Neurologic and psychiatric manifestations in a family with a mutation in exon 2 of the guanosine triphosphate-cyclohydrolase gene

Objective: To investigate the range of clinical features to correlate genot ypic and phenotypic manifestations in hereditary progressive and/or levodop a-responsive dystonia due to a defect in the guanosine triphosphate-cyclohy drolase (GCH1) gene. Design and Setting: A large family from Texas was studied in an ambulatory setting by clinicians in genetics, neurology, and psychiatry using structur ed interviews and examinations. Patients: The family was selected after neurometabolic investigations of a young boy (proband) with foot dystonia and fatigue and his father, who had a long history of anxiety and depression. Results of metabolic studies show ed decreased levels of metabolites of biopterin and biogenic amines in cere brospinal fluid. Subsequently, a novel mutation (37-base pair deletion) in exon 2 of the GCH1 gene was demonstrated in 11 family members. There was no observed female sex bias, but there was a wide variability of motor dysfun ctions in family members. Approximately 50% had clinical deafness and a sim ilar number had significant psychiatric dysfunction, including depression a nd anxiety. Conclusion: Study of additional families with hereditary progressive and/or levodopa-responsive dystonia using modern molecular methods will be necess ary to confirm the neuropsychiatric spectrum of this disorder, in which imp ortant clinical features may be unrecognized and thus inappropriately manag ed.