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Dihydropteridine reductase deficiency(HPABH4C)

MedGen UID:
75682
Concept ID:
C0268465
Disease or Syndrome
Synonyms: BH4-Deficient Hyperphenylalaninemia C; HPABH4C; Hyperphenylalaninemia due to dihydropteridine reductase deficiency; Hyperphenylalaninemia, BH-4-deficient, C; HYPERPHENYLALANINEMIA, TETRAHYDROBIOPTERIN-DEFICIENT, DUE TO DHPR DEFICIENCY; Phenylketonuria II; Phenylketonuria type 2; Quinoid dihydropteridine reductase deficiency
SNOMED CT: DHPR - Dihydropteridine reductase deficiency (58256000); Dihydropteridine reductase deficiency (58256000); Atypical phenylketonuria (58256000); DHPR deficiency (58256000); Hyperphenylalaninemia, type IV (58256000); Atypical PKU (58256000); Phenylketonuria II (58256000)
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): QDPR (4p15.32)
 
Monarch Initiative: MONDO:0009862
OMIM®: 261630
Orphanet: ORPHA226

Definition

Tetrahydrobiopterin deficiency is a rare disorder characterized by a shortage (deficiency) of a molecule called tetrahydrobiopterin or BH4. This condition alters the levels of several substances in the body, including phenylalanine. Phenylalanine is a building block of proteins (an amino acid) that is obtained through the diet. It is found in foods that contain protein and in some artificial sweeteners. High levels of phenylalanine are present from early infancy in people with untreated tetrahydrobiopterin deficiency. This condition also alters the levels of chemicals called neurotransmitters, which transmit signals between nerve cells in the brain.

Infants with tetrahydrobiopterin deficiency appear normal at birth, but medical problems ranging from mild to severe become apparent over time. Signs and symptoms of this condition can include intellectual disability, progressive problems with development, movement disorders, difficulty swallowing, seizures, behavioral problems, and an inability to control body temperature. [from MedlinePlus Genetics]

Clinical features

From HPO
Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
Difficulty in swallowing.
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.
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Finding
Very brief, involuntary random muscular contractions occurring at rest, in response to sensory stimuli, or accompanying voluntary movements.
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.
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.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Hypertonia
MedGen UID:
10132
Concept ID:
C0026826
Finding
A condition in which there is increased muscle tone so that arms or legs, for example, are stiff and difficult to move.
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.
Cerebral calcification
MedGen UID:
124360
Concept ID:
C0270685
Finding
The presence of calcium deposition within the cerebrum.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
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.
Diminished tissue dihydropteridine reductase activity
MedGen UID:
1054414
Concept ID:
CN378318
Finding
Concentration or activity of dihydropteridine reductase (EC 1.6.99.7) below the lower limit of normal. This enzyme can be measured in multiple tissues including leukocytes and erythrocytes.
Excessive salivation
MedGen UID:
11419
Concept ID:
C0037036
Disease or Syndrome
Excessive production of saliva.

Professional guidelines

PubMed

Mastrangelo M
Metab Brain Dis 2021 Jan;36(1):29-43. Epub 2020 Oct 23 doi: 10.1007/s11011-020-00635-x. PMID: 33095372
Opladen T, López-Laso E, Cortès-Saladelafont E, Pearson TS, Sivri HS, Yildiz Y, Assmann B, Kurian MA, Leuzzi V, Heales S, Pope S, Porta F, García-Cazorla A, Honzík T, Pons R, Regal L, Goez H, Artuch R, Hoffmann GF, Horvath G, Thöny B, Scholl-Bürgi S, Burlina A, Verbeek MM, Mastrangelo M, Friedman J, Wassenberg T, Jeltsch K, Kulhánek J, Kuseyri Hübschmann O; International Working Group on Neurotransmitter related Disorders (iNTD)
Orphanet J Rare Dis 2020 May 26;15(1):126. doi: 10.1186/s13023-020-01379-8. PMID: 32456656Free PMC Article
Ponzone A, Spada M, Ferraris S, Dianzani I, de Sanctis L
Med Res Rev 2004 Mar;24(2):127-50. doi: 10.1002/med.10055. PMID: 14705166

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

Lokhande RV, Dherai AJ, Bhagure GR, Udani VP, Kulkarni SD, Ashavaid TF
Indian J Pediatr 2021 Dec;88(12):1241-1243. Epub 2021 Sep 20 doi: 10.1007/s12098-021-03956-6. PMID: 34541626
Kuseyri Hübschmann O, Mohr A, Friedman J, Manti F, Horvath G, Cortès-Saladelafont E, Mercimek-Andrews S, Yildiz Y, Pons R, Kulhánek J, Oppebøen M, Koht JA, Podzamczer-Valls I, Domingo-Jimenez R, Ibáñez S, Alcoverro-Fortuny O, Gómez-Alemany T, de Castro P, Alfonsi C, Zafeiriou DI, López-Laso E, Guder P, Santer R, Honzík T, Hoffmann GF, Garbade SF, Sivri HS, Leuzzi V, Jeltsch K, García-Cazorla A, Opladen T; International Working Group on Neurotransmitter Related Disorders (iNTD), Harting I
J Inherit Metab Dis 2021 Jul;44(4):1070-1082. Epub 2021 Jan 28 doi: 10.1002/jimd.12360. PMID: 33443316
Opladen T, López-Laso E, Cortès-Saladelafont E, Pearson TS, Sivri HS, Yildiz Y, Assmann B, Kurian MA, Leuzzi V, Heales S, Pope S, Porta F, García-Cazorla A, Honzík T, Pons R, Regal L, Goez H, Artuch R, Hoffmann GF, Horvath G, Thöny B, Scholl-Bürgi S, Burlina A, Verbeek MM, Mastrangelo M, Friedman J, Wassenberg T, Jeltsch K, Kulhánek J, Kuseyri Hübschmann O; International Working Group on Neurotransmitter related Disorders (iNTD)
Orphanet J Rare Dis 2020 May 26;15(1):126. doi: 10.1186/s13023-020-01379-8. PMID: 32456656Free PMC Article
Lu DY, Ye J, Han LS, Qiu WJ, Zhang HW, Zhou JD, Bao PZ, Zhang YF, Gu XF
World J Pediatr 2014 Aug;10(3):219-26. Epub 2014 Aug 15 doi: 10.1007/s12519-014-0496-7. PMID: 25124972
Ponzone A, Spada M, Ferraris S, Dianzani I, de Sanctis L
Med Res Rev 2004 Mar;24(2):127-50. doi: 10.1002/med.10055. PMID: 14705166

Diagnosis

Lokhande RV, Dherai AJ, Bhagure GR, Udani VP, Kulkarni SD, Ashavaid TF
Indian J Pediatr 2021 Dec;88(12):1241-1243. Epub 2021 Sep 20 doi: 10.1007/s12098-021-03956-6. PMID: 34541626
Opladen T, López-Laso E, Cortès-Saladelafont E, Pearson TS, Sivri HS, Yildiz Y, Assmann B, Kurian MA, Leuzzi V, Heales S, Pope S, Porta F, García-Cazorla A, Honzík T, Pons R, Regal L, Goez H, Artuch R, Hoffmann GF, Horvath G, Thöny B, Scholl-Bürgi S, Burlina A, Verbeek MM, Mastrangelo M, Friedman J, Wassenberg T, Jeltsch K, Kulhánek J, Kuseyri Hübschmann O; International Working Group on Neurotransmitter related Disorders (iNTD)
Orphanet J Rare Dis 2020 May 26;15(1):126. doi: 10.1186/s13023-020-01379-8. PMID: 32456656Free PMC Article
Pearl PL
Handb Clin Neurol 2013;113:1819-25. doi: 10.1016/B978-0-444-59565-2.00051-4. PMID: 23622404
Ramaekers VT, Blau N
Dev Med Child Neurol 2004 Dec;46(12):843-51. doi: 10.1017/s0012162204001471. PMID: 15581159
Ponzone A, Spada M, Ferraris S, Dianzani I, de Sanctis L
Med Res Rev 2004 Mar;24(2):127-50. doi: 10.1002/med.10055. PMID: 14705166

Therapy

Opladen T, López-Laso E, Cortès-Saladelafont E, Pearson TS, Sivri HS, Yildiz Y, Assmann B, Kurian MA, Leuzzi V, Heales S, Pope S, Porta F, García-Cazorla A, Honzík T, Pons R, Regal L, Goez H, Artuch R, Hoffmann GF, Horvath G, Thöny B, Scholl-Bürgi S, Burlina A, Verbeek MM, Mastrangelo M, Friedman J, Wassenberg T, Jeltsch K, Kulhánek J, Kuseyri Hübschmann O; International Working Group on Neurotransmitter related Disorders (iNTD)
Orphanet J Rare Dis 2020 May 26;15(1):126. doi: 10.1186/s13023-020-01379-8. PMID: 32456656Free PMC Article
Trefz F, Lichtenberger O, Blau N, Muntau AC, Feillet F, Bélanger-Quintana A, van Spronsen F, Munafo A
Mol Genet Metab 2015 Apr;114(4):564-9. Epub 2015 Feb 7 doi: 10.1016/j.ymgme.2015.01.013. PMID: 25726095
Porta F, Mussa A, Concolino D, Spada M, Ponzone A
Mol Genet Metab 2012 Apr;105(4):582-4. Epub 2012 Jan 25 doi: 10.1016/j.ymgme.2012.01.013. PMID: 22325981
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
Woody RC, Brewster MA, Glasier C
Neurology 1989 May;39(5):673-5. doi: 10.1212/wnl.39.5.673. PMID: 2785251

Prognosis

Trefz F, Lichtenberger O, Blau N, Muntau AC, Feillet F, Bélanger-Quintana A, van Spronsen F, Munafo A
Mol Genet Metab 2015 Apr;114(4):564-9. Epub 2015 Feb 7 doi: 10.1016/j.ymgme.2015.01.013. PMID: 25726095
Lu DY, Ye J, Han LS, Qiu WJ, Zhang HW, Zhou JD, Bao PZ, Zhang YF, Gu XF
World J Pediatr 2014 Aug;10(3):219-26. Epub 2014 Aug 15 doi: 10.1007/s12519-014-0496-7. PMID: 25124972
Shintaku H, Ohwada M
Brain Dev 2013 May;35(5):406-10. Epub 2012 Jul 24 doi: 10.1016/j.braindev.2012.06.010. PMID: 22832064
Ponzone A, Spada M, Ferraris S, Dianzani I, de Sanctis L
Med Res Rev 2004 Mar;24(2):127-50. doi: 10.1002/med.10055. PMID: 14705166
Coşkun T, Besim A, Ozalp I, Eryilmaz M
Turk J Pediatr 1990 Oct-Dec;32(4):259-64. PMID: 2135679

Clinical prediction guides

Batllori M, Molero-Luis M, Arrabal L, Heras JL, Fernandez-Ramos JA, Gutiérrez-Solana LG, Ibáñez-Micó S, Domingo R, Campistol J, Ormazabal A, Sedel F, Opladen T, Zouvelou B, Pons R, Garcia-Cazorla A, Lopez-Laso E, Artuch R
Sci Rep 2017 Nov 7;7(1):14675. doi: 10.1038/s41598-017-15063-8. PMID: 29116116Free PMC Article
Shintaku H, Ohwada M
Brain Dev 2013 May;35(5):406-10. Epub 2012 Jul 24 doi: 10.1016/j.braindev.2012.06.010. PMID: 22832064
Porta F, Mussa A, Concolino D, Spada M, Ponzone A
Mol Genet Metab 2012 Apr;105(4):582-4. Epub 2012 Jan 25 doi: 10.1016/j.ymgme.2012.01.013. PMID: 22325981
Ramaekers VT, Blau N
Dev Med Child Neurol 2004 Dec;46(12):843-51. doi: 10.1017/s0012162204001471. PMID: 15581159
Ponzone A, Guardamagna O, Dianzani I, Ponzone R, Ferrero GB, Spada M, Cotton RG
Pediatr Res 1993 Feb;33(2):125-8. doi: 10.1203/00006450-199302000-00007. PMID: 8433887

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.
    • Bookshelf
      See practice and clinical guidelines in NCBI Bookshelf. 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

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