Genetics and mechanisms of essential tremor and related disorders

Abstract

Neurodegenerative disorders are characterized by progressive nervous system dysfunction, and they remain as one of the most challenging disorders known to humankind. These disorders have devastating effects on patients and currently there are no effective therapeutic approaches. Approved medicines provide only symptomatic relief, and inadequacy of information about the molecular mechanisms underlying these conditions restricts the development of new effective therapies. In this thesis, I presented the genetic analysis of two different neurodegenerative disorders and investigate the molecular mechanisms underlying these two disorders: essential tremor and Troyer syndrome. Essential tremor is one of the most prevalent movement disorders; however, its genetic cause and molecular mechanisms remain unknown because of its clinical heterogeneity, age-dependent penetrance, variable expressivity, and relation to other neurodegenerative disorders. In a six-generation consanguineous Turkish family with both essential tremor and Parkinson’s disease, we identified a rare missense mutation of HTRA2 as the causative allele. Family members homozygous for this allele were more severely affected than those heterozygous for this allele. Troyer syndrome is a very rare autosomal recessive neurodegenerative disorder with only several described cases. Only two reports with truncating mutations have been described. In a consanguineous Turkish kindred with two affected siblings presenting tremor of the hands as well as clinical features similar to that of Troyer syndrome, we identified a novel missense mutation in SPG20. We presented a genotype-phenotype correlation in this family, and the missense SPG20 p.G580R mutation was found to result in a milder form of Troyer syndrome without skeletal abnormalities. Overall, this study provides solutions to complexities of neurodegenerative disorders by suggesting a novel and unifying molecular mechanism underlying essential tremor and Parkinson’s disease. Furthermore, correlation of genotypes and phenotypic differences in patients with Troyer syndrome explains the clinical heterogeneity and variable expressivity of neurodegenerative disorders.