Homocystinuria
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Homocystinuria
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Authors: Margaret Means, MDSonika Agarwal, MBBS, MD
Children’s Hospital of Philadelphia 

Reviewed: November 2021 

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SUMMARY

Homocystinuria is a rare condition that affects amino acid levels in the body. In particular, it affects an amino acid called homocysteine. In children with this disorder, levels of homocysteine in the blood and urine are higher than normal. This may be caused by: 

  • A genetic mutation 
  • A vitamin deficiency 

High homocysteine levels can lead to increased risk for:  

  • Stroke 
  • Heart attack 
  • Blood clots 

The genetic form of the disorder is associated with: 

  • Dislocation of the lens of the eyes 
  • Eyesight—specifically, nearsightedness
  • Developmental delays and learning/intellectual disabilities
  • Tall stature 
  • Long fingers 
  • Difficulty in gaining weight, such as “failure to thrive” 
  • Weak bones (osteoporosis) 
  • Curvature of the spine (scoliosis) 
  • Caved-in chest (pectus excavatum) 

Treatment depends on the underlying cause, but can include: 

  • Restricting certain types of protein in the diet 
  • Taking vitamins 
  • Sometimes, a medication called betaine 
cerebral ALD 1

Disorder Overview

DESCRIPTION 

Homocysteine is an amino acid. Amino acids make up proteins in the body. Children with this disorder can’t break down homocysteine. For this reason, high levels of homocysteine can build up in the blood and urine. 

Homocystinuria is rare. The most common form of the disease affects about 1 in 200,000 to 335,000 people worldwide. It is more common in certain countries, including: 

  • Ireland 
  • Germany 
  • Norway 
  • Qatar 

Types of Homocystinuria 

This disorder can be understood as having several distinct types.  

Classic (genetic) homocystinuria

This is the most common genetic form of the disorder. It is caused by a mutation in the gene that helps make the enzyme that breaks down homocysteine.  The most common mutation is cystathionine beta synthase or CBS deficiency.

Other genetic forms

There are other, rarer mutations in different genes that can also lead to high homocysteine levels in the blood. These are much less common. 

Nongenetic forms

Various nongenetic forms of the disorder also exist. They are more common than the genetic forms of the disease. 

SIGNS AND SYMPTOMS 

The signs and symptoms of homocystinuria can begin in childhood or adolescence. They are due to the effects of high homocysteine levels on different tissues in the body. 

The classic form of the disorder can lead to symptoms in all different parts of the body: 

Neurologic

Symptoms involving the brain can include: 

  • Developmental delay
  • Intellectual disability 
  • Seizures 
  • Strokes 
  • Psychiatric problems 

Skin

Effects on the skin can include: 

  • fair complexion 
  • flushing or redness, especially around the cheeks 

Blood

This disorder can raise the risk of blood clots.  

Heart

This disorder can raise the risk of heart attacks. 

Musculoskeletal

This disorder can affect the muscles, joints and bones. Many children with this disorder have a specific set of features called Marfanoid features. Muscle, joint, and bone differences can include: 

  • Brittle bones (osteoporosis) 
  • Caved-in chest (pectus excavatum) 
  • Curvature of the spine (scoliosis) 
  • Long, thin limbs and fingers 
  • Knock knees (genu valgum)
  • Highly arched feet 

Eyes

Effects on the eyes can include: 

  • Lens dislocation 
  • Nearsightedness 
  • Quivering of the colored portion of eyes (iridodonesis)
  • Clouding of the lens of eye (cataracts) 
  • Degeneration of the nerve that sends signals from the eye to the brain (the optic nerve) 

Systemic

Some children with this disorder will experience problems with weight gain or growth. This is also known as “failure to thrive.”  

Transverse Myelitis 2

CAUSES

Both genetic and nongenetic causes can lead to homocystinuria.  

Genetic Causes

Various genetic mutations can impact the enzymes that are important for breaking down amino acids.  

CBS enzyme

The classic form of this disorder is caused by mutations in the gene that helps produce the cystathionine beta-synthase (CBS) enzyme. CBS is needed to break down certain proteins and to make sure that homocysteine is used properly in the body. If CBS is not working correctly, homocysteine can build up in the blood and urine. 

Other enzymes

Other, rarer mutations in genes that produces enzymes can also lead to high homocysteine levels in the blood. 

Most genetic causes are inherited in an autosomal recessive manner. This means that there must be two mutated copies of the gene for a child to have symptoms. One gene will be inherited from the child’s mother, and one from the child’s father. However, the mother and father will not show any symptoms of the disease. They will be considered carriers. 

Nongenetic Causes 

There are other nongenetic causes of high homocysteine in the blood and urine. These causes are more common than genetic causes. They can have different signs and symptoms. Nongenetic causes can include: 

  • Vitamin deficiencies, particularly Vitamin B6 or Vitamin B12 deficiencies 
  • Low thyroid hormone levels 
  • Diabetes 
  • High cholesterol 
  • High blood pressure 
  • Medications, such as carbamazepine, phenytoin, atorvastatin, methotrexate 
  • Smoking 
  • Advanced age 

LAB INVESTIGATIONS

Most states in the US test for the more common genetic form of this disorder, classic homocystinuria, during a newborn screening at birth. The disorder can also be diagnosed through a blood test. The blood test will measure the total amount of homocysteine in the blood. Genetic testing can also be helpful in making the diagnosis later in life. 

TREATMENT AND THERAPIES

Types of treatment can vary based on how severe the disease is and on other factors.

Treatments include: 

Protein-restricted diet

For the more severe forms of disease, children will need to be on a protein-restricted diet. Because amino acids are the building blocks of proteins, this can help prevent a buildup of amino acids in the body.

Vitamin supplementation

Some forms of the disorder may get better after adding certain vitamins to the diet. This is especially true for milder forms of the disorder. Helpful vitamins include vitamins B6 and B12 as well as folate.  

Medication

There is a type of medication called betaine that can help some patients lower levels of homocysteine in the body. Betaine occurs naturally in the body and in many regular foods, such as beets and seafood. It usually causes only minor side effects. 

Homocystinuria

OUTLOOK

Patients with this disorder can do well with treatments that lower the level of homocysteine in the body. Treatments help to prevent some of the complications of the disease. They can help patients have normal development and growth. However, some patients will still have eye problems and blood clots. These patients will need to be closely monitored. 

Resources 

HCU Network America
The mission of HCU Network America is to help patients with Homocystinuria and related disorders manage their disease and to find a cure. HCU Network America provides resources and information which includes: finding a clinic, guidelines for diagnosis and management, tool kits and a checklist, as well as videos. The website has an extensive research section which highlights grants, the organization’s projects, and publications. One of the goals of HCU Network American is to create connections across the community and facilitate sharing of information and best practices through in-person and virtual events and discussions. Another key goal is to improve newborn screening for HCU. An online survey is accessible on the website to build support for improving that process. The Homocystinuria Awareness and Support private Facebook group is hosted by HCU Network America. 

HCU Network Australia 
HCU Network Australia’s vision is to be a driving force in the journey to a cure for Homocystinuria, improving quality of life along the wayThey provide community and resource news updates, educational resources and supportand drives research for improved outcomes for those impacted by homocystinuria. HCU Network Australia also hosts a private Facebook group for Australian patients and caregivers with over 50 members. 

Childhood Stroke 1

Child Neurology Foundation (CNF) solicits resources from the community to be included on this webpage through an application process. CNF reserves the right to remove entities at any time if information is deemed inappropriate or inconsistent with the mission, vision, and values of CNF. 

Research 

ClinicalTrials.gov for Homocystinuria are clinical trials that are recruiting or will be recruiting. Updates are made daily, so you are encouraged to check back frequently.  

ClinicalTrials.gov is a database of privately and publicly funded clinical studies conducted around the world. This is a resource provided by the U.S. National Library of Medicine (NLM), which is an institute within the National Institutes of Health (NIH). Listing a study does not mean it has been evaluated by the U.S. Federal Government. Please read the NLM disclaimer for details.  

Before participating in a study, you are encouraged to talk to your health care provider and learn about the risks and potential benefits. 

Family Stories

HCU Network America shares many classical Homocystinuria patient stories from around the world.  

Read the stories of hope and inspiration from individuals and families who bravely share their journey of Homocystinuria. From HCU Network Australia. 

The information in the CNF Child Neurology Disorder Directory is not intended to provide diagnosis, treatment, or medical advice and should not be considered a substitute for advice from a healthcare professional. Content provided is for informational purposes only.  CNF is not responsible for actions taken based on the information included on this webpage. Please consult with a physician or other healthcare professional regarding any medical or health related diagnosis or treatment options. 

References

Swaiman KF. In: Swaiman’s Pediatric Neurology: Principles and Practice. Edinburgh: Elsevier; 2018:283.  

Pina-Garza JE. In: Fenichel’s Clinical Pediatric Neurology. London: Elsevier Saunders; 2013:122-123.  

Homocystinuria due to cystathionine beta-synthase deficiency. National Organization for Rare Disorders (NORD). 2021. https://rarediseases.org/rare-diseases/homocystinuria-due-to-cystathionine-beta-synthase-deficiency/ 

Homocystinuria. Genetics Home Reference (GHR). March, 2016. https://ghr.nlm.nih.gov/condition=homocystinuria 

Homocystinuria. National Institutes of Health (NIH) Genetic and Rare Diseases Information Center (GARD). Last updated Dec 28, 2018. https://rarediseases.info.nih.gov/diseases/10770/homocystinuria 

Homocysteine. Cleveland Clinic. Last reviewed May 7, 2021. https://my.clevelandclinic.org/health/articles/21527-homocysteine 

Thank you to our 2022 Disorder Directory partner Jazz Pharmaceuticals. And to our 2021 partners Acadia, Aeglea, Amicus Therapeutics, bluebird bio, Eisai, Greenwich Biosciences (now Jazz Pharmaceuticals), Liva Nova, Origin, Ovid, PTC Therapeutics and UCB for their support of the Disorder Directory.

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