Hypermethionemia (HMET)
Hypermethioninemia is most often inherited in an autosomal recessive pattern. Normally a person has two functional copies of the AHCY, GNMT and MAT1A genes. In people with hypermethioninemia, both copies of any one of these genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with hypermethioninemia typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers for the same gene, the chance of a newborn inheriting two mutated genes is 25%. There have been reports of autosomal dominant hypermethioninemia, which means that a mutation in one copy of the gene causes the disease and the chance for each child of a person with the disease to inherit it is 50%.
Carriers of hypermethioninemia do not typically have symptoms.
Hypermethioninemia due to mutations in the AHCY gene is a rare, but serious disorder. The symptoms include developmental delay, loss of white matter in the brain and liver disease.
Hypermethioninemia due to mutations in MAT1A is usually a benign disorder. Very rarely, people with hypermethioninemia have neurological symptoms including developmental delay and muscle weakness.
Hypermethioninemia due to mutations in GNMT has been reported in a small number of patients with elevated liver enzymes and mildly enlarged liver.
- Incidence: The published incidence of hypermethioninemia due to MAT1A mutations is estimated at 1 in 28,163 births. However, the incidence in New York State has been much lower. Hypermethioninemia due to mutations in the other genes appears to be rare with only a few cases reported in the literature.
- New York State Method of Screening (First Tier): Screening for hypermethioninemia 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 hypermethioninemia are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of hypermethioninemia.
Diagnostic testing may include plasma S-adenosylmethionine, plasma S-adenosylhomocysteine, plasma homocysteine and plasma amino acid analysis.
Treatment is often not needed for the most common causes of hypermethioninemia. For patients with MAT1A-related hypermethioninemia and symptoms, treatment may include S-adenosylmethionine. Patients with GNMT-related hypermethioninemia may benefit from a low methionine diet and cystine supplementation. Treatment is not well defined for AHCY-related hypermethioninemia, but some patients benefited from a low methionine diet with phosphatidylcholine supplementation.
Some patients with hypermethioninemia never develop symptoms. For patients with symptoms, prognosis is variable and dependent on response to treatments and severity of disease.
Hypermethioninemia is a term used to describe several metabolic disorders with a common finding of elevated methionine. Multiple steps in the body are required to breakdown the component of protein (amino acid), methionine. The AHCY, GNMT and MAT1A genes provide instructions for three important enzymes in this process. If there are mutations in any one of these genes, then the enzymes do not function and methionine is not broken down.