Myoclonus-dystonia syndrome due to tyrosine hydroxylase deficiency

Abstract

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.

Figure 1

Family pedigree

Figure 2. EMG recordings and back-averaged EEG

(A) EMG recordings from patient II:2 showing irregular, myoclonic bursts with duration range from 20 to >100 msec. (B) Back-averaging shows no premyoclonic cortical potential.

Figure 3. Genetic studies

(A) Chromatograms of TH mutations identified in the present study. (B) Amino acid alignment of TH protein showing conservation of the p.G428R residue in different species.