Recessively inherited L-DOPA-responsive parkinsonism in infancy caused by a point mutation (L205P) in the tyrosine hydroxylase gene

Tyrosine hydroxylase (TH) catalyzes the conversion of L-tyrosine to L-dihydroxyphenylalanine (L-DOPA), the rate-limiting step in the biosynthesis of dopamine. This report describes a missense point mutation in the human TH (hTH) gene in a girl presenting parkinsonian symptoms in early infancy and a very low level of the dopamine metabolite homovanillic acid in the CSF. DNA sequencing revealed a T614-to-C transition in exon 5 (L205P), Both parents and the patient's brother are heterozygous for the mutation, Site-directed mutagenesis and expression in different systems revealed that the recombinant mutant enzyme had a low homospecific activity, i.e. similar to 1.5% of wt-hTH in E. coli and similar to 16% in a cell-free in vitro transcription-translation system, When transiently expressed in human embryonic kidney (A293) cells a very low specific activity (- 0.3% of wt-hTH) and immunoreactive hTH (< 2%) was obtained, The expression studies are compatible with the severe clinical phenotype of the L205P homozygous patient carrying this recessively inherited mutation, Treatment with L-DOPA resulted in normalisation of the CSF homovanillic acid concentration and a sustained improvement in parkinsonian symptoms.