A marked contrast between serotonergic and dopaminergic changes in dopa-responsive dystonia

Dopa-responsive dystonia (DRD) is a clinical syndrome characterized by childhood-onset dystonia and a dramatic and sustained response to low doses of levodopa.¹ Autosomal dominant DRD is caused by mutations in GCH1, which encodes GTP cyclohydrolase 1 (GTPCH), the rate-limiting enzyme in the biosynthesis of tetrahydrobiopterin (BH4; the cofactor for phenylalanine and tyrosine and tryptophan hydroxylases [TH and TPH]).¹ Recently, the phenotype of this major form of DRD (GTPCH-deficient DRD) was expanded to include nonmotor symptoms, such as depression, anxiety, and obsessive-compulsive disorder, and these psychiatric symptoms were attributed to serotonin deficiency.^2,3 However, the actual status of brain serotonergic involvement in GTPCH-deficient DRD is unknown. To evaluate possible serotonin deficiency, we measured levels of serotonin markers in the striatum (one of the serotonin- and dopamine-rich brain regions)⁴ in a 19-year-old woman with DRD and a GCH1 nonsense mutation.⁵ Her dystonia (onset at 5 years of age) was well controlled by levodopa (without a decarboxylase inhibitor) 750 mg/d for 11 years (no psychiatric symptoms and residual motor signs) until her automobile accidental death. Neuropathologic studies revealed a normal population of cells with reduced melanin in the substantia nigra and also no evidence of degeneration in other brain areas.^1,5 This study was approved by the institutional review board of the Centre for Addiction and Mental Health.