Genetic analysis reveals phenotypic variability in three Colombian families with dopa-responsive dystonia: novel genotype-phenotype correlations.

backgroundDopa-responsive Dystonia (DRD) due to GTP cyclohydrolase 1 (GTPCH1) deficiency is a neurogenetic disorder caused by pathogenic GCH1 variants. Tetrahydrobiopterin (BH4) deficiency impairs dopamine synthesis in the basal ganglia, leading to childhood-onset dystonia with excellent response to levodopa. CASE PRESENTATION: We report eight patients from three unrelated families with GCH1 (NM_000161.3) variants: c.142 C > T; p.(Gln48*), c.241T > C; p.(Ser81Pro), and c.607G > A; p.(Gly203Arg). Two individuals homozygous for c.142 C > T showed phenotypic discordance. Mean age at onset was 7.3 years (range: 6–12), with an average diagnostic delay of 13.4 years. All symptomatic individuals responded well to low-dose levodopa. DISCUSSION: This is the first report to describe variable expressivity among individuals homozygous for p.(Gln48*). Previous literature has focused on heterozygous carriers with incomplete penetrance, and homozygous variability remains scarcely documented.

conclusionsOur findings expand the clinical and molecular spectrum of DRD and challenge the assumption that autosomal recessive GCH1 variants invariably cause a severe phenotype. This report underscores the importance of family-based genetic studies, detailed pedigrees, and careful clinical surveillance of asymptomatic carriers. A low threshold for levodopa trials is warranted, even when inheritance patterns or symptom severity deviate from classical expectations. These insights are critical to improving early recognition and timely treatment.