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 CϾT) and a novel nonsynonymous substitution in exon 12 (c.1282GϾA, 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. Tyrosine hydroxylase deficiency (THD) is a rare autosomal recessive, dopa-responsive dystonia due to mutations in the TH gene.1 The phenotype of THD is thought to be a spectrum with overlap of clinical features between 2 main phenotypes 2 : one with onset of symptoms in the first year presenting as progressive hypokinetic-rigid syndrome, generalized dystonia, and good response to levodopa and the other with earlier onset presenting as a more complex encephalopathy, perinatal abnormalities, diurnal fluctuations, autonomic disturbances, and less response to levodopa.3-7 Here we present a new family with THD and a new phenotype of prominent levodopa-responsive myoclonus-dystonia (M-D) 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 Standard protocol approvals, registrations, and patient consents.

Isolated and combined dystonia syndromes – an update on new genes and their phenotypes

“…Prominent myoclonus in the context of dystonia with childhood onset and a positive family history can also be seen in some of the dopa‐responsive dystonias. This unusual presentation has been reported in a kindred with GTP cyclohydrolase 1 (GCH‐1) mutation and has now been described in a family with tyrosine hydroxylase (TH) deficiency . DYT5a with GCH‐1 mutations is inherited in an autosomal dominant fashion, whereas DYT5b with TH deficiency is an autosomal recessive condition.…”

Assessment of patients with isolated or combined dystonia: An update on dystonia syndromes

“…The SGCE gene undergoes imprinting, so that only 10% of patients who inherit a mutated maternal gene will express the phenotype; therefore, a family history can appear absent. The gene(s) responsible for SGCE‐negative families remains unknown, but a number of other known autosomal dominantly and (rarely) recessively inherited dystonias (tyrosine hydroxylase mutations) can have a myoclonus dystonia phenotype (see Supporting Table 6).…”

Treatable Inherited Movement Disorders in Children: Spotlight on Clinical and Biochemical Features

“…Milder and late-onset presentations have been described for autosomal recessive GTP-CH, TH, and sepiapterin reductase defects, with dopa-responsive dystonia and parkinsonism-dystonia syndrome. 82,85 Mild forms of 6-pyruvoyl-tetrahydropterin synthase deficiency may remain asymptomatic or develop chorea or parkinsonism later in the disease course. 86 Biogenic amine synthesis defects are potentially treatable disorders even though the outcome is less favorable than in AD-GTP-CH deficiency.…”