Sorted By Test Name - Mayo Medical Laboratories

MAHKM
89135
Clinical Information: Multiple causes of inborn errors of cobalamin (cbl; better known as vitamin
B12) metabolism have been identified. These disorders have been classified into 9 distinct
complementation classes (cblA-cblH and mut, caused by mutations in the gene encoding methylmalonyl
coenzyme A mutase). Complementation analysis utilizes cells from the patient to determine at what stage
of the cbl metabolism pathway an error is occurring, and uses this information to differentiate between the
various complementation class disorders. Depending on the complementation class involved, errors in cbl
metabolism can result in methylmalonic aciduria, homocystinuria, or both. The most common disorder in
this group is methylmalonic aciduria and homocystinuria, cblC (cobalamin C) type, which results in both
methylmalonic aciduria and homocystinuria. cblC type is an autosomal recessive disorder with a variable
age of onset. In the early onset form, symptoms appear in the first several years of life and include failure
to thrive, developmental delay, seizures, metabolic crisis, and hydrocephalus. Patients may also have
hemolytic uremic syndrome. Adults can present with confusion or other changes in mental status,
cognitive decline, and megaloblastic anemia. Biochemical presentation includes methylmalonic aciduria
and homocystinuria in urine organic acid or plasma amino acid analysis. Other complementation class
disorders, such as cblD and cblF, can result in a similar biochemical phenotype, and complementation
testing or molecular testing is utilized to distinguish between these different types. Mutations in the
MMACHC gene are responsible for the cblC type disorder. The most common mutation (identified in
approximately 40% of mutant alleles) is 271dupA. This multi-ethnic mutation is most frequently
associated with early-onset disease, especially when present in the homozygous state. Another early-onset
mutation is R111X, which is common in the Cajun and French Canadian populations. R132X is a
late-onset mutation that has been identified in individuals of Indian, Pakistani, and Middle Eastern
ethnicity. Although these genotype-phenotype correlations are well-established, there is often
considerable variability in age of onset and expression of symptoms, even within families.
Useful For: Confirmation of diagnosis of methylmalonic aciduria and homocystinuria, cblC type
Distinguishing between cblC, cblD, and cblF types when methylmalonic aciduria and homocystinuria are
identified Carrier screening in cases where there is a family history of methylmalonic aciduria and
homocystinuria, but disease causing mutations have not been identified in an affected individual
Interpretation: An interpretive report will be provided.
Reference Values:
An interpretive report will be provided.
Clinical References: 1. Lerner-Ellis JP, Tirone JC, Pawelek PD, et al: Identification of the gene
responsible for methylmalonic aciduria and homocystinuria, cblC type. Nat Genet 2006;38:93-100 2.
Morel CF, Lerner-Ellis JP, Rosenblatt DS: Combined methylmalonic aciduria and homocystinuria (cblC):
Phenotype-genotype correlations and ethnic-specific observations. Mol Genet Metab 2006;88:315-321 3.
Martinelli D, Deodato F, Dionisi-Vici C: Cobalamin C defect: natural history, pathophysiology, and
treatment. J Inherit Metab Dis 2011;34(1):127-135
Methylmalonic Aciduria and Homocystinuria, cblC Type, Known
Mutation
Clinical Information: Multiple causes of inborn errors of cobalamin (cbl; better known as vitamin
B12) metabolism have been identified. These disorders have been classified into 9 distinct
complementation classes (cblA-cblH and mut, caused by mutations in the gene encoding methylmalonyl
coenzyme A mutase). Complementation analysis utilizes cells from the patient to determine at what stage
of the cbl metabolism pathway an error is occurring, and uses this information to differentiate between the
various complementation class disorders. Depending on the complementation class involved, errors in cbl
metabolism can result in methylmalonic aciduria, homocystinuria, or both. The most common disorder in
this group is methylmalonic aciduria and homocystinuria, cblC (cobalamin C) type, which results in both
methylmalonic aciduria and homocystinuria. cblC type is an autosomal recessive disorder with a variable
age of onset. In the early onset form, symptoms appear in the first several years of life and include failure
to thrive, developmental delay, seizures, metabolic crisis, and hydrocephalus. Patients may also have
hemolytic uremic syndrome. Adults can present with confusion or other changes in mental status,
cognitive decline, and megaloblastic anemia. Biochemical presentation includes methylmalonic aciduria
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