Clinical, Genetic, and Experimental Research of Hyperphenylalaninemia

Overview

Journal Front Genet

Date 2023 Jan 23

PMID 36685931

Authors

Anqi Chen

Yukun Pan

Jinzhong Chen

Affiliations

Soon will be listed here.

Abstract

Hyperphenylalaninemia (HPA) is the most common amino acid metabolism defect in humans. It is an autosomal-recessive disorder of the phenylalanine (Phe) metabolism, in which high Phe concentrations and low tyrosine (Tyr) concentrations in the blood cause phenylketonuria (PKU), brain dysfunction, light pigmentation and musty odor. Newborn screening data of HPA have revealed that the prevalence varies worldwide, with an average of 1:10,000. Most cases of HPA result from phenylalanine hydroxylase (PAH) deficiency, while a small number of HPA are caused by defects in the tetrahydrobiopterin (BH4) metabolism and DnaJ heat shock protein family (Hsp40) member C12 (DNAJC12) deficiency. Currently, the molecular pathophysiology of the neuropathology associated with HPA remains incompletely understood. Dietary restriction of Phe has been highly successful, although outcomes are still suboptimal and patients find it difficult to adhere to the treatment. Pharmacological treatments, such as BH4 and phenylalanine ammonia lyase, are available. Gene therapy for HPA is still in development.

Citing Articles

Impaired cognitive function and decreased monoamine neurotransmitters in the DNAJC12 gene knockout mouse model.

Wang S, Shen M, Pang B, Zhou B, Yuan Y, Lu M Orphanet J Rare Dis. 2025; 20(1):60.

PMID: 39923104 PMC: 11806585. DOI: 10.1186/s13023-025-03580-z.

A Rare Combination of Compound Heterozygous Mutations in the Gene in Three Unrelated Consanguineous Iranian Families with Classical Phenylketonuria.

Rahimzadeh A, Khosravi T, Motallebi F, Al Sudani Z, Vaghefi F, Kowsari A Adv Biomed Res. 2024; 13:64.

PMID: 39434944 PMC: 11493218. DOI: 10.4103/abr.abr_471_23.

Assessment of Pathogenic Variants in the PAH Gene and Genotype-Phenotype Correlation in Phenylketonuria Patients from Turkey.

Balasar O, Kadioglu Yilmaz B, Basdemirci M, Eker H, Eser Cavdartepe B, Simsek L Biochem Genet. 2024; 63(1):896-905.

PMID: 39039323 DOI: 10.1007/s10528-024-10892-5.

PAH deficient pathology in humanized c.1066-11G>A phenylketonuria mice.

Martinez-Pizarro A, Pico S, Lopez-Marquez A, Rodriguez-Lopez C, Montalvo E, Alvarez M Hum Mol Genet. 2024; 33(12):1074-1089.

PMID: 38520741 PMC: 11153335. DOI: 10.1093/hmg/ddae051.

Splice-Modulating Antisense Oligonucleotides as Therapeutics for Inherited Metabolic Diseases.

Chen S, Heendeniya S, Le B, Rahimizadeh K, Rabiee N, Zahra Q BioDrugs. 2024; 38(2):177-203.

PMID: 38252341 PMC: 10912209. DOI: 10.1007/s40259-024-00644-7.

References

Evers R, van Wegberg A, Anjema K, Lubout C, van Dam E, van Vliet D . The first European guidelines on phenylketonuria: Usefulness and implications for BH responsiveness testing. J Inherit Metab Dis. 2019; 43(2):244-250. DOI: 10.1002/jimd.12173. View

Mendell J, Al-Zaidy S, Shell R, Arnold W, Rodino-Klapac L, Prior T . Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. N Engl J Med. 2017; 377(18):1713-1722. DOI: 10.1056/NEJMoa1706198. View

Burlina A, Cazzorla C, Massa P, Loro C, Gueraldi D, Burlina A . The Impact of a Slow-Release Large Neutral Amino Acids Supplement on Treatment Adherence in Adult Patients with Phenylketonuria. Nutrients. 2020; 12(7). PMC: 7400920. DOI: 10.3390/nu12072078. View

JERVIS G . Studies on phenylpyruvic oligophrenia; phenylpyruvic acid content on blood. Proc Soc Exp Biol Med. 1952; 81(3):715-20. DOI: 10.3181/00379727-81-19998. View

SHEFER S, Tint G, Daikhin E, Kendler A, Nguyen L, Yudkoff M . Is there a relationship between 3-hydroxy-3-methylglutaryl coenzyme a reductase activity and forebrain pathology in the PKU mouse?. J Neurosci Res. 2000; 61(5):549-63. DOI: 10.1002/1097-4547(20000901)61:5<549::AID-JNR10>3.0.CO;2-0. View

Rebuffat A, Harding C, Ding Z, Thony B . Comparison of adeno-associated virus pseudotype 1, 2, and 8 vectors administered by intramuscular injection in the treatment of murine phenylketonuria. Hum Gene Ther. 2009; 21(4):463-77. PMC: 2865356. DOI: 10.1089/hum.2009.127. View

Sun W, Zheng W, Simeonov A . Drug discovery and development for rare genetic disorders. Am J Med Genet A. 2017; 173(9):2307-2322. PMC: 5662129. DOI: 10.1002/ajmg.a.38326. View

Xiang L, Tao J, Deng K, Li X, Li Q, Yuan X . Phenylketonuria incidence in China between 2013 and 2017 based on data from the Chinese newborn screening information system: a descriptive study. BMJ Open. 2019; 9(8):e031474. PMC: 6707664. DOI: 10.1136/bmjopen-2019-031474. View

van Vliet D, Bruinenberg V, Mazzola P, van Faassen M, Blaauw P, Pascucci T . Therapeutic brain modulation with targeted large neutral amino acid supplements in the Pah-enu2 phenylketonuria mouse model. Am J Clin Nutr. 2016; 104(5):1292-1300. DOI: 10.3945/ajcn.116.135996. View

10.

Sarkissian C, Shao Z, Blain F, Peevers R, Su H, Heft R . A different approach to treatment of phenylketonuria: phenylalanine degradation with recombinant phenylalanine ammonia lyase. Proc Natl Acad Sci U S A. 1999; 96(5):2339-44. PMC: 26785. DOI: 10.1073/pnas.96.5.2339. View

11.

Dobrowolski S, Lyons-Weiler J, Spridik K, Vockley J, Skvorak K, Biery A . DNA methylation in the pathophysiology of hyperphenylalaninemia in the PAH(enu2) mouse model of phenylketonuria. Mol Genet Metab. 2016; 119(1-2):1-7. PMC: 8958364. DOI: 10.1016/j.ymgme.2016.01.001. View

12.

Anikster Y, Haack T, Vilboux T, Pode-Shakked B, Thony B, Shen N . Biallelic Mutations in DNAJC12 Cause Hyperphenylalaninemia, Dystonia, and Intellectual Disability. Am J Hum Genet. 2017; 100(2):257-266. PMC: 5294665. DOI: 10.1016/j.ajhg.2017.01.002. View

13.

van Spronsen F, Himmelreich N, Rufenacht V, Shen N, van Vliet D, Al-Owain M . Heterogeneous clinical spectrum of DNAJC12-deficient hyperphenylalaninemia: from attention deficit to severe dystonia and intellectual disability. J Med Genet. 2017; . DOI: 10.1136/jmedgenet-2017-104875. View

14.

Scriver C . A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants, by Robert Guthrie and Ada Susi, Pediatrics, 1963;32:318-343. Pediatrics. 1998; 102(1 Pt 2):236-7. View

15.

Longo N, Harding C, Burton B, Grange D, Vockley J, Wasserstein M . Single-dose, subcutaneous recombinant phenylalanine ammonia lyase conjugated with polyethylene glycol in adult patients with phenylketonuria: an open-label, multicentre, phase 1 dose-escalation trial. Lancet. 2014; 384(9937):37-44. PMC: 4447208. DOI: 10.1016/S0140-6736(13)61841-3. View

16.

Garbade S, Shen N, Himmelreich N, Haas D, Trefz F, Hoffmann G . Allelic phenotype values: a model for genotype-based phenotype prediction in phenylketonuria. Genet Med. 2018; 21(3):580-590. DOI: 10.1038/s41436-018-0081-x. View

17.

Winn S, Scherer T, Thony B, Harding C . High dose sapropterin dihydrochloride therapy improves monoamine neurotransmitter turnover in murine phenylketonuria (PKU). Mol Genet Metab. 2015; 117(1):5-11. PMC: 4706464. DOI: 10.1016/j.ymgme.2015.11.012. View

18.

Pogue R, Cavalcanti D, Shanker S, Andrade R, Aguiar L, de Carvalho J . Rare genetic diseases: update on diagnosis, treatment and online resources. Drug Discov Today. 2017; 23(1):187-195. DOI: 10.1016/j.drudis.2017.11.002. View

19.

Wang D, Tai P, Gao G . Adeno-associated virus vector as a platform for gene therapy delivery. Nat Rev Drug Discov. 2019; 18(5):358-378. PMC: 6927556. DOI: 10.1038/s41573-019-0012-9. View

20.

Richards D, Winn S, Dudley S, Nygaard S, Mighell T, Grompe M . AAV-Mediated CRISPR/Cas9 Gene Editing in Murine Phenylketonuria. Mol Ther Methods Clin Dev. 2020; 17:234-245. PMC: 6962637. DOI: 10.1016/j.omtm.2019.12.004. View