A novel heterozygous GCH1 gene variant in a family with dopa-responsive dystonia: a case report

Dopa-responsive dystonia (DRD), also known as Segawa disease, is a treatable childhood-onset movement disorder most commonly caused by heterozygous variants in the GCH1 gene. Reduced penetrance and sex-related differences in disease expression may obscure recognition of autosomal dominant inheritance in affected families. An 11-year-old girl developed a right-predominant in-toeing gait at age 10, followed by limitation of ankle dorsiflexion and diurnal worsening of dystonia. Brain and spinal magnetic resonance imaging and dopamine transporter imaging were normal. Cerebrospinal fluid (CSF) analysis revealed reduced neopterin and biopterin levels with decreased active tetrahydrobiopterin (BH 4 ), while CSF homovanillic acid and 5-hydroxyindoleacetic acid levels were normal. Oral levodopa/carbidopa administration completely resolved dystonia, confirming the diagnosis of DRD. Genetic testing identified a heterozygous GCH1 variant (c.704G>C, p.Arg235Pro). Her paternal cousin, a 12-year-old girl, showed early-childhood onset of progressive gait disturbance with lower-limb stiffness, equinus gait, and marked diurnal fluctuation. CSF pteridine analysis demonstrated markedly reduced neopterin levels with only mildly decreased biopterin levels, accompanied by profoundly decreased active BH 4 . Brain imaging was normal, and symptoms responded to levodopa therapy. Despite carrying the identical GCH1 variant, the two patients differed substantially in age at onset and clinical severity, whereas the proband's father and paternal uncle were asymptomatic. This family highlights marked intrafamilial variability in GCH1 -related DRD. Awareness of such variability, together with low penetrance and sex-related differences in disease expression, is important for accurate diagnosis and genetic counseling.