Hyperphenylalaninemia, Bh4-Deficient, a

Categories: Genetic diseases, Rare diseases, Neuronal diseases, Metabolic diseases

Aliases & Classifications for Hyperphenylalaninemia, Bh4-Deficient, a

MalaCards integrated aliases for Hyperphenylalaninemia, Bh4-Deficient, a:

Name: Hyperphenylalaninemia, Bh4-Deficient, a 54 24 71 13
6-Pyruvoyl-Tetrahydropterin Synthase Deficiency 12 50 24 56 71 29 42 69
Pts Deficiency 12 50 71
Hyperphenylalaninemia Due to 6-Pyruvoyltetrahydropterin Synthase Deficiency 12 56
Hpabh4a 12 71
Hyperphenylalaninemia Due to 6-Pyruvoyl-Tetrahydropterin Synthase Deficiency 50
Hyperphenylalaninemia Tetrahydrobiopterin-Deficient Due to Pts Deficiency 71
Tetrahydobioperin-Deficient Hyperphenylalaninemia Due to Pts Deficiency 12
6-Alpha Pyruvoyltetrahydropterin Synthase Deficiency 24
6-Pyruvoyltetrahydropterin Synthase Deficiency 24
Dihydrobiopterin Synthetase Deficiency 24
Bh4-Deficient Hyperphenylalaninemia a 12
Hyperphenylalanemia, Bh4-Deficient, a 50
6-Pyruvoyltetrahydropterin Synthase 13
Ptps Deficiency 24


Orphanet epidemiological data:

6-pyruvoyl-tetrahydropterin synthase deficiency
Inheritance: Autosomal recessive; Age of onset: Infancy,Neonatal; Age of death: any age;


autosomal recessive

defect in tetrahydrobiopterin (bh4) synthesis
treatment with bh4 is effective
neurotransmitter treatment with l-dopa and serotonin or precursors is effective
early treatment can reduce neurologic symptoms
progressive neurologic deterioration if untreated
diurnal fluctuation of neurologic symptoms
onset in infancy (average 4 months, but may be earlier)
variable severity, ranging from central severe to peripheral to transient
prevalence in caucasians is 1 in 1,000,000
prevalence in taiwan is 1 in 132,000


hyperphenylalaninemia, bh4-deficient, a:
Onset and clinical course infantile onset
Inheritance autosomal recessive inheritance


Summaries for Hyperphenylalaninemia, Bh4-Deficient, a

NIH Rare Diseases : 50 the following summary is from orphanet, a european reference portal for information on rare diseases and orphan drugs.orpha number: 13old section part 16-pyruvoyl-tetrahydropterin synthase (ptps) deficiency, an autosomal recessive genetic disorder, is one of the causes of malignant hyperphenylalaninemia due to tetrahydrobiopterin deficiency. not only does tetrahydrobiopterin deficiency cause hyperphenylalaninemia, it is also responsible for defective neurotransmission of monoamines because of malfunctioning tyrosine and tryptophan hydroxylases, both tetrahydrobiopterin-dependent hydroxylases. ptps deficiency should be suspected in all infants with a positive neonatal screening test for phenylketonuria, especially when hyperphenylalaninemia is moderate. the most effective way to diagnose the disorder is to measure pteridine levels in urine and to confirm the result by measuring neurotransmitters 5-hydroxyindolacetic acid (5-hiaa) and homovanillic acid (hva) in cerebrospinal fluid and with an oral tetrahydrobiopterin-loading test (20 mg/kg). when left untreated, the deficiency causes neurological signs at age 4 or 5 months, although clinical signs are often obvious from birth. the principal symptoms include psychomotor retardation, tonus disorders, convulsions, drowsiness, irritability, abnormal movements, hyperthermia, hypersalivation and difficulty swallowing. treatment attempts to bring phenylalaninemia levels back to normal (diet with restricted phenylalanine intake or prescription of tetrahydrobiopterin) and to restore normal monoaminergic neurotransmission by administering precursors (l-dopa/carbidopa and 5-hydroxytryptophan).old section part 2visit the orphanet disease page for more resources. last updated: 2/15/2005

MalaCards based summary : Hyperphenylalaninemia, Bh4-Deficient, a, also known as 6-pyruvoyl-tetrahydropterin synthase deficiency, is related to dystonia, dopa-responsive, due to sepiapterin reductase deficiency and hyperphenylalaninemia, bh4-deficient, d, and has symptoms including poor head control, dysphagia and dystonia. An important gene associated with Hyperphenylalaninemia, Bh4-Deficient, a is PTS (6-Pyruvoyltetrahydropterin Synthase). Affiliated tissues include testes.

UniProtKB/Swiss-Prot : 71 Hyperphenylalaninemia, BH4-deficient, A: An autosomal recessive disorder characterized by hyperphenylalaninemia, depletion of the neurotransmitters dopamine and serotonin, and progressive cognitive and motor deficits. Neurological symptoms are unresponsive to the classic phenylalanine-low diet.

OMIM : 54
Tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia (HPA) comprises a genetically heterogeneous group of progressive neurologic disorders caused by autosomal recessive mutations in the genes encoding enzymes involved in the synthesis or regeneration of BH4. BH4 is a cofactor for phenylalanine hydroxylase (PAH; 612349), tyrosine hydroxylase (TH; 191290) and tryptophan hydroxylase (TPH1; 191060), the latter 2 of which are involved in neurotransmitter synthesis. The BH4-deficient HPAs are characterized phenotypically by hyperphenylalaninemia, depletion of the neurotransmitters dopamine and serotonin, and progressive cognitive and motor deficits (Dudesek et al., 2001). HPABH4A, caused by mutations in the PTS gene, represents the most common cause of BH4-deficient hyperphenylalaninemia (Dudesek et al., 2001). Other forms of BH4-deficient HPA include HPABH4B (233910), caused by mutation in the GCH1 gene (600225), HPABH4C (261630), caused by mutation in the QDPR gene (612676), and HPABH4D (264070), caused by mutation in the PCBD1 gene (126090). Niederwieser et al. (1982) noted that about 1 to 3% of patients with hyperphenylalaninemia have one of these BH4-deficient forms. These disorders are clinically and genetically distinct from classic phenylketonuria (PKU; 261600), caused by mutation in the PAH gene. Two additional disorders associated with BH4 deficiency and neurologic symptoms do not have overt hyperphenylalaninemia as a feature: dopa-responsive dystonia (612716), caused by mutation in the SPR gene (182125), and autosomal dominant dopa-responsive dystonia (DYT5; 128230), caused by mutation in the GCH1 gene. Patients with these disorders may develop hyperphenylalaninemia when stressed. (261640)

Disease Ontology : 12 An amino acid metabolic disorder characterized by autosomal recessive inheritance of hyperphenylalaninemia, depletion of the neurotransmitters dopamine and serotonin, and progressive cognitive and motor deficits that has material_basis_in mutation in the PTS gene on chromosome 11q23.1.

Related Diseases for Hyperphenylalaninemia, Bh4-Deficient, a

Diseases in the Hyperphenylalaninemia, Bh4-Deficient, C family:

Hyperphenylalaninemia, Bh4-Deficient, D Hyperphenylalaninemia, Bh4-Deficient, a
Hyperphenylalaninemia, Bh4-Deficient, B

Diseases related to Hyperphenylalaninemia, Bh4-Deficient, a via text searches within MalaCards or GeneCards Suite gene sharing:

id Related Disease Score Top Affiliating Genes
1 dystonia, dopa-responsive, due to sepiapterin reductase deficiency 10.8
2 hyperphenylalaninemia, bh4-deficient, d 10.8
3 tetrahydrobiopterin deficiency 10.4
4 dystonia 10.2
5 hyperphenylalaninemia 10.2
6 mild hyperphenylalaninemia 10.2

Graphical network of the top 20 diseases related to Hyperphenylalaninemia, Bh4-Deficient, a:

Diseases related to Hyperphenylalaninemia, Bh4-Deficient, a

Symptoms & Phenotypes for Hyperphenylalaninemia, Bh4-Deficient, a

Symptoms via clinical synopsis from OMIM:


Neurologic- Central Nervous System:
mental retardation
Neurologic- Behavioral Psychiatric Manifestations:

Head And Neck- Eyes:
oculogyric crises

Head And Neck- Mouth:

Laboratory- Abnormalities:
decreased homovanillic acid (hva) and 5-hydroxyindoleacetic acid (5hiaa) in csf
increased neopterin in urine and csf
decreased or absent pts activity

Head And Neck- Head:

Abdomen- Gastroin testinal:
swallowing difficulties
poor sucking

Growth- Other:
small for gestational age
poor feeding in infancy

Metabolic Features:
hyperthermia, episodic

Clinical features from OMIM:


Human phenotypes related to Hyperphenylalaninemia, Bh4-Deficient, a:

56 32 (show all 43)
id Description HPO Frequency Orphanet Frequency HPO Source Accession
1 poor head control 56 32 occasional (7.5%) Occasional (29-5%) HP:0002421
2 dysphagia 56 32 occasional (7.5%) Occasional (29-5%) HP:0002015
3 dystonia 56 32 Occasional (29-5%) HP:0001332
4 myoclonus 56 32 occasional (7.5%) Occasional (29-5%) HP:0001336
5 ataxia 56 32 occasional (7.5%) Occasional (29-5%) HP:0001251
6 hyperreflexia 56 32 Occasional (29-5%) HP:0001347
7 choreoathetosis 56 32 occasional (7.5%) Occasional (29-5%) HP:0001266
8 seizures 56 32 occasional (7.5%) Occasional (29-5%) HP:0001250
9 ptosis 56 32 occasional (7.5%) Occasional (29-5%) HP:0000508
10 hypsarrhythmia 56 32 occasional (7.5%) Occasional (29-5%) HP:0002521
11 global developmental delay 56 32 occasional (7.5%) Occasional (29-5%) HP:0001263
12 bradykinesia 56 32 occasional (7.5%) Occasional (29-5%) HP:0002067
13 rigidity 56 32 occasional (7.5%) Occasional (29-5%) HP:0002063
14 depression 56 32 occasional (7.5%) Occasional (29-5%) HP:0000716
15 intellectual disability 56 32 occasional (7.5%) Occasional (29-5%) HP:0001249
16 clonus 56 32 occasional (7.5%) Occasional (29-5%) HP:0002169
17 motor delay 56 32 occasional (7.5%) Occasional (29-5%) HP:0001270
18 drowsiness 56 32 occasional (7.5%) Occasional (29-5%) HP:0002329
19 falls 56 32 occasional (7.5%) Occasional (29-5%) HP:0002527
20 muscular hypotonia 56 32 frequent (33%) Frequent (79-30%) HP:0001252
21 agitation 56 32 occasional (7.5%) Occasional (29-5%) HP:0000713
22 opisthotonus 56 32 frequent (33%) Frequent (79-30%) HP:0002179
23 pallor 56 32 occasional (7.5%) Occasional (29-5%) HP:0000980
24 hyperkinesis 56 32 occasional (7.5%) Occasional (29-5%) HP:0002487
25 delayed speech and language development 56 32 occasional (7.5%) Occasional (29-5%) HP:0000750
26 excessive salivation 56 32 occasional (7.5%) Occasional (29-5%) HP:0003781
27 oculogyric crisis 56 32 occasional (7.5%) Occasional (29-5%) HP:0010553
28 chorea 56 Occasional (29-5%)
29 tremor 32 HP:0001337
30 hypertonia 56 Occasional (29-5%)
31 microcephaly 32 HP:0000252
32 irritability 32 HP:0000737
33 parkinsonism 32 HP:0001300
34 progressive neurologic deterioration 32 HP:0002344
35 small for gestational age 32 HP:0001518
36 poor suck 32 HP:0002033
37 restlessness 56 Occasional (29-5%)
38 hyperphenylalaninemia 32 HP:0004923
39 episodic fever 32 HP:0001954
40 intellectual disability, progressive 32 HP:0006887
41 abnormality of extrapyramidal motor function 56 Occasional (29-5%)
42 muscular hypotonia of the trunk 32 HP:0008936
43 excessive daytime somnolence 32 HP:0001262

UMLS symptoms related to Hyperphenylalaninemia, Bh4-Deficient, a:

ataxia, muscle rigidity, seizures, tremor, bradykinesia, abnormality of extrapyramidal motor function, stiffness

Drugs & Therapeutics for Hyperphenylalaninemia, Bh4-Deficient, a

Interventional clinical trials:

id Name Status NCT ID Phase Drugs
1 Observational Study on the Long Term Safety of Kuvan® Treatment in Patients With Hyperphenylalaninemia (HPA) Due to Phenylketonuria (PKU) or BH4 Deficiency Recruiting NCT01016392

Search NIH Clinical Center for Hyperphenylalaninemia, Bh4-Deficient, a

Cochrane evidence based reviews: 6-pyruvoyl-tetrahydropterin synthase deficiency

Genetic Tests for Hyperphenylalaninemia, Bh4-Deficient, a

Genetic tests related to Hyperphenylalaninemia, Bh4-Deficient, a:

id Genetic test Affiliating Genes
1 6-Pyruvoyl-Tetrahydropterin Synthase Deficiency 29
2 6-Pyruvoyltetrahydropterin Synthase Deficiency 24 PTS

Anatomical Context for Hyperphenylalaninemia, Bh4-Deficient, a

MalaCards organs/tissues related to Hyperphenylalaninemia, Bh4-Deficient, a:


Publications for Hyperphenylalaninemia, Bh4-Deficient, a

Variations for Hyperphenylalaninemia, Bh4-Deficient, a

UniProtKB/Swiss-Prot genetic disease variations for Hyperphenylalaninemia, Bh4-Deficient, a:

71 (show all 24)
id Symbol AA change Variation ID SNP ID
1 PTS p.Arg16Cys VAR_006816 rs104894274
2 PTS p.Arg25Gly VAR_006817
3 PTS p.Arg25Gln VAR_006818 rs104894273
4 PTS p.Glu35Gly VAR_006819
5 PTS p.Asn36Lys VAR_006820
6 PTS p.Asn52Ser VAR_006821 rs104894275
7 PTS p.Val56Met VAR_006822 rs104894277
8 PTS p.Thr67Met VAR_006824 rs370340361
9 PTS p.Val70Asp VAR_006825
10 PTS p.Pro87Leu VAR_006826 rs765406631
11 PTS p.Pro87Ser VAR_006827 rs104894276
12 PTS p.Asp96Asn VAR_006828 rs104894280
13 PTS p.Phe100Val VAR_006829
14 PTS p.Thr106Met VAR_006830 rs200712908
15 PTS p.Ile114Val VAR_006831
16 PTS p.Lys129Glu VAR_006832
17 PTS p.Asp136Val VAR_006833
18 PTS p.Asn47Asp VAR_008040 rs104894278
19 PTS p.Asp116Gly VAR_008041 rs104894279
20 PTS p.Leu26Phe VAR_058265
21 PTS p.Val97Met VAR_058266 rs750455879
22 PTS p.Tyr99Cys VAR_058267
23 PTS p.Val124Leu VAR_058268 rs150726932
24 PTS p.Asp136Gly VAR_058269

ClinVar genetic disease variations for Hyperphenylalaninemia, Bh4-Deficient, a:

id Gene Variation Type Significance SNP ID Assembly Location
1 PTS NM_000317.2(PTS): c.74G> A (p.Arg25Gln) single nucleotide variant Pathogenic rs104894273 GRCh37 Chromosome 11, 112097240: 112097240
2 PTS NM_000317.2(PTS): c.155A> G (p.Asn52Ser) single nucleotide variant Pathogenic rs104894275 GRCh37 Chromosome 11, 112099388: 112099388
3 PTS NM_000317.2(PTS): c.259C> T (p.Pro87Ser) single nucleotide variant Pathogenic rs104894276 GRCh37 Chromosome 11, 112103901: 112103901
4 PTS NM_000317.2(PTS): c.166G> A (p.Val56Met) single nucleotide variant Pathogenic rs104894277 GRCh37 Chromosome 11, 112100933: 112100933
5 PTS NM_000317.2(PTS): c.347A> G (p.Asp116Gly) single nucleotide variant Pathogenic/Likely pathogenic rs104894279 GRCh37 Chromosome 11, 112104187: 112104187
6 PTS NM_000317.2(PTS): c.286G> A (p.Asp96Asn) single nucleotide variant Pathogenic rs104894280 GRCh37 Chromosome 11, 112103928: 112103928
7 PTS NM_000317.2(PTS): c.163+694_163+748del55 deletion Pathogenic GRCh38 Chromosome 11, 112229367: 112229421
8 PTS NM_000317.2(PTS): c.84-323A> T single nucleotide variant Pathogenic rs794726657 GRCh38 Chromosome 11, 112228271: 112228271
9 PTS NM_000317.2(PTS): c.297C> A (p.Tyr99Ter) single nucleotide variant Likely pathogenic rs145882709 GRCh37 Chromosome 11, 112103939: 112103939

Expression for Hyperphenylalaninemia, Bh4-Deficient, a

Search GEO for disease gene expression data for Hyperphenylalaninemia, Bh4-Deficient, a.

Pathways for Hyperphenylalaninemia, Bh4-Deficient, a

GO Terms for Hyperphenylalaninemia, Bh4-Deficient, a

Sources for Hyperphenylalaninemia, Bh4-Deficient, a

9 Cosmic
10 dbSNP
11 DGIdb
16 ExPASy
18 FMA
28 GO
29 GTR
32 HPO
33 ICD10
34 ICD10 via Orphanet
38 LifeMap
40 MedGen
42 MeSH
43 MESH via Orphanet
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46 NCI
47 NCIt
52 Novoseek
55 OMIM via Orphanet
59 PubMed
66 SNOMED-CT via Orphanet
68 Tocris
70 UMLS via Orphanet
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