MCID: HYP368
MIFTS: 35

Hyperphenylalaninemia, Bh4-Deficient, C

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

Aliases & Classifications for Hyperphenylalaninemia, Bh4-Deficient, C

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

Name: Hyperphenylalaninemia, Bh4-Deficient, C 57 75 13
Dihydropteridine Reductase Deficiency 57 53 59 75 29 6 40
Quinoid Dihydropteridine Reductase Deficiency 57 53 75
Dhpr Deficiency 57 53 75
Qdpr Deficiency 57 53 75
Hyperphenylalaninemia Due to Dihydropteridine Reductase Deficiency 53 59
Phenylketonuria Type 2 53 59
Pku Type 2 53 59
Hpabh4c 57 75
Hyperphenylalaninemia, Tetrahydrobiopterin-Deficient, Due to Dhpr Deficiency 57
Hyperphenylalaninemia Tetrahydrobiopterin-Deficient Due to Dhpr Deficiency 75
Hyperphenylalaninemia, Bh-4-Deficient, C 53
Quinoid Dihydropteridine Reductase 13
Phenylketonuria Ii 73

Characteristics:

Orphanet epidemiological data:

59
dihydropteridine reductase deficiency
Inheritance: Autosomal recessive; Age of onset: Infancy,Neonatal; Age of death: any age;

OMIM:

57
Inheritance:
autosomal recessive

Miscellaneous:
onset in infancy
variable severity
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


HPO:

32
hyperphenylalaninemia, bh4-deficient, c:
Onset and clinical course variable expressivity infantile onset
Inheritance autosomal recessive inheritance


Classifications:



Summaries for Hyperphenylalaninemia, Bh4-Deficient, C

NIH Rare Diseases : 53 Dihydropteridine reductase deficiency (DHPR) is a severe form of hyperphenylalaninemia (high levels of the amino acidphenylalanine in the blood) due to impaired renewal of a substance known as tetrahydrobiopterin (BH4). Tetrahydrobiopterin normally helps process several amino acids, including phenylalanine, and it is also involved in the production of neurotransmitters. If little or no tetrahydrobiopterin is available to help process phenylalanine, this amino acid can build up in the blood and other tissues and the levels of neurotransmitters (dopamine, serotonin) and folate in cerebrospinal fluid are also decreased. This results in neurological symptoms such as psychomotor delay, low muscle tone (hypotonia), seizures, abnormal movements, too much salivation, and swallowing difficulties. DHPR deficiency is caused by mutations in the QDPR gene. It is inherited in an autosomal recessive manner. Treatment should be started as soon as possible and includes BH4 supplementation usually combined with a diet without phenylalanine, folate supplementation, and specific medications to restore the levels of neurotransmitters in the brain.

MalaCards based summary : Hyperphenylalaninemia, Bh4-Deficient, C, also known as dihydropteridine reductase deficiency, is related to hyperphenylalaninemia, bh4-deficient, a and hyperphenylalaninemia, and has symptoms including seizures and tremor. An important gene associated with Hyperphenylalaninemia, Bh4-Deficient, C is QDPR (Quinoid Dihydropteridine Reductase). Affiliated tissues include brain and testes, and related phenotypes are intellectual disability and dysphagia

UniProtKB/Swiss-Prot : 75 Hyperphenylalaninemia, BH4-deficient, C: Rare autosomal recessive disorder characterized by hyperphenylalaninemia and severe neurologic symptoms (malignant hyperphenylalaninemia) including axial hypotonia and truncal hypertonia, abnormal thermogenesis, and microcephaly. These signs are attributable to depletion of the neurotransmitters dopamine and serotonin, whose syntheses are controlled by tryptophan and tyrosine hydroxylases that use BH-4 as cofactor. Patients do not respond to phenylalanine-restricted diet. HPABH4C is lethal if untreated.

Description from OMIM: 261630

Related Diseases for Hyperphenylalaninemia, Bh4-Deficient, C

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, C via text searches within MalaCards or GeneCards Suite gene sharing:

# Related Disease Score Top Affiliating Genes
1 hyperphenylalaninemia, bh4-deficient, a 10.9
2 hyperphenylalaninemia 10.4
3 phenylketonuria 10.3
4 neuroblastoma 10.0
5 leukemia, acute lymphoblastic 10.0
6 leukemia 10.0
7 lymphoblastic leukemia 10.0
8 mild hyperphenylalaninemia 10.0

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



Diseases related to Hyperphenylalaninemia, Bh4-Deficient, C

Symptoms & Phenotypes for Hyperphenylalaninemia, Bh4-Deficient, C

Symptoms via clinical synopsis from OMIM:

57
Neurologic Central Nervous System:
seizures
tremor
dystonia
choreoathetosis
mental retardation
more
Neurologic Behavioral Psychiatric Manifestations:
irritability

Growth Other:
poor feeding in infancy

Abdomen Gastrointestinal:
swallowing difficulties

Head And Neck Head:
microcephaly

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

Metabolic Features:
hyperthermia, episodic

Head And Neck Mouth:
hypersalivation


Clinical features from OMIM:

261630

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

59 32 (show all 17)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 intellectual disability 59 32 hallmark (90%) Very frequent (99-80%) HP:0001249
2 dysphagia 59 32 hallmark (90%) Very frequent (99-80%) HP:0002015
3 global developmental delay 59 32 hallmark (90%) Very frequent (99-80%) HP:0001263
4 microcephaly 59 32 hallmark (90%) Very frequent (99-80%) HP:0000252
5 seizures 32 HP:0001250
6 muscular hypotonia 32 HP:0001252
7 tremor 32 HP:0001337
8 cerebral calcification 32 HP:0002514
9 hypertonia 32 HP:0001276
10 irritability 32 HP:0000737
11 myoclonus 32 HP:0001336
12 dystonia 32 HP:0001332
13 choreoathetosis 32 HP:0001266
14 excessive salivation 32 HP:0003781
15 episodic fever 32 HP:0001954
16 progressive neurologic deterioration 32 HP:0002344
17 hyperphenylalaninemia 32 HP:0004923

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


seizures, tremor

Drugs & Therapeutics for Hyperphenylalaninemia, Bh4-Deficient, C

Search Clinical Trials , NIH Clinical Center for Hyperphenylalaninemia, Bh4-Deficient, C

Genetic Tests for Hyperphenylalaninemia, Bh4-Deficient, C

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

# Genetic test Affiliating Genes
1 Dihydropteridine Reductase Deficiency 29 QDPR

Anatomical Context for Hyperphenylalaninemia, Bh4-Deficient, C

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

41
Brain, Testes

Publications for Hyperphenylalaninemia, Bh4-Deficient, C

Articles related to Hyperphenylalaninemia, Bh4-Deficient, C:

(show top 50) (show all 62)
# Title Authors Year
1
QDPR gene mutation and clinical follow-up in Chinese patients with dihydropteridine reductase deficiency. ( 25124972 )
2014
2
Clinical characteristics of epileptic seizures in a case of dihydropteridine reductase deficiency. ( 25667865 )
2014
3
Dihydropteridine reductase deficiency and treatment with tetrahydrobiopterin: a case report. ( 23430801 )
2013
4
Dopamine agonists in dihydropteridine reductase deficiency. ( 22325981 )
2012
5
[Diagnosis, treatment and gene mutation analysis of the first case with dihydropteridine reductase deficiency in the mainland of China]. ( 19099731 )
2008
6
Dihydropteridine reductase deficiency: levodopa's long-term effectiveness without dyskinesia. ( 17190955 )
2006
7
Dihydropteridine reductase deficiency in man: from biology to treatment. ( 14705166 )
2004
8
Evaluation of a fetus at risk for dihydropteridine reductase deficiency by direct mutation analysis using denaturing gradient gel electrophoresis. ( 11746132 )
2001
9
Genotype-phenotype correlation in dihydropteridine reductase deficiency. ( 10896287 )
2000
10
Clinical and EEG video-polygraphic features of epileptic spasms in a child with dihydropteridine reductase deficiency. Efficiency of hydrocortisone. ( 11174152 )
2000
11
[Treatment of phenylketonuria due to dihydropteridine reductase deficiency]. ( 11062962 )
2000
12
Variant of dihydropteridine reductase deficiency without hyperphenylalaninaemia: effect of oral phenylalanine loading. ( 10384371 )
1999
13
Dihydropteridine reductase deficiency localized to the central nervous system. ( 9700606 )
1998
14
Dihydropteridine reductase deficiency: physical structure of the QDPR gene, identification of two new mutations and genotype-phenotype correlations. ( 9744478 )
1998
15
Juvenile form of dihydropteridine reductase deficiency in 2 Tunisian patients. ( 10029353 )
1998
16
Dihydropteridine reductase deficiency in a large consanguineous Tunisian family: clinical, biochemical, and neuropathologic findings. ( 9796752 )
1998
17
Molecular analysis of dihydropteridine reductase deficiency: identification of two novel mutations in Japanese patients. ( 9341885 )
1997
18
Electromyographic alterations in hyperphenylalaninemia due to dihydropteridine reductase deficiency. ( 9075022 )
1997
19
Molecular basis of dihydropteridine reductase deficiency. ( 7627180 )
1995
20
Monoaminergic effects of folinic acid, L-DOPA, and 5-hydroxytryptophan in dihydropteridine reductase deficiency. ( 7760062 )
1995
21
Catalytic activity of tetrahydrobiopterin in dihydropteridine reductase deficiency and indications for treatment. ( 8433887 )
1993
22
The spectrum of mutations in dihydropteridine reductase deficiency. ( 8304097 )
1993
23
Identification and in vitro expression of mutations causing dihydropteridine reductase deficiency. ( 8518287 )
1993
24
Tetrahydrobiopterin and quinonoid dihydrobiopterin concentrations in CSF from patients with dihydropteridine reductase deficiency. ( 7609464 )
1993
25
Atypical (mild) forms of dihydropteridine reductase deficiency: neurochemical evaluation and mutation detection. ( 1283784 )
1992
26
Cortical dysgenesis in a variant of phenylketonuria (dihydropteridine reductase deficiency). ( 1745643 )
1991
27
Successful treatment of dihydropteridine reductase deficiency, with an interesting effect of 5-hydroxytryptophan deficiency on sleep patterns. ( 1861459 )
1991
28
Molecular analysis of dihydropteridine reductase deficiency and restoration of the enzyme activity by gene transfer. ( 2174091 )
1990
29
Neuroblastoma in a patient with dihydropteridine reductase deficiency. ( 2209664 )
1990
30
Intracranial calcification in dihydropteridine reductase deficiency. ( 2135679 )
1990
31
Adverse effects of trimethoprim-sulfamethoxazole in a child with dihydropteridine reductase deficiency. ( 2391014 )
1990
32
Insertion of an extra codon for threonine is a cause of dihydropteridine reductase deficiency. ( 2116088 )
1990
33
Brain CT and MR findings in hyperphenylalaninemia due to dihydropteridine reductase deficiency (variant of phenylketonuria). ( 2398144 )
1990
34
Hyperphenylalaninemia caused by dihydropteridine reductase deficiency in children receiving chemotherapy for acute lymphoblastic leukemia. ( 2795366 )
1989
35
Progressive intracranial calcification in dihydropteridine reductase deficiency prior to folinic acid therapy. ( 2785251 )
1989
36
The use of restriction fragment length polymorphisms in prenatal diagnosis of dihydropteridine reductase deficiency. ( 2895188 )
1988
37
Two mutations of dihydropteridine reductase deficiency. ( 2894818 )
1988
38
Folinic acid therapy in treatment of dihydropteridine reductase deficiency. ( 2878984 )
1987
39
Human dihydropteridine reductase: characterisation of a cDNA clone and its use in analysis of patients with dihydropteridine reductase deficiency. ( 3031582 )
1987
40
Tetrahydrobiopterin and "non-responsive" dihydropteridine reductase deficiency. ( 2885683 )
1987
41
Tetrahydrobiopterin non-responsiveness in dihydropteridine reductase deficiency is associated with the presence of mutant protein. ( 3099067 )
1986
42
Tetrahydrobiopterin in dihydropteridine reductase deficiency. ( 3945285 )
1986
43
Genetic analysis of partial dihydropteridine reductase deficiency in families with mental retardation. ( 3104679 )
1986
44
Neonatal screening for dihydropteridine reductase deficiency. ( 3930876 )
1985
45
Phenylketonuria due to dihydropteridine reductase deficiency: presentation of two cases. ( 3930875 )
1985
46
Cranial computerized tomography in dihydropteridine reductase deficiency. ( 2433499 )
1985
47
Dihydropteridine reductase deficiency: non-response to oral tetrahydrobiopterin load test. ( 6434829 )
1984
48
A mild case of dihydropteridine reductase deficiency with residual activity in erythrocytes. ( 6438398 )
1984
49
Hyperphenylalaninemia due to dihydropteridine reductase deficiency: diagnosis by enzyme assays on dried blood spots. ( 7110817 )
1982
50
Diagnosis of dihydropteridine reductase deficiency by erythrocyte enzyme assay. ( 7322696 )
1981

Variations for Hyperphenylalaninemia, Bh4-Deficient, C

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

75 (show all 16)
# Symbol AA change Variation ID SNP ID
1 QDPR p.Gly23Asp VAR_006960 rs104893863
2 QDPR p.Trp36Arg VAR_006961 rs104893865
3 QDPR p.Leu74Pro VAR_006962
4 QDPR p.Trp108Gly VAR_006963 rs104893864
5 QDPR p.Pro145Leu VAR_006965
6 QDPR p.Tyr150Cys VAR_006966 rs104893866
7 QDPR p.Gly151Ser VAR_006967
8 QDPR p.His158Tyr VAR_006968 rs750201480
9 QDPR p.Gly170Ser VAR_006969 rs769460415
10 QDPR p.Phe212Cys VAR_006970
11 QDPR p.Leu14Pro VAR_008121 rs756639609
12 QDPR p.Gly17Val VAR_008122
13 QDPR p.Gly17Arg VAR_021767 rs757483045
14 QDPR p.Gly18Asp VAR_021768
15 QDPR p.Gln66Arg VAR_021769
16 QDPR p.Gly149Arg VAR_021770 rs1028029163Hyperphenylalaninemia,

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

6
(show all 30)
# Gene Variation Type Significance SNP ID Assembly Location
1 QDPR QDPR, 3-BP INS, 390ACT insertion Pathogenic
2 QDPR NM_000320.2(QDPR): c.68G> A (p.Gly23Asp) single nucleotide variant Pathogenic rs104893863 GRCh37 Chromosome 4, 17513610: 17513610
3 QDPR NM_000320.2(QDPR): c.68G> A (p.Gly23Asp) single nucleotide variant Pathogenic rs104893863 GRCh38 Chromosome 4, 17511987: 17511987
4 QDPR NM_000320.2(QDPR): c.322T> G (p.Trp108Gly) single nucleotide variant Pathogenic rs104893864 GRCh37 Chromosome 4, 17503456: 17503456
5 QDPR NM_000320.2(QDPR): c.322T> G (p.Trp108Gly) single nucleotide variant Pathogenic rs104893864 GRCh38 Chromosome 4, 17501833: 17501833
6 QDPR NM_000320.2(QDPR): c.106T> C (p.Trp36Arg) single nucleotide variant Pathogenic rs104893865 GRCh37 Chromosome 4, 17510986: 17510986
7 QDPR NM_000320.2(QDPR): c.106T> C (p.Trp36Arg) single nucleotide variant Pathogenic rs104893865 GRCh38 Chromosome 4, 17509363: 17509363
8 QDPR QDPR, IVS3, A-G, 152-BP INS insertion Pathogenic
9 QDPR NM_000320.2(QDPR): c.449A> G (p.Tyr150Cys) single nucleotide variant Pathogenic rs104893866 GRCh37 Chromosome 4, 17493951: 17493951
10 QDPR NM_000320.2(QDPR): c.449A> G (p.Tyr150Cys) single nucleotide variant Pathogenic rs104893866 GRCh38 Chromosome 4, 17492328: 17492328
11 QDPR NM_000320.2(QDPR): c.270G> A (p.Trp90Ter) single nucleotide variant Pathogenic rs104893867 GRCh37 Chromosome 4, 17506027: 17506027
12 QDPR NM_000320.2(QDPR): c.270G> A (p.Trp90Ter) single nucleotide variant Pathogenic rs104893867 GRCh38 Chromosome 4, 17504404: 17504404
13 QDPR NM_000320.2(QDPR): c.396G> A (p.Leu132=) single nucleotide variant Benign rs2597775 GRCh37 Chromosome 4, 17503382: 17503382
14 QDPR NM_000320.2(QDPR): c.396G> A (p.Leu132=) single nucleotide variant Benign rs2597775 GRCh38 Chromosome 4, 17501759: 17501759
15 QDPR NM_000320.2(QDPR): c.96C> T (p.Ala32=) single nucleotide variant Benign rs2518608 GRCh37 Chromosome 4, 17513582: 17513582
16 QDPR NM_000320.2(QDPR): c.96C> T (p.Ala32=) single nucleotide variant Benign rs2518608 GRCh38 Chromosome 4, 17511959: 17511959
17 QDPR NM_000320.2(QDPR): c.255C> T (p.Cys85=) single nucleotide variant Benign/Likely benign rs12645938 GRCh38 Chromosome 4, 17504419: 17504419
18 QDPR NM_000320.2(QDPR): c.255C> T (p.Cys85=) single nucleotide variant Benign/Likely benign rs12645938 GRCh37 Chromosome 4, 17506042: 17506042
19 QDPR NM_000320.2(QDPR): c.344C> T (p.Ser115Leu) single nucleotide variant Pathogenic GRCh37 Chromosome 4, 17503434: 17503434
20 QDPR NM_000320.2(QDPR): c.344C> T (p.Ser115Leu) single nucleotide variant Pathogenic GRCh38 Chromosome 4, 17501811: 17501811
21 QDPR NM_000320.2(QDPR): c.365C> A (p.Ala122Asp) single nucleotide variant Uncertain significance GRCh38 Chromosome 4, 17501790: 17501790
22 QDPR NM_000320.2(QDPR): c.365C> A (p.Ala122Asp) single nucleotide variant Uncertain significance GRCh37 Chromosome 4, 17503413: 17503413
23 QDPR NM_000320.2(QDPR): c.472C> T (p.His158Tyr) single nucleotide variant Likely pathogenic rs750201480 GRCh38 Chromosome 4, 17492305: 17492305
24 QDPR NM_000320.2(QDPR): c.472C> T (p.His158Tyr) single nucleotide variant Likely pathogenic rs750201480 GRCh37 Chromosome 4, 17493928: 17493928
25 QDPR NM_000320.2(QDPR): c.630-17T> C single nucleotide variant Likely benign rs201581320 GRCh38 Chromosome 4, 17487253: 17487253
26 QDPR NM_000320.2(QDPR): c.630-17T> C single nucleotide variant Likely benign rs201581320 GRCh37 Chromosome 4, 17488876: 17488876
27 QDPR NM_000320.2(QDPR): c.423G> A (p.Leu141=) single nucleotide variant Likely benign GRCh38 Chromosome 4, 17501732: 17501732
28 QDPR NM_000320.2(QDPR): c.423G> A (p.Leu141=) single nucleotide variant Likely benign GRCh37 Chromosome 4, 17503355: 17503355
29 QDPR NM_000320.2(QDPR): c.450C> T (p.Tyr150=) single nucleotide variant Likely benign rs140949360 GRCh37 Chromosome 4, 17493950: 17493950
30 QDPR NM_000320.2(QDPR): c.450C> T (p.Tyr150=) single nucleotide variant Likely benign rs140949360 GRCh38 Chromosome 4, 17492327: 17492327

Expression for Hyperphenylalaninemia, Bh4-Deficient, C

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

Pathways for Hyperphenylalaninemia, Bh4-Deficient, C

GO Terms for Hyperphenylalaninemia, Bh4-Deficient, C

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