Two new mutations on tyrosine hydroxylase gene (TH) presenting as late onset dystonic-dyskinetic syndrome

TH (E.C. 1.14.16.2) defciency is a rare disorder causing the recessive form of Dopa-responsive dystonia. We report a new Italian patient presenting with a mild phenotype who carried two new mutations on TH gene. This 17-year-old boy was born after an uncomplicated pregnancy and labour. Psychomotor development was normal until the second year of life when toe-walking gait, frequent falls and delay in language development progressively became apparent. Starting from the age of 5 he su¡ered from generalized epilepsy requiring antiepileptic drugs. At the age of 11 he developed a dystonic-dyskinetic syndrome which worsened in the following months. At the first examination, at the age of 14, he suffered from generalized dystonia, choreoathetosis and myoclonic jerks of upper limbs, oculogyric crisis with vertical gaze paresis, severe dysarthria, and mild mental retardation. Brain MRI, blood prolactin and the Phe/Tyr ratio at conventional Phe loading test were all normal.A trial with L-Dopare sulted in adoubtful response, while CSF assessment revealed a defect of dopamine synthesis (HVA: 68 nmol/L, n.v. 148-434; 5HIAA 143 nmol/L, n.v. 68-115) with normal pterins (neopterin 2 mg/L, n.v. 2-4; biopterin 5.3 mg/L, n.v. 6-13). Molecular analysis of TH gene (mRNA variant 1, NM__000360) revealed two missense mutations, c.1179G4A(exon11;G383R)and c.1437T4A (exon13;L479Q),which(a) are both located in the catalytic domain of the enzyme, (b) affect two highly conserved amino acids in the eukaryotic species, and (c) were not found in any of 100 alleles of control subjects.