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Autosomal-dominant GTPCH1-deficient DRD: clinical characteristics and long-term outcome of 34 patients
  1. Iris Trender-Gerhard (iristrendergerhard{at}googlemail.com)
  1. Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, Queen Square, United Kingdom
    1. Mary G Sweeney (mary.sweeney{at}uclh.nhs.uk)
    1. Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London, United Kingdom
      1. Petra Schwingenschuh (p.schwingenschuh{at}ion.ucl.ac.uk)
      1. Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, Queen Square, United Kingdom
        1. Pablo Mir (pablo.mir.sspa{at}juntadeandalucia.es)
        1. Servicio de Neurología, Hospitales Universitarios Virgen del Rocío, CIBERNED, Seville, Spain
          1. Mark J Edwards (m.edwards{at}ion.ucl.ac.uk)
          1. Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, Queen Square, United Kingdom
            1. Alexander Gerhard (alex.gerhard{at}manchester.ac.uk)
            1. Wolfson Molecular Imaging Centre, The University of Manchester, United Kingdom
              1. James M Polke
              1. Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London, United Kingdom
                1. Mike G Hanna (mhanna{at}ion.ucl.ac.uk)
                1. Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, Queen Square, United Kingdom
                  1. Mary B Davis (mary.davis{at}uclh.nhs.uk)
                  1. Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London, United Kingdom
                    1. Nick W Wood (n.wood{at}ion.ucl.ac.uk)
                    1. Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London, United Kingdom
                      1. Kailash P Bhatia (kbhatia{at}ion.ucl.ac.uk)
                      1. Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, Queen Square, United Kingdom

                        Abstract

                        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 recognized 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. We present a detailed clinical evaluation of 34 patients (19 women, 15 men) with confirmed mutations in the GCH1 gene. We found that 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’s 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. We also describe 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). We report that levodopa was used effectively and safely in 20 pregnancies, and did not cause any foetal abnormalities.

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