U.S. flag

An official website of the United States government

Format

Send to:

Choose Destination

GTP cyclohydrolase I deficiency with hyperphenylalaninemia(HPABH4B)

MedGen UID:
988270
Concept ID:
CN305333
Disease or Syndrome
Synonyms: HPABH4B; Hyperphenylalaninemia, BH4-Deficient, B; Hyperphenylalaninemia, tetrahydrobiopterin-deficient, due to GTP cyclohydrolase 1 deficiency; HYPERPHENYLALANINEMIA, TETRAHYDROBIOPTERIN-DEFICIENT, DUE TO GTP CYCLOHYDROLASE I DEFICIENCY
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): GCH1 (14q22.2)
 
Monarch Initiative: MONDO:0100186
OMIM®: 233910
Orphanet: ORPHA2102

Definition

GTP-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. [from ORDO]

Clinical features

From HPO
Decreased urinary biopterin level
MedGen UID:
1054812
Concept ID:
CN376438
Finding
The amount of biopterin in the urine, normalized for urine concentration, is below the lower limit of normal.
Decreased urinary neopterin level
MedGen UID:
1054290
Concept ID:
CN376441
Finding
The amount of neopterin in the urine, normalized for urine concentration, is below the lower limit of normal.
Elevated urinary sulfatide level
MedGen UID:
1053367
Concept ID:
CN376629
Finding
The amount of sulfatides in the urine, normalized for urine concentration, is above the upper limit of normal. Sulfatides are derived from GalCer via esterification of a sulfate group to 3-hydroxyl of the galactose moiety.
Limb hypertonia
MedGen UID:
333083
Concept ID:
C1838391
Finding
Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
Difficulty in swallowing.
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Poor suck
MedGen UID:
324693
Concept ID:
C1837142
Finding
An inadequate sucking reflex, resulting in the difficult of newborns to be breast-fed.
Dystonic disorder
MedGen UID:
3940
Concept ID:
C0013421
Sign or Symptom
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Lethargy
MedGen UID:
7310
Concept ID:
C0023380
Sign or Symptom
A state of fatigue, either physical or mental slowness and sluggishness, with difficulties in initiating or performing simple tasks. Distinguished from apathy which implies indifference and a lack of desire or interest in the task. A person with lethargy may have the desire, but not the energy to engage in personal or socially relevant tasks.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Tremor
MedGen UID:
21635
Concept ID:
C0040822
Sign or Symptom
An unintentional, oscillating to-and-fro muscle movement about a joint axis.
Choreoathetosis
MedGen UID:
39313
Concept ID:
C0085583
Disease or Syndrome
Involuntary movements characterized by both athetosis (inability to sustain muscles in a fixed position) and chorea (widespread jerky arrhythmic movements).
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Intellectual disability, progressive
MedGen UID:
337397
Concept ID:
C1846149
Mental or Behavioral Dysfunction
The term progressive intellectual disability should be used if intelligence decreases/deteriorates over time.
Progressive neurologic deterioration
MedGen UID:
381506
Concept ID:
C1854838
Finding
Irritability
MedGen UID:
397841
Concept ID:
C2700617
Mental Process
A proneness to anger, i.e., a tendency to become easily bothered or annoyed.
Hyperkinetic movements
MedGen UID:
854367
Concept ID:
C3887506
Disease or Syndrome
Motor hyperactivity with excessive movement of muscles of the body as a whole.
Increased CSF phenylalanine concentration
MedGen UID:
1692227
Concept ID:
C5139608
Finding
Abnormally increased levels of phenylalanine in cerebrospinal fluid.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Rigidity
MedGen UID:
7752
Concept ID:
C0026837
Sign or Symptom
Continuous involuntary sustained muscle contraction. When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched. This feature helps to distinguish rigidity from muscle spasticity.
Severe muscular hypotonia
MedGen UID:
326544
Concept ID:
C1839630
Finding
A severe degree of muscular hypotonia characterized by markedly reduced muscle tone.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Hyperphenylalaninemia
MedGen UID:
155558
Concept ID:
C0751435
Disease or Syndrome
An increased concentration of L-phenylalanine in the blood.
Recurrent fever
MedGen UID:
811468
Concept ID:
C3714772
Sign or Symptom
Periodic (episodic or recurrent) bouts of fever.
Excessive salivation
MedGen UID:
11419
Concept ID:
C0037036
Disease or Syndrome
Excessive production of saliva.
Abnormality of eye movement
MedGen UID:
99227
Concept ID:
C0497202
Finding
An abnormality in voluntary or involuntary eye movements or their control.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  

Professional guidelines

PubMed

Souza CAA, Alves MRA, Soares RDL, Kanufre VC, Rodrigues VM, Norton RC, Starling ALP, Aguiar MJB
J Pediatr (Rio J) 2018 Mar-Apr;94(2):170-176. Epub 2017 Aug 9 doi: 10.1016/j.jped.2017.04.005. PMID: 28801146
Niederwieser A, Ponzone A, Curtius HC
J Inherit Metab Dis 1985;8 Suppl 1:34-8. doi: 10.1007/BF01800657. PMID: 3930839

Curated

American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated Phenylalanine, Phenylalanine hydroxylase deficiency (PAH), 2022

American College of Medical Genetics and Genomics, Algorithm, PAH deficiency: Elevated Phenylalanine, 2022

Recent clinical studies

Etiology

Gundorova P, Kuznetcova IA, Baydakova GV, Stepanova AA, Itkis YS, Kakaulina VS, Alferova IP, Lyazina LV, Andreeva LP, Kanivets I, Zakharova EY, Kutsev SI, Polyakov AV
PLoS One 2021;16(4):e0249608. Epub 2021 Apr 6 doi: 10.1371/journal.pone.0249608. PMID: 33822819Free PMC Article
Rudakou U, Ouled Amar Bencheikh B, Ruskey JA, Krohn L, Laurent SB, Spiegelman D, Liong C, Fahn S, Waters C, Monchi O, Fon EA, Dauvilliers Y, Alcalay RN, Dupré N, Gan-Or Z
Neurobiol Aging 2019 Jan;73:231.e1-231.e6. Epub 2018 Sep 15 doi: 10.1016/j.neurobiolaging.2018.09.008. PMID: 30314816Free PMC Article
Souza CAA, Alves MRA, Soares RDL, Kanufre VC, Rodrigues VM, Norton RC, Starling ALP, Aguiar MJB
J Pediatr (Rio J) 2018 Mar-Apr;94(2):170-176. Epub 2017 Aug 9 doi: 10.1016/j.jped.2017.04.005. PMID: 28801146
Opladen T, Hoffmann GF, Blau N
J Inherit Metab Dis 2012 Nov;35(6):963-73. Epub 2012 Jun 23 doi: 10.1007/s10545-012-9506-x. PMID: 22729819
Opladen T, Abu Seda B, Rassi A, Thöny B, Hoffmann GF, Blau N
J Inherit Metab Dis 2011 Jun;34(3):819-26. Epub 2011 Mar 17 doi: 10.1007/s10545-011-9300-1. PMID: 21416196

Diagnosis

Gundorova P, Kuznetcova IA, Baydakova GV, Stepanova AA, Itkis YS, Kakaulina VS, Alferova IP, Lyazina LV, Andreeva LP, Kanivets I, Zakharova EY, Kutsev SI, Polyakov AV
PLoS One 2021;16(4):e0249608. Epub 2021 Apr 6 doi: 10.1371/journal.pone.0249608. PMID: 33822819Free PMC Article
Dayasiri KC, Suraweera N, Nawarathne D, Senanayake UE, Dayanath BKTP, Jasinge E, Weerasekara K
BMC Pediatr 2019 Jun 15;19(1):199. doi: 10.1186/s12887-019-1580-x. PMID: 31202265Free PMC Article
Souza CAA, Alves MRA, Soares RDL, Kanufre VC, Rodrigues VM, Norton RC, Starling ALP, Aguiar MJB
J Pediatr (Rio J) 2018 Mar-Apr;94(2):170-176. Epub 2017 Aug 9 doi: 10.1016/j.jped.2017.04.005. PMID: 28801146
Opladen T, Abu Seda B, Rassi A, Thöny B, Hoffmann GF, Blau N
J Inherit Metab Dis 2011 Jun;34(3):819-26. Epub 2011 Mar 17 doi: 10.1007/s10545-011-9300-1. PMID: 21416196
Longo N
J Inherit Metab Dis 2009 Jun;32(3):333-42. Epub 2009 Feb 9 doi: 10.1007/s10545-009-1067-2. PMID: 19234759

Therapy

Sato H, Uematsu M, Endo W, Nakayama T, Kobayashi T, Hino-Fukuyo N, Sakamoto O, Shintaku H, Kure S
Brain Dev 2014 Mar;36(3):268-71. Epub 2013 May 6 doi: 10.1016/j.braindev.2013.04.003. PMID: 23660475
Lee JY, Yang HJ, Kim JM, Jeon BS
Parkinsonism Relat Disord 2013 Dec;19(12):1156-9. Epub 2013 Sep 7 doi: 10.1016/j.parkreldis.2013.08.003. PMID: 24018121
Opladen T, Abu Seda B, Rassi A, Thöny B, Hoffmann GF, Blau N
J Inherit Metab Dis 2011 Jun;34(3):819-26. Epub 2011 Mar 17 doi: 10.1007/s10545-011-9300-1. PMID: 21416196
Opladen T, Hoffmann G, Hörster F, Hinz AB, Neidhardt K, Klein C, Wolf N
Mov Disord 2011 Jan;26(1):157-61. Epub 2010 Sep 3 doi: 10.1002/mds.23329. PMID: 20818608
Niederwieser A, Blau N, Wang M, Joller P, Atarés M, Cardesa-Garcia J
Eur J Pediatr 1984 Feb;141(4):208-14. doi: 10.1007/BF00572762. PMID: 6734669

Prognosis

Himmelreich N, Blau N, Thöny B
Mol Genet Metab 2021 Jun;133(2):123-136. Epub 2021 Apr 19 doi: 10.1016/j.ymgme.2021.04.003. PMID: 33903016
Gundorova P, Kuznetcova IA, Baydakova GV, Stepanova AA, Itkis YS, Kakaulina VS, Alferova IP, Lyazina LV, Andreeva LP, Kanivets I, Zakharova EY, Kutsev SI, Polyakov AV
PLoS One 2021;16(4):e0249608. Epub 2021 Apr 6 doi: 10.1371/journal.pone.0249608. PMID: 33822819Free PMC Article
Opladen T, Hoffmann G, Hörster F, Hinz AB, Neidhardt K, Klein C, Wolf N
Mov Disord 2011 Jan;26(1):157-61. Epub 2010 Sep 3 doi: 10.1002/mds.23329. PMID: 20818608

Clinical prediction guides

Jiang X, Shao Y, Liao Y, Zheng X, Peng M, Cai Y, Wang M, Liu H, Zeng C, Lin Y, Zhang W, Liu L
Eur J Pharmacol 2024 Mar 15;967:176379. Epub 2024 Feb 10 doi: 10.1016/j.ejphar.2024.176379. PMID: 38342361
Himmelreich N, Blau N, Thöny B
Mol Genet Metab 2021 Jun;133(2):123-136. Epub 2021 Apr 19 doi: 10.1016/j.ymgme.2021.04.003. PMID: 33903016
Opladen T, Hoffmann GF, Kühn AA, Blau N
Mol Genet Metab 2013 Mar;108(3):195-7. Epub 2013 Jan 12 doi: 10.1016/j.ymgme.2013.01.001. PMID: 23375473
Niederwieser A, Blau N, Wang M, Joller P, Atarés M, Cardesa-Garcia J
Eur J Pediatr 1984 Feb;141(4):208-14. doi: 10.1007/BF00572762. PMID: 6734669

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • ACMG ACT, 2022
      American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated Phenylalanine, Phenylalanine hydroxylase deficiency (PAH), 2022
    • ACMG Algorithm, 2022
      American College of Medical Genetics and Genomics, Algorithm, PAH deficiency: Elevated Phenylalanine, 2022

    Recent activity

    Your browsing activity is empty.

    Activity recording is turned off.

    Turn recording back on

    See more...