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Congenital tyrosine hydroxylase deficiency ( THD ) is found in autosomal‐recessive  Dopa ‐responsive dystonia and related neurological syndromes. The clinical manifestations of  THD  are variable, ranging from early‐onset lethal disease to mild  P arkinson disease‐like symptoms appearing in adolescence. Until 2014, approximately 70  THD  patients with a total of 40 different disease‐related missense mutations, five nonsense mutations, and three mutations in the promoter region of the tyrosine hydroxylase (  TH  ) gene have been reported. We collected clinical and biochemical data in the literature for all variants, and also generated mutant forms of  TH  variants previously not studied ( N  = 23). We compared the in vitro solubility, thermal stability, and kinetic properties of the  TH  variants to determine the cause(s) of their impaired enzyme activity, and found great heterogeneity in all these properties among the mutated forms. Some  TH  variants had specific kinetic anomalies and phenylalanine hydroxylase, and  Dopa  oxidase activities were measured for variants that showed signs of altered substrate binding. p. A rg233 H is, p. G ly247 S er, and p. P he375 L eu had shifted substrate specificity from tyrosine to phenylalanine and  Dopa , whereas p. C ys359 P he had an impaired activity toward these substrates. The new data about pathogenic mechanisms presented are expected to contribute to develop individualized therapy for  THD  patients.

Functional Studies of Tyrosine Hydroxylase Missense Variants Reveal Distinct Patterns of Molecular Defects in Dopa ‐Responsive Dystonia