Hyperphenylalaninemia due to tetrahydrobiopterin deficiency

Summary

Hyperphenylalaninemia due to tetrahydrobiopterin deficiency (MONDO:0016543) is a disease with 3 cohort genes and 6 clinical trials. Top therapeutic interventions include sapropterin and sepiapterin.

At a glance

• Prevalence: 1-9 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 3
• Phenotypes (HPO): 24
• Clinical trials: 6

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.2	Worldwide	Validated
Point prevalence	1-9 / 1 000 000	0.21	Brazil	Validated
Prevalence at birth	1-9 / 1 000 000	0.22	Japan	Validated

Signs & symptoms

Clinical features (HPO)

24 HPO clinical features (Orphanet curated; top 24 by frequency):

HPO ID	Term	Frequency
HP:0004923	Hyperphenylalaninemia	Very frequent (80-99%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0003781	Excessive salivation	Frequent (30-79%)
HP:0003785	Decreased CSF homovanillic acid concentration	Frequent (30-79%)
HP:0012758	Neurodevelopmental delay	Frequent (30-79%)
HP:0040206	Abnormal circulating neopterin concentration	Frequent (30-79%)
HP:0040210	Abnormal circulating biopterin concentration	Frequent (30-79%)
HP:0040416	Abnormal urinary nitrogen compound level	Frequent (30-79%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000750	Delayed speech and language development	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001276	Hypertonia	Occasional (5-29%)
HP:0001300	Parkinsonism	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0002135	Basal ganglia calcification	Occasional (5-29%)
HP:0002360	Sleep abnormality	Occasional (5-29%)
HP:0002421	Poor head control	Occasional (5-29%)
HP:0002917	Hypomagnesemia	Occasional (5-29%)
HP:0004904	Maturity-onset diabetes of the young	Occasional (5-29%)
HP:0010553	Oculogyric crisis	Occasional (5-29%)
HP:0033594	Elevated urinary 7-biopterin level	Occasional (5-29%)
HP:0100543	Cognitive impairment	Occasional (5-29%)
HP:6000482	Decreased circulating catecholamine concentration	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperphenylalaninemia due to tetrahydrobiopterin deficiency
Mondo ID	MONDO:0016543
Orphanet	238583
SNOMED CT	68528007
UMLS	C0751436
MedGen	199656
GARD	0007751
Is cancer (heuristic)	no

Also known as: hyperphenylalaninemia · hyperphenylalaninemia due to BH4 deficiency · hyperphenylalaninemia due to tetrahydrobiopterin deficiency · non-phenylketonuric hyperphenylalaninemia

Data availability: 3 ClinVar variants.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › hyperphenylalaninemia due to tetrahydrobiopterin deficiency

Related subtypes (32): disorder of methionine catabolism, inborn serine deficiency, cerebral creatine deficiency syndrome, inborn organic aciduria, gamma-amino butyric acid metabolism disorder, homocystinuria, urea cycle disorder, adenylosuccinate lyase deficiency, systemic primary carnitine deficiency disease, cystathioninuria, hyperlysinemia, Brunner syndrome, glycine encephalopathy, aminoacylase 1 deficiency, adenine phosphoribosyltransferase deficiency, inborn disorder of tryptophan metabolism, inborn disorder of proline metabolism, inborn disorder of ornithine metabolism, inborn disorder of amino acid transport, inborn disorder of histidine metabolism, inborn disorder of phenylalanine and tyrosine metabolism, inborn disorder of branched-chain amino acid metabolism, arakawa syndrome 2, 2-methylacetoacetyl CoA thiolase deficiency, albinism, hyperphenylalaninemia due to DNAJC12 deficiency, inborn disorder of the metabolism of sulfur-containing amino acids and hydrogen sulfide, inborn disorder of glycine and serine metabolism, inborn disorder of ornithine, proline and hydroxyproline metabolism, inborn disorder of glutamate/glutamine and aspartate/asparagine metabolism, hyperglycinemia, transient neonatal, tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia

Subtypes (4): dihydropteridine reductase deficiency, BH4-deficient hyperphenylalaninemia A, pterin-4 alpha-carbinolamine dehydratase 1 deficiency, GTP cyclohydrolase I deficiency with hyperphenylalaninemia

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

3 retrieved; paginated sample, class counts are floors:

1 conflicting classifications of pathogenicity, 1 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
480	NM_000317.3(PTS):c.259C>T (p.Pro87Ser)	PTS	Pathogenic	criteria provided, multiple submitters, no conflicts
490	NM_000320.3(QDPR):c.68G>A (p.Gly23Asp)	QDPR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
161247	NM_000161.3(GCH1):c.206C>T (p.Pro69Leu)	GCH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GCH1	Orphanet:2102	GTP cyclohydrolase I deficiency
GCH1	Orphanet:98808	Autosomal dominant dopa-responsive dystonia
PTS	Orphanet:13	6-pyruvoyl-tetrahydropterin synthase deficiency
QDPR	Orphanet:226	Dihydropteridine reductase deficiency

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GCH1	HGNC:4193	ENSG00000131979	P30793	GTP cyclohydrolase 1	clinvar
PTS	HGNC:9689	ENSG00000150787	Q03393	6-pyruvoyl tetrahydrobiopterin synthase	clinvar
QDPR	HGNC:9752	ENSG00000151552	P09417	Dihydropteridine reductase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GCH1	GTP cyclohydrolase 1	Positively regulates nitric oxide synthesis in umbilical vein endothelial cells (HUVECs).
PTS	6-pyruvoyl tetrahydrobiopterin synthase	Involved in the biosynthesis of tetrahydrobiopterin, an essential cofactor of aromatic amino acid hydroxylases.
QDPR	Dihydropteridine reductase	Catalyzes the conversion of quinonoid dihydrobiopterin into tetrahydrobiopterin.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	3	12.0×	6e-04

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GCH1	Enzyme (other)	yes	3.5.4.16	GTP_CycHdrlase_I, GTP_CycHdrlase_I_CS, GTP_CycHdrlase_I_dom
PTS	Enzyme (other)	yes	4.2.3.12	6-PTP_synth/QueD, PTPS_His_AS, PTPS_Cys_AS
QDPR	Enzyme (other)	yes	1.5.1.34	SDR_fam, Sc_DH/Rdtase_CS, NAD(P)-bd_dom_sf

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	1
secondary oocyte	1
type B pancreatic cell	1
adrenal tissue	1
left adrenal gland cortex	1
right adrenal gland	1
inferior vagus X ganglion	1
lateral globus pallidus	1
superior vestibular nucleus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GCH1	275	ubiquitous	marker	secondary oocyte, oocyte, type B pancreatic cell
PTS	298	ubiquitous	marker	adrenal tissue, right adrenal gland, left adrenal gland cortex
QDPR	283	ubiquitous	marker	inferior vagus X ganglion, lateral globus pallidus, superior vestibular nucleus

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
QDPR	3,732
GCH1	2,123
PTS	1,897

Intra-cohort edges

A	B	Sources
GCH1	PTS	string_interaction
GCH1	QDPR	string_interaction
PTS	QDPR	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GCH1	P30793	11
QDPR	P09417	2
PTS	Q03393	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 3 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation	2	761.3×	4e-06	GCH1, PTS
Phenylalanine metabolism	1	634.4×	0.002	QDPR

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
tetrahydrobiopterin biosynthetic process	3	2407.4×	8e-10	GCH1, PTS, QDPR
amino acid metabolic process	2	535.0×	4e-05	PTS, QDPR
pteridine-containing compound biosynthetic process	1	5617.3×	8e-04	GCH1
dihydrobiopterin metabolic process	1	5617.3×	8e-04	QDPR
regulation of lung blood pressure	1	2808.7×	0.001	GCH1
positive regulation of nitric-oxide synthase activity	1	1872.4×	0.002	GCH1
tetrahydrofolate biosynthetic process	1	936.2×	0.003	GCH1
regulation of removal of superoxide radicals	1	936.2×	0.003	GCH1
L-phenylalanine catabolic process	1	702.2×	0.003	QDPR
dopamine biosynthetic process	1	624.1×	0.003	GCH1
neuromuscular process controlling posture	1	351.1×	0.005	GCH1
response to pain	1	295.6×	0.005	GCH1
nitric oxide biosynthetic process	1	234.1×	0.006	GCH1
positive regulation of heart rate	1	234.1×	0.006	GCH1
response to tumor necrosis factor	1	208.1×	0.006	GCH1
response to type II interferon	1	175.5×	0.007	GCH1
regulation of blood pressure	1	73.9×	0.015	GCH1
response to lipopolysaccharide	1	41.6×	0.025	GCH1
central nervous system development	1	38.5×	0.026	PTS

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GCH1	0	0
PTS	0	0
QDPR	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
QDPR	5	Binding:5
PTS	1	ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GCH1	3.5.4.16	GTP cyclohydrolase I
PTS	4.2.3.12	6-pyruvoyltetrahydropterin synthase
QDPR	1.5.1.34	6,7-dihydropteridine reductase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	3	GCH1, PTS, QDPR
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
GCH1	0	—
PTS	1	—
QDPR	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	5
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03519711	PHASE1/PHASE2	COMPLETED	A Study of PTC923 (CNSA-001) in Primary Tetrahydrobiopterin (BH4) Deficient Participants With Hyperphenylalaninemia
NCT04896281	Not specified	RECRUITING	Phenylalanine-free Diet for Patients With Secondary Hyperphenylalaninemia in ICU
NCT01541397	Not specified	TERMINATED	Bone Mineral Density in Adults With Hyperphenylalaninemia on Kuvan Therapy
NCT01619722	Not specified	COMPLETED	Study of a National Cohort of Adult Patients With Phenylketonuria
NCT01869972	Not specified	COMPLETED	Biological Variation of Phenylalanine in Patients With Hyperphenylalaninemia
NCT02212288	Not specified	COMPLETED	Antioxidant Signature in Adult Patients With Phenylketonuria

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SAPROPTERIN	4	2
SEPIAPTERIN	3	1