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 biosynt hesis 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 homovani llic acid in the CSF. DNA sequencing revealed a T614-to-C transition i n exon 5 (L205P), Both parents and the patient's brother are heterozyg ous for the mutation, Site-directed mutagenesis and expression in diff erent systems revealed that the recombinant mutant enzyme had a low ho mospecific activity, i.e. similar to 1.5% of wt-hTH in E. coil and sim ilar to 16% in a cell-free in vitro transcription-translation system, When transiently expressed in human embryonic kidney (A293) cells a ve ry low specific activity (- 0.3% of wt-hTH) and immunoreactive hTH (< 2%) was obtained, The expression studies are compatible with the sever e clinical phenotype of the L205P homozygous patient carrying this rec essively inherited mutation, Treatment with L-DOPA resulted in normali sation of the CSF homovanillic acid concentration and a sustained impr ovement in parkinsonian symptoms.