Cobalamin C disease, also known as methylmalonic aciduria with homocystinuria, is a rare inherited metabolic disorder. It impacts the body’s ability to properly process vitamin B12, or cobalamin, which serves as a cofactor for two enzymes: methylmalonyl-CoA mutase and methionine synthase. This dysfunction affects various cellular processes throughout the body.
Understanding Cobalamin C Disease
Cobalamin C disease arises from mutations in the MMACHC gene. This gene provides instructions for a protein involved in the early stages of cobalamin processing. The disease follows an autosomal recessive inheritance pattern, meaning an individual must inherit two mutated copies of the MMACHC gene—one from each parent—to develop the condition. Parents who carry one mutated copy are unaffected.
The defect in the MMACHC gene prevents dietary vitamin B12 from converting into its active forms, methylcobalamin and adenosylcobalamin. This impaired conversion leads to the accumulation of toxic substances, specifically methylmalonic acid and homocysteine. The buildup of these compounds disrupts several cellular processes, including DNA synthesis and the metabolism of certain amino acids and fats. This metabolic disruption can lead to mitochondrial dysfunction and affect various organ systems.
Recognizing the Signs
The symptoms associated with Cobalamin C disease can vary significantly in presentation and severity, with onset ranging from early infancy to later childhood or even adulthood. Most individuals show initial symptoms within their first year of life, sometimes triggered by fasting, illness, infection, or consuming large amounts of protein. Early-onset symptoms often include poor appetite and growth, lethargy, and low muscle tone.
Neurological manifestations are common, such as developmental delays, intellectual disability, seizures, and an unusually small head size (microcephaly). Eye abnormalities, like infantile-onset macular and retinal degeneration leading to severe vision loss, are also frequently observed. Hematological issues can include megaloblastic anemia, where red blood cells are low in number and larger than normal. Kidney problems and skin rashes may also occur.
Diagnosis and Management
Diagnosing Cobalamin C disease begins with newborn screening programs, which detect elevated levels of propionylcarnitine (C3). If screening results are abnormal, further biochemical tests are conducted, including measuring methylmalonic acid and total homocysteine levels in urine and blood. These elevated levels are strong indicators of the condition.
Confirmatory diagnosis relies on genetic testing to identify specific mutations in the MMACHC gene. Once diagnosed, the primary treatment involves lifelong intramuscular injections of hydroxocobalamin, a form of vitamin B12, which helps reduce the accumulation of harmful metabolites. Adjunctive therapies often include betaine supplementation, which aids in converting homocysteine to methionine. Dietary modifications may also be considered. Early diagnosis and consistent treatment are important for improving outcomes and mitigating complications.
Living with Cobalamin C Disease
The long-term prognosis and quality of life for individuals with Cobalamin C disease are significantly influenced by early diagnosis and consistent treatment. While outcomes can still be challenging despite early intervention, continuous therapy can help manage metabolic abnormalities and reduce the risk of severe complications.
Ongoing management requires a multidisciplinary care team, including metabolic specialists, neurologists, and dietitians. Regular follow-up appointments are necessary to monitor growth, nutritional status, and neurocognitive progress, especially during the first year of life, with evaluations potentially shifting to a yearly basis for teens and adults. Adjustments to medication dosages and dietary plans are made as needed to maintain metabolic balance and support the individual’s health.