TH – TH-deficient Dopa-Responsive Dystonia

Tyrosine hydroxylase (TH) catalyzes the rate-limiting step in catecholamine biosynthesis. Autosomal recessive biallelic TH mutations underlie TH-deficient dopa-responsive dystonia (DRD), presenting with infantile hypotonia, hypokinesia, ptosis, and oculogyric crises. Molecular testing confirms the diagnosis and guides L-DOPA therapy and potential BH4 supplementation.

Clinical Validity

Based on four probands from three unrelated families, including homozygous and compound heterozygous missense variants, and segregation in two affected siblings, the gene–disease link is assessed as Moderate. Functional studies across multiple variants show concordant loss-of-function effects.

Genetic Evidence

Inheritance is Autosomal recessive. Four probands (3 unrelated) have been described: a homozygous c.983G>T (p.Cys328Phe) in exon 10 resulting in severe DRD (PMID:10585338), and compound heterozygosity for c.1229G>T (p.Arg410Leu) and c.1400A>G (p.Asp467Gly) in a separate case (PMID:23939262). Segregation in two additional affected siblings carrying c.1141C>A (p.Gln381Lys) further supports causality (PMID:8528210). Predominantly missense variants with no common founder allele have been reported.

Functional Evidence

Recombinant enzyme assays demonstrate that p.Gln381Lys (Q381K) retains ~15% of wild-type activity in vitro (PMID:8528210), while p.Leu205Pro shows <2% activity and protein instability (PMID:8817341). Tetrahydrobiopterin (BH₄) acts as a chaperone, stabilizing mutant TH in vitro and in vivo (PMID:18419768), consistent with a loss-of-function mechanism.

Conflicting Evidence

No studies have refuted the association or identified alternative etiologies for AR DRD in TH.

Integration & Clinical Utility

Biallelic TH missense mutations reliably cause early-onset DRD, with biochemical confirmation via CSF homovanillic acid levels and robust genotype–phenotype correlations. L-DOPA produces substantial biochemical improvement, and BH₄ supplementation offers a potential stabilizing therapy. Routine sequencing of TH should be considered in early-onset DRD with characteristic oculogyric crises.

Key Take-home: Biallelic missense TH variants cause autosomal recessive dopa-responsive dystonia; combined genetic and functional data support diagnostic testing and tailored therapeutic strategies.

References

• Clinical chemistry • 1999 • Biochemical and molecular genetic characteristics of the severe form of tyrosine hydroxylase deficiency. PMID:10585338
• Journal of Parkinson's disease • 2011 • A novel compound heterozygous tyrosine hydroxylase mutation (p.R441P) with complex phenotype. PMID:23939262
• Human molecular genetics • 1995 • Recessively inherited L-DOPA-responsive dystonia caused by a point mutation (Q381K) in the tyrosine hydroxylase gene. PMID:8528210
• Human molecular genetics • 1996 • Recessively inherited L-DOPA-responsive parkinsonism in infancy caused by a point mutation (L205P) in the tyrosine hydroxylase gene. PMID:8817341
• Journal of neurochemistry • 2008 • Tetrahydrobiopterin shows chaperone activity for tyrosine hydroxylase. PMID:18419768

Evidence Based Scoring (AI generated)