The clinical manifestations of disorders of intracellular cobalamin metabolism, identified by complementation class as cblC, cblD, cblD variant 1, cblD variant 2, cblF, cblE, and cblG, can be highly variable even within a single complementation class. The prototype and best understood is cblC; it is also the most common of these disorders. The age of initial presentation of cblC ranges from (1) newborns who can be small for gestational age (SGA) and have microcephaly; to (2) infants who can have poor feeding, failure to thrive, pallor, and neurologic signs, and occasionally hemolytic uremic syndrome (HUS) and/or seizures including infantile spasms; to (3) toddlers who can have failure to thrive, poor head growth, cytopenias (including megaloblastic anemia), global developmental delay, encephalopathy, and neurologic signs such as hypotonia and seizures; and to (4) young adults/adults who can have confusion, other mental status changes, cognitive decline, and megaloblastic anemia.
Metabolic screening tests such as urine organic acid analysis and plasma amino acid analysis help categorize the clinical syndrome. Analysis in specialized laboratories can establish the specific complementation class. Mutations in the following five genes (and their complementation groups) cause the known disorders of intracellular cobalamin metabolism: MMACHC (cblC), MMADHC (cblD), MTRR (cblE), LMBRD1 (cblF), and MTR (cblG). The role of molecular genetic testing in diagnosis is evolving; molecular genetic testing may be faster and less expensive than complementation class analysis in establishing a specific diagnosis in a family.
All disorders of intracellular cobalamin metabolism are inherited in an autosomal recessive manner. Heterozygotes (carriers) are asymptomatic. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutations in a family are known. Enzyme analysis of cultured fetal cells can also be used for prenatal diagnosis if the diagnosis has been confirmed in an affected family member using biochemical methods.