title: Novel GCH1 variant in Dopa-responsive dystonia and Parkinson's disease.
abstract: BACKGROUND
  GTP cyclohydrolase I (GCH1) mutations are the commonest cause of Dopa-responsive dystonia (DRD). Clinical phenotypes can be broad, even within a single family.
  
  
  METHODS
  We present clinical, genetic and functional imaging data on a British kindred in which affected subjects display phenotypes ranging from DRD to Parkinson's disease (PD). Twelve family members were studied. Clinical examination, dopamine transporter (DAT) imaging, and molecular genetic analysis of GCH1 and the commonest known familial PD-related genes were performed.
  
  
  RESULTS
  We have identified a novel missense variant, c.5A > G, p.(Glu2Gly), within the GCH1 gene in affected family members displaying a range of phenotypes. Two affected subjects carrying this variant had abnormal DAT imaging. These two with abnormal DAT imaging had a PD phenotype, while the remaining three subjects with the novel GCH1 variant had normal DAT imaging and a DRD phenotype.
  
  
  CONCLUSIONS
  We propose that this GCH1 variant is pathogenic in this family and these findings suggest that similar mechanisms involving abnormal GTP cyclohydolase I may underlie both PD and DRD. GCH1 genetic testing should be considered in patients with PD and a family history of DRD.
authors: Department of Neurology, Queen Elizabeth Hospital, Birmingham, UK; Department of Neurology, The Dudley Group NHS Foundation Trust, Dudley, UK; School of Clinical and Experimental Medicine, College of Medicine and Dentistry, University of Birmingham, Birmingham, UK.
authors: A J
authors: AJ
authors: Lewthwaite
authors: Department of Neurology, Queen Elizabeth Hospital, Birmingham, UK.
authors: T D
authors: TD
authors: Lambert
authors: Department of Radiology, Queen Elizabeth Hospital, Birmingham, UK.
authors: E B
authors: EB
authors: Rolfe
authors: Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.
authors: S
authors: S
authors: Olgiati
authors: Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.
authors: M
authors: M
authors: Quadri
authors: Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.
authors: E J
authors: EJ
authors: Simons
authors: Department of Neurology, Queen Elizabeth Hospital, Birmingham, UK; School of Clinical and Experimental Medicine, College of Medicine and Dentistry, University of Birmingham, Birmingham, UK.
authors: K E
authors: KE
authors: Morrison
authors: Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.
authors: V
authors: V
authors: Bonifati
authors: Department of Neurology, Queen Elizabeth Hospital, Birmingham, UK; Department of Radiology, Queen Elizabeth Hospital, Birmingham, UK; Department of Neurology, Sandwell & West Birmingham Hospitals NHS Trust, Birmingham, UK. Electronic address: David.Nicholl@nhs.net.
authors: D J
authors: DJ
authors: Nicholl
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020821:Dystonic Disorders / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D006136:GTP Cyclohydrolase / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010300:Parkinson Disease / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D010641:Phenotype
chemical_list: D006136:GTP Cyclohydrolase
keywords: Dopa responsive dystonia; GCH1; Parkinson's disease; SPECT DAT imaging
references: Hum Mutat. 2011 Apr;32(4):358-68
references: 21412949
references: Hell J Nucl Med. 2012 May-Aug;15(2):134-8
references: 22833860
references: Nat Genet. 2014 Sep;46(9):989-93
references: 25064009
references: Parkinsonism Relat Disord. 2012 Jun;18(5):666-8
references: 22030322
references: Tremor Other Hyperkinet Mov (N Y). 2013 Oct 10;3:null
references: 24255805
references: Mov Disord. 2007 Nov 15;22(15):2210-5
references: 17712858
references: Mov Disord. 2006 May;21(5):679-82
references: 16267845
references: J Neurol Neurosurg Psychiatry. 2004 Dec;75(12):1749-52
references: 15548497
references: Parkinsonism Relat Disord. 2015 Feb;21(2):87-94
references: 25487733
references: J Neurol Neurosurg Psychiatry. 2008 Feb;79(2):183-6
references: 17898029
references: Brain. 2014 Sep;137(Pt 9):2480-92
references: 24993959
references: Neurology. 2013 Jul 16;81(3):301-2
references: 23771491