Methylmalonic Aciduria and Homocystinuria, cblC Type, Known Mutation
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
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.
Diagnostic confirmation of methylmalonic aciduria and homocystinuria, cblC type when familial mutations have been previously identified
Carrier screening of at-risk individuals when a mutation in the MMACHC gene has been identified in an affected family member
An interpretive report will be provided.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
The identification of a disease-causing mutation in an affected family member is necessary before predictive testing for other family members can be offered. If a familial mutation(s) has not been previously identified, order MAHMS/89436 Methylmalonic Aciduria and Homocystinuria, cblC type, Full Gene Analysis.
Analysis is performed for the familial mutation(s) provided only. This assay does not rule out the presence of other mutations within this gene or within other genes that may be associated with metabolic disease.
Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Any error in the diagnosis or in the pedigree provided to us, including false-paternity, could lead to erroneous interpretation of test results.
A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories for instructions for testing patients who have received a bone marrow transplant.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
An interpretive report will be provided.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
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