Dopa-Responsive Dystonia and Related Disorders

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 characteristic diurnal fluctuation of symptoms. There are three known causative genes for DRD: (1) GCH1, coding for GTP cyclohydrolase 1 (GTPCH1) that catalyzes the rate-limiting step in tetrahydrobiopterin (BH4; the cofactor for tyrosine hydroxylase [TH]) biosynthesis; (2) TH, coding for TH in catecholamine biosynthesis; and (3) SPR, coding for sepiapterin reductase (SR), which is involved in the last step in BH4 biosynthesis. Many DRD patients have shown dominantly inherited GCH1 mutations (GTPCH1-deficient DRD; the major form of DRD), whereas a relatively small number of DRD patients have demonstrated recessively inherited TH mutations (TH-deficient DRD; the mild form of TH deficiency) or SPR mutations (SR-deficient DRD; the very mild form of SR deficiency). As clinical suspicion is a key to the diagnosis of DRD, physicians should know the broad phenotypic spectrum in DRD families. Furthermore, because (1) administration of levodopa and “5-hydroxytryptophan” is necessary for severe autosomal recessive SR deficiency, (2) administration of levodopa, 5-hydroxytryptophan, and “BH4” is indispensable for severe autosomal recessive GTPCH1 deficiency, and (3) very low-dose levodopa must be used initially for infantile-onset patients with autosomal recessive TH deficiency having overt delay in motor development, physicians should also know symptoms of these genetically related disorders. This chapter summarizes clinical features and advances in the genetics and biochemistry of DRD and related disorders.KeywordsDystoniaParkinsonismDopa-responsiveDYT5LevodopaStriatal dopamineTetrahydrobiopterinBiopterinNeopterinGTP cyclohydrolase 1Tyrosine hydroxylaseSepiapterin reductaseGCH1 geneTH geneSPR geneParkinson’s diseaseCerebral palsySpastic paraplegia