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Tyrosine hydroxylase (TH) deficiency (MONDO:0100064) is a rare autosomal recessive disorder characterized by impaired catecholamine synthesis leading to dopa-responsive dystonia (DRD) and progressive infantile encephalopathy. The clinical spectrum ranges from early-onset hypokinetic-rigid syndromes with dystonia (type A) to severe neonatal encephalopathy (type B), often presenting with oculogyric crises, tremor, hypotonia and autonomic dysfunction.[PMID:20430833]
An autosomal recessive mode of inheritance is established by biallelic TH variants in over 36 patients from multiple unrelated families, including consanguineous kindreds with homozygous c.698G>A and c.707T>C alleles and compound heterozygotes in non-consanguineous populations.[PMID:20430833] Segregation of pathogenic alleles with disease has been documented in at least 4 affected sib pairs, and founder effects are observed in Greek and Chinese cohorts. Experimental concordance across enzyme kinetics, iPSC-derived neuronal models, and knock-in mice supports a definitive gene-disease relationship.
TH deficiency is driven by biallelic missense and loss-of-function variants disrupting enzyme activity. Over 80 pathogenic alleles have been reported, including recurrent hotspots c.698G>A and c.707T>C and founder variant c.614T>C (p.Leu205Pro).[PMID:10407773] The variant spectrum comprises predominantly missense substitutions, with occasional splice and frameshift mutations. Carrier frequency in populations is low (C (p.Leu205Pro).
In vitro assays of recombinant TH variants such as p.Gln381Lys and p.Leu205Pro reveal residual enzyme activity of 15% or less, correlating with clinical severity.[PMID:8528210][PMID:8817341] iPSC-derived dopaminergic neurons from patients with THD show decreased TH expression, reduced dopamine metabolites, and neurite arborization defects that are rescued by L-Dopa in type A cells.[PMID:36740977] A TH knock-in mouse carrying the R233H equivalent displays hypotension, hypokinesia, catecholamine depletion and non-responsiveness to L-Dopa, mirroring human type B THD phenotypes.[PMID:26276013] BH4 supplementation stabilizes mutant TH in patient neurons and improves motor outcomes in THD mice, highlighting therapeutic potential.[PMID:38196161]
No studies have refuted the AR association of TH variants with THD. Variants in non-coding regulatory regions may modify phenotype but do not undermine overall pathogenicity.
Biallelic TH variants cause dopamine deficiency manifesting as DRD or encephalopathy. Biochemical CSF markers (low HVA, normal 5-HIAA) coupled with genetic testing confirm diagnosis. Functional studies and animal models corroborate loss-of-function mechanism and guide treatment strategies including L-Dopa and BH4. Early genetic diagnosis enables timely therapy and genetic counseling.
Key Take-home: TH deficiency is a definitively established autosomal recessive neurometabolic disorder with strong genetic and functional evidence; early molecular diagnosis directs effective dopaminergic and cofactor-based therapies.
Gene–Disease AssociationDefinitive36 patients from multiple cohorts, segregation in sib pairs, functional concordance Genetic EvidenceStrongOver 80 unique variants in >100 patients with biallelic pathogenic alleles in AR inheritance Functional EvidenceStrongEnzyme assays, iPSC models, and knock-in mice consistently demonstrate loss-of-function and rescue by L-Dopa/BH4 |