HPABH4B
MCID: HYP605
MIFTS: 39

Hyperphenylalaninemia, Bh4-Deficient, B (HPABH4B)

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

Aliases & Classifications for Hyperphenylalaninemia, Bh4-Deficient, B

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

Name: Hyperphenylalaninemia, Bh4-Deficient, B 58 54 76 13 74
Gtp Cyclohydrolase I Deficiency 58 54 60 30 56 6 41
Hpabh4b 58 76
Hyperphenylalaninemia, Tetrahydrobiopterin-Deficient, Due to Gtp Cyclohydrolase I Deficiency 58
Hyperphenylalaninemia, Tetrahydrobiopterin-Deficient, Due to Gtp Cyclohydrolase 1 Deficiency 54
Atypical Severe Phenylketonuria Due to Gtp Cyclohydrolase I Deficiency 76
Hyperphenylalaninemia Due to Gtp Cyclohydrolase Deficiency 60
Guanosine Triphosphate Cyclohydrolase I Deficiency 76
Hyperphenylalaninemia with Neopterin Deficiency 76
Gtp Cyclohydrolase 1 13
Gtpch Deficiency 60
Gch1 Deficiency 76

Characteristics:

Orphanet epidemiological data:

60
gtp cyclohydrolase i deficiency
Inheritance: Autosomal recessive; Prevalence: <1/1000000 (Worldwide); Age of onset: Infancy,Neonatal;

OMIM:

58
Inheritance:
autosomal recessive

Miscellaneous:
onset in infancy
variable severity
defect in tetrahydrobiopterin (bh4) synthesis
progressive neurologic deterioration if untreated
normal neonatal blood phenylalanine has been reported in rare patients
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
autosomal dominant dopa-responsive dystonia (dyt5, ) is an allelic disorder with overlapping features


HPO:

33
hyperphenylalaninemia, bh4-deficient, b:
Onset and clinical course variable expressivity infantile onset
Inheritance autosomal recessive inheritance


Classifications:



Summaries for Hyperphenylalaninemia, Bh4-Deficient, B

NIH Rare Diseases : 54 The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.Orpha Number: 2102Disease definitionGTP-cyclohydrolase I 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.Clinical descriptionWhen 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, tonicity disorders, convulsions, drowsiness, irritability, abnormal movements, hyperthermia, hypersalivation, and difficulty swallowing.Diagnostic methodsGTP-cyclohydrolase I 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, homovanillic acid) in cerebrospinal fluid and with an oral tetrahydrobiopterin-loading test (20 mg/kg).Management and treatmentThe 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-hydroxytryptophane).Visit the Orphanet disease page for more resources.

MalaCards based summary : Hyperphenylalaninemia, Bh4-Deficient, B, also known as gtp cyclohydrolase i deficiency, is related to dystonia, dopa-responsive and hyperphenylalaninemia, bh4-deficient, a, and has symptoms including seizures, tremor and lethargy. An important gene associated with Hyperphenylalaninemia, Bh4-Deficient, B is GCH1 (GTP Cyclohydrolase 1), and among its related pathways/superpathways are Metabolism and Folate biosynthesis. Affiliated tissues include testes and eye, and related phenotypes are abnormality of eye movement and seizures

UniProtKB/Swiss-Prot : 76 Hyperphenylalaninemia, BH4-deficient, B: A disease characterized by malignant hyperphenylalaninemia due to tetrahydrobiopterin deficiency, and defective neurotransmission due to depletion of the neurotransmitters dopamine and serotonin. The principal symptoms include: psychomotor retardation, tonicity disorders, convulsions, drowsiness, irritability, abnormal movements, hyperthermia, hypersalivation, and difficulty swallowing. Some patients may present a phenotype of intermediate severity between severe hyperphenylalaninemia and mild dystonia. In this intermediate phenotype, there is marked motor delay, but no mental retardation and only minimal, if any, hyperphenylalaninemia.

Description from OMIM: 233910

Related Diseases for Hyperphenylalaninemia, Bh4-Deficient, B

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



Diseases related to Hyperphenylalaninemia, Bh4-Deficient, B

Symptoms & Phenotypes for Hyperphenylalaninemia, Bh4-Deficient, B

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

33 (show all 18)
# Description HPO Frequency HPO Source Accession
1 abnormality of eye movement 33 HP:0000496
2 seizures 33 HP:0001250
3 tremor 33 HP:0001337
4 dysphagia 33 HP:0002015
5 global developmental delay 33 HP:0001263
6 irritability 33 HP:0000737
7 dystonia 33 HP:0001332
8 intellectual disability, progressive 33 HP:0006887
9 rigidity 33 HP:0002063
10 choreoathetosis 33 HP:0001266
11 lethargy 33 HP:0001254
12 severe muscular hypotonia 33 HP:0006829
13 excessive salivation 33 HP:0003781
14 hyperkinesis 33 HP:0002487
15 episodic fever 33 HP:0001954
16 progressive neurologic deterioration 33 HP:0002344
17 limb hypertonia 33 HP:0002509
18 hyperphenylalaninemia 33 HP:0004923

Symptoms via clinical synopsis from OMIM:

58
Neurologic Central Nervous System:
seizures
tremor
dystonia
rigidity
choreoathetosis
more
Laboratory Abnormalities:
hyperphenylalaninemia
decreased homovanillic acid (hva) and 5-hydroxyindoleacetic acid (5hiaa) in csf
decreased neopterin and biopterin in urine
decreased neopterin and biopterin in csf
decreased or absent gch1 activity

Metabolic Features:
hyperthermia, episodic

Head And Neck Eyes:
abnormal ocular movements

Neurologic Behavioral Psychiatric Manifestations:
irritability

Growth Other:
poor feeding in infancy

Abdomen Gastrointestinal:
swallowing difficulties

Head And Neck Mouth:
hypersalivation

Clinical features from OMIM:

233910

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


seizures, tremor, lethargy, muscle rigidity

Drugs & Therapeutics for Hyperphenylalaninemia, Bh4-Deficient, B

Interventional clinical trials:


# Name Status NCT ID Phase Drugs
1 Study of Kuvan Treatment in Adults With GTPCH Deficiency Completed NCT01425528 Phase 1, Phase 2 Sapropterin

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

Genetic Tests for Hyperphenylalaninemia, Bh4-Deficient, B

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

# Genetic test Affiliating Genes
1 Gtp Cyclohydrolase I Deficiency 30 GCH1

Anatomical Context for Hyperphenylalaninemia, Bh4-Deficient, B

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

42
Testes, Eye

Publications for Hyperphenylalaninemia, Bh4-Deficient, B

Articles related to Hyperphenylalaninemia, Bh4-Deficient, B:

# Title Authors Year
1
Clinical and biochemical characterization of patients with early infantile onset of autosomal recessive GTP cyclohydrolase I deficiency without hyperphenylalaninemia. ( 20818608 )
2011
2
Autosomal recessive GTP cyclohydrolase I deficiency without hyperphenylalaninemia: evidence of a phenotypic continuum between dominant and recessive forms. ( 18276179 )
2008
3
Dopa-responsive dystonia and early-onset Parkinson's disease in a patient with GTP cyclohydrolase I deficiency? ( 16267845 )
2006
4
Characterization of mouse and human GTP cyclohydrolase I genes. Mutations in patients with GTP cyclohydrolase I deficiency. ( 7730309 )
1995
5
Increase of GTP cyclohydrolase I activity in mononuclear blood cells by stimulation: detection of heterozygotes of GTP cyclohydrolase I deficiency. ( 3159515 )
1985
6
GTP cyclohydrolase I deficiency, a new enzyme defect causing hyperphenylalaninemia with neopterin, biopterin, dopamine, and serotonin deficiencies and muscular hypotonia. ( 6734669 )
1984

Variations for Hyperphenylalaninemia, Bh4-Deficient, B

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

76
# Symbol AA change Variation ID SNP ID
1 GCH1 p.Arg184His VAR_002643 rs104894445
2 GCH1 p.Met211Ile VAR_002647 rs104894443
3 GCH1 p.Lys224Arg VAR_002648 rs41298442
4 GCH1 p.Gly108Asp VAR_016894 rs104894435
5 GCH1 p.Met221Thr VAR_016905 rs104894434

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

6 (show top 50) (show all 150)
# Gene Variation Type Significance SNP ID Assembly Location
1 GCH1 NM_000161.2(GCH1): c.206C> T (p.Pro69Leu) single nucleotide variant Conflicting interpretations of pathogenicity rs56127440 GRCh37 Chromosome 14, 55369176: 55369176
2 GCH1 NM_000161.2(GCH1): c.206C> T (p.Pro69Leu) single nucleotide variant Conflicting interpretations of pathogenicity rs56127440 GRCh38 Chromosome 14, 54902458: 54902458
3 GCH1 NM_000161.2(GCH1): c.323G> A (p.Gly108Asp) single nucleotide variant Likely pathogenic rs104894435 GRCh37 Chromosome 14, 55369059: 55369059
4 GCH1 NM_000161.2(GCH1): c.323G> A (p.Gly108Asp) single nucleotide variant Likely pathogenic rs104894435 GRCh38 Chromosome 14, 54902341: 54902341
5 GCH1 NM_000161.2(GCH1): c.671A> G (p.Lys224Arg) single nucleotide variant Conflicting interpretations of pathogenicity rs41298442 GRCh37 Chromosome 14, 55310817: 55310817
6 GCH1 NM_000161.2(GCH1): c.671A> G (p.Lys224Arg) single nucleotide variant Conflicting interpretations of pathogenicity rs41298442 GRCh38 Chromosome 14, 54844099: 54844099
7 GCH1 NM_000161.2(GCH1): c.633G> A (p.Met211Ile) single nucleotide variant Pathogenic rs104894443 GRCh37 Chromosome 14, 55310855: 55310855
8 GCH1 NM_000161.2(GCH1): c.633G> A (p.Met211Ile) single nucleotide variant Pathogenic rs104894443 GRCh38 Chromosome 14, 54844137: 54844137
9 GCH1 NM_000161.2(GCH1): c.551G> A (p.Arg184His) single nucleotide variant Pathogenic rs104894445 GRCh37 Chromosome 14, 55312561: 55312561
10 GCH1 NM_000161.2(GCH1): c.551G> A (p.Arg184His) single nucleotide variant Pathogenic rs104894445 GRCh38 Chromosome 14, 54845843: 54845843
11 GCH1 NM_000161.2(GCH1): c.-40C> T single nucleotide variant Benign rs28458175 GRCh37 Chromosome 14, 55369421: 55369421
12 GCH1 NM_000161.2(GCH1): c.-40C> T single nucleotide variant Benign rs28458175 GRCh38 Chromosome 14, 54902703: 54902703
13 GCH1 NM_000161.2(GCH1): c.*1824A> C single nucleotide variant Uncertain significance rs754395380 GRCh37 Chromosome 14, 55308911: 55308911
14 GCH1 NM_000161.2(GCH1): c.*1824A> C single nucleotide variant Uncertain significance rs754395380 GRCh38 Chromosome 14, 54842193: 54842193
15 GCH1 NM_000161.2(GCH1): c.*1230C> T single nucleotide variant Benign rs56130647 GRCh38 Chromosome 14, 54842787: 54842787
16 GCH1 NM_000161.2(GCH1): c.*1230C> T single nucleotide variant Benign rs56130647 GRCh37 Chromosome 14, 55309505: 55309505
17 GCH1 NM_000161.2(GCH1): c.*892_*894delCTT deletion Benign rs145762799 GRCh38 Chromosome 14, 54843123: 54843125
18 GCH1 NM_000161.2(GCH1): c.*892_*894delCTT deletion Benign rs145762799 GRCh37 Chromosome 14, 55309841: 55309843
19 GCH1 NM_000161.2(GCH1): c.*617A> G single nucleotide variant Uncertain significance rs886050546 GRCh38 Chromosome 14, 54843400: 54843400
20 GCH1 NM_000161.2(GCH1): c.*617A> G single nucleotide variant Uncertain significance rs886050546 GRCh37 Chromosome 14, 55310118: 55310118
21 GCH1 NM_000161.2(GCH1): c.*507C> G single nucleotide variant Uncertain significance rs886050547 GRCh38 Chromosome 14, 54843510: 54843510
22 GCH1 NM_000161.2(GCH1): c.*507C> G single nucleotide variant Uncertain significance rs886050547 GRCh37 Chromosome 14, 55310228: 55310228
23 GCH1 NM_000161.2(GCH1): c.*367G> A single nucleotide variant Uncertain significance rs886050548 GRCh38 Chromosome 14, 54843650: 54843650
24 GCH1 NM_000161.2(GCH1): c.*367G> A single nucleotide variant Uncertain significance rs886050548 GRCh37 Chromosome 14, 55310368: 55310368
25 GCH1 NM_000161.2(GCH1): c.*278C> T single nucleotide variant Uncertain significance rs756583192 GRCh38 Chromosome 14, 54843739: 54843739
26 GCH1 NM_000161.2(GCH1): c.*278C> T single nucleotide variant Uncertain significance rs756583192 GRCh37 Chromosome 14, 55310457: 55310457
27 GCH1 NM_000161.2(GCH1): c.297C> T (p.Ala99=) single nucleotide variant Uncertain significance rs776450369 GRCh38 Chromosome 14, 54902367: 54902367
28 GCH1 NM_000161.2(GCH1): c.297C> T (p.Ala99=) single nucleotide variant Uncertain significance rs776450369 GRCh37 Chromosome 14, 55369085: 55369085
29 GCH1 NM_000161.2(GCH1): c.68C> T (p.Pro23Leu) single nucleotide variant Conflicting interpretations of pathogenicity rs41298432 GRCh37 Chromosome 14, 55369314: 55369314
30 GCH1 NM_000161.2(GCH1): c.68C> T (p.Pro23Leu) single nucleotide variant Conflicting interpretations of pathogenicity rs41298432 GRCh38 Chromosome 14, 54902596: 54902596
31 GCH1 NM_000161.2(GCH1): c.-72C> T single nucleotide variant Uncertain significance rs886050551 GRCh37 Chromosome 14, 55369453: 55369453
32 GCH1 NM_000161.2(GCH1): c.-72C> T single nucleotide variant Uncertain significance rs886050551 GRCh38 Chromosome 14, 54902735: 54902735
33 GCH1 NM_000161.2(GCH1): c.-106G> A single nucleotide variant Uncertain significance rs886050553 GRCh37 Chromosome 14, 55369487: 55369487
34 GCH1 NM_000161.2(GCH1): c.-106G> A single nucleotide variant Uncertain significance rs886050553 GRCh38 Chromosome 14, 54902769: 54902769
35 GCH1 NM_000161.2(GCH1): c.*1915T> C single nucleotide variant Likely benign rs17128017 GRCh38 Chromosome 14, 54842102: 54842102
36 GCH1 NM_000161.2(GCH1): c.*1915T> C single nucleotide variant Likely benign rs17128017 GRCh37 Chromosome 14, 55308820: 55308820
37 GCH1 NM_000161.2(GCH1): c.*1628A> C single nucleotide variant Likely benign rs185031007 GRCh37 Chromosome 14, 55309107: 55309107
38 GCH1 NM_000161.2(GCH1): c.*1628A> C single nucleotide variant Likely benign rs185031007 GRCh38 Chromosome 14, 54842389: 54842389
39 GCH1 NM_000161.2(GCH1): c.*1463_*1464dupAT duplication Likely benign rs55885280 GRCh37 Chromosome 14, 55309271: 55309272
40 GCH1 NM_000161.2(GCH1): c.*1463_*1464dupAT duplication Likely benign rs55885280 GRCh38 Chromosome 14, 54842553: 54842554
41 GCH1 NM_000161.2(GCH1): c.*1257C> T single nucleotide variant Uncertain significance rs763425111 GRCh38 Chromosome 14, 54842760: 54842760
42 GCH1 NM_000161.2(GCH1): c.*1257C> T single nucleotide variant Uncertain significance rs763425111 GRCh37 Chromosome 14, 55309478: 55309478
43 GCH1 NM_000161.2(GCH1): c.*1176C> G single nucleotide variant Likely benign rs113211390 GRCh38 Chromosome 14, 54842841: 54842841
44 GCH1 NM_000161.2(GCH1): c.*1176C> G single nucleotide variant Likely benign rs113211390 GRCh37 Chromosome 14, 55309559: 55309559
45 GCH1 NM_000161.2(GCH1): c.*1130C> G single nucleotide variant Likely benign rs543818323 GRCh38 Chromosome 14, 54842887: 54842887
46 GCH1 NM_000161.2(GCH1): c.*1130C> G single nucleotide variant Likely benign rs543818323 GRCh37 Chromosome 14, 55309605: 55309605
47 GCH1 NM_000161.2(GCH1): c.*727A> G single nucleotide variant Likely benign rs138578359 GRCh38 Chromosome 14, 54843290: 54843290
48 GCH1 NM_000161.2(GCH1): c.*727A> G single nucleotide variant Likely benign rs138578359 GRCh37 Chromosome 14, 55310008: 55310008
49 GCH1 NM_000161.2(GCH1): c.*715G> T single nucleotide variant Uncertain significance rs886050545 GRCh38 Chromosome 14, 54843302: 54843302
50 GCH1 NM_000161.2(GCH1): c.*715G> T single nucleotide variant Uncertain significance rs886050545 GRCh37 Chromosome 14, 55310020: 55310020

Expression for Hyperphenylalaninemia, Bh4-Deficient, B

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

Pathways for Hyperphenylalaninemia, Bh4-Deficient, B

Pathways related to Hyperphenylalaninemia, Bh4-Deficient, B according to GeneCards Suite gene sharing:

# Super pathways Score Top Affiliating Genes
1
Show member pathways
12.89 GCH1 PTS QDPR TH
2
Show member pathways
10.39 GCH1 PTS QDPR TH

GO Terms for Hyperphenylalaninemia, Bh4-Deficient, B

Biological processes related to Hyperphenylalaninemia, Bh4-Deficient, B according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 response to lipopolysaccharide GO:0032496 9.4 GCH1 TH
2 cellular response to drug GO:0035690 9.37 QDPR TH
3 cellular amino acid metabolic process GO:0006520 9.32 PTS QDPR
4 cofactor metabolic process GO:0051186 9.26 GCH1 PTS
5 dopamine biosynthetic process GO:0042416 9.16 GCH1 TH
6 dihydrobiopterin metabolic process GO:0051066 8.96 GCH1 QDPR
7 tetrahydrobiopterin biosynthetic process GO:0006729 8.8 GCH1 PTS QDPR

Molecular functions related to Hyperphenylalaninemia, Bh4-Deficient, B according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 protein homodimerization activity GO:0042803 8.8 GCH1 PTS QDPR

Sources for Hyperphenylalaninemia, Bh4-Deficient, B

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
20 FMA
29 GO
30 GTR
31 HGMD
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33 HPO
34 ICD10
35 ICD10 via Orphanet
36 ICD9CM
37 IUPHAR
38 KEGG
39 LifeMap
41 LOVD
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45 MeSH
46 MESH via Orphanet
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58 OMIM
59 OMIM via Orphanet
63 PubMed
65 QIAGEN
70 SNOMED-CT via HPO
71 SNOMED-CT via Orphanet
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75 UMLS via Orphanet
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