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HelpTest Code MMAGP Methylmalonic Aciduria Gene Panel, Varies
Ordering Guidance
The recommended first-tier tests to screen for methylmalonic aciduria include plasma acylcarnitine profile (ACRN / Acylcarnitines, Quantitative, Plasma), quantitative plasma amino acids (AAQP / Amino Acids, Quantitative, Plasma), urine organic acids (OAU / Organic Acids Screen, Random, Urine), and homocysteine (HCYSP / Homocysteine, Total, Plasma or HCYSS / Homocysteine, Total, Serum).
Customization of this panel and single gene analysis for any gene present on this panel is available. For more information see CGPH / Custom Gene Panel, Hereditary, Next-Generation Sequencing, Varies. To modify this panel via CGPH, please use the Inborn Errors of Metabolism disease state for step 1 on the custom gene ordering tool.
Targeted testing for familial variants (also called site-specific or known mutations testing) is available for the genes on this panel. See FMTT / Familial Variant, Targeted Testing, Varies. To obtain more information about this testing option, call 800-533-1710.
Shipping Instructions
Specimen Required
Patient Preparation: A previous hematopoietic stem cell transplant from an allogenic donor will interfere with testing. For information about testing patients who have received a hematopoietic stem cell transplant, call 800-533-1710.
Submit only 1 of the following specimens:
Specimen Type: Whole blood
Container/Tube:
Preferred: Lavender top (EDTA) or yellow top (ACD)
Acceptable: Green top (Sodium heparin)
Specimen Volume: 3 mL
Collection Instructions:
1. Invert several times to mix blood.
2. Send whole blood specimen in original tube. Do not aliquot.
Specimen Stability Information: Ambient (preferred) 4 days/Refrigerated 4 days/Frozen 4 days
Additional Information:
1. Specimens are preferred to be received within 4 days of collection. Extraction will be attempted for specimens received after 4 days, and DNA yield will be evaluated to determine if testing may proceed.
2. To ensure minimum volume and concentration of DNA is met, the requested volume must be submitted. Testing may be canceled if DNA requirements are inadequate.
Specimen Type: Cord blood
Container/Tube:
Preferred: Lavender top (EDTA) or yellow top (ACD)
Acceptable: Green top (Sodium heparin)
Specimen Volume: 3 mL
Collection Instructions:
1. Invert several times to mix blood.
2. Send cord blood specimen in original tube. Do not aliquot.
Specimen Stability Information: Ambient (preferred) 4 days/Refrigerated 4 days/Frozen 4 days
Additional Information:
1. Specimens are preferred to be received within 4 days of collection. Extraction will be attempted for specimens received after 4 days, and DNA yield will be evaluated to determine if testing may proceed.
2. To ensure minimum volume and concentration of DNA is met, the requested volume must be submitted. Testing may be canceled if DNA requirements are inadequate.
3. While a properly collected cord blood sample may not be at risk for maternal cell contamination, unanticipated complications may occur during collection. Therefore, maternal cell contamination studies are recommended to ensure the test results reflect that of the patient tested and are available at an additional charge. Order MATCC / Maternal Cell Contamination, Molecular Analysis, Varies on the maternal specimen.
Specimen Type: Saliva
Patient Preparation: Patient should not eat, drink, smoke, or chew gum 30 minutes prior to collection.
Supplies: Saliva Swab Collection Kit (T786)
Specimen Volume: 2 Swabs
Collection Instructions: Collect and send specimen per kit instructions.
Specimen Stability Information: Ambient (preferred) 30 days/Refrigerated 30 days
Additional information: Saliva specimens are acceptable but not recommended. Due to lower quantity/quality of DNA yielded from saliva, some aspects of the test may not perform as well as DNA extracted from a whole blood sample. When applicable, specific gene regions that were unable to be interrogated will be noted in the report. Alternatively, additional specimen may be required to complete testing.
Specimen Type: Blood spot
Supplies: Card-Blood Spot Collection (Filter Paper) (T493)
Container/Tube:
Preferred: Collection card (Whatman Protein Saver 903 Paper)
Acceptable: PerkinElmer 226 filter paper or blood spot collection card
Specimen Volume: 2 to 5 Blood spots
Collection Instructions:
1. An alternative blood collection option for a patient older than 1 year is a fingerstick. For detailed instructions, see How to Collect a Dried Blood Spot Sample.
2. Let blood dry on the filter paper at ambient temperature in a horizontal position for a minimum of 3 hours.
3. Do not expose specimen to heat or direct sunlight.
4. Do not stack wet specimens.
5. Keep specimen dry
Send: Ambient (preferred)/Refrigerated
Additional Information:
1. Blood spot specimens are acceptable but not recommended. Due to lower quantity/quality of DNA yielded from blood spots, some aspects of the test may not perform as well as DNA extracted from a whole blood sample. When applicable, specific gene regions that were unable to be interrogated will be noted in the report. Alternatively, additional specimen may be required to complete testing.
2. Due to lower concentration of DNA yielded from blood spot, it is possible that additional specimen may be required to complete testing.
3. For collection instructions, see Blood Spot Collection Instructions
4. For collection instructions in Spanish, see Blood Spot Collection Card-Spanish Instructions (T777)
5. For collection instructions in Chinese, see Blood Spot Collection Card-Chinese Instructions (T800)
Specimen Type: Cultured fibroblasts
Source: Skin
Container/Tube: T-25 flask
Specimen Volume: 2 Flasks
Collection Instructions: Submit confluent cultured fibroblast cells from a skin biopsy. Cultured cells from a prenatal specimen will not be accepted.
Specimen Stability Information: Ambient (preferred) <24 hours/Refrigerated <24 hours
Additional Information:
1. Specimens are preferred to be received within 24 hours of collection. Culture and/or extraction will be attempted for specimens received after 24 hours and will be evaluated to determine if testing may proceed.
2. A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing. An additional 3 to 4 weeks are required to culture fibroblasts before genetic testing can occur.
Specimen Type: Skin biopsy
Supplies: Fibroblast Biopsy Transport Media (T115)
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.
Specimen Volume: 4-mm punch
Specimen Stability Information: Ambient (preferred) <24 hours/Refrigerated <24 hours
Additional Information:
1. Specimens are preferred to be received within 24 hours of collection. Culture and/or extraction will be attempted for specimens received after 24 hours and
will be evaluated to determine if testing may proceed.
2. A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing. An additional 3 to 4 weeks are required
to culture fibroblasts before genetic testing can occur.
Specimen Type: Extracted DNA
Container/Tube:
Preferred: Screw Cap Micro Tube, 2mL with skirted conical base
Acceptable: Matrix tube, 1mL
Collection Instructions:
1. The preferred volume is at least 100 mcL at a concentration of 75 ng/mcL.
2. Include concentration and volume on tube.
Specimen Stability Information: Frozen (preferred) 1 year/Ambient/Refrigerated
Additional Information: DNA must be extracted in a CLIA-certified laboratory or equivalent and must be extracted from a specimen type listed as acceptable for this test (including applicable anticoagulants). Our laboratory has experience with Chemagic, Puregene, Autopure, MagnaPure, and EZ1 extraction platforms and cannot guarantee that all extraction methods are compatible with this test. If testing fails, one repeat will be attempted, and if unsuccessful, the test will be reported as failed and a charge will be applied. If applicable, specific gene regions that were unable to be interrogated due to DNA quality will be noted in the report.
PRENATAL SPECIMENS
Due to its complexity, consultation with the laboratory is required for all prenatal testing; call 800-533-1710 to speak to a genetic counselor.
Specimen Type: Amniotic fluid
Container/Tube: Amniotic fluid container
Specimen Volume: 20 mL
Specimen Stability Information: Ambient (preferred) <24 hours/Refrigerated <24 hours
Additional Information: Specimen will only be tested after culture.
1. Specimens are preferred to be received within 24 hours of collection. Culture and extraction will be attempted for specimens received after 24 hours and will be evaluated to determine if testing may proceed.
2. A separate culture charge will be assessed under CULAF / Culture for Genetic Testing, Amniotic Fluid. An additional 2 to 3 weeks are required to culture amniotic fluid before genetic testing can occur.
3. All prenatal specimens must be accompanied by a maternal blood specimen; order MATCC / Maternal Cell Contamination, Molecular Analysis, Varies on the maternal specimen.
Specimen Type: Confluent cultured amniocytes
This does not include cultured chorionic villi.
Container/Tube: T-25 flask
Specimen Volume: 2 Flasks
Collection Instructions: Submit confluent cultured cells from another laboratory
Specimen Stability Information: Ambient (preferred) <24 hours/Refrigerated <24 hours
Additional Information:
1. Specimens are preferred to be received within 24 hours of collection. Culture and extraction will be attempted for specimens received after 24 hours and will be evaluated to determine if testing may proceed.
2. A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing.
3. All prenatal specimens must be accompanied by a maternal blood specimen; order MATCC / Maternal Cell Contamination, Molecular Analysis, Varies on the maternal specimen.
Specimen Type: Chorionic villi
Container/Tube: 15-mL tube containing 15 mL of transport media
Specimen Volume: 20 mg
Specimen Stability Information: Ambient (preferred) <24 hours/Refrigerated <24 hours
Additional Information: Specimen will only be tested after culture.
1. Specimens are preferred to be received within 24 hours of collection. Culture and extraction will be attempted for specimens received after 24 hours and will be evaluated to determine if testing may proceed.
2. A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing. An additional 3 to 4 weeks are required to culture fibroblasts before genetic testing can occur.
3. All prenatal specimens must be accompanied by a maternal blood specimen; order MATCC / Maternal Cell Contamination, Molecular Analysis, Varies on the maternal specimen.
Specimen Type: Cultured chorionic villi
Container/Tube: T-25 flasks
Specimen Volume: 2 full flasks
Collection Instructions: Submit confluent cultured cells from another laboratory
Specimen Stability Information: Ambient (preferred) <24 hours/Refrigerated <24 hours
Additional Information:
1. Specimens are preferred to be received within 24 hours of collection. Culture and extraction will be attempted for specimens received after 24 hours and will be evaluated to determine if testing may proceed.
2. A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing.
3. All prenatal specimens must be accompanied by a maternal blood specimen; order MATCC / Maternal Cell Contamination, Molecular Analysis, Varies on the maternal specimen.
Forms
1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available:
-Informed Consent for Genetic Testing (T576)
-Informed Consent for Genetic Testing (Spanish) (T826)
2. Molecular Genetics: Biochemical Disorders Patient Information (T527)
3. If not ordering electronically, complete, print, and send a Biochemical Genetics Test Request (T798) with the specimen.
Secondary ID
608021Useful For
Follow up for abnormal biochemical results suggestive of a methylmalonic acidemia (MMA)
Establishing a molecular diagnosis for patients with MMA
Identifying variants within genes known to be associated with MMA, allowing for predictive testing of at-risk family members
Special Instructions
- Molecular Genetics: Biochemical Disorders Patient Information
- Informed Consent for Genetic Testing
- Blood Spot Collection Card-Spanish Instructions
- Blood Spot Collection Card-Chinese Instructions
- Informed Consent for Genetic Testing (Spanish)
- Blood Spot Collection Instructions
- Targeted Genes and Methodology Details for Methylmalonic Aciduria Gene Panel
Method Name
Sequence Capture and Targeted Next-Generation Sequencing (NGS) followed by Polymerase Chain Reaction (PCR) and Sanger Sequencing
Reporting Name
Methylmalonic Aciduria Gene PanelSpecimen Type
VariesSpecimen Minimum Volume
See Specimen Required
Specimen Stability Information
| Specimen Type | Temperature | Time |
|---|---|---|
| Varies | Varies | |
Reject Due To
All specimens will be evaluated at Mayo Clinic Laboratories for test suitability.Clinical Information
Elevated levels of methylmalonic acid (MMA) result from inherited defects of enzymes involved in MMA metabolism. MMA is a specific diagnostic marker for the group of disorders collectively called methylmalonic acidemia, which include at least 7 different complementation groups. Two of them (mut0 and mut-) reflect deficiencies of the apoenzyme portion of the enzyme methylmalonyl-CoA mutase caused by pathogenic variants in the mutase gene (MUT). Two other disorders (CblA and CblB) are associated with abnormalities of the adenosylcobalamin (Cbl) synthesis pathway. CblC, CblD, and CblF deficiencies lead to impaired synthesis of both adenosyl- and methylcobalamin.
Since the first reports of this disorder in 1967, hundreds of cases have been diagnosed worldwide. Newborn screening identifies approximately 1 in 30,000 live births with methylmalonic acidemia. The most frequent clinical manifestations are neonatal or infantile metabolic ketoacidosis, failure to thrive, and developmental delay. Excessive protein intake may cause life-threatening episodes of metabolic decompensation and remains a life-long risk unless treatment is closely monitored, including plasma and urine MMA levels (MMAP / Methylmalonic Acid, Quantitative, Plasma and MMAU / Methylmalonic Acid, Quantitative, Urine).
Plasma acylcarnitine profile (ACRN / Acylcarnitines, Quantitative, Plasma), quantitative plasma amino acids (AAQP / Amino Acids, Quantitative, Plasma), urine organic acids (OAU / Organic Acids Screen, Random, Urine), and homocysteine (HCYSP / Homocysteine, Total, Plasma or HCYSS / Homocysteine, Total, Serum) are recommended first-tier biochemical tests to screen patients for methylmalonic acidemia.
A comprehensive gene panel is a helpful tool to establish a targeted diagnosis for patients with suggestive clinical and biochemical features of methylmalonic acidemia.
Treatment is most effective when tailored to the specific type of methylmalonic acidemia. For example, intramuscular injections of hydroxocobalamin are critical in the treatment of CblC, whereas oral cyanocobalamin is effective for methylmalonic acidemia mutase subtypes as well as other cobalamin subtypes. Acute treatment for methylmalonic acidemia consists of dialysis and administration of nitrogen scavenger drugs to reduce ammonia concentration. Chronic management typically involves restriction of dietary protein with essential amino acid supplementation. More recently, liver transplantation has been successful in treating some patients.
Reference Values
An interpretive report will be provided.
Interpretation
All detected alterations are evaluated according to American College of Medical Genetics and Genomics recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.
Method Description
Next-generation sequencing (NGS) and/or Sanger sequencing are performed to test for the presence of variants in coding regions and intron/exon boundaries of the genes analyzed, as well as some other regions that have known disease-causing variants. The human genome reference GRCh37/hg19 build was used for sequence read alignment. At least 99% of the bases are covered at a read depth over 30X. Sensitivity is estimated to be over 99% for single nucleotide variants, over 94% for deletions-insertions (delins) less than 40 base pairs (bp), and over 95% for deletions up to 75 bp and insertions up to 47 bp. NGS and/or a polymerase chain reaction-based quantitative method is performed to test for the presence of deletions and duplications in the genes analyzed.
There may be regions of genes that cannot be effectively evaluated by sequencing or deletion and duplication analysis as a result of technical limitations of the assay, including regions of homology, high guanine-cytosine (GC) content, and repetitive sequences. For details regarding the targeted genes analyzed and the specific gene regions not routinely covered, see Targeted Genes and Methodology Details for Methylmalonic Aciduria Gene Panel.(Unpublished Mayo method)
Genes analyzed: ABCD4, ACSF3, ALDH6A1, AMN, CD320, CUBN, CBLIF, HCFC1, LMBRD1, MCEE, MMAA, MMAB, MMACHC, MMADHC, MTHFR, MTR, MTRR, MMUT, PRDX1, SUCLA2, SUCLG1, TCN1, TCN2, THAP11, and ZNF143
Performing Laboratory
Mayo Clinic Laboratories in Rochester
Test Classification
This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. It has not been cleared or approved by the US Food and Drug Administration.CPT Code Information
81443
88233-Tissue culture, skin, solid tissue biopsy (if appropriate)
88240-Cryopreservation (if appropriate)
LOINC Code Information
| Test ID | Test Order Name | Order LOINC Value |
|---|---|---|
| MMAGP | Methylmalonic Aciduria Gene Panel | 105347-9 |
| Result ID | Test Result Name | Result LOINC Value |
|---|---|---|
| 608656 | Test Description | 62364-5 |
| 608657 | Specimen | 31208-2 |
| 608658 | Source | 31208-2 |
| 608659 | Result Summary | 50397-9 |
| 608660 | Result | 82939-0 |
| 608661 | Interpretation | 69047-9 |
| 608662 | Resources | 99622-3 |
| 608663 | Additional Information | 48767-8 |
| 608664 | Method | 85069-3 |
| 608665 | Genes Analyzed | 48018-6 |
| 608666 | Disclaimer | 62364-5 |
| 608667 | Released By | 18771-6 |
Day(s) Performed
Varies
Reflex Tests
| Test ID | Reporting Name | Available Separately | Always Performed |
|---|---|---|---|
| CULFB | Fibroblast Culture for Genetic Test | Yes | No |
| MATCC | Maternal Cell Contamination, B | Yes | No |
| CULAF | Amniotic Fluid Culture/Genetic Test | Yes | No |
Testing Algorithm
Prenatal specimens only:
If an amniotic fluid specimen or cultured amniocytes are received, an amniotic fluid culture will be performed at an additional charge.
If a chorionic villi specimen or cultured chorionic villi are received, a fibroblast culture will be performed at an additional charge.
For any prenatal specimen that is received, maternal cell contamination testing will be performed at an additional charge.
Skin biopsy or cultured fibroblast specimens:
For skin biopsy or cultured fibroblast specimens, a fibroblast culture will be performed at an additional charge.