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Letter
Brain structural alterations in patients with GCH1 mutations associated DOPA-responsive dystonia
  1. Vladimir S Kostić1,
  2. Federica Agosta2,3,
  3. Aleksandra Tomic1,
  4. Elisabetta Sarasso2,
  5. Nikola Kresojevic1,
  6. Silvia Basaia2,
  7. Marina Svetel1,
  8. Massimiliano Copetti4,
  9. Massimo Filippi2,3,5
  1. 1 Clinic of Neurology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
  2. 2 Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
  3. 3 Vita-Salute San Raffaele University, Milan, Italy
  4. 4 Biostatistics Unit, IRCCS-Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy
  5. 5 Neurology Unit and Neurophysiology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
  1. Correspondence to Professor Massimo Filippi, Neuroimaging Research Unit, Institute of Experimental Neurology; Neurology Unit; and Neurophysiology Unit, San Raffaele Hospital, Milano 20132, Lombardia, Italy; filippi.massimo{at}hsr.it

https://doi.org/10.1136/jnnp-2020-324535

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    GCH1 gene encodes the guanosine-5'-triphosphate (GTP) cyclohydrolase 1 (GTP-CH1), which is the enzyme involved in the first and rate-limiting step of the de novo biosynthesis of tetrahydrobiopterin and an essential cofactor for the synthesis of dopamine in nigrostriatal neurons. GCH1 mutation is the most common cause of the DOPA-responsive dystonia (DRD).1 This rare autosomal-dominant movement disorder is characterised predominantly by limb dystonia during childhood, although parkinsonian features may also be present.1 The hallmark of the disease is an excellent and sustained response to small doses of levodopa, generally without the occurrence of motor complications.1 Lack of changes in neuropathological and in majority of dopaminergic imaging studies in patients with GCH1-related DRD suggest that this is a neurotransmitter rather than a neurodegenerative disorder.1 However, case reports showed a nigrostriatal dopaminergic denervation (abnormal DaTSCAN) in some individuals carrying GCH1 mutation with adult-onset dystonia-parkinsonism.2 Residual symptoms might partially result from a lack of timely therapy, possibly suggesting underlying neurodegeneration. It has been hypothesised that, after a period of compensation, chronic reduction of dopamine levels resulting from GTP-CH1 deficiency could predispose to nigral cell damage by making them more vulnerable to environmental or other genetic factors.2

    To the best of our knowledge, no MRI studies have been performed to assess the presence of structural damage supporting the possible neurodegenerative process underlying DRD. In order to fill the gap in line with previous suggestions, in this study we used structural MRI (1.5 T) to evaluate patterns of cortical thickness, basal ganglia volumes, and white matter (WM) microstructural alterations …

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    Footnotes

    • Contributors VSK: design and conceptualisation of study; interpretation of data; drafting and revising the manuscript for intellectual content; obtaining funding. FA: design and conceptualisation of study; interpretation of data; revising the manuscript for intellectual content. AT: acquisition, analysis and interpretation of data; revising the manuscript for intellectual content. ES: analysis and interpretation of data; revising the manuscript for intellectual content. NK: acquisition, analysis and interpretation of data; revising the manuscript for intellectual content. SB: analysis and interpretation of data; revising the manuscript for intellectual content. MS: acquisition, analysis and interpretation of data; revising the manuscript for intellectual content. MC: statistical analysis and interpretation of data; revising the manuscript for intellectual content. MF: design and conceptualisation of study; interpretation of data; revising the manuscript for intellectual content; obtaining funding.

    • Funding Ministry of Education, Science, and Technological Development of the Republic of Serbia (project #175090).

    • Competing interests VSK has received speaker honoraria from Roche and Alkaloid; and receives research supports from the Swiss Pharm and Serbian Ministry of Education, Science and Development and Serbian Academy of Sciences and Art. FA is Section Editor of NeuroImage: Clinical; has received speaker honoraria from Philips, Novartis and Biogen Idec; and receives or has received research supports from the Italian Ministry of Health, AriSLA (Fondazione Italiana di Ricerca per la SLA), and the European Research Council. MF is Editor-in-Chief of the Journal of Neurology; received compensation for consulting services and/or speaking activities from Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA).

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.