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

Useful For

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

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

MMADHC 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/Frozen

 

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

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.

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. 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

3. 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

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

5. 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

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

81479-Unlisted molecular pathology procedure

 

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
MHDZ MMADHC Gene, Full Gene Analysis In Process

 

Result ID Test Result Name Result LOINC Value
53992 Result Summary 50397-9
53993 Result In Process
53994 Interpretation In Process
53995 Additional Information 48767-8
53996 Specimen In Process
53997 Source 31208-2
53998 Released By No LOINC Needed

Forms

1. 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.

2. Molecular Genetics: Biochemical Disorders Patient Information (T527) 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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