The Clinical Neurogenetics Unit research program is focused on identification and characterization of genes and genetic mechanisms involved in hereditary a) movement disorders, b) neuromuscular disorders, and c) prion diseases. Major findings: Twenty-two causative mutations in the desmin gene have now been identified and described, and adverse effects of each mutation tested in a cell culture expression system. Several clinically and pathologically distinct variants of desminopathy have been outlined: Variant 1, uncomplicated progressive skeletal myopathy Variant 2, skeletal myopathy followed by cardiomyopathy Variant 3, skeletal myopathy followed by respiratory muscle involvement, but no cardiac disease Variant 4, cardiomyopathy followed by skeletal myopathy Variant 5, isolated cardiomyopathy There is a correlation between the clinical syndromes and the position and type of the causative mutation in the desmin gene. Two disorders previously considered to be independent, type 5 of distal spinal muscular atrophy (dSMA-V) and type 2D of Charcot-Marie-Tooth disease (CMT2D) are associated with mutations in the same GARS gene, suggesting that these disorders are allelic, or perhaps represent the same disease, since phenotypic differences are not significant. This conclusion requires changes in the existing classification of peripheral neuropathies. Genetic susceptibility to kuru and new variant Creutzfeldt-Jakob disease is tightly linked to a M/V polymorphism in the PRNP gene, providing a model for predictions of the expected length and size of the developing epidemic of variant CJD associated with mad cow disease. Tremor-dystonia type of essential tremor in two large American families is shown to be linked to a 7 cM locus on chromosome 6p and a 21 cM region on chromosome 1p. Patients with definite Viliuisk encephalomyelitis show evidence for intrathecal IgG synthesis correlating with the clinical manifestations of the disease. The detection of oligoclonal IgG banding will be used as a valuable diagnostic assay.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Intramural Research (Z01)
Project #
1Z01NS002973-05
Application #
6843040
Study Section
(OCD)
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2003
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
Platonov, Fedor A; Tyryshkin, Kathrin; Tikhonov, Dmitriy G et al. (2016) Genetic fitness and selection intensity in a population affected with high-incidence spinocerebellar ataxia type 1. Neurogenetics 17:179-85
Goldfarb, Lev G; Dalakas, Marinos C (2009) Tragedy in a heartbeat: malfunctioning desmin causes skeletal and cardiac muscle disease. J Clin Invest 119:1806-13
Vladimirtsev, Vsevolod A; Nikitina, Raisa S; Renwick, Neil et al. (2007) Family clustering of Viliuisk encephalomyelitis in traditional and new geographic regions. Emerg Infect Dis 13:1321-6
Salajegheh, M; Rakocevic, G; Raju, R et al. (2007) T cell receptor profiling in muscle and blood lymphocytes in sporadic inclusion body myositis. Neurology 69:1672-9
Olive, Montse; Armstrong, Judith; Miralles, Francesc et al. (2007) Phenotypic patterns of desminopathy associated with three novel mutations in the desmin gene. Neuromuscul Disord 17:443-50
Kostera-Pruszczyk, Anna; Pruszczyk, Piotr; Kaminska, Anna et al. (2007) Diversity of cardiomyopathy phenotypes caused by mutations in desmin. Int J Cardiol :
Bar, Harald; Goudeau, Bertrand; Walde, Sarah et al. (2007) Conspicuous involvement of desmin tail mutations in diverse cardiac and skeletal myopathies. Hum Mutat 28:374-86
Dalakas, Marinos C; Rakocevic, Goran; Shatunov, Alexey et al. (2007) Inclusion body myositis with human immunodeficiency virus infection: four cases with clonal expansion of viral-specific T cells. Ann Neurol 61:466-75
Pruszczyk, Piotr; Kostera-Pruszczyk, Anna; Shatunov, Alexey et al. (2007) Restrictive cardiomyopathy with atrioventricular conduction block resulting from a desmin mutation. Int J Cardiol 117:244-53
Shatunov, Alexey; Sambuughin, Nyamkhishig; Jankovic, Joseph et al. (2006) Genomewide scans in North American families reveal genetic linkage of essential tremor to a region on chromosome 6p23. Brain 129:2318-31

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