Genetic Studies on Patients Affected With Six Related Neurodegenerative Diseases

Background and aim: neurodegenerative diseases often cause disability and death in patients. amyotrophic lateral sclerosis (als), is the most common neurodegenerative disorder and bvvl, fazio londe, charcot-marie-tooth type 2 (cmt2), hmsn-p and arhsp are five disorders whose symptoms are related to and sometimes overlap with als. although causative genes for all the disorders are known, mutations in these do not account for diseases in most affected individuals. our goal was to identify causative genes for these related neurodegenerative diseases in iranian patients.methods: the most common causative genes were screened for mutations in the probands of 130 families. subsequently, whole exome sequencing was performed for 30 members of 17 families without mutations in said genes. novel candidate causative genes were identified and segregation analysis, and screenings of ethnically matched control individuals were performed. functional studies were performed on one new als gene.results: thirty-two probands had mutations in known causative genes. exome sequencing identified six novel genes in als, bvvl, fazio londe and cmt2 families. also, we found spg11 mutations in eight mixed arhsp/jals families. all mutations segregated with diseases status and mutations in the novel genes were not observed in 1000 control individuals. genetic analysis is ongoing in some of the families without mutations in known genes. real time pcr, western blot and flow cytometry data confirmed the possibility of pathogenesis for the new als gene.conclusion: six candidate new genes for neurodegenerative diseases were identified, two of which have roles in apoptosis. identification of these will enhanced our understanding the etiology of the diseases. rather than arhsp or jals, designation of arhsp/jals disease is suggested for the disease of some patients with spg11 mutation. we have by now identified sixteen unrelated bvvl patients in iran. this number is notable, considering that less than 100 cases have been reported worldwide. our findings emphasize potential commonalities among the etiologies of the six neurodegenerative disorders.