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Test ID: MHCZ Methylmalonic Aciduria and Homocystinuria, cblC Type, Full Gene Analysis

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

Reflex Tests

Test ID Reporting Name Available Separately Always Performed
CULFB Fibroblast Culture for Genetic Test Yes No

Testing Algorithm

If skin biopsy is received, fibroblast culture for genetic test will be added and charged separately.

Method Name

Polymerase Chain Reaction (PCR) Followed by DNA Sequence Analysis

Reporting Name

MMACHC Gene, Full Gene Analysis

Specimen Type

Varies


Specimen Required


Specimen preferred to arrive within 96 hours of collection.

 

Submit only 1 of the following specimens:

 

Preferred:

Specimen Type: Whole blood

Container/Tube:

Preferred: Lavender top (EDTA) or yellow top (ACD)

Acceptable: Any anticoagulant

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send specimen in original tube.

Specimen Stability Information: Ambient (preferred)/Refrigerated

 

Specimen Type: Cultured fibroblasts

Container/Tube: T-75 or T-25 flask

Specimen Volume: 1 Full T-75 or 2 full T-25 flasks

Specimen Stability Information: Ambient (preferred)/Refrigerated <24 hours

 

Specimen Type: Skin biopsy

Container/Tube: Sterile container with any standard cell culture media (eg, minimal essential media, RPMI 1640). The solution should be supplemented with 1% penicillin and streptomycin. Tubes can be supplied upon request (Eagle's minimum essential medium with 1% penicillin and streptomycin [T115]).

Specimen Volume: 4-mm punch

Specimen Stability Information: Refrigerated (preferred)/Ambient

 

Specimen Type: Blood spot

Container/Tube:

Preferred: Collection card (Whatman Protein Saver 903 Paper)

Acceptable: Ahlstrom 226 filter paper, or Blood Spot Collection Card (T493)

Specimen Volume: 2 to 5 Blood Spots on collection card (Whatman Protein Saver 903 Paper; Ahlstrom 226 filter paper; or Blood Spot Collection Card, T493)

Collection Instructions:

1. An alternative blood collection option for a patient >1 year of age is finger stick.

2. Let blood dry on the filter paper at ambient temperature in a horizontal position for 3 hours.

3. Do not expose specimen to heat or direct sunlight.

4. Do not stack wet specimens.

5. Keep specimen dry

Specimen Stability Information: Ambient (preferred)/Refrigerated


Specimen Minimum Volume

Blood: 1 mL/Blood Spots: 5 punches, 3-mm diameter

Specimen Stability Information

Specimen Type Temperature Time
Varies Varies

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 multiethnic 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.

Reference Values

An interpretive report will be provided.

Interpretation

All detected alterations are evaluated according to American College of Medical Genetics recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

Clinical Reference

1. Richards S, Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015 May;17(5):405-424

2. 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

3. 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

4. Martinelli D, Deodato F, Dionisi-Vici C: Cobalamin C defect: natural history, pathophysiology, and treatment. J Inherit Metab Dis 2011;34(1):127-135

Day(s) and Time(s) Performed

Performed weekly; Varies

Analytic Time

14 days

Test Classification

This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the U.S. Food and Drug Administration.

CPT Code Information

81404-MMACHC (methylmalonic aciduria [cobalamin deficiency] cblC type, with homocystinuria) (eg, methylmalonic acidemia and homocystinuria), full gene sequence

 

Fibroblast Culture for Genetic Test

88233-Tissue culture, skin or solid tissue biopsy (if appropriate)

88240-Cryopreservation (if appropriate)

LOINC Code Information

Test ID Test Order Name Order LOINC Value
MHCZ MMACHC Gene, Full Gene Analysis In Process

 

Result ID Test Result Name Result LOINC Value
53957 Result Summary 50397-9
53958 Result In Process
53959 Interpretation In Process
53960 Additional Information 48767-8
53961 Specimen In Process
53962 Source 31208-2
53963 Released By No LOINC Needed

Forms

1. Molecular Genetics: Biochemical Disorders Patient Information (T527) in Special Instructions

2. New York Clients-Informed consent is required. Please document on the request form or electronic order that a copy is on file. An Informed Consent for Genetic Testing (T576) is available in Special Instructions.

3. If not ordering electronically, complete, print, and send a Benign Hematology Test Request Form (T755) with the specimen (http://www.mayomedicallaboratories.com/it-mmfiles/benign-hematology-test-request-form.pdf)

Mayo Medical Laboratories | Genetics and Pharmacogenomics Catalog Additional Information:

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