Article Text

PDF
Autosomal-dominant GTPCH1-deficient DRD: clinical characteristics and long-term outcome of 34 patients
  1. I Trender-Gerhard1,
  2. M G Sweeney2,
  3. P Schwingenschuh1,3,
  4. P Mir1,4,
  5. M J Edwards1,
  6. A Gerhard5,
  7. J M Polke2,
  8. M G Hanna6,
  9. M B Davis2,
  10. N W Wood2,
  11. K P Bhatia1
  1. 1
    Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, London, UK
  2. 2
    Department of Molecular Neuroscience, Institute of Neurology, London, UK
  3. 3
    Department of Neurology, Medical University Graz, Austria
  4. 4
    Unidad de Trastornos del Movimiento, Servicio de Neurología, Hospitales Universitarios Virgen del Rocío, CIBERNED, Seville, Spain
  5. 5
    Wolfson Molecular Imaging Centre, The University of Manchester, Manchester, UK
  6. 6
    MRC Centre for Neuromuscular Disease, Institute of Neurology, London, UK
  1. Professor K P Bhatia, Sobell Department, Institute of Neurology, UCL, Queen Square, London WC1N 3BG, UK; k.bhatia{at}ion.ucl.ac.uk

Abstract

Background: An autosomal dominantly inherited defect in the GCH1 gene that encodes guanosine triphosphate cyclohydrolase 1 (GTPCH1) is the most common cause of dopa-responsive dystonia (DRD). A classic phenotype of young-onset lower-limb dystonia, diurnal fluctuations and excellent response to levodopa has been well recognised in association with GCH1 mutations, and rare atypical presentations have been reported. However, a number of clinical issues remain unresolved including phenotypic variability, long-term response to levodopa and associated non-motor symptoms, and there are limited data on long-term follow-up of genetically proven cases.

Methods: A detailed clinical evaluation of 34 patients (19 women, 15 men), with confirmed mutations in the GCH1 gene, is presented.

Results and conclusions: The classic phenotype was most frequent (n = 23), with female predominance (F:M = 16:7), and early onset (mean 4.5 years) with involvement of legs. However, a surprisingly large number of patients developed craniocervical dystonia, with spasmodic dysphonia being the predominant symptom in two subjects. A subset of patients, mainly men, presented with either a young-onset (mean 6.8 years) mild DRD variant not requiring treatment (n = 4), or with an adult-onset (mean 37 years) Parkinson disease-like phenotype (n = 4). Two siblings were severely affected with early hypotonia and delay in motor development, associated with compound heterozygous GCH1 gene mutations. The study also describes a number of supplementary features including restless-legs-like symptoms, influence of female sex hormones, predominance of tremor or parkinsonism in adult-onset cases, initial reverse reaction to levodopa, recurrent episodes of depressive disorder and specific levodopa-resistant symptoms (writer’s cramp, dysphonia, truncal dystonia). Levodopa was used effectively and safely in 20 pregnancies, and did not cause any fetal abnormalities.

Statistics from Altmetric.com

Footnotes

  • Competing interests: None.

  • Ethics approval: Ethics approval was provided by Joint Research Ethics Committee of the Institute of Neurology and the National Hospital for Neurology and Neurosurgery, London, UK.

  • Patient consent: Obtained.

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.