Homocystinuria (Classic)

Guidance for primary care clinicians receiving a positive newborn screen result

Other Names

Cystathionine beta-synthase (CBS) deficiency
Homocystinuria

ICD-10 Coding

E72.11, Homocystinuria

Disorder Category

Amino acidemia

Screening

Abnormal Finding

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

Tested By

Tandem mass spectrometry (MS/MS)

Description

Classic homocystinuria is caused by a deficiency of cystathionine beta-synthase (CBS) enzyme activity that results in the inability to metabolize 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.

Clinical Characteristics

With treatment, normal cognitive development is possible if started early enough. Additionally, the risk for morbidity/mortality relating to ectopia lentis, seizures, osteoporosis, and especially thromboembolic events can be significantly reduced with proper management.
Without treatment, symptoms vary widely depending on the severity and age of presentation. The majority will experience ectopia lentis before 8 years of age and will develop a marfanoid type habitus with tall thin stature compared to relatives, scoliosis, and pectus deformities. Most will also have mild intellectual disability with a typical IQ in the 50-80 range and a risk for various psychiatric problems as well. Thromboembolisms have the potential to affect any vessel and can occur at any age, including infancy.
Initial symptoms of homocystinuria 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

Incidence

The incidence of homocystinuria is about 1:200,000 - 1:300,000 live births. [Shinawi: 2007]

Inheritance

Autosomal recessive

Primary Care Management

Next Steps After a Positive Screen

Confirming the Diagnosis

  • To confirm the diagnosis of homocystinuria, work with Newborn Screening Services (see RI providers [2]).
  • Diagnosis will be confirmed by quantitative plasma amino acid analysis and 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. A normal homocysteine with highly elevated methionine is not consistent with homocystinuria and requires further evaluation for hypermethioninemia - see Confirmatory Algorithm for Elevated Methionine +/- Elevated Homocysteine (ACMG) (PDF Document 209 KB).
  • The diagnosis also can be confirmed by identifying biallelic pathogenic variants in CBS through genetic testing. Enzyme analysis of CBS activity may also be performed if genetic testing is indeterminant.

If the Diagnosis is Confirmed

Resources

Information & Support

Related Portal Content
Homocystinuria
Assessment and management information for the primary care clinician caring for the child with homocystinuria.

Homocystinuria (FAQ)
Answers to questions families often have about caring for their child with homocystinuria.

After a Diagnosis or Problem is Identified
Families can face a big change when their baby tests positive for a newborn condition. Find information about A New Diagnosis - You Are Not Alone; Caring for Children with Special Health Care Needs; Assistance in Choosing Providers; Partnering with Healthcare Providers; Top Ten Things to Do After a Diagnosis.

For Professionals

Communicating Newborn Screening Results to Families (ACHDNC) (PDF Document 289 KB)
One-page guide to help clinicians effectively communicate positive newborn screening results to parents; Advisory Committee on Heritable Disorders in Newborns and Children.

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

Homocystinuria - Information for Professionals (STAR-G)
Contains a structured list of information about homocystinuria; Screening, Technology, and Research in Genetics.

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.

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

Tools

RI ACT Sheet for Methionine (Homocystinuria) (ACMG) (PDF Document 139 KB)
Provides recommendations for clinical and laboratory follow-up of the newborn with out-of-range screening results, along with national and local resources for clinicians and families; American College of Medical Genetics.

Confirmatory Algorithm for Elevated Methionine +/- Elevated Homocysteine (ACMG) (PDF Document 209 KB)
An algorithm of the basic steps involved in determining the final diagnosis of an infant with a positive newborn screen; American College of Medical Genetics.

Services for Patients & Families in Rhode Island (RI)

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.

Authors & Reviewers

Initial publication: July 2012; last update/revision: May 2022
Current Authors and Reviewers:
Author: Christopher Torsitano, MD
Senior Author: Brian J. Shayota, MD, MPH
Authoring history
2021: update: Christopher Torsitano, MDA; Brian J. Shayota, MD, MPHSA
2012: first version: Nicola Longo, MD, Ph.D.A
AAuthor; CAContributing Author; SASenior Author; RReviewer

Page Bibliography

Shinawi M.
Hyperhomocysteinemia and cobalamin disorders.
Mol Genet Metab. 2007;90(2):113-21. PubMed abstract