L-Dopa Responsive Dystonia/Infantile Parkinsonism Associated with Mutations at the Human Tyrosine Hydroxylase Locus
The L-DOPA responsive dystonias (DRD) represent a group of hereditary neurometabolic disorders with some common clinical features, but with a locus heterogeneity and different genotypes. The first described and best characterized is the hereditary progressive dystonia (HPD/DRD)(for review, see Segawa, 2000), an autosomal dominantly inherited motoric dysfunction caused by mutations at the GTP cyclohydrolase I (GCH 1; EC 184.108.40.206) locus on chromosome 14 (gen map locus 14q22.1-q22.2)(Ichinose et al., 1994). An autosomal recessive form of DRD was later described and found to be associated with a point mutation (Q381K) at the human tyrosine hydroxylase (hTH; EC 220.127.116.11) locus (gene map locus 11pl5.5)(Lüdecke et al., 1995; Knappskog et al., 1995). Subsequently, a recessively inherited L-DOPA responsive infantile parkinsonism (DRIP), also caused by a point mutation (L205P) at the hTH locus, was reported (Lüdecke et al., 1996). Both hTH mutations were considered sufficient to explain the deficient function of the hydroxylase, the attendant neurometabolic pattern and the resultant clinical signs and symptoms. A total of twelve different mutations at the hTH locus are now known to be associated with DRD/DRIP (Table 1). The patients with mutations at the hTH locus show larger variations in and often more severe clinical phenotypes as well as an earlier onset than in the classical Segawa’s syndrome (HPD/DRD). The disease is manifested only in homozygotes and compound heterorygote, whereas the autosomal dominant form of HPD/DRD is observed also in heterozygotes.
KeywordsTyrosine Hydroxylase Autosomal Recessive Form Autosomal Dominant Form Tyrosine Hydroxylase Gene Facial Mimicry
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