Clinical and Basic Research on Dopa-Responsive Dystonia: Neuropathological and Neurochemical Findings

Dopa-responsive dystonia (DRD) is a clinical syndrome characterized by childhood-onset dystonia and a dramatic and sustained response to low doses of levodopa. Typically, DRD presents with gait disturbance due to foot dystonia, later development of parkinsonism, and diurnal fluctuation of symptoms. Since the discovery of mutations responsible for DRD in GCH1, coding for GTP cyclohydrolase 1 (GTPCH) that catalyzes the rate-limiting step in tetrahydrobiopterin (BH₄: the cofactor for tyrosine hydroxylase [TH]) biosynthesis, and in TH, coding for TH in catecholamine biosynthesis, our understanding of this syndrome has greatly increased. However, the underlying mechanisms of phenotypic heterogeneity are still unknown and physicians should learn from genetic, pathological, and biochemical findings of DRD. Neuropathological studies have shown a normal population of cells with decreased melanin and no Lewy bodies in the substantia nigra of classic GTPCH-deficient and TH-deficient DRD. Neurochemical investigations in GTPCH-deficient DRD have indicated that dopamine reduction in the striatum is caused not only by decreased TH activity resulting from low cofactor content but also by actual loss of TH protein without nerve terminal loss. This striatal TH protein loss may be due to a diminished regulatory effect of BH₄ on stability of TH molecules. Neurochemical findings in an asymptomatic GCH1 mutation carrier versus symptomatic cases suggest that there may be additional genetic and/or environmental factors modulating the regulatory BH₄ effect on TH stability and that the extent of striatal protein loss in TH (rather than that in GTPCH) may be critical in determining the symptomatic state of GTPCH-deficient DRD.