Homocystinuria (Classic)

Other Names

Cystathionine beta-synthase (CBS) deficiency

Homocystinuria

Diagnosis Coding

E72.11, Homocystinuria

Disorder Category

An amino acidemia

Screening

Finding

Elevated methionine (can also be seen in a few other metabolic conditions)

Tested By

Tandem mass spectrometry (MS/MS); sensitivity=NA; specificity=NA.

Overview

A deficiency of cystathionine beta-synthase (CBS) that results in the inability to degrade homocysteine 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), thereby interfering with the formation of disulfide bonds and impairing endothelial function. As a result, untreated patients are at significant risk for thromboembolic events, making up the leading cause of morbidity and early death in affected patients.

Incidence

About 1:200,000 - 1:300,000 live births, as high as 1:1,800 in Qatar.

Inheritance

Autosomal recessive

Prenatal Testing

DNA testing by amniocentesis or chorionic villus sampling (CVS) if both disease-causing mutations of an affected family member have been identified.

Clinical Characteristics

With treatment, normal IQ is possible. The reduction of thromboembolic events may decrease the incidence of other sequelae, such as ectopia lentis, seizures, and psychiatric problems as well.

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 behavioral challenges
  • Thromboembolism
  • 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 (knock knees), pes cavus (high arch)
  • Osteoporosis
  • Decreased hair, skin, iris pigmentation
  • Seizures
  • Vascular disease and stroke
  • Extrapyramidal signs (e.g., dystonia)
  • Psychiatric abnormalities
  • Intellectual disability

Follow-up Testing after Positive Screen

Obtain quantitative plasma amino acid analysis, total plasma homocysteine. Homocysteine measured on plasma amino acid analysis only measures free homocysteine, so a separate total homocysteine sample is necessary. Confirmed by markedly increased total homocysteine and methionine.

It can also be confirmed by identifying biallelic pathogenic variants in CBS through genetic testing but is not always sensitive. Enzyme analysis of CBS activity may also be performed if genetic testing is indeterminant.

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 - Information for Parents (STAR-G)).
  • The geneticist may want to do a pyridoxine (B6) trial prior to starting treatment in order to evaluate B6 responsiveness.
  • Assist in implementation and maintenance of a diet low in methionine and proteins.
  • Provision of vitamin B6, betaine, vitamin B12, and methylfolate may be indicated.
  • For those identified after irreversible consequences, assist in management, particularly with developmental and educational interventions.

Specialty Care Collaboration

Initial consultation with the following service(s): Pediatric Genetics (see MT providers [7]) and ongoing collaboration if the child is affected. A dietician may work with the family to devise an optimal approach to dietary management. Obtain genetic counseling for the family. CBS enzyme replacement therapy is currently in preclinical phase, but participation in clinical trials may be available.

Resources

Information & Support

For Professionals

Homocystinuria (GeneReviews)
Detailed information addressing clinical characteristics, diagnosis/testing, management, genetic counseling, and molecular pathogenesis; from the University of Washington and the National Library of Medicine.

Disease InfoSearch for Homocystinuria (Genetic Alliance)
Comprehensive compilation of links to information, articles, research, case studies, genetics, and more.

Homocystinuria (OMIM)
Information about clinical features, diagnosis, management, and molecular and population genetics; Online Mendelian Inheritance in Man, authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine

For Parents and Patients

Homocystinuria - Information for Parents (STAR-G)
A fact sheet, written by a genetic counselor and reviewed by metabolic and genetic specialists, for families who have received an initial diagnosis of this newborn disorder; Screening, Technology and Research in Genetics.

Homocystinuria (MedlinePlus)
Information for families that includes description, frequency, causes, inheritance, other names, and additional resources; from the National Library of Medicine.

Tools

ACT Sheet for Homocystinuria (ACMG)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical Genetics.

Services for Patients & Families in Montana (MT)

Genetics clinic services throughout the US can be found through the Genetics Clinic Services Search Engine (ACMG).

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Helpful Articles

PubMed search for homocystinuria and neonatal screening, 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
Discusses briefly the genetic and non-genetic conditions that sometimes lead to abnormally elevated methionine. Focuses on recent developments and differential diagnosis of hypermethioninemia.

Authors & Reviewers

Initial publication: March 2007; last update/revision: September 2021
Current Authors and Reviewers:
Author: Christopher Torsitano, MD
Senior Author: Brian J. Shayota, MD, MPH
Authoring history
2012: revision: Kimberly Hart, MS, LCGCR
2011: first version: Nicola Longo, MD, Ph.D.A
AAuthor; CAContributing Author; SASenior Author; RReviewer