DeCure for GTP cyclohydrolase I deficiency with hyperphenylalaninemia
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for GTP cyclohydrolase I deficiency with hyperphenylalaninemia — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleGTP cyclohydrolase I deficiency with hyperphenylalaninemia maps to a 2-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for gtp cyclohydrolase i deficiency with hyperphenylalaninemia is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
GTP cyclohydrolase 1 (GCH1) — GCH1 is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet qbqdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6Z86 · 2.206 Å · ligand 7-deaza-GTP (QBQ). Experimental structure, not a prediction.
What the evidence adds up to
GTP cyclohydrolase I deficiency with hyperphenylalaninemia is caused by mutations in the GCH1 gene, but only three mutations in that gene have been reported to cause the autosomal recessive form with hyperphenylalaninemia; most other GCH1 mutations are heterozygous and associated with dominant DOPA-responsive dystonia. More than 30 molecular lesions in the GTP cyclohydrolase I and 6-pyruvoyl-tetrahydropterin synthase genes had been identified by 1997. In Chinese patients with 6-pyruvoyl-tetrahydropterin synthase deficiency, seven single base mutations were detected in the PTPS gene from 38 mutant alleles in 19 unrelated families. Two common mutations, N52S and P87S, accounted for 71% of Chinese PTPS mutant alleles; N52S made up 48% of southern Chinese PTPS mutations but only 9% of northern Chinese ones. The V56M mutation was associated with a mild form of PTPS deficiency, while R25G, N52S, P87S, and D96N were found mainly in patients with severe clinical symptoms.
Two patients with autosomal recessive GTP cyclohydrolase I deficiency presented in early infancy with severe motor retardation, hypokinesia, and truncal hypotonia but without hyperphenylalaninemia. Cerebrospinal fluid homovanillic acid, 5-hydroxyindoleacetic acid, tetrahydrobiopterin, and neopterin were all decreased. One patient had a novel homozygous mutation and the other a compound-heterozygous mutation of GCH1. Treatment with Levodopa/Carbidopa produced striking clinical improvement, and both patients achieved age-appropriate development at follow-up at 6 years. The authors recommend that autosomal recessive GTPCH deficiency be considered in infants with severe truncal hypotonia even when hyperphenylalaninemia or classical extrapyramidal symptoms are absent.
What remains missing is systematic newborn screening for the non-hyperphenylalaninemic form of GTP cyclohydrolase I deficiency, which would require routine cerebrospinal fluid neurotransmitter analysis. Larger prospective cohorts are needed to determine how often the recessive form presents without elevated phenylalanine. No controlled trial of Levodopa dosing has been done in this rare population, and the long-term outcomes beyond age 6 are not reported. Mutation-specific genotype-phenotype correlations for the PTPS-deficient patients remain incomplete, particularly for the milder V56M variant.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Human Mutation · 1997 · 69 citations
Mutations in the GTP cyclohydrolase I and 6-pyruvoyl-tetrahydropterin synthase genes
AbstractTetrahydrobiopterin deficiencies are highly heterogeneous disorders, with more than 30 molecular lesions identified in the past 2 years in the GTP cyclohydrolase I and 6-pyruvoyl-tetrahydropterin synthase genes. The spectrum of mutations causing a reduction of these two biosynthetic enzymes is reviewed. Only three mutations, two present homozygously, are reported in the GTP cyclohydrolase I gene to cause the rare autosomal recessively inherited form of hyperphenylalaninemia. Most of the other mutations, which are scattered over the entire coding region for the six exon-containing GTP cyclohydrolase I gene, are observed in a heterozygous state with the wild-type allele and are associated with the dominant DOPA-responsive dystonia. Compound heterozygous or homozygous mutations spread over all six exons encoding the 6-pyruvoyl-tetrahydropterin synthase cause an autosomal recessively inherited variant of hyperphenylalaninemia, mostly accompanied by a deficiency of dopamine and serotonin.
Clinical and biochemical characterization of patients with early infantile onset of autosomal recessive GTP cyclohydrolase I deficiency without hyperphenylalaninemia
AbstractAutosomal recessive guanosine triphosphate cyclohydrolase (GTPCH) type I deficiency is characterized by complex neurological dysfunction. Patients are usually diagnosed with hyperphenylalaninemia in newborn screening. We describe two unrelated patients without hyperphenylalaninemia who presented during early infancy with severe motor retardation, hypokinesia, and truncal hypotonia. CSF homovanillic acid and 5-hydroxyindoleacetic acid as well as tetrahydrobiopterin and neopterin were decreased. Diagnosis of recessive GTPCH deficiency was confirmed biochemically, and a novel homozygous mutation was identified in one patient and a compound-heterozygous mutation of GCH1 in the other. Treatment with Levodopa/Carbidopa resulted in striking clinical improvement, with age-appropriate development at follow-up at 6 years. Autosomal recessive GTPCH deficiency should be considered in infants with severe truncal hypotonia even if hyperphenylalaninemia or classical extrapyramidal symptoms are missing. Neurotransmitter analysis followed by enzyme or mutation analysis can confirm the diagnosis, and Levodopa treatment should be started at high-doses.
Mutation analysis of the 6-pyruvoyl-tetrahydropterin synthase gene in Chinese hyperphenylalaninemia caused by tetrahydrobiopterin synthesis deficiency
AbstractHyperphenylalaninemia (HPA) may be caused by deficiency of phenylalanine hydroxylase or tetrahydrobiopterin (BH4), the essential cofactor for the aromatic amino acid hydroxylases. 6-Pyruvoyl-tetrahydropterin synthase (PTPS) deficiency is a major cause of BH4 deficient HPA. In this study, seven single base mutations at nucleotides 73 (C>G), 155 (A>G), 166 (G>A), 209 (T>A), 259 (C>T), 286 (G>A), and 317 (C>T) on PTPS cDNA were detected in Chinese PTPS-deficient HPA by polymerase chain reaction and solid phase DNA sequencing. These nucleotide alterations result in R25G, N52S, V56M, V70D, P87S, D96N, and T106M amino acid substitutions, respectively. The R25G, V56M, V70D, and T106M were novel mutations found in PTPS gene. By analysis of 38 PTPS mutant alleles from 19 unrelated Chinese PTPS-deficient HPA families, the allele frequency of these mutations in Chinese PTPS-deficient HPA were determined to be approximately 5.3% (R25G), 34.2% (N52S), 7.9% (V56M), 2.6% (V70D), 36.8% (P87S), 7.9% (D96N), and 2.6% (T106M), respectively. Two common mutations, N52S and P87S, were found to account for 71% of the Chinese PTPS mutant alleles. The N52S mutation accounts for 48% of the southern Chinese PTPS mutation, but only one (9%) of the northern Chinese PTPS mutant allele was found to be N52S, which suggested that the N52S mutation might be southern Chinese. Clinically, the V56M mutation was found to associate with the mild form of PTPS deficiency. However, the R25G, N52S, P87S, and D96N were found mainly in the patients with severe clinical symptom. Using polymerase chain reaction-based mutation analysis, a fetus at risk of PTPS deficiency was diagnosed prenatally to be a carrier of N52S mutation.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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