Brain Advance Access published online on June 2, 2009
Brain, doi:10.1093/brain/awp084
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Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia
1 AP-HP, Département de Génétique et Cytogénétique, Groupe Hospitalier Pitié Salpêtrière, Paris, France 2 AP-HP, Département de Neurologie, Hôpital Pitié-Salpêtrière, Paris, France 3 INSERM, UMR_S679 Neurologie & Thérapeutique Expérimentale, Paris, France 4 Université Pierre et Marie Curie, Paris 06, Paris, France 5 Hôpital Clocheville, Neuropédiatrie & INSERM U930, Université & CHRU, Tours, France 6 Hôpital de la Timone, CHU, Marseille, France 7 Service de Neurologie Pédiatrique, CHU Paris Sud Hôpital Bicêtre, Le Kremlin-Bicêtre, France 8 AP-HP, Service de Neuropédiatrie, Hôpital Armand Trousseau, Paris, France 9 Service de Neurologie, CHU de Bab El-Oued, Alger, Algérie, France 10 CHU Nantes, INSERM, CIC 0004, Nantes, France 11 Departement de Neurologie, CHU et Université, Poitiers, France 12 Hôpital Pierre Wertheimer, Service de Neurologie, Lyon, France 13 Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland 14 Department of Neurology, St Vincent's University Hospital, Dublin 4, Ireland 15 Hôpital Bretonneau, Service de Génétique, CHRU, Tours, France 16 Hôpitaux Universitaires de Genève, Service de Neurologie, Genève, Suisse
Correspondence to:
Prof. Alexis Brice, INSERM U679, IFR de Neurosciences, Groupe Hospitalier Pitié Salpêtrière, 47 Bd de l’Hôpital, 75 651 Paris Cedex 13, France. E-mail: alexis.brice{at}upmc.fr
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.
Key Words: Dopa-responsive dystonia; GCH1 gene; SPR gene; TH gene; PARK2 gene
Abbreviations: CRE, cyclic monophosphate response element; CSF, cerebrospinal fluid; DRD, L-Dopa-responsive dystonia; PCR, polymerase chain reaction; PTS, 6-pyruvoyl tetrahydropterin synthase; QDPR, dihydropteridin reductase; SPR, sepiapterin reductase
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Received November 19, 2008. Revised February 13, 2009. Accepted February 23, 2009.
*These authors contributed equally to this work.
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