Abstract:
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease (NDD), characterized by degeneration of both upper and lower motor neurons leading to muscle wasting. With an incidence of two and a prevalence of four in 100.000/year, it is the third most common NDD after Alzheimer’s and Parkinson’s diseases. The last decade has proven that the ‘condition’ called ALS is both clinically and genetically heterogenous, and that the genetic component in 90% of the cases that are considered as sporadic, might be stronger than expected. In this thesis, we investigated the complex genetics of ALS in the ethnically heterogeneous yet inbred Turkish population. Familial ALS account for 22% of our cases (159/722) and 563 cases were classified as sporadic (78%). Consanguinity is calculated as 25% among familial and 17% in sporadic cases. Conventional screening of the most common ALS genes (C9orf72, SOD1, TARDBP and FUS) in patients with a family history of disease, explained the disease cause in only 33%, pointing towards marked locus heterogeneity within the population. C9orf72 hexanucleotide repeat expansion was further detected in 3% of ‘apparently sporadic’ patients. Application of whole exome sequencing (WES) in dominant and recessive Turkish pedigrees presenting with ALS or non-ALS motor neuron diseases (MNDs), revealed distinct rare or novel mutations in 20 out of 39 families and enabled differential diagnosis in cases with atypical ALS features. Common current themes in ALS, like oligogenic inheritance and possible genetic modifiers are addressed in families with incomplete penetrance and in C9orf72 expansion carriers. Oligogenic inheritance of known ALS genes was not prominent in the Turkish C9orf72-positive cases. Hypermethylation in the promoter region of C9orf72 was confirmed in Turkish patients, however it did not seem to modify age of onset. Finally, analyses of whole genome sequencing data of 625 Turkish ALS patients and 152 healthy controls in the framework of Project MinE showed population-specific aspects and once more substantiated the concept of low penetrance of rare ALS genes among sporadic patients.
