GCH1 mutations in hereditary spastic paraplegia

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.