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Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with dopa-responsive dystonia
Brain, 06/05/09

Clot F et al. – Despite >80% yield of mutations in pure Dopa-responsive dystonia and Dopa-responsive dystonia-plus syndromes groups, the involved genes clearly differ: GCH1 gene (GTP cyclohydrolase1) in the former and TH (tyrosine hydroxylase) or SPR (sepiapterin reductase) genes in the latter.

• Study of relative frequency of these gene mutations: autosomal dominant mutations in GCH1 gene; autosomal recessive mutations in TH or SPR genes; mutations in PARK2 gene (parkin)
• Study of genes involved in biosynthesis and recycling of BH4
• Evaluation of associated clinical spectrum
• Subjects: 64 index pts with Dopa-responsive dystonia improved ≥ 50% after L-Dopa treatment
• Pt classification: 57 as pure Dopa-responsive dystonia; 7 as Dopa-responsive dystonia-plus syndromes
• Screen for point mutations and large rearrangements in GCH1 gene, then sequencing of TH and SPR genes, then PTS (pyruvoyl tetrahydropterin synthase), PCBD (pterin-4a-carbinolamine dehydratase), QDPR (dihydropteridin reductase) and parkin genes
• Identification of 34 different heterozygous point mutations in 40 pts, and 6 different large deletions in 7 pts in GCH1 gene

• Stereotyped clinical features, characterized by pure Dopa-responsive dystonia with onset in lower limbs and excellent response to low-doses L-Dopa for all pts except 1 pt with mental retardation and large deletion of 2.3 Mb encompassing 10 genes
• Dystonia started in first life decade in 40 pts (85%) and age <1 yr in 1 pt (2.2%)
• Of 17 negative GCH1 pts, mutations for 3 in TH gene, 2 in SPR gene, and 1 in PARK2 gene
• No mutations in the 3 genes involved in biosynthesis and recycling of BH4
• Clinical presentations of pts with TH and SPR gene mutations much more complex: A) characterized by mental retardation, oculogyric crises and parkinsonism; B) all classified as Dopa-responsive dystonia-plus syndromes
• Pts with PARK2 gene mutation had Dopa-responsive dystonia with good improvement with L-Dopa, similar to Dopa-responsive dystonia secondary to GCH1 mutations

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