**8. Conclusions**

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

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

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‐

Optineurin is an inhibitor protein that play an important role in the maintenance of the Golgi complex, in membrane trafficking and in exocytosis. Alternative splicing results in multiple

The human *OPTN* gene (Entrez Gene ID 10133) is located on chromosome 10p13, and it codes for a protein of 577 amino acids. In 2010 *OPTN* mutations have been described, for the first time, in ALS patients [63]. In the first paper about OPTN mutation three type of mutation have been found, two point mutation and one deletion. In 2011, a screening in the Caucasian population in SALS and FALS patients showed that *OPTN* mutations causing ALS are rare, especially in mainly Caucasian ALS subjects [64]. About Italian population, Del Bo and collaborators screened 274 ALS patients, 161 FALS and 113 SALS and the results showed six novel variants in both FALS and SALS patients, all occurring in an heterozygous state [13]. This data support the involvement of *OPTN* in ALS, especially in FALS patients, due to the

Del Bo et al. [13] suggested that ALS patients carrying OPTN mutations showed a prevalent lower-limb onset, with large variable age of onset (from 24 to 71 years of age) and progression (very aggressive forms with survival time < 1 year and very slow disease course over 10 years)

transcript variants encoding the same protein., three different isoforms are known.

persecutory delusions, aggressive behaviour and/or suicidal thoughts.

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

86 Current Advances in Amyotrophic Lateral Sclerosis

nuclei.

types.

**7. Optineurin**

**7.1. Genotype**

**7.2. Phenotype**

1.2% cases found mutated [13].

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

In this chapter we have identified cases in which connection between phenotype and genotype is possible and relevant.

We started from the ALS patients part of the recruitment of our Institute to define the possible clinical features that may be related to specific genes alteration.

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

*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 clinical pattern.

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

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‐ type.

For other genes it's difficult discovering association between genotype and phenotype for rarity of manifestation compared with more frequent mutations.

In conclusion, at this time, in front of a patient with ALS, a neurologist should has some "milestones" considering clinical phenotype:

**•** if patient's history suggests a familial form, it is important to perform a screening of four principal genes (SOD1, TARDBP, FUS, C9ORF) because they cover more than 50% of FALS;

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Our idea is that a specific mutation can cause a particular clinical onset, involvement and evolution of ALS, with a pathogenetic mechanism still unknown.

On the other side, now we have some ideas for type of disease correlated with particular mutations (i.e. FUS and TARDBP give a early onset, short duration of disease for early bulbar involvement) but it's impossible predict exactly what kind of phenotype can be developed by patient.

Different genes are involved in ALS disease, the importance of a good clinical characterization may help in choosing the genetic approach. We hypothesized that in the future, the symptoms observation may became more specific to indicate which gene is the most probably mutated. This idea may proceed in the same time of a better collaboration between clinicians and biologist to create a direct link from bed to bench.

This approach may be relevant for diagnostic use, so starting from neurological exam, that remains the essential element, and we can formulate diagnostic hypothesis that it can be surely confirmed by genetic test.

Acknowledgement

We are grateful to the patients and their families. We thank other members of General Neurology Department and Laboratory of Experimental Neurobiology for continuous working activity.
