Interpretive Handbook

Test 61097 :
Methylmalonic Aciduria and Homocystinuria, cblD Type, Full Gene Analysis

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Several causes of inborn errors of cobalamin (cbl; better known as vitamin B12) metabolism have been identified. These disorders have been classified into 8 distinct complementation classes (cblA-cblH). 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. 


cblD type is a rare autosomal recessive disorder with variable clinical presentations. It can present as cblD variant 1, associated with isolated homocystinuria; cblD variant 2, associated with isolated methylmalonic aciduria; or as cblD combined, associated with both methylmalonic aciduria and homocystinuria. cblD variant 1 is associated with clinical features of isolated homocystinuria, including megaloblastic anemia and neurological abnormalities, as well as developmental delays. cblD variant 2 is associated with clinical features of isolated methylmalonic aciduria, including metabolic decomposition, which can result in lethargy, failure to thrive, feeding problems, and hypotonia. cblD combined is associated with clinical features of both methylmalonic aciduria and homocystinuria. Biochemical presentation includes methylmalonic aciduria and/or homocystinuria in urine organic acid or plasma amino acid analysis.(1) Other complementation class disorders can result in a similar biochemical phenotype, and complementation testing or molecular testing is utilized to distinguish between these different types.


Mutations in the MMADHC gene are responsible for the cblD type disorder. To date, 9 mutations in 7 individuals have been identified.(2) Three missense mutations identified in exons 6 and 8 have been associated with cblD variant 1. One nonsense mutation, 1 in-frame duplication, and 1 frame-shift deletion in exons 3 and 4 have been associated with cblD variant 2. One nonsense mutation, 1 frame-shift duplication, and 1 splice-site deletion in exons 5 and 8 and intron 7 have been associated with cblD combined.

Useful For Suggests clinical disorders or settings where the test may be helpful

Confirmation of diagnosis of disorders belonging to the cblD complementation group


Distinguishing between cblC, cblD, and cblF types when methylmalonic aciduria and homocystinuria are identified


Distinguishing between cblA, cblB, and cblD variant 2 when methylmalonic aciduria is identified


Distinguishing between cblD variant 1, cblE, and cblG when homocystinuria is identified 


Carrier screening in cases where there is a family history of methylmalonic aciduria or homocystinuria, but disease-causing mutations have not been identified in an affected individual

Interpretation Provides information to assist in interpretation of the test results

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

A small percentage of individuals who are carriers or have a diagnosis of methylmalonic aciduria and homocystinuria, cblD type (MMADHC) may have a mutation that is not identified by this method (eg, large genomic deletions, promoter mutations). The absence of a mutation, therefore, does not eliminate the possibility of positive carrier status or the diagnosis of MMADHC. For carrier testing, it is important to first document the presence of a MMADHC gene mutation in an affected family member.


In some cases, DNA alterations of undetermined significance may be identified.


Rare polymorphisms exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.


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.  


Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.

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. Suormala T, Baumgartner MR, Coelho D, et al: The cblD Defect Causes Either Isolated or Combined Deficiency of Methylcobalamin and Adenosylcobalamin Synthesis. J Biol Chem 2004;279(41):42742-42749

2. Coelho D, Suormala T, Stucki M, et al: Gene Identification for the cblD Defect of Vitamin B12 Metabolism. N Engl J Med 2008;358:1454-1464

3. Goodman SI, Moe PG, Hammond KB, et al: Homocystinuria with methylmalonic aciduria: two cases in a sibship. Biochem Med 1970;4(5):500-515

4. Cooper BA, Rosenblatt DS, Watkins D: Methylmalonic Aciduria Due to a New Defect in Adenosylcobalamin Accumulation by Cells. Am J Hematol 1990;34:115-120