Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia

Abstract

Dopa-responsive dystonia is a childhood-onset dystonic disorder, characterized by a dramatic response to low dose of L-Dopa. Dopa-responsive dystonia is mostly caused by autosomal dominant mutations in the GCH1 gene (GTP cyclohydrolase1) and more rarely by autosomal recessive mutations in the TH (tyrosine hydroxylase) or SPR (sepiapterin reductase) genes. In addition, mutations in the PARK2 gene (parkin) which causes autosomal recessive juvenile parkinsonism may present as Dopa-responsive dystonia. In order to evaluate the relative frequency of the mutations in these genes, but also in the genes involved in the biosynthesis and recycling of BH4, and to evaluate the associated clinical spectrum, we have studied a large series of index patients (n = 64) with Dopa-responsive dystonia, in whom dystonia improved by at least 50% after L-Dopa treatment. Fifty seven of these patients were classified as pure Dopa-responsive dystonia and seven as Dopa-responsive dystonia-plus syndromes. All patients were screened for point mutations and large rearrangements in the GCH1 gene, followed by sequencing of the TH and SPR genes, then PTS (pyruvoyl tetrahydropterin synthase), PCBD (pterin-4a-carbinolamine dehydratase), QDPR (dihydropteridin reductase) and PARK2 (parkin) genes. We identified 34 different heterozygous point mutations in 40 patients, and six different large deletions in seven patients in the GCH1 gene. Except for one patient with mental retardation and a large deletion of 2.3 Mb encompassing 10 genes, all patients had stereotyped clinical features, characterized by pure Dopa-responsive dystonia with onset in the lower limbs and an excellent response to low doses of L-Dopa. Dystonia started in the first decade of life in 40 patients (85%) and before the age of 1 year in one patient (2.2%). Three of the 17 negative GCH1 patients had mutations in the TH gene, two in the SPR gene and one in the PARK2 gene. No mutations in the three genes involved in the biosynthesis and recycling of BH4 were identified. The clinical presentations of patients with mutations in TH and SPR genes were strikingly more complex, characterized by mental retardation, oculogyric crises and parkinsonism and they were all classified as Dopa-responsive dystonia-plus syndromes. Patient with mutation in the PARK2 gene had Dopa-responsive dystonia with a good improvement with L-Dopa, similar to Dopa-responsive dystonia secondary to GCH1 mutations. Although the yield of mutations exceeds 80% in pure Dopa-responsive dystonia and Dopa-responsive dystonia-plus syndromes groups, the genes involved are clearly different: GCH1 in the former and TH and SPR in the later.

Recent Advances in the Molecular Pathogenesis of Dystonia-Plus Syndromes and Heredodegenerative Dystonias

“…Recessive forms of DRD have also been identified with mutations in the genes for tyrosine hydroxylase (TH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), sepiapterin reductase (SR), dihydropteridine reductase (DHPR) and aromatic acid decarboxylase (AADC). These forms usually have a more complicated and severe phenotype [4]. …”

Advances in Our Understanding of Dystonia - Pathophysiology and Treatment Options

“…20 Over 100 different GCH1 mutations have been identified, 21 but GCH1 mutations are not found in approximately 25 % of patients with DRD. 22 Recessive genetic causes account for some of the mutation negative cases, but a small proportion of DRD cases remain unexplained. 22 There are several autosomal recessive forms of DRD to be found, which are due to varying mutations in genes encoding other enzymes involved in dopamine synthesis, including tyrosine hydroxylase (TH), 23 6-pyruvoyltetrahydropterin synthase (6-PTPS) 24 and sepiapterin reductase.…”

“…25 Typically, the clinical picture in these conditions is different from GCH1 DRD, with infantile-onset severe neurologic symptoms, including hypotonia, severe bradykinesia, drooling, ptosis, miosis, oculogyria, cognitive impairment and seizures. 22 Another important autosomal-recessive cause of the DRD phenotype are mutations in the 'juvenile' parkinsonism parkin gene. 22,26,27 Generally the presence of early prominent parkinsonism and severe dyskinesias favours parkin mutations.…”

“…22 Another important autosomal-recessive cause of the DRD phenotype are mutations in the 'juvenile' parkinsonism parkin gene. 22,26,27 Generally the presence of early prominent parkinsonism and severe dyskinesias favours parkin mutations.…”

Combined Sepiapterin Reductase and Methylmalonyl-CoA Epimerase Deficiency in a Second Patient: Cerebrospinal Fluid Polyunsaturated Fatty Acid Level and Follow-Up Under l-DOPA, 5-HTP and BH4 Trials

“…Most of the patients present symptoms in the first years of age, but the diagnosis is delayed when neurotransmitters in CSF are missed. Commonly, patients exhibit progressive psychomotor retardation, tremor, seizures, oculogyric crises and notably dystonia with diurnal fluctuations (Clot et al 2009). Sleep disorders and marked hypersomnolence are also described (Friedman et al 2006).…”