CblA and cblB are inherited in autosomal recessive patterns. Normally a person has two functional copies of the MMAA and MMAB genes. In people with cblA, both copies of the MMAA gene have a mutation and there is a deficiency of the critical enzyme. Each parent of a newborn with cblA typically has one functional and one mutated copy of the gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%. The same is true for cblB and MMAB mutations.
Carriers of cblA or cblB do not typically have symptoms.
CblA: Onset of symptoms occurs in the first few months or years of life. Infants with cblA may exhibit vomiting, anorexia, failure to thrive, hypotonia, and developmental delay. Some individuals may present with an aversion to protein, and/or have vomiting or lethargy after protein intake. These babies are at risk for catastrophic decompensation.
CblB: Onset of symptoms usually occurs in the first few weeks or months of life. While normal-appearing at birth, babies with cblB quickly develop lethargy, vomiting, dehydration, hepatomegaly, hypotonia and encephalopathy. Laboratory tests done at this point will typically show metabolic acidosis, ketosis and ketonuria, hyperammonemia, and hyperglycemia. A less severe clinical presentation of cblB is also possible.
- Incidence: Methylmalonic acidemia has an incidence of approximately 1 in 50,000 to 1 in 100,000. CblA and CblB are rare.
- New York State Method of Screening (First Tier): Screening for cblA and cblB is accomplished by measuring the acylcarnitines C3 (propionylcarnitine) and C4DC (methylmalonylcarnitine) by tandem mass spectrometry (MS/MS).
- Second Tier Screening: None
- Testing can be affected by: Maternal B12 deficiency
- 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 cblA or cblB are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of cblA and cblB.
Diagnostic testing may include urine and plasma organic acid analyses, vitamin B12 analysis, enzyme analysis and genetic testing of the MMAA or MMAB genes.
Management requires a low-protein, high-calorie diet, as well as carnitine supplementation. Individuals with cblA and cblB are usually responsive to vitamin B12 therapy. It is recommended that children and adults with cblA and cblB should avoid going for long periods without food. Special management protocols are recommended for critically ill individuals.
If the low-protein diet is started promptly, most children with cblA and cblB have normal growth and development and symptoms may be prevented. A delay in treatment can not reverse symptoms that are already present.
Cobalamin A cofactor deficiency (cblA) and cobalamin B cofactor deficiency (cblB) are forms of methylmalonic acidemia, a disorder of organic acid metabolism. Methylmalonyl-CoA is a product of the breakdown of several amino acids, as well as some fats and cholesterol. Methylmalonyl-CoA mutase breaks down methylmalonyl-CoA. Partial or complete absence of methylmalonyl-CoA mutase results in accumulation of methylmalonic acid and other damaging substances.
Cobalamin A cofactor deficiency results from a reduction or absence of adenosylcobalamin (AdoCbl), a coenzyme for methylmalonyl-CoA mutase. Mutations in the MMAA gene cause dysfunction or absence of AdoCbl, which results in accumulation of methylmalonic acid.
Cobalamin B cofactor deficiency results from a reduction or absence of cob(I)alamin transferase, which is involved in the synthesis of adenosylcobalamin (AdoCbl). Mutations in the MMAB gene cause dysfunction or absence of cob(I)alamin transferase, and therefore, AdoCbl.