Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review

Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency

In: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993.
[updated ].
Affiliations
Free Books & Documents
Review

Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency

Stephanie J Sacharow et al.
Free Books & Documents

Excerpt

Clinical characteristics: Homocystinuria caused by cystathionine β-synthase (CBS) deficiency is characterized by involvement of the eye (ectopia lentis and/or severe myopia), skeletal system (excessive height, long limbs, scolioisis, and pectus excavatum), vascular system (thromboembolism), and CNS (developmental delay/intellectual disability). All four ‒ or only one ‒ of the systems can be involved; expressivity is variable for all of the clinical signs. It is not unusual for a previously asymptomatic individual to present in adult years with only a thromboembolic event that is often cerebrovascular. Two phenotypic variants are recognized, B6-responsive homocystinuria and B6-non-responsive homocystinuria. B6-responsive homocystinuria is usually milder than the non-responsive variant.

Thromboembolism is the major cause of early death and morbidity. IQ in individuals with untreated homocystinuria ranges widely, from 10 to 138. In B6-responsive individuals the mean IQ is 79 versus 57 for those who are B6-non-responsive. Other features that may occur include: seizures, psychiatric problems, extrapyramidal signs (e.g., dystonia), hypopigmentation of the skin and hair, malar flush, livedo reticularis, and pancreatitis.

Diagnosis/testing: The cardinal biochemical features of homocystinuria include markedly increased concentrations of plasma total homocysteine and methionine. The diagnosis can be substantiated by detection of biallelic pathogenic variants in CBS, the gene encoding cystathionine β-synthase.

Management: Treatment of manifestations: Treatment aims to correct the biochemical abnormalities, especially to control the plasma homocysteine concentrations and prevent thrombosis. Complications of homocystinuria should be managed appropriately; e.g., by surgery for ectopia lentis.

Prevention of primary manifestations: Individuals are treated to maintain normal or near-normal plasma total homocysteine concentrations using vitamin B6 (pyridoxine) therapy (if shown to be B6 responsive), a methionine-restricted diet, and folate and vitamin B12 supplementation. Betaine therapy is usually added to the therapeutic regimen; in adolescents and adults, betaine may be the major form of treatment, but it is preferable to remain on life-long metabolic diet.

Surveillance: Affected individuals should be monitored at regular intervals to detect any clinical complications that may develop, for dietary compliance and for measurement of plasma total homocysteine and amino acids.

Agents/circumstances to avoid: Oral contraceptives in affected females. Surgery if possible. If surgery is required, intravenous fluid with 5% dextrose in 0.5 normal saline at 1.5 times maintenance should be given and continued until oral fluids are taken ad lib, with close monitoring to avoid fluid overload.

Evaluation of relatives at risk: Measurement of total homocysteine and amino acids in at-risk sibs immediately after birth ensures reduction of morbidity and mortality by early diagnosis and treatment. If the CBS pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of sibs

Pregnancy management: For women with classic homocystinuria: dietary treatment and betaine, and vitamin B6 for those B6 responsive, with careful biochemical monitoring throughout pregnancy. Prophylactic anticoagulation with low molecular-weight heparin is recommended during the third trimester and post partum to reduce risk of thromboembolism.

Genetic counseling: Homocystinuria is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for a pregnancy at increased risk are possible if the CBS pathogenic variants have been identified in an affected family member.

PubMed Disclaimer

Similar articles

  • Citrullinemia Type I.
    Quinonez SC, Lee KN. Quinonez SC, et al. 2004 Jul 7 [updated 2022 Aug 18]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2025. 2004 Jul 7 [updated 2022 Aug 18]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2025. PMID: 20301631 Free Books & Documents. Review.
  • Beta-Thalassemia.
    Langer AL. Langer AL. 2000 Sep 28 [updated 2024 Feb 8]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2025. 2000 Sep 28 [updated 2024 Feb 8]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2025. PMID: 20301599 Free Books & Documents. Review.
  • Maple Syrup Urine Disease.
    Strauss KA, Puffenberger EG, Carson VJ. Strauss KA, et al. 2006 Jan 30 [updated 2020 Apr 23]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2025. 2006 Jan 30 [updated 2020 Apr 23]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2025. PMID: 20301495 Free Books & Documents. Review.
  • FBN1-Related Marfan Syndrome.
    Dietz H. Dietz H. 2001 Apr 18 [updated 2022 Feb 17]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2025. 2001 Apr 18 [updated 2022 Feb 17]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2025. PMID: 20301510 Free Books & Documents. Review.
  • Disorders of Intracellular Cobalamin Metabolism.
    Sloan JL, Carrillo N, Adams D, Venditti CP. Sloan JL, et al. 2008 Feb 25 [updated 2021 Dec 16]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2025. 2008 Feb 25 [updated 2021 Dec 16]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2025. PMID: 20301503 Free Books & Documents. Review.

References

Published Guidelines / Consensus Statements

    1. Morris AAM, Kožich V, Santra S, Andria G, Ben-Omran TIM, Chakrapani AB, Crushell E, Henderson MJ, Hochuli M, Huemer M, Janssen MCH, Maillot F, Mayne PD, McNulty J, Morrison TM, Ogier H, O’Sullivan S, Pavlíková M, Talvares de Almeida I, Terry A, Yap S, Blom HJ, Chapman KA. Guidelines for the diagnosis and management of cystathionine β-synthase deficiency. J Inherit Metab Dis. 2017;40:49–74. - PMC - PubMed

Literature Cited

    1. Alcaide P, Krijt J, Ruiz-Sala P, Ješina P, Ugarte M, Kožich V, Merinero B. Enzymatic diagnosis of homocystinuria by determination of cystathionine-ß-synthase activity in plasma using LC-MS/MS. Clin Chim Acta. 2015;438:261–5. - PubMed
    1. Barić I, Staufner C, Augoustides-Savvopoulou P, Chien YH, Dobbelaere D, Grünert S, Opladen T, Petković Ramadža D, Rakić B, Wedell A, Blom H. Consensus recommendations for the diagnosis, treatment and follow-up of inherited methylation disorders. J Inherit Metab Dis. 2017;40:5–20. - PMC - PubMed
    1. Braverman NE, Mudd SH, Barker PB, Pomper MG. Characteristic MR imaging changes in severe hypermethioninemic states. AJNR Am J Neuroradiol. 2005;26:2705–6. - PMC - PubMed
    1. Bublil EM, Majtan T, Park I, Carrillo RS, Hůlková H, Krijt J, Kožich V, Kraus JP. Enzyme replacement with PEGylated cystathionine β-synthase ameliorates homocystinuria in murine model. J Clin Invest. 2016;126:2372–84. - PMC - PubMed
    1. Cottington EM, LaMantia C, Stabler SP, Allen RH, Tangerman A, Wagner C, Zeisel SH, Mudd SH. Adverse event associated with methionine loading test: a case report. Arterioscler Thromb Vasc Biol. 2002;22:1046–50. - PubMed

LinkOut - more resources