Homocystinuria

What happens in homocystinuria

Methionine is an amino acid found in protein foods. The body converts it to homocysteine, which is normally processed further by the enzyme cystathionine beta-synthase (CBS), using vitamin B6 as a helper. In classic homocystinuria, CBS does not work properly. Homocysteine and methionine build up to very high levels.

High homocysteine damages connective tissue (including the fibers holding the eye lens), blood vessel linings and bone, and affects brain development. It also makes blood more likely to clot.

Rarer forms are caused by defects in remethylation (the pathway converting homocysteine back to methionine), such as MTHFR deficiency or problems processing vitamin B12. These cause low or normal methionine and often more severe early brain involvement.

Symptoms

Babies usually appear healthy at birth. Problems develop over childhood.

Eyes

• ectopia lentis: dislocation of the lens, typically downward, in most untreated patients by age 10
• severe nearsightedness
• glaucoma and retinal detachment

Skeleton

• tall, thin build with long arms and legs (a "Marfanoid" appearance)
• osteoporosis at a young age, causing fractures
• curved spine (scoliosis), chest wall deformities, knock knees

Brain and behavior

• developmental delay and intellectual disability in many untreated patients, especially those who do not respond to B6
• seizures
• psychiatric problems: depression, anxiety, behavior and personality disorders

Blood vessels

• blood clots in veins and arteries: deep vein thrombosis, pulmonary embolism, stroke and heart attack at young ages
• clotting is the leading cause of serious illness and death in untreated homocystinuria

Homocystinuria vs Marfan syndrome

Diagnosis

• Newborn screening: many US states screen for raised methionine, but some B6-responsive cases are missed because methionine is not high enough in the first days of life.
• Plasma total homocysteine: markedly raised, often above 100 micromoles per liter.
• Plasma amino acids: high methionine in CBS deficiency.
• Vitamin B12 and folate levels to exclude nutritional causes of raised homocysteine.
• Genetic testing of the CBS gene.
• B6 responsiveness test: a trial of vitamin B6 to see whether homocysteine falls.

Mildly raised homocysteine in adults (hyperhomocysteinemia) is common and usually caused by B12 or folate deficiency, kidney disease or a common MTHFR variant. It is a different and much milder problem.

Treatment

The goal is to lower homocysteine as much as possible, ideally below 50 micromoles per liter.

• Vitamin B6 (pyridoxine): about half of patients respond, sometimes completely. Doses are set by a metabolic specialist.
• Low-methionine (low-protein) diet with a special methionine-free amino acid formula, for those who do not respond fully to B6. Supervised by a metabolic dietitian.
• Betaine: helps convert homocysteine back to methionine.
• Folic acid and vitamin B12 to support the remethylation pathway.
• Clot prevention: avoiding estrogen-containing contraceptives, preventing dehydration, and using anticoagulants around surgery, pregnancy, and immobility.
• Eye care: glasses, and lens surgery if needed.
• Bone care: vitamin D, calcium, weight-bearing exercise, and bone density monitoring.

Outlook

Early diagnosis and good homocysteine control prevent or greatly reduce lens dislocation, bone disease, intellectual disability and blood clots. People who are B6-responsive generally have a milder course. Lifelong treatment and follow-up with a metabolic team are needed. Pregnancy is possible with careful management and anticoagulation.

Frequently asked questions

What is homocystinuria?

Homocystinuria is a rare inherited metabolic disorder in which the body cannot break down the amino acid methionine properly, usually because of cystathionine beta-synthase deficiency. Homocysteine builds up and damages the eyes, bones, brain and blood vessels.

What are the symptoms of homocystinuria?

Common features are dislocated eye lenses, severe nearsightedness, a tall thin build with long limbs, weak bones and scoliosis, developmental delay or learning difficulties, seizures, psychiatric problems and blood clots at a young age. Symptoms develop over childhood if untreated.

How is homocystinuria different from Marfan syndrome?

Both cause tall stature and dislocated lenses. In homocystinuria the lens usually moves downward, intellectual disability and blood clots are common, and homocysteine is very high. In Marfan syndrome the lens moves upward, intelligence is normal, and the main risk is aortic enlargement.

How is homocystinuria treated?

Treatment includes vitamin B6 for patients who respond, a low-methionine diet with a special formula, betaine, folic acid and vitamin B12. Clot prevention around surgery and pregnancy, eye care and bone health measures are also important. Treatment is lifelong.

Is homocystinuria inherited?

Yes. Classic homocystinuria is autosomal recessive: a child must inherit a non-working CBS gene from each parent. Parents who are both carriers have a 1 in 4 chance with each pregnancy of having an affected child. Genetic counseling is recommended.