Objective: To report a family with a novel variant of the GCH1 gene presenting as early-onset DOPA-responsive dystonia (DRD) and late-onset Parkinson’s disease.

Background: Autosomal dominant DYT/PARK-GCH1 is the most common form of monogenic DRD, typically presenting with early-onset lower limb dystonia, an excellent response to levodopa, and diurnal fluctuations

Method: Case study

Results:

A 50-year-old woman presented to the clinic with a three-year history of right upper limb bradykinesia and discomfort. Her consultation with an orthopedic specialist did not result in any improvement. Neurological assessments indicated hypomimia, bradykinesia, stiffness on the right side, and diminished right arm swing, without dystonic movements or postural abnormalities. MRI imaging of the brain and cervical spine was unremarkable, and dopamine transporter uptake was reduced in the left caudate and putamen; treatment with L-DOPA showed significant improvement.

The patient disclosed during a history-taking session that both of her daughters are taking the same medication. She has two daughters with DRD; the elder began experiencing significant diurnal gait fluctuations before the age of 7 and was identified with DRD after clinical improvement with L-DOPA, without a genetic diagnosis. The younger daughter, at the age of 20, had right leg discomfort and an inability to walk, showing significant improvement with a low dosage of L-DOPA (200 mg/day).

Whole exome sequencing (WES) for the proband and the oldest daughter revealed a new heterozygous likely pathogenic variation, c.184G>T (p. Glu62Ter), in the GCH1 gene in both subjects, with no other genetic variations discovered that might explain their characteristics. Confirmation and segregation by Sanger sequencing confirmed the same variant in the affected individual and ruled out its occurrence in unaffected family members.

Conclusion:

We emphasize intra-familial phenotypic heterogeneity associated with a new mutation in DYT/PARK-GCH1 seen in two daughters with Dystonia-Related Disorders (DRD) exhibiting differing ages of onset, alongside their mother, who presents with late-onset Parkinsonism.

References: Weissbach, Pauly et al. (2022)

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MDS Abstracts - https://www.mdsabstracts.org/abstract/intra-familial-phenotypic-variability-in-a-novel-autosomal-dominant-gch1-variant/