MCID: HYP331
MIFTS: 36

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 53 71 13
6-Pyruvoyl-Tetrahydropterin Synthase Deficiency 53 12 72 49 55 71 28 41 69
Pts Deficiency 53 12 49 71
Hpabh4a 53 12 71
Hyperphenylalaninemia Due to 6-Pyruvoyltetrahydropterin Synthase Deficiency 12 55
Hyperphenylalaninemia Due to 6-Pyruvoyl-Tetrahydropterin Synthase Deficiency 49
Hyperphenylalaninemia, Tetrahydrobiopterin-Deficient, Due to Pts Deficiency 53
Hyperphenylalaninemia Tetrahydrobiopterin-Deficient Due to Pts Deficiency 71
Tetrahydobioperin-Deficient Hyperphenylalaninemia Due to Pts Deficiency 12
6-Pyruvoyltetrahydropterin Synthase Deficiency 72
Bh4-Deficient Hyperphenylalaninemia a 12
Hyperphenylalanemia, Bh4-Deficient, a 49
6-Pyruvoyltetrahydropterin Synthase 13

Characteristics:

Orphanet epidemiological data:

55
6-pyruvoyl-tetrahydropterin synthase deficiency
Inheritance: Autosomal recessive; Age of onset: Infancy,Neonatal; Age of death: any age;

OMIM:

53
Inheritance:
autosomal recessive

Miscellaneous:
defect in tetrahydrobiopterin (bh4) synthesis
progressive neurologic deterioration if untreated
diurnal fluctuation of neurologic symptoms
treatment with bh4 is effective
neurotransmitter treatment with l-dopa and serotonin or precursors is effective
early treatment can reduce 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


HPO:

31
hyperphenylalaninemia, bh4-deficient, a:
Onset and clinical course infantile onset
Inheritance autosomal recessive inheritance


Classifications:



Summaries for Hyperphenylalaninemia, Bh4-Deficient, a

NIH Rare Diseases : 49 The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.Orpha Number: 13Disease definition6-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).Visit 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 hyperphenylalaninemia, bh4-deficient, d and dystonia, dopa-responsive, due to sepiapterin reductase deficiency, and has symptoms including ataxia, seizures and myoclonus. An important gene associated with Hyperphenylalaninemia, Bh4-Deficient, a is PTS (6-Pyruvoyltetrahydropterin Synthase). Affiliated tissues include testes.

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.

OMIM : 53 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)

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.

Wikipedia : 72 6-Pyruvoyltetrahydropterin synthase deficiency is an autosomal recessive disorder that causes malignant... more...

Related Diseases for Hyperphenylalaninemia, Bh4-Deficient, a

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

Hyperphenylalaninemia, Bh4-Deficient, C Hyperphenylalaninemia, Bh4-Deficient, a
Hyperphenylalaninemia, Bh4-Deficient, D

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

# Related Disease Score Top Affiliating Genes
1 hyperphenylalaninemia, bh4-deficient, d 10.9
2 dystonia, dopa-responsive, due to sepiapterin reductase deficiency 10.9
3 tetrahydrobiopterin deficiency 10.5
4 dystonia 10.3
5 hyperphenylalaninemia 10.3
6 mild hyperphenylalaninemia 10.3

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:

53
Neurologic Central Nervous System:
ataxia
seizures
tremor
dystonia
bradykinesia
more
Neurologic Behavioral Psychiatric Manifestations:
irritability

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

Abdomen Gastroin testinal:
swallowing difficulties
poor sucking

Head And Neck Eyes:
oculogyric crises

Head And Neck Head:
microcephaly

Growth Other:
small for gestational age
poor feeding in infancy

Metabolic Features:
hyperthermia, episodic

Head And Neck Mouth:
hypersalivation


Clinical features from OMIM:

261640

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

55 31 (show all 44)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 ataxia 55 31 occasional (7.5%) Occasional (29-5%) HP:0001251
2 seizures 55 31 occasional (7.5%) Occasional (29-5%) HP:0001250
3 myoclonus 55 31 occasional (7.5%) Occasional (29-5%) HP:0001336
4 agitation 55 31 occasional (7.5%) Occasional (29-5%) HP:0000713
5 dystonia 55 31 Occasional (29-5%) HP:0001332
6 opisthotonus 55 31 frequent (33%) Frequent (79-30%) HP:0002179
7 clonus 55 31 occasional (7.5%) Occasional (29-5%) HP:0002169
8 bradykinesia 55 31 occasional (7.5%) Occasional (29-5%) HP:0002067
9 ptosis 55 31 occasional (7.5%) Occasional (29-5%) HP:0000508
10 intellectual disability 55 31 occasional (7.5%) Occasional (29-5%) HP:0001249
11 muscular hypotonia 55 31 frequent (33%) Frequent (79-30%) HP:0001252
12 hyperreflexia 55 31 Occasional (29-5%) HP:0001347
13 dysphagia 55 31 occasional (7.5%) Occasional (29-5%) HP:0002015
14 global developmental delay 55 31 occasional (7.5%) Occasional (29-5%) HP:0001263
15 delayed speech and language development 55 31 occasional (7.5%) Occasional (29-5%) HP:0000750
16 pallor 55 31 occasional (7.5%) Occasional (29-5%) HP:0000980
17 falls 55 31 occasional (7.5%) Occasional (29-5%) HP:0002527
18 rigidity 55 31 occasional (7.5%) Occasional (29-5%) HP:0002063
19 motor delay 55 31 occasional (7.5%) Occasional (29-5%) HP:0001270
20 choreoathetosis 55 31 occasional (7.5%) Occasional (29-5%) HP:0001266
21 excessive salivation 55 31 occasional (7.5%) Occasional (29-5%) HP:0003781
22 hyperkinesis 55 31 occasional (7.5%) Occasional (29-5%) HP:0002487
23 drowsiness 55 31 occasional (7.5%) Occasional (29-5%) HP:0002329
24 poor head control 55 31 occasional (7.5%) Occasional (29-5%) HP:0002421
25 hypsarrhythmia 55 31 occasional (7.5%) Occasional (29-5%) HP:0002521
26 oculogyric crisis 55 31 occasional (7.5%) Occasional (29-5%) HP:0010553
27 tremor 31 HP:0001337
28 abnormality of extrapyramidal motor function 55 Occasional (29-5%)
29 excessive daytime somnolence 31 HP:0001262
30 restlessness 55 Occasional (29-5%)
31 depression 55 Occasional (29-5%)
32 chorea 55 Occasional (29-5%)
33 microcephaly 31 HP:0000252
34 hypertonia 55 Occasional (29-5%)
35 irritability 31 HP:0000737
36 intellectual disability, progressive 31 HP:0006887
37 poor suck 31 HP:0002033
38 parkinsonism 31 HP:0001300
39 episodic fever 31 HP:0001954
40 small for gestational age 31 HP:0001518
41 progressive neurologic deterioration 31 HP:0002344
42 muscular hypotonia of the trunk 31 HP:0008936
43 hyperphenylalaninemia 31 HP:0004923
44 depressivity 31 occasional (7.5%) HP:0000716

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


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

Drugs & Therapeutics for Hyperphenylalaninemia, Bh4-Deficient, a

Search Clinical Trials , 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:

# Genetic test Affiliating Genes
1 6-Pyruvoyl-Tetrahydropterin Synthase Deficiency 28 PTS

Anatomical Context for Hyperphenylalaninemia, Bh4-Deficient, a

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

38
Testes

Publications for Hyperphenylalaninemia, Bh4-Deficient, a

Articles related to Hyperphenylalaninemia, Bh4-Deficient, a:

(show all 24)
# Title Authors Year
1
Pseudoexon exclusion by antisense therapy in 6-pyruvoyl-tetrahydropterin synthase deficiency. ( 21542064 )
2011
2
Disorders of BH4 metabolism and the treatment of patients with 6-pyruvoyl-tetrahydropterin synthase deficiency in Taiwan. ( 21880449 )
2011
3
WITHDRAWN: Disorders of BH4 metabolism and the treatment of patients with 6-pyruvoyl-tetrahydropterin synthase deficiency in Taiwan. ( 21696901 )
2011
4
Phenotypic variability, neurological outcome and genetics background of 6-pyruvoyl-tetrahydropterin synthase deficiency. ( 20059486 )
2010
5
Dopamine agonists in 6-pyruvoyl tetrahydropterin synthase deficiency. ( 19704083 )
2009
6
Maternal tetrahydrobiopterin deficiency: the course of two pregnancies and follow-up of two children in a mother with 6-pyruvoyl-tetrahydropterin synthase deficiency. ( 19322676 )
2009
7
A case of 6-pyruvoyl-tetrahydropterin synthase deficiency demonstrates a more significant correlation of L-Dopa dosage with serum prolactin levels than CSF homovanillic acid levels. ( 17590551 )
2008
8
Long-term follow-up of Taiwanese Chinese patients treated early for 6-pyruvoyl-tetrahydropterin synthase deficiency. ( 18332253 )
2008
9
Long-term follow-up of Chinese patients who received delayed treatment for 6-pyruvoyl-tetrahydropterin synthase deficiency. ( 16364672 )
2006
10
Long-term follow-up and adult outcome of 6-pyruvoyl-tetrahydropterin synthase deficiency. ( 16161143 )
2006
11
6-pyruvoyl-tetrahydropterin synthase deficiency with mild hyperphenylalaninemia. ( 15984017 )
2005
12
Subtle brain dysfunction in treated 6-pyruvoyl-tetrahydropterin synthase deficiency: relationship to motor tasks and neurophysiological tests. ( 15036427 )
2004
13
6-pyruvoyl tetrahydropterin synthase deficiency: a case report. ( 15906733 )
2003
14
Molecular analysis and long-term follow-up of patients with different forms of 6-pyruvoyl-tetrahydropterin synthase deficiency. ( 11388593 )
2001
15
Diagnosis and treatment of 6-pyruvoyl-tetrahydropterin synthase deficiency. ( 10984672 )
2000
16
Molecular characterization of 6-pyruvoyl-tetrahydropterin synthase deficiency in Japanese patients. ( 10319579 )
1999
17
Identification of mutations causing 6-pyruvoyl-tetrahydropterin synthase deficiency in four Italian families. ( 9222757 )
1997
18
6-pyruvoyl-tetrahydropterin synthase deficiency with generalized dystonia and diurnal fluctuation of symptoms: a clinical and molecular study. ( 9159737 )
1997
19
Prenatal diagnosis of 6-pyruvoyl tetrahydropterin synthase deficiency in seven subjects. ( 8051934 )
1994
20
Response of 6-pyruvoyl-tetrahydropterin synthase deficiency to tetrahydrobiopterin. ( 1588012 )
1992
21
A case of 6-pyruvoyl-tetrahydropterin synthase deficiency after screening 1,500,000 newborns in Greece. ( 1779640 )
1991
22
Progression of 6-pyruvoyl-tetrahydropterin synthase deficiency from a peripheral into a central phenotype. ( 1700190 )
1990
23
On-off phenomenon in a child with tetrahydrobiopterin deficiency due to 6-pyruvoyl tetrahydropterin synthase deficiency (BH4 deficiency). ( 2646129 )
1989
24
"Peripheral" tetrahydrobiopterin deficiency with hyperphenylalaninaemia due to incomplete 6-pyruvoyl tetrahydropterin synthase deficiency or heterozygosity. ( 3297709 )
1987

Variations for Hyperphenylalaninemia, Bh4-Deficient, a

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

71 (show all 24)
# 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 rs1040441824Hyperphenylalaninemia,
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:

6 (show all 11)
# 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
10 PTS NM_000317.2(PTS): c.73C> G (p.Arg25Gly) single nucleotide variant Likely pathogenic GRCh38 Chromosome 11, 112226516: 112226516
11 PTS NM_000317.2(PTS): c.200C> T (p.Thr67Met) single nucleotide variant Pathogenic rs370340361 GRCh37 Chromosome 11, 112101362: 112101362

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

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