Mutations in the Tyrosine Hydroxylase Gene Cause Various Forms of L-Dopa-Responsive Dystonia

Abstract

Publisher Summary This chapter correlates various forms of l -Dopa-responsive dystonia (DRD) with the known molecular defect; many further mutations can be expected. Because DRD remains a little-known diagnosis and can be treated easily, more attention can be drawn to dystonias in adults and in children. Many attempts have failed to correlate a specific disease with deficient tyrosine hydroxylase (TH) levels. Because the reduced enzyme activity of TH causes low levels of l -dopa, the expected clinical symptoms should be similar to those seen in Parkinsonism. The clinical manifestation of DRD has a broad spectrum. The dominant form seems to be caused by a deficiency of GTP-cyclohydrolase I. Various mutations in the TH gene causing DRD in the mild as well as in the severe form has been found. The mild form of DRD is characterized by a dystonia of the lower extremities, diurnal fluctuations, and a good response to l -dopa therapy. Two siblings with this condition carried a point mutation in exon 11 of the TH gene. This mutation (Q381K) converts glutamine to lysine. This mutation was expressed by a coupled in vitro transcription–translation system in which the activity of the mutant enzyme was about 15% of the wild-type form. On the other hand, there is the severe form of DRD caused by a point mutation in exon 5 (L205P) changing leucine into proline. The recombinant mutant enzyme revealed a residual activity of 0.3 to 16% of the wild-type TH in three complementary expression systems.