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Clinical/Scientific Notes
March 22, 2018
Open Access

Mutation in the GCH1 gene with dopa-responsive dystonia and phenotypic variability

Dopa-responsive dystonia (DRD) is an autosomal dominant neurologic disorder characterized by incomplete penetrance and high variability of its phenotypic expression.1 The usual phenotype is defined by early-onset isolated dystonia, predominant in the lower limb, with marked diurnal fluctuations and a dramatic and sustained response to low doses of l-DOPA.2 We report 2 members of the same family (mother and daughter) with a nonsense heterozygous mutation (c.706G>T; p.Glu236*) in the GCH1 gene and having DRD with phenotypic variability.

Case (Index case)

A 23-year-old woman presented 10 months ago with severe cervical dystonia. At the age of 19 years, she had transient right lower limb dystonia that appeared immediately after physical effort and lasted 18 months. At the age of 22 years, she presented with left cervical dystonia lasting 2 weeks. Neurologic examination showed severe cervical dystonia with right laterocollis associated with a moderate retrocaput (video segment 1, links.lww.com/NXG/A40). The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS3) score was 49/85, with a severity score of 19/35, a disability score of 24/30 and a pain score of 6/20. Standard biological testing and brain MRI were normal. Levodopa/carbidopa 125 mg per day led to the complete regression of symptoms within 2 months (video segment 2). After 4 months of therapy, she decided to stop her medication. After 30 months of follow-up, her symptoms had not reappeared (video segment 3).
Her mother is 54 years old. At the age of 15 years, she had dystonia in the left foot during exercise, and at the age of 20 years, she had right upper limb dystonia. Diurnal fluctuations and task-specific dystonia appeared progressively over time. Indeed, she has writer's cramp and experiences left lower limb dystonia during prolonged walking. However, she refused to be treated. A molecular study revealed a nonsense mutation in exon 6 of the GCH1 gene (c.706G>T; p.Glu236*) in both of these patients.

Discussion

We report a novel DYT-5a mutation in exon 6 of the GCH1 gene (c.706G>T, p.Glu236*) manifesting as DRD with phenotypic variability, including cervical dystonia. This change is predicted to replace a glutamic acid residue by a stop codon. To date, 214 mutations have been reported in the gene (The Human Gene Mutation Database: hgmd.cf.ac.uk/ac/gene.php?gene=GCH1). A mutation in the GCH1 gene is found in most patients with DRD. It encodes GTP cyclohydrolase 1, an enzyme that catalyzes the first step in the biosynthesis of tetrahydrobiopterin. The latter is an essential cofactor for tyrosine hydroxylase, which is the rate-limiting enzyme for dopamine synthesis.4 As reported in the literature, there is a female-dominant penetration4 but no clear anticipation phenomenon.
The clinical presentations and evolution of our cases were uncommon compared with the phenotypes usually recognized.5 Indeed, our index case initially had severe cervical dystonia, and her mother presented with writer's cramp. However, clinical presentations of DRD can be heterogeneous and encompass a wide variety of symptoms including focal-task dystonia6 and parkinsonism7 or share some clinical similarities with cerebral palsy.8 The time course of symptoms was also very unusual for DRD. Although cervical dystonia quickly and completely abated after levodopa therapy, no relapse occurred after medication withdrawal during the 30 months of follow-up. This is surprising but could potentially be explained by corticostriatal synaptic homeostatic practice-dependent plasticity over time in patients with subtle dopaminergic alterations linked to the GCH1 mutation.9
These 2 patients presented with DRD. Focal dystonia is usually idiopathic with no clear genetic background or relation to basal ganglia lesions.1,10 However, clinicians should be aware of the fact that patients exhibiting focal dystonia can present a GCH1 mutation and dopa responsiveness. This new mutation could potentially explain the unusual phenotype presented by our patients throw further light on the pathophysiology of dystonia.

References

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Albanese A, Bhatia K, Bressman SB, et al. Phenomenology and classification of dystonia: a consensus update. Mov Disord 2013;28:863–873.
2.
Maas R, Wassenberg T, Lin JP, van de Warrenburg BPC, Willemsen M. l-Dopa in dystonia: a modern perspective. Neurology 2017;88:1865–1871.
3.
Consky ES. Clinical assessment of patients with cervical dystonia. In: Therapy Botulinum Toxin. New York: Marcel Dekker; 1994:211–237.
4.
Phukan J, Albanese A, Gasser T, Warner T. Primary dystonia and dystonia-plus syndromes: clinical characteristics, diagnosis, and pathogenesis. Lancet Neurol 2011;10:1074–1085.
5.
Albanese A, Asmus F, Bhatia KP, et al. EFNS guidelines on diagnosis and treatment of primary dystonias. Eur J Neurol 2011;18:5–18.
6.
Trender-Gerhard I, Sweeney MG, Schwingenschuh P, et al. Autosomal-dominant GTPCH1-deficient DRD: clinical characteristics and long-term outcome of 34 patients. J Neurol Neurosurg Psychiatry 2009;80:839–845.
7.
Tadic V, Kasten M, Bruggemann N, Stiller S, Hagenah J, Klein C. Dopa-responsive dystonia revisited: diagnostic delay, residual signs, and nonmotor signs. Arch Neurol 2012;69:1558–1562.
8.
Nygaard TG, Waran SP, Levine RA, Naini AB, Chutorian AM. Dopa-responsive dystonia simulating cerebral palsy. Pediatr Neurol 1994;11:236–240.
9.
Quartarone A, Pisani A. Abnormal plasticity in dystonia: disruption of synaptic homeostasis. Neurobiol Dis 2011;42:162–170.
10.
Waddy HM, Fletcher NA, Harding AE, Marsden CD. A genetic study of idiopathic focal dystonias. Ann Neurol 1991;29:320–324.

Information & Authors

Information

Published In

Neurology® Genetics
Volume 4Number 2April 2018
PubMed: 29577080

Publication History

Received: October 3, 2017
Accepted: January 31, 2018
Published online: March 22, 2018
Published in print: April 2018

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Disclosure

The authors report no disclosures. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NG.

Study Funding

No targeted funding reported.

Authors

Affiliations & Disclosures

Elsa Krim, MD*
From the Centre Hospitalier de Pau (E.K., M.B.), Service de Neurologie; Département de Neurosciences Cliniques (J.A., P.B., D.G.), Centre Hospitalier Universitaire de Bordeaux; Université de Bordeaux (J.A., P.B., D.G.), Institut des Maladies Neurodégénératives, CNRS UMR 5293; and AP-HP (F.C.), Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Unité Fonctionnelle de Neurogénétique Moléculaire et Cellulaire, Département de Génétique et Cytogénétique, Paris, France.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Jerome Aupy, MD*
From the Centre Hospitalier de Pau (E.K., M.B.), Service de Neurologie; Département de Neurosciences Cliniques (J.A., P.B., D.G.), Centre Hospitalier Universitaire de Bordeaux; Université de Bordeaux (J.A., P.B., D.G.), Institut des Maladies Neurodégénératives, CNRS UMR 5293; and AP-HP (F.C.), Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Unité Fonctionnelle de Neurogénétique Moléculaire et Cellulaire, Département de Génétique et Cytogénétique, Paris, France.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Fabienne Clot, MD, PhD
From the Centre Hospitalier de Pau (E.K., M.B.), Service de Neurologie; Département de Neurosciences Cliniques (J.A., P.B., D.G.), Centre Hospitalier Universitaire de Bordeaux; Université de Bordeaux (J.A., P.B., D.G.), Institut des Maladies Neurodégénératives, CNRS UMR 5293; and AP-HP (F.C.), Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Unité Fonctionnelle de Neurogénétique Moléculaire et Cellulaire, Département de Génétique et Cytogénétique, Paris, France.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Mickael Bonnan, MD
From the Centre Hospitalier de Pau (E.K., M.B.), Service de Neurologie; Département de Neurosciences Cliniques (J.A., P.B., D.G.), Centre Hospitalier Universitaire de Bordeaux; Université de Bordeaux (J.A., P.B., D.G.), Institut des Maladies Neurodégénératives, CNRS UMR 5293; and AP-HP (F.C.), Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Unité Fonctionnelle de Neurogénétique Moléculaire et Cellulaire, Département de Génétique et Cytogénétique, Paris, France.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Pierre Burbaud, MD, PhD
From the Centre Hospitalier de Pau (E.K., M.B.), Service de Neurologie; Département de Neurosciences Cliniques (J.A., P.B., D.G.), Centre Hospitalier Universitaire de Bordeaux; Université de Bordeaux (J.A., P.B., D.G.), Institut des Maladies Neurodégénératives, CNRS UMR 5293; and AP-HP (F.C.), Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Unité Fonctionnelle de Neurogénétique Moléculaire et Cellulaire, Département de Génétique et Cytogénétique, Paris, France.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Dominique Guehl, MD, PhD
From the Centre Hospitalier de Pau (E.K., M.B.), Service de Neurologie; Département de Neurosciences Cliniques (J.A., P.B., D.G.), Centre Hospitalier Universitaire de Bordeaux; Université de Bordeaux (J.A., P.B., D.G.), Institut des Maladies Neurodégénératives, CNRS UMR 5293; and AP-HP (F.C.), Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Unité Fonctionnelle de Neurogénétique Moléculaire et Cellulaire, Département de Génétique et Cytogénétique, Paris, France.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE

Notes

Correspondence Dr. Guehl [email protected]
*
These authors contributed equally to the manuscript.
Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NG.
The Article Processing Charge was funded by the authors.

Author Contributions

E.K.: acquisition of data and writing of the first draft of the manuscript. J.A.: writing of the first draft of the manuscript and critical revision of the manuscript for intellectual content. F.C. and M.B.: acquisition of data and critical revision of the manuscript for intellectual content. P.B.: study supervision and critical revision of the manuscript for intellectual content. D.G.: acquisition of data, study concept and design, and critical revision of the manuscript for intellectual content.

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  1. Mechanisms of GNAL linked dystonia, Dystonia, 3, (2024).https://doi.org/10.3389/dyst.2024.12079
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  2. Dystonia genes and their biological pathways, , (61-103), (2023).https://doi.org/10.1016/bs.irn.2023.04.009
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  3. Recognizing Atypical Dopa-Responsive Dystonia and Its Mimics, Neurology Clinical Practice, 11, 6, (e876-e884), (2021)./doi/10.1212/CPJ.0000000000001125
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