Genotype-Phenotype Correlations In Movement and Neuromuscular Disorders

National Institute Of Neurological Disorders And Stroke

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Abstract

The Clinical Neurogenetics research program is focused on identification and characterization of genes and genetic mechanisms involved in hereditary movement and neuromuscular disorders. MYOFIBRILLAR MYOPATHIES: We have previously identified desmin gene as the cause of cardiac and skeletal myopathies. To-date, 45 mutations in this gene have been proven pathogenic. New studies conducted in this laboratory have shown that mutations in desmin gene caused the disease in only 62% of 147 patients with a definite diagnosis of myofibrillar myopathy we have studied over the year. The remaining 33% have now been associated with mutations in four other genes, MYOT in 28%, ZASP in 3%, CRYAB and FLNC in 1% each, and 5% of patients had mutations in more than one gene. Our analysis established sufficient clinical, electrophysiological and myopathological similarity between these diverse genetic subtypes allowing to classify them as Myofibrillar myopathies;at the same time, we uncovered substantial phenotypic distinctions between the genetically identified subtypes that should be considered in future studies of disease pathogenesis, and used for optimization of subtype-specific treatments and management. CHARCOT-MARIE-TOOTH DISEASE TYPE 2D AND SPINAL MUSCULAR ATROPHY TYPE V: We have previously identified glycyl-tRNA synthetase (GARS) gene mutations as the cause of autosomal dominant motor distal neuronopathy/axonopathy. We now tested a group of sporadic patients with a presumptive diagnosis of CMT2D for mutations in GARS gene, and, in addition, conducted a study of possible GARS involvement in patients with juvenile-onset muscular atrophy of the distal upper extremity classified as Hirayamas disease. Our preliminary conclusion was that GARS was not a factor in the etiology of Hirayamas disease in this specific cohort. CHROMOSOMAL MAPPING OF GENES CAUSING ESSENTIAL TREMOR: Essential tremor is the most common neurological disease affecting 4 to 6% of people at the age older than 40. Previously, we reported a new promising locus on chromosome 6p23 in two American families. We have now tested for mutations 14 candidate genes located in the 600-kB linked region. Some sequence variants are under study. Two other families, American and Spanish, show linkage to a different locus on chromosome 11p15 with LOD score of 2.45 spanning 9 cM, which suggests that more than one or even two genes are likely to be responsible for familial Essential tremor. High density single nucleotide polymorphism genotyping did not improve the LOD score but was able to narrow the linked region to 3.5 cM. We tested candidate genes in this region, which are functionally relevant. We sequenced coding regions of SYT8 and KCNQ1DN genes and demonstrated that RNA expression level of another candidate gene, DRD4, was increased in a muscle biopsy sample from one of the patients. We are planning to follow up on these results by examining more genes and additional tissue samples from affected family members.