U.S. flag

An official website of the United States government

Format

Send to:

Choose Destination

Mild hyperphenylalaninemia

MedGen UID:
1843033
•Concept ID:
C5680207
•
Disease or Syndrome
Synonyms: mHPA; Mild HPA; mild HPA; mild hyperphenylalaninemia; Non-PKU HPA; non-PKU HPA
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).
Autosomal recessive inheritance (Orphanet)
 
Monarch Initiative: MONDO:0019335
Orphanet: ORPHA79651

Definition

A rare form of phenylketonuria, an inborn error of amino acid metabolism, characterized by blood phenylalanine (Phe) concentrations of 120-600 micromol/L with or without clinical manifestations of impaired cognitive function, and behavioral and developmental disorders. [from ORDO]

Professional guidelines

PubMed

Assessment of Pathogenic Variants in the PAH Gene and Genotype-Phenotype Correlation in Phenylketonuria Patients from Turkey.
Balasar Ö, Kadıoğlu Yılmaz B, Başdemirci M, Koçak Eker H, Eser Çavdartepe B, Şimşek L, Tunçez E, Duymuş F
Biochem Genet 2025 Feb;63(1):896-905. Epub 2024 Jul 22 doi: 10.1007/s10528-024-10892-5. PMID: 39039323
Relationship between genotype, phenylalanine hydroxylase expression and in vitro activity and metabolic phenotype in phenylketonuria.
Himmelreich N, Shen N, Okun JG, Thiel C, Hoffmann GF, Blau N
Mol Genet Metab 2018 Sep;125(1-2):86-95. Epub 2018 Jun 23 doi: 10.1016/j.ymgme.2018.06.011. PMID: 30037505
Molecular epidemiology, genotype-phenotype correlation and BH4 responsiveness in Spanish patients with phenylketonuria.
Aldámiz-Echevarría L, Llarena M, Bueno MA, Dalmau J, Vitoria I, Fernández-Marmiesse A, Andrade F, Blasco J, Alcalde C, Gil D, García MC, González-Lamuño D, Ruiz M, Ruiz MA, Peña-Quintana L, González D, Sánchez-Valverde F, Desviat LR, Pérez B, Couce ML
J Hum Genet 2016 Aug;61(8):731-44. Epub 2016 Apr 28 doi: 10.1038/jhg.2016.38. PMID: 27121329

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

Cognitive function in untreated subjects with mild hyperphenylalaninemia: a systematic review.
Rostampour N, Chegini R, Hovsepian S, Zamaneh F, Hashemipour M
Neurol Sci 2022 Sep;43(9):5593-5603. Epub 2022 Jun 21 doi: 10.1007/s10072-022-06194-6. PMID: 35729439
Phenylalanine hydroxylase deficiency in the Slovak population: genotype-phenotype correlations and genotype-based predictions of BH4-responsiveness.
Polak E, Ficek A, Radvanszky J, Soltysova A, Urge O, Cmelova E, Kantarska D, Kadasi L
Gene 2013 Sep 10;526(2):347-55. Epub 2013 Jun 10 doi: 10.1016/j.gene.2013.05.057. PMID: 23764561
Phenylalanine hydroxylase deficiency.
Mitchell JJ, Trakadis YJ, Scriver CR
Genet Med 2011 Aug;13(8):697-707. doi: 10.1097/GIM.0b013e3182141b48. PMID: 21555948
Five human phenylalanine hydroxylase proteins identified in mild hyperphenylalaninemia patients are disease-causing variants.
Daniele A, Cardillo G, Pennino C, Carbone MT, Scognamiglio D, Esposito L, Correra A, Castaldo G, Zagari A, Salvatore F
Biochim Biophys Acta 2008 Jun;1782(6):378-84. Epub 2008 Feb 20 doi: 10.1016/j.bbadis.2008.01.012. PMID: 18346471
"Hypotyrosinemia" in phenylketonuria.
Hanley WB, Lee AW, Hanley AJ, Lehotay DC, Austin VJ, Schoonheyt WE, Platt BA, Clarke JT
Mol Genet Metab 2000 Apr;69(4):286-94. doi: 10.1006/mgme.2000.2985. PMID: 10870846

Diagnosis

Neurotransmitters Disorders with Mild Hyperphenylalaninemia: The Ones That Should Not Be Missed.
Thoalnoon OA, Kareem AA, Hammoodi HZ
Arch Razi Inst 2023 Apr;78(2):667-673. Epub 2023 Apr 30 doi: 10.22092/ARI.2022.359480.2431. PMID: 37396747Free PMC Article
Variations in genotype-phenotype correlations in phenylalanine hydroxylase deficiency in Chinese Han population.
Zhu T, Ye J, Han L, Qiu W, Zhang H, Liang L, Gu X
Gene 2013 Oct 15;529(1):80-7. Epub 2013 Aug 7 doi: 10.1016/j.gene.2013.07.079. PMID: 23932990
Phenylalanine hydroxylase deficiency in the Slovak population: genotype-phenotype correlations and genotype-based predictions of BH4-responsiveness.
Polak E, Ficek A, Radvanszky J, Soltysova A, Urge O, Cmelova E, Kantarska D, Kadasi L
Gene 2013 Sep 10;526(2):347-55. Epub 2013 Jun 10 doi: 10.1016/j.gene.2013.05.057. PMID: 23764561
Phenylalanine hydroxylase deficiency.
Mitchell JJ, Trakadis YJ, Scriver CR
Genet Med 2011 Aug;13(8):697-707. doi: 10.1097/GIM.0b013e3182141b48. PMID: 21555948
Tetrahydrobiopterin deficiencies: preliminary analysis from an international survey.
Dhondt JL
J Pediatr 1984 Apr;104(4):501-8. doi: 10.1016/s0022-3476(84)80537-5. PMID: 6142937

Therapy

Neurotransmitters Disorders with Mild Hyperphenylalaninemia: The Ones That Should Not Be Missed.
Thoalnoon OA, Kareem AA, Hammoodi HZ
Arch Razi Inst 2023 Apr;78(2):667-673. Epub 2023 Apr 30 doi: 10.22092/ARI.2022.359480.2431. PMID: 37396747Free PMC Article
Phenylketonuric diet negatively impacts on butyrate production.
Verduci E, Moretti F, Bassanini G, Banderali G, Rovelli V, Casiraghi MC, Morace G, Borgo F, Borghi E
Nutr Metab Cardiovasc Dis 2018 Apr;28(4):385-392. Epub 2018 Jan 31 doi: 10.1016/j.numecd.2018.01.004. PMID: 29502926
Variations in genotype-phenotype correlations in phenylalanine hydroxylase deficiency in Chinese Han population.
Zhu T, Ye J, Han L, Qiu W, Zhang H, Liang L, Gu X
Gene 2013 Oct 15;529(1):80-7. Epub 2013 Aug 7 doi: 10.1016/j.gene.2013.07.079. PMID: 23932990
Phenylalanine hydroxylase deficiency in the Slovak population: genotype-phenotype correlations and genotype-based predictions of BH4-responsiveness.
Polak E, Ficek A, Radvanszky J, Soltysova A, Urge O, Cmelova E, Kantarska D, Kadasi L
Gene 2013 Sep 10;526(2):347-55. Epub 2013 Jun 10 doi: 10.1016/j.gene.2013.05.057. PMID: 23764561
Phenylalanine hydroxylase deficiency.
Mitchell JJ, Trakadis YJ, Scriver CR
Genet Med 2011 Aug;13(8):697-707. doi: 10.1097/GIM.0b013e3182141b48. PMID: 21555948

Prognosis

The Genetic Landscape and Epidemiology of Phenylketonuria.
Hillert A, Anikster Y, Belanger-Quintana A, Burlina A, Burton BK, Carducci C, Chiesa AE, Christodoulou J, Đorđević M, Desviat LR, Eliyahu A, Evers RAF, Fajkusova L, Feillet F, Bonfim-Freitas PE, Giżewska M, Gundorova P, Karall D, Kneller K, Kutsev SI, Leuzzi V, Levy HL, Lichter-Konecki U, Muntau AC, Namour F, Oltarzewski M, Paras A, Perez B, Polak E, Polyakov AV, Porta F, Rohrbach M, Scholl-Bürgi S, Spécola N, Stojiljković M, Shen N, Santana-da Silva LC, Skouma A, van Spronsen F, Stoppioni V, Thöny B, Trefz FK, Vockley J, Yu Y, Zschocke J, Hoffmann GF, Garbade SF, Blau N
Am J Hum Genet 2020 Aug 6;107(2):234-250. Epub 2020 Jul 14 doi: 10.1016/j.ajhg.2020.06.006. PMID: 32668217Free PMC Article
Variations in genotype-phenotype correlations in phenylalanine hydroxylase deficiency in Chinese Han population.
Zhu T, Ye J, Han L, Qiu W, Zhang H, Liang L, Gu X
Gene 2013 Oct 15;529(1):80-7. Epub 2013 Aug 7 doi: 10.1016/j.gene.2013.07.079. PMID: 23932990
Phenylalanine hydroxylase deficiency in the Slovak population: genotype-phenotype correlations and genotype-based predictions of BH4-responsiveness.
Polak E, Ficek A, Radvanszky J, Soltysova A, Urge O, Cmelova E, Kantarska D, Kadasi L
Gene 2013 Sep 10;526(2):347-55. Epub 2013 Jun 10 doi: 10.1016/j.gene.2013.05.057. PMID: 23764561
Genotype-phenotype correlations analysis of mutations in the phenylalanine hydroxylase (PAH) gene.
Bercovich D, Elimelech A, Zlotogora J, Korem S, Yardeni T, Gal N, Goldstein N, Vilensky B, Segev R, Avraham S, Loewenthal R, Schwartz G, Anikster Y
J Hum Genet 2008;53(5):407-418. Epub 2008 Feb 26 doi: 10.1007/s10038-008-0264-4. PMID: 18299955
Mild hyperphenylalaninemia and heterozygosity of the phenylalanine hydroxylase gene.
Koch R, Güttler F, Guldberg P, Rouse B
Mol Genet Metab 1998 Feb;63(2):148-50. doi: 10.1006/mgme.1997.2619. PMID: 9562969

Clinical prediction guides

The Genetic Landscape and Epidemiology of Phenylketonuria.
Hillert A, Anikster Y, Belanger-Quintana A, Burlina A, Burton BK, Carducci C, Chiesa AE, Christodoulou J, Đorđević M, Desviat LR, Eliyahu A, Evers RAF, Fajkusova L, Feillet F, Bonfim-Freitas PE, Giżewska M, Gundorova P, Karall D, Kneller K, Kutsev SI, Leuzzi V, Levy HL, Lichter-Konecki U, Muntau AC, Namour F, Oltarzewski M, Paras A, Perez B, Polak E, Polyakov AV, Porta F, Rohrbach M, Scholl-Bürgi S, Spécola N, Stojiljković M, Shen N, Santana-da Silva LC, Skouma A, van Spronsen F, Stoppioni V, Thöny B, Trefz FK, Vockley J, Yu Y, Zschocke J, Hoffmann GF, Garbade SF, Blau N
Am J Hum Genet 2020 Aug 6;107(2):234-250. Epub 2020 Jul 14 doi: 10.1016/j.ajhg.2020.06.006. PMID: 32668217Free PMC Article
Long-Term Growth in Phenylketonuria: A Systematic Review and Meta-Analysis.
Ilgaz F, Pinto A, Gökmen-Özel H, Rocha JC, van Dam E, Ahring K, Bélanger-Quintana A, Dokoupil K, Karabulut E, MacDonald A
Nutrients 2019 Sep 3;11(9) doi: 10.3390/nu11092070. PMID: 31484352Free PMC Article
Variations in genotype-phenotype correlations in phenylalanine hydroxylase deficiency in Chinese Han population.
Zhu T, Ye J, Han L, Qiu W, Zhang H, Liang L, Gu X
Gene 2013 Oct 15;529(1):80-7. Epub 2013 Aug 7 doi: 10.1016/j.gene.2013.07.079. PMID: 23932990
Phenylalanine hydroxylase deficiency in the Slovak population: genotype-phenotype correlations and genotype-based predictions of BH4-responsiveness.
Polak E, Ficek A, Radvanszky J, Soltysova A, Urge O, Cmelova E, Kantarska D, Kadasi L
Gene 2013 Sep 10;526(2):347-55. Epub 2013 Jun 10 doi: 10.1016/j.gene.2013.05.057. PMID: 23764561
Genotype-phenotype correlations analysis of mutations in the phenylalanine hydroxylase (PAH) gene.
Bercovich D, Elimelech A, Zlotogora J, Korem S, Yardeni T, Gal N, Goldstein N, Vilensky B, Segev R, Avraham S, Loewenthal R, Schwartz G, Anikster Y
J Hum Genet 2008;53(5):407-418. Epub 2008 Feb 26 doi: 10.1007/s10038-008-0264-4. PMID: 18299955

Recent systematic reviews

Morphofunctional Assessment beyond Malnutrition: Fat Mass Assessment in Adult Patients with Phenylketonuria-Systematic Review.
Luengo-Pérez LM, Fernández-Bueso M, Guzmán-Carmona C, López-Navia A, García-Lobato C
Nutrients 2024 Jun 11;16(12) doi: 10.3390/nu16121833. PMID: 38931188Free PMC Article
Cognitive function in untreated subjects with mild hyperphenylalaninemia: a systematic review.
Rostampour N, Chegini R, Hovsepian S, Zamaneh F, Hashemipour M
Neurol Sci 2022 Sep;43(9):5593-5603. Epub 2022 Jun 21 doi: 10.1007/s10072-022-06194-6. PMID: 35729439
Long-Term Growth in Phenylketonuria: A Systematic Review and Meta-Analysis.
Ilgaz F, Pinto A, Gökmen-Özel H, Rocha JC, van Dam E, Ahring K, Bélanger-Quintana A, Dokoupil K, Karabulut E, MacDonald A
Nutrients 2019 Sep 3;11(9) doi: 10.3390/nu11092070. PMID: 31484352Free PMC Article
Phenylketonuria mutations in Europe.
Zschocke J
Hum Mutat 2003 Apr;21(4):345-56. doi: 10.1002/humu.10192. PMID: 12655544

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

    Reviews

    Related information

    • ClinVar
      Related medical variations
    • PMC Articles
      Related information in PubMed Central Links
    • PubMed
      Related literature resources in PubMed

    Recent activity

    Clear Turn Off Turn On

    Your browsing activity is empty.

    Activity recording is turned off.

    Turn recording back on

    See more...