Homocystinuria (HCY)
Homocystinuria is inherited in an autosomal recessive pattern. Normally a person has two functional CBS genes. In people with homocystinuria, both copies of this gene have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with homocystinuria typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.
Carriers do not typically have symptoms.
There are two types of homocystinuria: vitamin B6 responsive and non-vitamin B6 responsive. The symptoms of vitamin B6 responsive homocystinuria are usually milder. The symptoms of untreated homocystinuria vary from one person to the next, but may include developmental delay, near sightedness (myopia), skeletal abnormalities (long limbs) and increased risk of blood clots (thromboembolism). There is also a risk for a dislocation of the lens in the eye (ectopia lentis). Intellectual disability is usually more severe in untreated non-vitamin B6 responsive homocystinuria.
- Incidence: The incidence of homocystinuria is not well known, but it is estimated at 1 in 200,000. It is more common in people from Qatar, Ireland, Germany and Norway.
- New York State Method of Screening (First Tier): Screening for homocystinuria is accomplished by measuring methionine by tandem mass spectrometry (MS/MS).
- Second Tier Screening: None. Testing can be affected by: Methionine may be elevated in newborns receiving total parenteral nutrition, who are premature, or who have liver immaturity. A newborn screening sample collected prior to 24 hours of age may be negative in infants with hypermethioninemia who have not been fed enough protein to have an elevated methionine concentration. In some cases of hypermethioninemia, methionine may not be elevated enough for a positive screen until after 5 days of age.
- Interpretation/reporting of data: Results are reported as screen negative, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
- Referral to Specialty Care Center: Patients with an abnormal newborn screen for homocystinuria are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of homocystinuria.
Diagnostic testing may include plasma homocysteine, plasma amino acids, urine homocysteine and CBS gene testing.
Treatment usually includes a low protein diet and the oral medication, betaine. Vitamin B6 responsive homocystinuria is also treated with pyridoxine. Surgery may be needed for the dislocation of the lens (ectopia lentis).
On treatment, prognosis is significantly improved.
Homocystinuria is a disorder of amino acid metabolism (inherited metabolic disorder). Multiple steps in the body are required to break down components of protein (amino acids), homocysteine and methionine. The CBS gene provides instructions for an important enzyme in this process, cystathionine β-synthase. If there are mutations in this gene, then the enzyme does not function and the amino acids are not broken down. Toxic metabolites accumulate and cause symptoms.