GCH1 – GTP Cyclohydrolase I Deficiency

Autosomal recessive GTP cyclohydrolase I (GTPCH) deficiency (MONDO:0100184) is characterized by early-onset extrapyramidal and pyramidal signs, including dystonia and progressive spasticity, often without hyperphenylalaninemia. A male infant presented with spasticity, dystonia and oculogyric crises; CSF biopterin and neopterin were low, phenylalanine loading revealed impaired clearance, and fibroblasts showed reduced GTPCH activity. A homozygous missense variant c.617T>C (p.Val206Ala) was identified (PMID:18276179).

A recent multi-patient study described 45 individuals with autosomal recessive GTPCH deficiency, delineating three phenotypic subgroups: early-infantile encephalopathy (24/45), dystonia–parkinsonism (7/45), and late-onset DRD-like presentation (14/45). All subtypes responded to BH₄ and L-Dopa/carbidopa therapy, with earlier treatment preventing severe neurodevelopmental outcomes (PMID:39001623).

Genetically, biallelic GCH1 variants include missense and frameshift changes dispersed across the gene. The variant c.617T>C (p.Val206Ala) exemplifies loss-of-function in the canonical transcript. No common founder alleles have been reported, and carrier frequency data remain limited.

Segregation analyses demonstrate familial occurrence: the index case and a younger brother were homozygous for p.Val206Ala, with early neonatal diagnosis and treatment in the sibling leading to normal development ([PMID:18276179]). Two siblings with compound heterozygous variants also manifested severe choreic dyskinesia ameliorated by amantadine (PMID:15389992).

Functional assays corroborate pathogenicity: patient fibroblasts display markedly reduced GTPCH enzyme activity and biopterin synthesis ([PMID:18276179]). The hph-1 mouse model exhibits lifelong BH₄ deficiency and reduced enzyme activity, mirroring the human biochemical defect (PMID:7524491). Yeast complementation studies of novel missense and frameshift alleles confirm loss-of-function effects (PMID:15303002).

Taken together, strong genetic and experimental evidence supports a loss-of-function mechanism for AR GTPCH deficiency, with consistent clinical–biochemical correlation and treatment responsiveness. Early molecular and biochemical testing is recommended for unexplained pediatric spasticity or dystonia to initiate timely BH₄ and dopamine precursor therapy.

References

• Molecular genetics and metabolism • 2008 • Autosomal recessive GTP cyclohydrolase I deficiency without hyperphenylalaninemia: evidence of a phenotypic continuum between dominant and recessive forms. PMID:18276179
• Movement disorders clinical practice • 2024 • Autosomal Recessive Guanosine Triphosphate Cyclohydrolase I Deficiency: Redefining the Phenotypic Spectrum and Outcomes. PMID:39001623
• Biochemical and biophysical research communications • 1994 • Molecular characterization of HPH-1: a mouse mutant deficient in GTP cyclohydrolase I activity. PMID:7524491
• Journal of inherited metabolic disease • 2004 • GTP-cyclohydrolase I gene mutations in patients with autosomal dominant and recessive GTP-CH1 deficiency: identification and functional characterization of four novel mutations. PMID:15303002
• Movement disorders : official journal of the Movement Disorder Society • 2004 • Amantadine for levodopa-induced choreic dyskinesia in compound heterozygotes for GCH1 mutations. PMID:15389992

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