**6. Chromosome 9 open reading frame 72 (C9orf72)**

Chromosome 9 open reading frame 72 is a protein localized on plasma membrane and cytoskeleton. There are two isoforms of C9orf72 that are produced as a result of alternative splicing events and the molecular weight of *C9orf72* isoforms is 54/25 kDa. Normally, it is nuclear protein, even if the mutated form has been described in the cytoplasm [54].

#### **6.1. Genotype**

In 2011 Lai SL et al. [50] described 4 Italian patients with sporadic ALS and FUS mutations (p.Y66Y, p.G507D, p.R521C, p.R521H). All of these cases initially manifested limb weakness

In 2009 Chiò et al. [51] described a patient with mutation in FUS and a very young age at onset

In literature [37, 45] confirmed this correlations between genotype and phenotype in FUS

Millecamps S et al. [43] suggested that FUS patients had a shorter lifespan, more rapid disease,

Angiogenin is a angiogenic ribonuclease whose activity is related to its ability in regulating ribosomal RNA (rRNA) transcription. ANG induces angiogenesis by activating vessel endothelial and smooth muscle cells and triggering a number of biological processes, including

The human *ANG* gene (Entrez Gene ID 283) is located on chromosome 14q11.1-q11.2, and it

*ANG*, encoding a 14 kDa angiogenic ribonuclease, is the first loss-of-function gene identified in ALS. Since original discovery of *ANG* as an ALS candidate gene, a total of 15 missense mutations in the coding region of ANG have been identified in 37 of the 4,193 ALS patients. Among them, 10 have been characterized in detail and shown to be loss-of-function mutations.

The percentage of *ANG* gene mutations has been confirmed in the Italian ALS population [11].

Gellera et al. [11] identified 9 patients with new ANG mutation, 6 SALS and 3 FALS. Two patients presented bulbar onset, while 7 patients spinal onset. Patients with P-4S mutation presented signs of LMN involvement in both legs at age of 55 years and subsequently a rapidly progressive course with signs of UMN and LMN involvement. Two patients had G20G mutation but two different clinical course: first patient had slowly progressive lower limb onset MND at age 62 with prevalence of LMN signs and 3 years later manifested cognitive dysfunc‐ tion of frontal lobe type, second patient presented distal weakness of upper limb at age 21 with a slowly progressive course characterized by prevalence of LMN signs. SALS Patient with V113I mutation developed spasticity of the right arm and atrophy of the right hand muscles at age 51, one year later the same symptoms appeared in the controlateral upper limb with prevalence of UMN signs. Patient with H114R mutation started with bulbar signs at age of 68.

ANG gene has been found mutated in 2.3% of FALS and 1% of SALS patients [53].

cell migration, invasion, proliferation, and formation of tubular structures [52].

and symptoms onset was before 50 years of age in more cases.

(<30 years) with a bulbar presentation and a short duration.

mutations in ALS both FALS and SALS patients.

younger onset than other mutations.

84 Current Advances in Amyotrophic Lateral Sclerosis

codes for a protein of 147 amino acids.

**5. Angiogenin (ANG)**

**5.1. Genotype**

**5.2. Phenotype**

The human *C9orf72* gene (Entrez Gene ID 203228) is located on chromosome 9p21.2, and it codes for a protein of 481 amino acids.

Recently, a hexanucleotide repeat expansion within the *C9orf72* gene was identified as the cause of chromosome 9p21-linked ALS-FTD [54, 55].

About the Italian population, a screening *C9orf72* in a large cohort of 259 familial ALS, 1275 sporadic ALS, and 862 control individuals has been performed [12]. It has been found RE in 23.9% familial ALS, 5.1% sporadic ALS, and 0.2% controls. Two cases carried the RE together with mutations in other ALS-associated genes.

Genotype data revealed that 95% of RE carriers shared a restricted 10-single nucleotide polymorphism haplotype within the previously reported 20-single nucleotide polymorphism risk haplotype, detectable in only 27% of nonexpanded ALS cases and in 28% of controls, suggesting a common founder with cohorts of North European ancestry. Although *C9orf72* RE segregates with disease, the identification of RE both in controls and in patients carrying additional pathogenic mutations suggests that penetrance and phenotypic expression of *C9orf72* RE may depend on additional genetic risk factors.

#### **6.2. Phenotype**

Ratti et al. [12] observed that the phenotype of RE carriers was characterized in higher proportion by bulbar-onset compared with nonexpanded patients, while in individuals with spinal onset expanded patients displayed an early involvement of the upper limbs less frequently than other patients, with predominance of upper motor neuron signs. RE carriers had a shorter survival compared with noncarriers. There was a correlation between more frequent bulbar onset in expanded patients and shorter survival time. The concurrence of FTD was significantly higher in expanded cases compared with wild type individuals and also ALS-FTD patients with RE manifested cognitive behaviour before the onset of motor symptoms. In most cases the phenotype was compatible with a behavioural variant of FTD and frequently dominated by psychiatric symptoms, such as visual hallucination, paranoid behaviour with persecutory delusions, aggressive behaviour and/or suicidal thoughts.

with no differencies between SALS and FALS patients. Many patients were characterized by

Genetics of ALS and Correlations Between Genotype and Phenotype in ALS — A Focus on Italian Population

http://dx.doi.org/10.5772/56547

87

Amyotrophic Lateral Sclerosis is a multifactorial and multigenic disease with still unknown aetiology and pathogenesis. We know many causative mutations in particular genes, both in familial and sporadic patients, and different clinical presentation of ALS. Genetic factors may play a role in determining the range of ALS phenotypes although in this moment no genes have been demonstrated to have a definite effect on phenotype (Chiò et al., 2011) [4]. Hetero‐ geneity between and among families and patients with same mutation suggests that environ‐ mental and other influences contribute to not only the rate of evolution and which signs

In this chapter we have identified cases in which connection between phenotype and genotype

We started from the ALS patients part of the recruitment of our Institute to define the possible

For ALS patients with mutations in some genes, such as *SOD1*, there are an important clinical phenotypic heterogeneity at onset and during evolution of disease, different time of survival

*TARDBP* is involved both in pathogenesis of frontotemporal dementia and ALS, but it's not sure that all patients with ALS will develop FTD and they don't demonstrated an homogenous

In particular we will focus attention on connection between FUS mutations, and clinical presentation with upper limbs onset, developed weakness of the neck flexor/extensor muscles and bilateral scapular girdle and proximal muscle. In many cases this phenotype is correlated with rapidly bulbar evolution and frontotemporal behaviour alterations, with negative prognosis in short time. This focus is in particular due to the presence of FUS mutated patients

Another interesting suggestion is that sometimes mutated patients (i.e. SOD1) can have particular clinical course modulated by other causative or associated modified genes (ANG). It is an important issue that maybe indicates a central role of genotype in developing pheno‐

For other genes it's difficult discovering association between genotype and phenotype for

In conclusion, at this time, in front of a patient with ALS, a neurologist should has some

and velocity of progression with rapidly or slowly involvement of bulbar functions.

in our cohort and the "poverty" of the literature about FUS and clinical features.

rarity of manifestation compared with more frequent mutations.

"milestones" considering clinical phenotype:

predominate but also whether the disease will appear at all during life.

clinical features that may be related to specific genes alteration.

a prevalence of upper motor neuron signs.

**8. Conclusions**

is possible and relevant.

clinical pattern.

type.

Reports in literature were in according [56-59].

Extrapyramidal and cerebellar signs were also observed in two patients, while a patients presented continuous lingual myclonus at disease onset. These cases suggested that clinical phenotype associated with RE in C9orf72 may be broader than originally thought, possibly involving extramotoneuronal structures such as the basal ganglia, cerebellum, brainstem nuclei.

Sabatelli et al. and Chiò et al. [60, 61, 62] studied clinical phenotype of patients with repeat expansion in large population and also two Sardinian families with neurodegenerative diseases (FTD-ALS) in which mutations in different genes (TARDBP p.A382T mutation and repeat expansion GGGGCC C9orf72) co-existed as pathogenetic causes, giving varied pheno‐ types.
