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GCH1 mutations in hereditary spastic paraplegia.

Parizad Varghaei1,2, Grace Yoon3, Mehrdad A Estiar2,4

  • 1Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, Quebec, Canada.

Clinical Genetics
|March 13, 2021
PubMed
Summary

Mutations in the GCH1 gene are now linked to hereditary spastic paraplegia (HSP). This study identified GCH1 variants in HSP patients, suggesting GCH1 as a potential cause of HSP and recommending levodopa treatment trials.

Keywords:
GCH1HSPdystoniaspastic paraplegia

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Area of Science:

  • Neurogenetics
  • Molecular Neurology
  • Genomic Medicine

Background:

  • GCH1 gene mutations are known causes of dopa-responsive dystonia and Parkinson's disease.
  • Recent reports suggest GCH1 mutations may also be implicated in hereditary spastic paraplegia (HSP).

Purpose of the Study:

  • To investigate the role of GCH1 gene variants in a cohort of 400 patients with hereditary spastic paraplegia (HSP).
  • To determine if GCH1 mutations are a potential cause of HSP and to evaluate treatment responses.

Main Methods:

  • Whole exome sequencing (WES) was performed on 400 HSP patients from 291 families across Canada.
  • Genetic variants in GCH1 were identified and analyzed for pathogenicity.
  • Clinical phenotypes of patients with GCH1 variants were documented and compared.

Main Results:

  • Three patients with heterozygous GCH1 variants (p.(Ser77_Leu82del) and p.(Val205Glu)) were identified.
  • The identified variants were predicted to be likely pathogenic or pathogenic.
  • Patients presented with childhood-onset spasticity; one showed diurnal fluctuations but no parkinsonism or dystonia.
  • Phenotypic variability was observed even in monozygotic twins, who responded well to levodopa treatment.

Conclusions:

  • GCH1 mutations are identified as a potential cause of hereditary spastic paraplegia (HSP).
  • A levodopa trial is recommended for HSP patients, and GCH1 should be considered in HSP gene screening panels.
  • Clinical variability in monozygotic twins suggests the influence of environmental factors, epigenetics, or stochasticity in HSP presentation.