Details of Disease

General Information of Disease (ID: DISK3N1S)

• Disease Name: Homocystinuria
• Synonyms: cystathionine beta synthase deficiency; CBS deficiency; cystathionine synthase deficiency; homocystinuria (disease); homocystinuria
• Disease Class: 5C50: Metabolism inborn error
• Definition: An autosomal recessive inherited metabolic disorder caused by mutations in the CBS, MTHFR, MTR, and MTRR genes. It is characterized by abnormalities in the methionine metabolism and is associated with deficiency of cystathionine synthase. It results in the accumulation of homocysteine in the serum. It may affect the cardiovascular, musculoskeletal and the central nervous systems.
• Disease Hierarchy:
  DISFWXCM: Inborn disorder of amino acid metabolism
  DISUP794: Inborn disorder of methionine cycle and sulfur amino acid metabolism
  DISK3N1S: Homocystinuria
• ICD Code:
  ICD-11: ICD-11: 5C50.B
  ICD-10: ICD-10: E72.1
  Expand ICD-11: '5C50.B
  Expand ICD-10: 'E72.1
• Disease Identifiers:
  MONDO ID: MONDO_0004737
  MESH ID: D006712
  UMLS CUI: C0019880
  MedGen ID: 42485
  HPO ID: HP:0002156
  SNOMED CT ID: 11282001

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
Betaine	DMGRZW2	Approved	Small molecular drug	[1]

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

Drug Name	Drug ID	Highest Status	Drug Type	REF
OT-58	DMWCJ1F	Phase 1/2	Recombinant protein	[2]
Pegtarviliase	DMP3NH6	Phase 1/2	Enzyme replacement	[3]

Molecular Interaction Atlas (MIA) of This Disease

This Disease Is Related to 5 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
F5	TT1O264	Limited	Biomarker	[4]
GOT1	TTU507L	Strong	Altered Expression	[5]
MTR	TTUTO39	Strong	Altered Expression	[6]
PEMT	TT735V2	Strong	Biomarker	[7]
SERPIND1	TT8XSKJ	Strong	Biomarker	[8]

This Disease Is Related to 1 DME Molecule(s)

Gene Name	DME ID	Evidence Level	Mode of Inheritance	REF
MTRR	DE6NIY9	Limited	Genetic Variation	[9]

This Disease Is Related to 3 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
MMADHC	OTP0UPL2	Disputed	Genetic Variation	[10]
HRG	OTPLUFOG	Strong	Biomarker	[8]
MMACHC	OTX0TT3W	Strong	Genetic Variation	[11]

References

• [1] Betaine FDA Label
• [2] ClinicalTrials.gov (NCT03406611) OT-58 as an Enzyme Therapy for Patients With Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency. U.S. National Institutes of Health.
• [3] ClinicalTrials.gov (NCT05154890) A Phase 1/2 Multiple Ascending-Dose Study in Subjects With Homocystinuria Due to Cystathionine beta-Synthase (CBS) Deficiency to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics of ACN00177. U.S.National Institutes of Health.
• [4] Interaction between hyperhomocysteinemia and inherited thrombophilic factors in venous thromboembolism.Semin Thromb Hemost. 2000;26(3):305-11. doi: 10.1055/s-2000-8473.
• [5] Altered hepatic sulfur metabolism in cystathionine -synthase-deficient homocystinuria: regulatory role of taurine on competing cysteine oxidation pathways.FASEB J. 2014 Sep;28(9):4044-54. doi: 10.1096/fj.14-253633. Epub 2014 Jun 2.
• [6] cblE type of homocystinuria due to methionine synthase reductase deficiency: functional correction by minigene expression. Hum Mutat. 2005 Mar;25(3):239-47. doi: 10.1002/humu.20131.
• [7] Cystathionine beta-synthase deficiency alters hepatic phospholipid and choline metabolism: Post-translational repression of phosphatidylethanolamine N-methyltransferase is a consequence rather than a cause of liver injury in homocystinuria.Mol Genet Metab. 2017 Apr;120(4):325-336. doi: 10.1016/j.ymgme.2017.02.010. Epub 2017 Mar 2.
• [8] Multicentre evaluation of combined prothrombotic defects associated with thrombophilia in childhood. Childhood Thrombophilia Study Group.Eur J Pediatr. 1999 Dec;158 Suppl 3:S97-104. doi: 10.1007/pl00014359.
• [9] Splice-shifting oligonucleotide (SSO) mediated blocking of an exonic splicing enhancer (ESE) created by the prevalent c.903+469T>C MTRR mutation corrects splicing and restores enzyme activity in patient cells.Nucleic Acids Res. 2015 May 19;43(9):4627-39. doi: 10.1093/nar/gkv275. Epub 2015 Apr 15.
• [10] Clinical and molecular heterogeneity in patients with the cblD inborn error of cobalamin metabolism.J Pediatr. 2009 Apr;154(4):551-6. doi: 10.1016/j.jpeds.2008.10.043. Epub 2008 Dec 5.
• [11] Molecular genetic characterization of cblC defects in 126 pedigrees and prenatal genetic diagnosis of pedigrees with combined methylmalonic aciduria and homocystinuria.BMC Med Genet. 2018 Aug 29;19(1):154. doi: 10.1186/s12881-018-0666-x.