Details of Disease

General Information of Disease (ID: DISCU56J)

• Disease Name: Phenylketonuria
• Synonyms: HPA, non-PKU mild; imbecilitus phenylpyruvica; oligophrenia phenylpyruvica; phenylpyruvic oligophrenia; phenylketonuria, maternal; oligophrenia Phenylpyruvica; PAH deficiency; phenylalanine hydroxylase deficiency; hyperphenylalaninemia, non-PKU mild; phenylalaninemia; phenylketonuria; PKU
• Disease Class: 5C50: Metabolism inborn error
• Definition: Phenylketonuria (PKU) is the most common inborn error of amino acid metabolism and is characterized by mild to severe mental disability in untreated patients.
• Disease Hierarchy:
  DISCPWH9: Autosomal recessive disease
  DISV6EQO: Disorder of phenylalanine metabolism
  DISCU56J: Phenylketonuria
• ICD Code:
  ICD-11: ICD-11: 5C50.0
  ICD-10: ICD-10: E70, E70.1
  Expand ICD-11: '5C50.0
  Expand ICD-10: 'E70; 'E70.1
• Disease Identifiers:
  MONDO ID: MONDO_0009861
  MESH ID: D010661
  UMLS CUI: C0031485
  MedGen ID: 19244
  Orphanet ID: 716
  SNOMED CT ID: 190687004

Drug-Interaction Atlas (DIA) of This Disease

This Disease is Treated as An Indication in 1 Approved Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
Pegvaliase	DM6NZ2P	Approved	NA	[1]

This Disease is Treated as An Indication in 5 Clinical Trial Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
PTC923	DMAOQO5	Phase 3	Small molecule	[2]
SYNB-1934	DMY9JA5	Phase 3	NA	[3]
BMN-307	DMY0SKM	Phase 1/2	Gene therapy	[4]
HMI-102	DM8B85Y	Phase 1/2	Gene therapy	[5]
RTX-134	DMTTBQA	Phase 1	Cell therapy	[6]

This Disease is Treated as An Indication in 1 Preclinical Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
mRNA-3283	DMSARKW	Preclinical	Vaccine	[7]

This Disease is Treated as An Indication in 2 Investigative Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
BMN-168	DM0VMZ4	Investigative	NA	[8]
Sapropterin	DM6GE21	Investigative	NA	[9]

Molecular Interaction Atlas (MIA) of This Disease

This Disease Is Related to 12 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
CACNA1A	TTX4QDJ	Limited	Biomarker	[10]
CNP	TT71P0H	Limited	Biomarker	[11]
GCH1	TTLSWP6	Limited	Biomarker	[12]
MBP	TT2RY5P	Limited	Biomarker	[13]
OTC	TT5KIO9	Limited	Biomarker	[14]
SLC38A7	TTEARWC	Limited	Biomarker	[15]
SLC7A5	TTPH2JB	Limited	Genetic Variation	[16]
HNF1A	TT01M3K	moderate	Biomarker	[17]
G6PD	TTKN8W0	Strong	Biomarker	[18]
PAM	TTF4ZPC	Strong	Biomarker	[19]
SHCBP1	TTZ9WGL	Strong	Biomarker	[19]
PAH	TTGSVH2	Definitive	Autosomal recessive	[20]

This Disease Is Related to 2 DTP Molecule(s)

Gene Name	DTP ID	Evidence Level	Mode of Inheritance	REF
SLC22A5	DT3HUVD	Limited	Genetic Variation	[21]
SLC6A19	DTOTAUP	Limited	Genetic Variation	[22]

This Disease Is Related to 2 DME Molecule(s)

Gene Name	DME ID	Evidence Level	Mode of Inheritance	REF
NAGS	DEGI1A9	Limited	Biomarker	[14]
PGM1	DEA3VM1	Limited	Genetic Variation	[23]

This Disease Is Related to 19 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
ACADM	OTA4P0FC	Limited	Biomarker	[24]
ASCC2	OT3B204T	Limited	Biomarker	[25]
COL25A1	OT7M23Z9	Limited	Genetic Variation	[23]
FARP2	OTNRQIMK	Limited	Genetic Variation	[26]
LAT	OTZC1XZ1	Limited	Genetic Variation	[16]
MMACHC	OTX0TT3W	Limited	Genetic Variation	[21]
NIF3L1	OT4MP90J	Limited	Biomarker	[27]
OAS3	OT6E5FYS	Limited	Biomarker	[25]
OLFM1	OTOYPEWW	Limited	Genetic Variation	[23]
OXCT1	OT536PE7	Limited	Genetic Variation	[28]
PCBD1	OTDSRUD5	Limited	Biomarker	[12]
PELI1	OTMLBCLC	Limited	Biomarker	[19]
PRDM6	OTKY12D9	Limited	Biomarker	[19]
QDPR	OTSKOIUX	Limited	Biomarker	[29]
NEFH	OTMSCW5I	moderate	Biomarker	[30]
LRIT1	OTNEQPMZ	Strong	Biomarker	[19]
PTS	OTTYWQXR	Strong	Biomarker	[12]
MCCD1	OTLS95WO	Definitive	Genetic Variation	[31]
PAH	OT6GT2K8	Definitive	Autosomal recessive	[20]

References

• [1] Induction, titration, and maintenance dosing regimen in a phase 2 study of pegvaliase for control of blood phenylalanine in adults with phenylketonuria.Mol Genet Metab. 2018 Nov;125(3):217-227.
• [2] ClinicalTrials.gov (NCT05099640) A Phase 3 Study of PTC923 in Subjects With Phenylketonuria. U.S.National Institutes of Health.
• [3] ClinicalTrials.gov (NCT05764239) A Phase 3, Double-blind, Placebo-controlled, Randomized Withdrawal Study to Evaluate the Efficacy and Safety of SYNB1934 in Patients With PKU (SYNPHENY-3). U.S.National Institutes of Health.
• [4] ClinicalTrials.gov (NCT04480567) A Phase 1/2 Open-Label, Dose Escalation Study to Determine the Safety and Efficacy of BMN 307, an Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Phenylalanine Hydroxylase in Subjects With Phenylketonuria. U.S.National Institutes of Health.
• [5] ClinicalTrials.gov (NCT03952156) A Phase 1/2 Open-Label, Randomized, Concurrently-Controlled, Dose Escalation Study to Evaluate the Safety and Efficacy of HMI-102 in Adult PKU Subjects With PAH Deficiency. U.S.National Institutes of Health.
• [6] ClinicalTrials.gov (NCT04110496) A Phase 1b Open-Label Single Dose Safety, Tolerability, and Pharmacokinetics Study of RTX-134 in Adults With Phenylketonuria. U.S.National Institutes of Health.
• [7] Clinical pipeline report, company report or official report of Moderna
• [8] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1240).
• [9] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [10] Spanish BH4-responsive phenylalanine hydroxylase-deficient patients: evolution of seven patients on long-term treatment with tetrahydrobiopterin.Mol Genet Metab. 2005 Dec;86 Suppl 1:S61-6. doi: 10.1016/j.ymgme.2005.07.024. Epub 2005 Sep 13.
• [11] Evidence for central nervous system glial cell plasticity in phenylketonuria.J Neuropathol Exp Neurol. 1996 Jul;55(7):795-814. doi: 10.1097/00005072-199607000-00005.
• [12] Mutation spectrum of six genes in Chinese phenylketonuria patients obtained through next-generation sequencing.PLoS One. 2014 Apr 4;9(4):e94100. doi: 10.1371/journal.pone.0094100. eCollection 2014.
• [13] A new therapy prevents intellectual disability in mouse with phenylketonuria.Mol Genet Metab. 2018 May;124(1):39-49. doi: 10.1016/j.ymgme.2018.03.009. Epub 2018 Apr 7.
• [14] Aminoacidopathies: Prevalence, Etiology, Screening, and Treatment Options.Biochem Genet. 2018 Apr;56(1-2):7-21. doi: 10.1007/s10528-017-9825-6. Epub 2017 Nov 1.
• [15] Cerebral protein synthesis in a genetic mouse model of phenylketonuria.Proc Natl Acad Sci U S A. 2000 Sep 26;97(20):11014-9. doi: 10.1073/pnas.97.20.11014.
• [16] LAT1 gene variants--potential factors influencing the clinical course of phenylketonuria.J Inherit Metab Dis. 2006 Oct;29(5):684. doi: 10.1007/s10545-006-0285-0. Epub 2006 Aug 5.
• [17] Defective insulin secretion in hepatocyte nuclear factor 1alpha-deficient mice.J Clin Invest. 1998 May 15;101(10):2215-22. doi: 10.1172/JCI2548.
• [18] Molecular newborn screening of four genetic diseases in Guizhou Province of South China.Gene. 2016 Oct 10;591(1):119-122. doi: 10.1016/j.gene.2016.07.019. Epub 2016 Jul 6.
• [19] Pegvaliase for the treatment of phenylketonuria: A pivotal, double-blind randomized discontinuation Phase 3 clinical trial.Mol Genet Metab. 2018 May;124(1):20-26. doi: 10.1016/j.ymgme.2018.03.003. Epub 2018 Mar 18.
• [20] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [21] Expanded Newborn Screening for Inborn Errors of Metabolism and Genetic Characteristics in a Chinese Population.Front Genet. 2018 Apr 20;9:122. doi: 10.3389/fgene.2018.00122. eCollection 2018.
• [22] Inhibiting neutral amino acid transport for the treatment of phenylketonuria.JCI Insight. 2018 Jul 26;3(14):e121762. doi: 10.1172/jci.insight.121762. eCollection 2018 Jul 26.
• [23] A maximum likelihood map of chromosome 1.Am J Hum Genet. 1979 Nov;31(6):680-96.
• [24] Establishing core outcome sets for phenylketonuria (PKU) and medium-chain Acyl-CoA dehydrogenase (MCAD) deficiency in children: study protocol for systematic reviews and Delphi surveys.Trials. 2017 Dec 19;18(1):603. doi: 10.1186/s13063-017-2327-3.
• [25] Effects of LC-PUFA Supplementation in Patients with Phenylketonuria: A Systematic Review of Controlled Trials.Nutrients. 2019 Jul 6;11(7):1537. doi: 10.3390/nu11071537.
• [26] Ethnic distribution of phenylketonuria in the north German population.Hum Genet. 1984;65(4):396-9. doi: 10.1007/BF00291566.
• [27] Comparison of epidermal keratinocytes and dermal fibroblasts as potential target cells for somatic gene therapy of phenylketonuria.Mol Genet Metab. 2002 Aug;76(4):313-8. doi: 10.1016/s1096-7192(02)00101-4.
• [28] When one disease is not enough: succinyl-CoA: 3-oxoacid coenzyme A transferase (SCOT) deficiency due to a novel mutation in OXCT1 in an infant with known phenylketonuria.J Pediatr Endocrinol Metab. 2017 Oct 26;30(10):1121-1124. doi: 10.1515/jpem-2017-0177.
• [29] Towards a systematic analysis of human short-chain dehydrogenases/reductases (SDR): Ligand identification and structure-activity relationships. Chem Biol Interact. 2015 Jun 5;234:114-25.
• [30] Retarded development of neurons and oligodendroglia in rat forebrain produced by hyperphenylalaninemia results in permanent deficits in myelin despite long recovery periods.Exp Neurol. 1993 Dec;124(2):357-67. doi: 10.1006/exnr.1993.1206.
• [31] Expanded Newborn Screening for Inborn Errors of Metabolism by Tandem Mass Spectrometry in Suzhou, China: Disease Spectrum, Prevalence, Genetic Characteristics in a Chinese Population.Front Genet. 2019 Oct 29;10:1052. doi: 10.3389/fgene.2019.01052. eCollection 2019.