Objective: To describe intrafamilial phenotypic variability associated with the coexisting LRRK2 G2385R and a novel GCH1 variant in a family presenting with parkinsonism and dystonia separately.

Background: The LRRK2 G2385R is a well-known risk factor for Parkinson’s disease (PD) in Asian populations, whereas GCH1 mutations typically cause dopa-responsive dystonia. The clinical phenotype of individuals carrying variants in both genes has not been previously reported.

Method: The proband, diagnosed with PD at age 50, initially presented with left-hand tremor and bradykinesia. He demonstrated a good response to levodopa. At age 66, he developed motor fluctuations with mild generalized peak-dose dyskinesia predominantly affecting the lower limbs.

His son developed foot dystonia during childhood, with dystonic posturing of the left upper limb at age 13, which worsened with fatigue and at night. Neurological examination revealed mild bradykinesia of the upper limbs, lower-limb dystonia during ambulation, and hyperreflexia without Babinski sign. He demonstrated a prominent response to low-dose levodopa.

Results: Dopamine transporter imaging showed bilateral dopaminergic deficits in the caudate and putamen in the father, while the son showed largely preserved striatal uptake. Both individuals carried heterozygous variants in LRRK2 (c.7153G>A, p.Gly2385Arg) and GCH1 (c.424G>A, p.Glu142Lys), the latter classified as a variant of uncertain significance according to ACMG criteria.

Conclusion: This family demonstrated phenotypic heterogeneity ranging from parkinsonism to dopa-responsive dystonia in individuals carrying both LRRK2 and GCH1 variants. The coexistence of these variants raises the possibility that genetic interactions may contribute to variability in clinical manifestations.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/intrafamilial-phenotypic-diversity-associated-with-coexisting-lrrk2-g2385r-and-a-novel-gch1-variant-a-case-report/