Journal
NEUROLOGY
Volume 79, Issue 5, Pages 435-441Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1212/WNL.0b013e318261714a
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Funding
- Medical Research Council (MRC)
- Wellcome Trust
- NORD, DMRF, NORD
- UCL/UCLH Biomedical Research Centre
- Ipsen
- Halley Stewart Trust through Dystonia Society UK
- Wellcome Trust MRC strategic neurodegenerative disease initiative award [WT089698]
- Dystonia Coalition
- Parkinson's UK [G-1009]
- Department of Health National Institute for Health Research Biomedical Research Centre
- MRC [G0701075, G108/638, G1001253, G0802760, MC_G1000735] Funding Source: UKRI
- Alzheimers Research UK [ART-PPG2011A-14, ART-PG2010-1] Funding Source: researchfish
- Medical Research Council [G1001253, G108/638, G0802760, G0701075, MC_G1000735] Funding Source: researchfish
- Parkinson's UK [G-1009, G-0907] Funding Source: researchfish
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Objective: To present a new family with tyrosine hydroxylase deficiency (THD) that presented with a new phenotype of predominant, levodopa-responsive myoclonus with dystonia due to compound heterozygosity of one previously reported mutation in the promoter region and a novel nonsynonymous mutation in the other allele, thus expanding the clinical and genetic spectrum of this disorder. Methods: We performed detailed clinical examination of the family and electrophysiology to characterize the myoclonus. We performed analysis of the TH gene and in silico prediction of the possible effect of nonsynonymous substitutions on protein structure. Results: Electrophysiology suggested that the myoclonus was of subcortical origin. Genetic analysis of the TH gene revealed compound heterozygosity of a point mutation in the promoter region (c.1-71 C > T) and a novel nonsynonymous substitution in exon 12 (c.1282G > A, p.Gly428Arg). The latter is a novel variant, predicted to have a deleterious effect on the TH protein function and is the first pathogenic TH mutation in patients of African ancestry. Conclusion: We presented a THD family with predominant myoclonus-dystonia and a new genotype. It is important to consider THD in the differential diagnosis of myoclonus-dystonia, because early treatment with levodopa is crucial for these patients. Neurology (R) 2012; 79: 435-441
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