Methylmalonic Aciduria and Homocystinuria, cblC Type: MMACHC Gene Sequencing

Condition Description

VitaminB12 (cobalamin)is a cofactor required by two enzymes, methionine synthase (MTR) andmethylmalonyl-CoA mutase (MUT). Disorders of intracellular cobalamin metabolismmay impair the function of either or both enzymes:

o        Clinical syndromes involvingdefects in MUT function alone are called methylmalonicacidemia. Such defects can be caused by defective MUT enzyme ormissing B12 cofactor. Certain subtypes of methylmalonic acidemia maybe further defined by complementation analysis. Complementation groups causing isolated methylmalonic acidemia include cblA and cblB.

o        Clinical syndromes involvingdefective MTR function can be caused by defective MTR enzyme, missing cofactor,or defects in an enzyme that regenerates MTR: methionine synthase reductase(MTRR). Defective MTR function is associated with variable hyperhomocysteinemiaand/or homocystinuria.

o        Disorders that cause isolated defects in MTR function, as well as disorders that cause combined defects inboth MTR and MUT function, are named by complementation group. MTR-only andcombined MUT/MTR cobalamin disorders include cblC, cblD, cblD variant 1, cblDvariant 2, cblE, cblF, and cblG

Theclinical manifestations of disorders of intracellular cobalamin metabolism,identified by complementation class as cblC, cblD, cblD variant 1, cblD variant2, cblF, cblE, and cblG, can be highly variable even within a singlecomplementation class. cblC is the most common of these disorders. The age ofinitial presentation of cblC ranges from (1) newborns who can be small forgestational age (SGA)and have microcephaly; to (2) infants who can have poor feeding, failure tothrive, pallor, and neurologic signs, and occasionally hemolytic uremicsyndrome (HUS) and/or seizures including infantile spasms; to (3) toddlers whocan have failure to thrive, poor head growth, cytopenias (including megaloblasticanemia), global developmental delay, encephalopathy, and neurologic signs suchas hypotonia and seizures; and to (4) young adults/adults who can haveconfusion, other mental status changes, cognitive decline, and megaloblasticanemia.

Metabolic screening tests such as urine organic acid analysis and plasma amino acid analysis helpcategorize the clinical syndrome. Analysis in specialized laboratories canestablish the specific complementation class. Mutations in the MMACHC (1p34.1)gene cause cblC. The role of molecular genetictesting in diagnosis is evolving; molecular genetictesting may be faster and less expensivethan complementation class analysis in establishing a specific diagnosis in afamily.

Alldisorders of intracellular cobalamin metabolism are inherited in an autosomalrecessive manner. Heterozygotes (carriers) are asymptomatic.

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Genes (1)


This test is indicated for:

  • Confirmation of a clinical/biochemical diagnosis of cblC
  • Carrier testing in adults with a family history of cblC


PCR amplification of 5 exons contained in the MMACHC gene is performed on the patient\'s genomic DNA. Direct sequencing of amplification products is performed in both forward and reverse directions, using automated fluorescence dideoxy sequencing methods. The patient\'s gene sequences are then compared to a normal reference sequence. Sequence variations are classified as mutations, benign variants unrelated to disease, or variations of unknown clinical significance. Variants of unknown clinical significance may require further studies of the patient and/or family members. This assay does not interrogate the promoter region, deep intronic regions, or other regulatory elements, and does not detect large deletions.


Clinical Sensitivity: Unknown. Mutations in the promoter region, some mutations in the introns and other regulatory element mutations cannot be detected by this analysis. Large deletions will not be detected by this analysis. Results of molecular analysis should be interpreted in the context of the patient\'s biochemical phenotype.

Analytical Sensitivity: ~99%

Specimen Requirements

Listed below are EGL's preferred sample criteria. For any questions, please call 470.378.2200 and ask to speak with client services (
Submit only 1 of the following specimen types

Oragene™ Saliva Collection Kit
Orangene™ Saliva Collection Kit used according to manufacturer instructions. Please contact EGL for a Saliva Collection Kit for patients that cannot provide a blood sample.
Collection and Shipping
Please do not refrigerate or freeze saliva sample. Please store and ship at room temperature.
Whole Blood (EDTA)

EDTA (Purple Top)
Infants and Young Children (<2 years of age): 2-3 ml
Children > 2 years of age to 10 years old: 3-5 ml
Older Children & Adults: 5-10 ml
Autopsy: 2-3 ml unclotted cord or cardiac blood
Collection and Shipping
Ship sample at room temperature for receipt at EGL within 72 hours of collection. Do not freeze.
DNA, Isolated

Isolation using the Perkin Elmer™Chemagen™ Chemagen™ Automated Extraction method or Qiagen™ Puregene kit for DNA extraction is recommended.
Collection and Shipping
Refrigerate until time of shipment in 100 ng/µL in TE buffer. Ship sample at room temperature with overnight delivery.

Special Instructions

Submit copies of diagnostic biochemical test results with the sample, if appropriate. Contact the laboratory if further information is needed.

  • Deletion/duplication analysis of the MMACHC gene is also available.
  • Custom diagnostic mutation analysis (KM) is available to family members if mutations are identified by targeted mutation testing or sequencing analysis.
  • Prenatal testing is available to couples who are confirmed carriers of mutations. Please contact the laboratory genetic counselor to discuss appropriate testing prior to collecting a prenatal specimen.

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