CblC and cblD are inherited in autosomal recessive patterns. Normally a person has two functional copies of the MMACHC gene and two of the MMADHC gene. In people with cblC, both copies of the MMACHC gene have a mutation and there is a deficiency of the critical enzyme. Each parent of a newborn with cblC 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 cblD and MMADHC mutations.
Carriers of cblC or cblD do not typically have symptoms.
CblC: CblC has a variable age of onset. Some infants with cblC are small for gestational age, or have congenital microcephaly. Within the first two weeks of life, failure to thrive is common and many infants experience acidosis. Infantile spasms are seen in some babies with cblC. Children with the deficiency may present with poor head growth, cytopenias, global developmental delay, encephalopathy, hypotonia and seizures. Adults may present with confusion, cognitive decline and megaloblastic anemia, and a brain MRI may show leukodystrophy. Retinopathy and renal and hepatic dysfunction are also seen in cblC at all ages.
CblD: CblD has a variable age of onset and presentation, however most children present in the first years of life with failure to thrive, megaloblastic anemia, developmental delay, weakness, hypotonia, seizures, and/or altered mental status.
- Incidence: Methylmalonic acidemia has an incidence of approximately 1 in 50,000 to 1 in 100,000. CblC and CblD are rare.
- New York State Method of Screening (First Tier): Screening for cblC and cblD is accomplished by measuring the acylcarnitine C3 (propionylcarnitine) and methionine 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 cblC or cblD are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of cblC and cblD.
Diagnostic testing may include urine and plasma organic acid analyses, vitamin B12 analysis, plasma and urine total homocysteine levels, enzyme analysis and genetic testing of the MMACHC or MMADHC genes.
A special diet is not needed for cblC or cblD, although supplementation with carnitine, pyridoxine, folate and methionine may be of benefit. Individuals with cblC and cblD are usually responsive to vitamin B12 therapy. Treatment with betaine is helpful for individuals with homocystinuria. Special management protocols are recommended for critically ill individuals.
Prognosis is variable and dependent on multiple factors including the severity of disease and response to treatment.
Cobalamin C cofactor deficiency (cblC) and cobalamin D cofactor deficiency (cblD) are forms of methylmalonic acidemia with homocystinuria, 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 C cofactor deficiency is caused by mutations in the MMACHC gene. This gene produces a protein that helps regulate cobalamin, which is converted into adenosylcobalamin (AdoCbl) or methylcobalamin (MeCbl). AdoCbl is a coenzyme for methylmalonyl-CoA mutase, so mutations in MMACHC result in accumulation of methylmalonic acid. MeCbl is a cofactor for methionine synthase, which converts homocysteine to methionine. Therefore, mutations in MMACHC also result in homocystinuria.
Cobalamin D cofactor deficiency is caused by mutations in the MMADHC gene. This gene produces a protein that helps to convert cobalamin into AdoCbl or MeCbl. AdoCbl is a coenzyme for methylmalonyl-CoA mutase, so mutations in MMADHC result in accumulation of methylmalonic acid. MeCbl is a cofactor for methionine synthase, which converts homocysteine to methionine. Therefore, mutations in MMADHC also result in homocystinuria.