Methylmalonic Aciduria and Homocystinuria, cblC Type: MMACHC Gene Deletion/Duplication

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.

For patients with suspected cblC, sequence analysis is recommended as the first step in mutation identification. For patients in whom mutations are not identified by full gene sequencing, deletion/duplication analysis is appropriate.

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Genes (1)


This test is indicated for:

  • Confirmation of a clinical/biochemical diagnosis of cblC in an individual in whom sequence analysis is negative
  • Carrier testing in adults with a family history of cblC in whom sequence analysis is negative


DNA isolated from peripheral blood is hybridized to a CGH array to detect deletions and duplications. The targeted CGH array has overlapping probes which cover the entire genomic region.


Detection is limited to duplications and deletions. The CGH array will not detect point or intronic mutations.

Results of molecular analysis must be interpreted in the context of the patient\'s clinical and/or biochemical phenotype.

Specimen Requirements

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

Sequence analysis is required before deletion/duplication analysis by targeted CGH array. If sequencing is performed outside of EGL Genetics, please submit a copy of the sequencing report with the test requisition.

  • Sequencing analysis of the MMACHC gene is available and is required before deletion/duplication 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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