Potential new HSP gene

GCH1 gene recommended for HSP panels

Mutations in the GCH1 gene have been reported in 5 people with HSP, while this large Canadian study of 400 people with HSP from 291 families identified a further three. Findings suggest that this gene shares similar features with other HSP-associated genes.

HSP associated with mutations in this gene responds well to levodopa treatment. The authors recommend adding these GCH1 mutations to HSP gene testing panels.


Ziv Gan-Or

GCH1 mutations have been associated with dopa-responsive dystonia (DRD), Parkinson’s disease (PD) and tetrahydrobiopterin (BH4 )-deficient hyperphenylalaninemia B. Recently, GCH1 mutations have been reported in five patients with hereditary spastic paraplegia (HSP).

Here, we analyzed a total of 400 HSP patients (291 families) from different centers across Canada by whole exome sequencing (WES). Three patients with heterozygous GCH1 variants were identified: monozygotic twins with a p.(Ser77_Leu82del) variant, and a patient with a p.(Val205Glu) variant.

Guy Rouleau

The former variant is predicted to be likely pathogenic and the latter is pathogenic. The three patients presented with childhood-onset lower limb spasticity, hyperreflexia and abnormal plantar responses. One of the patients had diurnal fluctuations, and none had parkinsonism or dystonia. Phenotypic differences between the monozygotic twins were observed, who responded well to levodopa treatment. Pathway enrichment analysis suggested that GCH1 shares processes and pathways with other HSP-associated genes, and structural analysis of the variants indicated a disruptive effect.

In conclusion, GCH1 mutations may cause HSP; therefore, we suggest a levodopa trial in HSP patients and including GCH1 in the screening panels of HSP genes. Clinical differences between monozygotic twins suggest that environmental factors, epigenetics, and stochasticity could play a role in the clinical presentation.

SOURCE:  Clin Genet. 2021 Mar 13. doi: 10.1111/cge.13955. Online ahead of print. PMID: 33713342 © 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

GCH1 mutations in hereditary spastic paraplegia

Parizad Varghaei  1   2 Grace Yoon  3 Mehrdad A Estiar  2   4 Simon Veyron  5 Etienne Leveille  6 Nicolas Dupré  7   8 Jean-François Trempe  5 Guy A Rouleau  2   4   9 Ziv Gan-Or  2   4   9

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

2. Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.

3. Divisions of Neurology and Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Canada.

4. Department of Human Genetics, McGill University, Montreal, Quebec, Canada.

5. Department of Pharmacology & Therapeutics and Centre de Recherche en Biologie Structurale – FRQS, McGill University, Montréal, Canada.

6. Faculty of Medicine, McGill University, Montreal, Quebec, Canada.

7. Axe Neurosciences, CHU de Québec-Université Laval, Quebec City, Québec, Canada.

8. Department of Medicine, Faculty of Medicine, Université Laval, Quebec City, Quebec, Canada.

9. Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.

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