Dopa-responsive dystonia (DRD) describes a group of neurometabolic disorders characterized by dystonia that typically shows diurnal fluctuations, that responds excellently to levodopa (L-dopa) and that is comprised of autosomal dominant dopa-responsive dystonia (DYT5a), autosomal recessive dopa-responsive dystonia (DYT5b) and dopa responsive dystonia due to sepiapterin reductase (SR) deficiency (see these terms).
The estimated European prevalence of DRD ranges from 1/1,000,000-1/200,000.
DRD usually has a pediatric onset, typically with lower limb dystonia that leads to gait disturbances and that usually worsens during the course of the day and is improved in the morning after sleeping. Parkinsonism can develop at a later age in some patients. Anxiety, depression, sleep disturbances and obsessive-compulsive disorders have also been reported in few patients with DYT5a. Rarer subtypes which are inherited in an autosomal recessive manner typically show a much more severe phenotype, with onset in the first year of life with additional manifestations of global developmental delay, axial hypotonia, oculogyric crises and encephalopathy. DRD responds dramatically and continuously to L-dopa therapy, and patients usually experience a significant improvement of symptoms once treatment is initiated. If untreated, patients can become wheel-chair bound.
DRD is due to mutations in genes that encode proteins essential for the biosynthesis of dopamine. DYT5a is due to mutations in the GTP cyclohydrolase 1 (GCH-1) gene (14q22.1 to q22.2) which encodes an enzyme needed for the biosynthesis of tetrahydrobiopterin, the essential co-factor for tyrosine hydroxylase. DYT5b is caused by mutations in the tyrosin-hydroxylase TH gene (11p15.5) encoding tyrosin-hydroxylase, the enzyme responsible for catalyzing the conversion of tyrosine to L-dopa, the precursor of dopamine. Finally, DRD due to an SRD is due to mutations in the SPR gene (2p14-p12), encoding the enzyme sepiapterin reductase (SR), which is also required for the biosynthesis of tetrahydrobiopterin.
DRD can be inherited in an autosomal dominant or autosomal recessive manner, depending on the subtype. It can also occur due to de novo mutations.
Last update: November 2013