The causative genes of two types of hereditary
dopa-responsive dystonia (DRD) due to
dopamine (DA) deficiency in the nigrostriatum DA neurons have been elucidated. Autosomal dominant DRD (AD-DRD) was originally described by Segawa as
hereditary progressive dystonia with marked diurnal fluctuation (HPD). We cloned the human
GTP cyclohydrolase I (GCH1) gene, and mapped the gene to chromosome 14q22.1-q22.2 within the HPD/DRD locus, which had been identified by linkage analysis. GCH1 isthe rate-limiting
enzyme for the biosynthesis of
tetrahydrobiopterin (BH4), the cofactor for
tyrosine hydroxylase (TH), which is the first and rate-limiting
enzyme of DA synthesis. We proved that the GCH1 gene is the causative gene for HPD/DRD based on the identification of mutations of the gene in the patients and decreases in the
enzyme activity expressed in mononuclear blood cells to 2-20% of the normal value. About 60 different mutations (missense, nonsense, and frameshift mutations) in the coding region or in the exon-intron junctions of the GCH1 gene have been reported in patients with AD-DRD all over the world. Recent findings indicate that the decreased GCH1 activity in AD-DRD may be caused by the negative interaction of the mutated subunit with the wild-type one, i.e., a dominant negative effect, and/or by decreases in the levels of GCH1
mRNA and
protein caused by inactivation of one allele of the GCH1 gene. Autosomal recessive DRD (AR-DRD) with Segawa's syndrome was discovered in Germany. The AR-DRD locus was mapped to chromosome 11p15.5 in the chromosomal site of the TH gene. In the AR-DRD with Segawa's syndrome, a point mutation in TH (Gln381Lys) resulted in a pronounced decrease in TH activity to about 15% of that of the wild type. Several missense mutations in the TH gene have been found in AR-DRD in Europe. The phenotype of AR-DRD with the Leu205Pro mutation in the TH gene, which produces a severe decrease in TH activity to 1.5% of that of the wild type, was severe, not
dystonia/Segawa's syndrome, but early-onset
parkinsonism. However, a marked improvement of all clinical symptoms with a low dose of
L-dopa was reported in AR-DRD/
parkinsonism patients. These findings on DRD indicate that the nigrostriatal DA neurons may be most susceptible to the decreases in GCH1 activity, BH4 level, TH activity, and DA level, and that DRD is the DA deficiency without neuronal death in contrast to
juvenile parkinsonism or
Parkinson's disease with DA cell death.