Answers to questions families often have about caring for their child with homocystinuria

Homocystinuria is an autosomal recessive inherited metabolic disorder caused by a defect in an enzyme that converts the amino acid homocysteine to cystathionine, resulting in accumulation of homocysteine in the blood and its excretion in urine. There are two main variants or types of homocystinuria: one is responsive to vitamin B6 (pyridoxine, the cofactor of cystathionine beta synthase) and the other does not respond to vitamin B6 and usually has more-pronounced symptoms than the first variant. It may affect the cardiovascular, musculoskeletal, and the central nervous systems. [American: 2012]

With early treatment, there may be fewer symptoms and complications. Without treatment, symptoms vary widely.

Initial symptoms in infants and toddlers may include:

• developmental delay
• emotional and behavior problems
• 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 (knocked knees), pes cavus (high arch/instep)
• osteoporosis (weak/brittle bones)
• malar flush (red cheeks)
• decreased hair, skin, iris pigmentation
• seizures
• vascular disease and stroke
• psychiatric abnormalities
• intellectual disabilities

Newborn metabolic screening measures an elevation of methionine that increases with homocysteine in affected individuals. Infants with milder variants, or in whom newborn screening is obtained too early, can be missed by newborn screening. There are many other types of homocystinuria caused by defects in the remethylation of homocysteine to methionine. These cases are not identified by most newborn screening programs because methionine is low and most programs do not have a low cut-off for methionine. The metabolic geneticist will test affected individuals to determine which variant is present. See the Portal's Newborn Disorder page on Missing link with id: ea629c53.xml for more information and response to a positive newborn screen.

Infants identified by newborn screening and treated to correct the biochemical abnormalities appear to have fewer manifestations of the condition, including decreased incidence of intellectual disability and thromboembolic events. [Yap: 2000]

Children from the same father and mother as the affected infant have a 1 in 4 chance of having homocystinuria. [New: 2010] Siblings of children with this condition should be screened with plasma amino acids and total plasma homocysteine. If the disease-producing mutation in the family has been identified, carrier testing can be performed.

Blood levels of homocysteine are maintained as close as possible to the normal range by restricting methionine in the diet (usually through restricted protein intake) and adding methylfolate and methyl B12 supplementation, betaine treatment, and vitamin B6 (pyridoxine) supplementation. This treatment needs to be continued and monitored throughout life. Other individuals may benefit by antiplatelet treatment such as daily baby aspirin. Eye complications are treated surgically. Other complications are treated symptomatically (psychiatric problems, osteoporosis, etc.). Children with significant disabilities should receive developmental therapies.

The family will be important in helping the child maintain a low-protein diet, restricting bread, pasta, eggs, dairy products, rice, nuts, and meat. Special formulas/powders are available with essential amino acids and no methionine or cystine. Keeping a diet record and completing blood tests will help manage the condition.

Breastfeeding an infant with homocystinuria usually needs to be limited and should be discussed in detail with the metabolic genetics team. Formulas are usually used to supplement breastfeeding in order to limit methionine.