Details of Disease

General Information of Disease (ID: DISFIL4X)

• Disease Name: GTP cyclohydrolase I deficiency
• Synonyms: GTP cyclohydrolase I deficiency; GTP-cyclohydrolase I deficiency
• Definition: A disease characterized by a deficiency in GTP cyclohydrolase I, which leads to a consequent reduction in BH4 and reduces the activity of three BH4-cofactor dependent enzymes - phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase. GTP cyclohydrolase I deficiency encompasses a spectrum of disease that includes autosomal dominant and autosomal recessive forms, with severity correlating with the residual enzyme activity. Individuals who are heterozygous for pathogenic variants in GCH1 have symptoms ranging from none (due to reduced penetrance) to dopa-responsive dystonia, which is the most common presentation in symptomatic cases, to rarer neurological presentations such as adult-onset "benign" parkinsonism, various types of focal dystonia, and symptoms simulating cerebral palsy or spastic paraplegia. Hyperphenylalaninemia is absent, and patients respond well to treatment with levodopa. Individuals who are homozygous or compound heterozygous for pathogenic variants in GCH1 typically present with hyperphenylalaninemia, often identified by newborn screening, and severe neurological features and due to very low or undetectable enzyme activity. Treatment with levodopa, BH4, and 5-hydroxytryptophan can improve the symptoms but does not prevent development of severe encephalopathy. Rare cases of GTP cyclohydrolase I deficiency with a phenotype that is intermediate in severity between dopa-responsive dystonia and the severe autosomal recessive form have also been described, supporting the existence a phenotypic spectrum of disease.
• Disease Hierarchy:
  DISJSFZR: Tetrahydrobiopterin metabolic process disease
  DISFIL4X: GTP cyclohydrolase I deficiency
• Disease Identifiers:
  MONDO ID: MONDO_0100184
  MESH ID: C562656
  UMLS CUI: C0268467
  OMIM ID: 233910
  MedGen ID: 75683
  SNOMED CT ID: 23447005

Molecular Interaction Atlas (MIA) of This Disease

This Disease Is Related to 2 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
GCH1	TTLSWP6	Limited	Genetic Variation	[1]
GCH1	TTLSWP6	Definitive	Semidominant	[2]

This Disease Is Related to 2 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
NIF3L1	OT4MP90J	Strong	Genetic Variation	[1]
GCH1	OTOZ6NSL	Definitive	Semidominant	[2]

References

• [1] A novel GTPCH deficiency mouse model exhibiting tetrahydrobiopterin-related metabolic disturbance and infancy-onset motor impairments.Metabolism. 2019 May;94:96-104. doi: 10.1016/j.metabol.2019.02.001. Epub 2019 Feb 10.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.