title: 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.
authors.affiliation: AP-HP, Département de Génétique et Cytogénétique, Groupe Hospitalier Pitié Salpêtrière, Paris, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Clot
authors.forename: David
authors.initials: D
authors.lastname: Grabli
authors.forename: Cécile
authors.initials: C
authors.lastname: Cazeneuve
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Roze
authors.forename: Pierre
authors.initials: P
authors.lastname: Castelnau
authors.forename: Brigitte
authors.initials: B
authors.lastname: Chabrol
authors.forename: Pierre
authors.initials: P
authors.lastname: Landrieu
authors.forename: Karine
authors.initials: K
authors.lastname: Nguyen
authors.forename: Gérard
authors.initials: G
authors.lastname: Ponsot
authors.forename: Myriem
authors.initials: M
authors.lastname: Abada
authors.forename: Diane
authors.initials: D
authors.lastname: Doummar
authors.forename: Philippe
authors.initials: P
authors.lastname: Damier
authors.forename: Roger
authors.initials: R
authors.lastname: Gil
authors.forename: Stéphane
authors.initials: S
authors.lastname: Thobois
authors.forename: Alana J
authors.initials: AJ
authors.lastname: Ward
authors.forename: Michael
authors.initials: M
authors.lastname: Hutchinson
authors.forename: Annick
authors.initials: A
authors.lastname: Toutain
authors.forename: Fabienne
authors.initials: F
authors.lastname: Picard
authors.forename: Agnès
authors.initials: A
authors.lastname: Camuzat
authors.forename: Estelle
authors.initials: E
authors.lastname: Fedirko
authors.forename: Chankannira
authors.initials: C
authors.lastname: Sân
authors.forename: Delphine
authors.initials: D
authors.lastname: Bouteiller
authors.forename: Eric
authors.initials: E
authors.lastname: LeGuern
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
authors.forename: Marie
authors.initials: M
authors.lastname: Vidailhet
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000429:Alcohol Oxidoreductases / Q000235:genetics; D001708:Biopterins / Q000031:analogs & derivatives* / Q000096:biosynthesis; D002648:Child; D002675:Child, Preschool; D004298:Dopamine / Q000096:biosynthesis*; D015259:Dopamine Agents / Q000627:therapeutic use*; D020821:Dystonic Disorders / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006136:GTP Cyclohydrolase / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007980:Levodopa / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D017354:Point Mutation; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D055815:Young Adult
chemical_list: D015259:Dopamine Agents; D001708:Biopterins; D007980:Levodopa; D000429:Alcohol Oxidoreductases; C022630:sepiapterin reductase; D014446:Tyrosine 3-Monooxygenase; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D006136:GTP Cyclohydrolase; C003402:sapropterin; D004298:Dopamine