS3 Adult AD 18q21 Unknown

ALS7 Adult AD 20p13 Unknown

ALS-FTD1 Adult AD 9q21-22 Unknown ALS-FTD2 Juvenile AD 9p13.2-21.3 Unknown

**Table 1.** Genes and loci associated with ALS.

74 Current Advances in Amyotrophic Lateral Sclerosis

[5-6].

neuron.

ALS1 Adult AD 21q22.1 *SOD1* Cu/Zn superoxide dismutase

ALS8 Adult AD 20q13.33 *VAPB* VAMP-associated protein B

ALS10 Adult AD 1q36 *TARDBP* TAR DNA-binding protein ALS11 Adult AD 6q21 *FIG4* PI(3,5)P(2)5-phosphatase

Discoveries in the clinical genetics of ALS in particular offer opportunities to deepen under‐ standing of various disease phenotypes that appear to share aspects of pathogenesis, confirm previous hypothesis around the concept of disease spectra, in terms of linkage to a specific proteinopathy, and increase the scope of pathological studies of human motor system disease.

Genetic factors may play a role in determining the range of ALS phenotypes although to date no genes have been shown to have a definite effect on phenotype [4]. In fact the genetic alteration is not the only factor that determines the clinical course of the disease, other factors must also contribute to phenotype and it is not yet possible to predict the evolution of patients based solely on presence of the mutation or rate of progression in other family members.

The diagnosis of ALS is based on the original El Escorial diagnostic criteria, revised from 2000

It is a generally accepted notion that the clinical spectrum of ALS includes different phenotypes marked by a varying involvement of spinal and bulbar upper and lower motor neurons. Accordingly, eight distinctive clinical phenotypes are recognised in the literature: classic, bulbar, flail arm, flail leg, pyramidal, respiratory, pure lower motor neuron, pure upper motor

**a.** Classic ALS phenotype is characterised by onset of symptomps in the upper or lower limbs, with clear but not predominant pyramidal signs. It is the commonest phenotype in men and the second in women, with a peak of incidence rate in the seventh decade in both


In two last categories there are forms with pathological deep tendon reflexes or Hoffmann and Babinski sign but without hypertonia or clonus.


**g.** Pure lower motor neuron phenotype is characterised by clinical and electrophysiological evidence of progressive LMN involvement. Patients with family history of inherited spinal muscular atrophy are excluded. It has a low incidence rate and is twice as frequent in men. Patients with this form are younger than those with any other ALS phenotype, with a peak of incidence rate in the seventh decade among men and in the sixth decade among women. Nobody has FTD and mean survival is the longest (7 years) [4].

In this chapter we would deep investigate the correlation between genetic and clinical features in the ALS population that we better know, the Italian one. However, heterogeneity between and among families implies that other environmental and genetic influences contribute to not only the rate of evolution and which signs predominate but also whether the disease will appear at all during life. Considerable work lies ahead in determining the genetic and environmental factors that most contribute to ALS. Altogether one determinant of ALS

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We will focus this book section on the correlation between genotype and phenotype in Italian ALS disease population. This chapter will be organized in different paragraphs about the genes mostly mutated in Italian ALS patients, *SOD1, FUS, TARDBP, ANG, C9orf72* and *OPTN* genes (Table 2), and each paragraphs will be subdivided in two parts about genotype and phenotype. Moreover we will try to define and understand particular connection between phenotype and genotype in Italian population and in our experience in Pavia to characterize the Italian ALS

Obviously in literature different mutations are known for every genes and many other ones

In this chapter we cannot deepen the importance of every mutation in relation to the pheno‐

For this reason in this book section we will develop speech on more frequent alterations and on which we have met during our daily activity in Pavia or in our collaborations with other

Superoxide dismutase [Cu-Zn] also known as superoxide dismutase 1 or SOD1 is a soluble protein acting as a 32 kDa homodimeric enzyme. SOD1 is one of three human superoxide

Its main function is the conversion, naturally occurring, but harmful, superoxide radicals to

SOD1 binds copper and zinc ions and is one of three superoxide dismutases responsible for destroying free superoxide radicals in the body. The encoded isozyme is a soluble cytoplasmic and mitochondrial inter-membrane space protein, acting as a homodimer to convert naturally occurring, but harmful, superoxide radicals to molecular oxygen and hydrogen peroxide

The human *SOD1* gene (Entrez Gene ID 6647) is located on chromosome 21q22.11, and it codes

for the monomeric SOD1 polypeptide (153 amino acids, molecular weight 16 kDa).

phenotype is the underlying causative mutation.

population in relation to the genetic aspects.

**2. Cu/Zn Superoxide Dismutase (SOD1 gene)**

molecular oxygen and hydrogen peroxide.

will be discovered in future.

groups.

dismutases.

**2.1. Genotype**

typic characteristic of ALS patients.

**h.** Patients with pure upper motor neuron have signs of UMN involvement (severe spastic para/tertaparesis associated with Babinski or Hoffmann sign, hyperactive reflexes, clonic jaw jerk, dysarthric speech and pseudobulbar affect). Patients with clinical or EMG signs of LMN involvement or with history of spastic para/tetraparesis in family such as hereditary spastic paraplegia are excluded. It has a low incidence rate with peak in the sixth decade in both genders, Median survival time is the longest among ALS phenotype (more than 10 years) [4].


**Table 2.** Mean age at onset, mean time delay from onset to diagnosis and frequency of frontotemporal dementia [4].


**Table 3.** Amyotrophic lateral sclerosis phenotypes. Overall and men versus women mean annual crude incidence raters (/100000 population), 95% CIs and gender incidence rate ratios [4].

In this chapter we would deep investigate the correlation between genetic and clinical features in the ALS population that we better know, the Italian one. However, heterogeneity between and among families implies that other environmental and genetic influences contribute to not only the rate of evolution and which signs predominate but also whether the disease will appear at all during life. Considerable work lies ahead in determining the genetic and environmental factors that most contribute to ALS. Altogether one determinant of ALS phenotype is the underlying causative mutation.

We will focus this book section on the correlation between genotype and phenotype in Italian ALS disease population. This chapter will be organized in different paragraphs about the genes mostly mutated in Italian ALS patients, *SOD1, FUS, TARDBP, ANG, C9orf72* and *OPTN* genes (Table 2), and each paragraphs will be subdivided in two parts about genotype and phenotype. Moreover we will try to define and understand particular connection between phenotype and genotype in Italian population and in our experience in Pavia to characterize the Italian ALS population in relation to the genetic aspects.

Obviously in literature different mutations are known for every genes and many other ones will be discovered in future.

In this chapter we cannot deepen the importance of every mutation in relation to the pheno‐ typic characteristic of ALS patients.

For this reason in this book section we will develop speech on more frequent alterations and on which we have met during our daily activity in Pavia or in our collaborations with other groups.
