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Homocystinuria

Disorder Category

an amino acid (urea cycle) disorder

Screening

Finding

elevated methionine

Tested By

tandem mass spectrometry (MS/MS); sensitivity=NA; specificity=NA

Names

Homocystinuria

Classic homocystinuria

Homocystinemia

Cystathionine beta-synthase deficiency (CBS)

ICD-9

270.4, Disturbance of sulphur-bearing amino-acid metabolism

Overview

A deficiency of cystathionine beta-synthase (CBS) results in the inability to degrade homocystine to cystathionine, resulting in increased levels of homocysteine and methionine. A variant that represents a minority of cases is responsive to vitamin B6 (pyridoxine), but this type may be missed by newborn screening. Elevated homocysteine impairs the function of several proteins (including fibrillin) interfering with the formation of disulfide bonds and impairs endothelial function, leading to thrombosis.

Prevalence

about 1/200,000 - 1/300,000 live births [Homocystinuria info for professionals (STAR-G)]; as high as 1:65,000 in Ireland [Homocystinuria (GeneReviews)]

Inheritance

autosomal recessive

Prenatal Testing

DNA testing by amniocentesis, or CVS; enzyme assay by amniocentesis.

Clinical Characteristics

With treatment normal IQ is possible and reduction of thromboembolic events may decrease the incidence of other sequelae, such as ectopia lentis, seizures, and psychiatric problems. Without treatment, symptoms vary widely and may present at different ages, ranging from lens dislocation, poor vision, developmental delays, marfanoid habitus, and acute thromboembolism.

Initial symptoms in infants and toddlers may include:
  • developmental delay;
  • emotional and behavior problems;
  • thromboembolism; and
  • ectopia lentis (dislocation of the ocular lens) or severe myopia (nearsightedness).

Findings in older children and adults may include:
  • Marfanoid habitus: tall/ thin build; long fingers, arms, and legs
  • genu valgum, pes cavus
  • osteoporosis
  • malar flush
  • decreased hair, skin, iris pigmentation
  • seizures
  • vascular disease and stroke
  • psychiatric abnormalities
  • mental retardation

Follow-up on positive screening test

Quantitative plasma amino acid analysis, total plasma homocysteine.

Primary care management

Upon notification of the + screen

If the diagnosis is confirmed

  • Educate the family regarding signs, symptoms, and the need for urgent care when the infant becomes ill (see Homocystinuria info for parents (STAR-G))
  • Assist in implementation and maintenance of a diet low in methionine and proteins; baby aspirin is also recommended starting in late teenager years
  • Provision of vitamin B6, betaine, vitamin B12, and methylfolate may be indicated
  • Regular blood and urine tests to monitor amino acid levels and diet may be indicated
  • For those identified after irreversible consequences, assist in management, particularly with developmental and educational interventions

Specialty Care Collaboration

Initial consultation and ongoing collaboration if the child is affected. A dietician may work with the family to devise an optimal approach to dietary management.

Resources

Information & Support

For Professionals

Homocystinuria info for professionals (STAR-G)
From the Screening, Technology and Research in Genetics (STAR-G) program, one of a series of Disorder Fact Sheets for Professionals; structured list of information about the condition, with links to more information.

ACT Sheet for Homocystinuria (ACMG) (PDF Document 347 KB)
Developed by the American College of Medical Genetics (ACMG), includes recommended responses to positive newborn screening test results, diagnostic evaluation, clinical expectations, and sources of additional information. See the ACMG ACT Sheets and Confirmatory Algorithms (link elsewhere on this page) for more info and sheets on other conditions.

ACT Sheets and Confirmatory Algorithms (ACMG)
The American College of Medical Genetics (ACMG) has developed ACTion (ACT) Sheets and algorithms for responding to positive newborn screening test results. This page contains a table with links to all of the ACT Sheets and related algorithms.

Homocystinuria (GeneReviews)
Excellent review by Jonathan D. Picker, MBChB, PhD and Harvey L. Levy, MD including clinical description, differential, management, genetic counseling, molecular genetics, and a bibliography.

Resources for homocystinuria (NLM)
Comprehensive compilation of links to information, articles, research, case studies, genetics, and more; from the National Library of Medicine and the Genetic Alliance.

Homocystinuria (OMIM)
Extensive review of the literature, including clinical features and genetics, from the Online Mendelian Inheritance in Man site, hosted by Johns Hopkins University, providing technical information for providers on genetic disorders, links to MEDLINE, and links to other scientific information and sites.

Utah Newborn Screening Program
The site provides information and statistics about the program and related legislation, training for practices, and the conditions screened for.

For Parents and Patients

Homocystinuria info for parents (STAR-G)
From the Screening, Technology and Research in Genetics (STAR-G) program, providing information for parents about homocystinuria and links to other sites including parent support groups.

Homocystinuria (Genetics Home Reference)
Excellent, detailed review aimed at patients and families from the National Library of Medicine's Genetics Home Reference site.

Services

Genetics-related clinical services throughout the world can be found through Genetics Clinic Directory (GeneTests).

Newborn Screening Programs

Utah Newborn Screening Program, more info...
44 Mario Capecchi Drive
Salt Lake City, UT 84114
Phone: 801-584-8256
Fax: 801-536-0966
http://health.utah.gov/newbornscreening

Pediatric Medical Genetics

See all Pediatric Medical Genetics services providers (3) in our database.

For other services related to this condition, browse our Services categories or search our database.

Helpful Articles

PubMed search for articles on homocystinuria in the last 5 years.

Mudd SH.
Hypermethioninemias of genetic and non-genetic origin: A review.
Am J Med Genet C Semin Med Genet. 2011;157(1):3-32. PubMed abstract
This review covers briefly the major conditions, genetic and non-genetic, sometimes leading to abnormally elevated methionine, with emphasis on recent developments. A major aim is to assist in the differential diagnosis of hypermethioninemia.

Authors

Reviewing Author: Nicola Longo MD, PhD, 3/2011
Compiled and edited by: Alfred Romeo RN, PhD, 3/2007
Content Last Updated: 4/2011