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HelpTest ID: 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.
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 preferred to arrive within 96 hours of collection.
Specimen Required
Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. For instructions for testing patients who have received a bone marrow transplant, call 800-533-1710.
Submit only 1 of the following specimens:
Specimen Type: Whole blood
Container/Tube: Lavender top (EDTA) or yellow top (ACD)
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 14 days
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: Refrigerated (preferred)/Ambient
Additional Information: A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing. An additional 3 to 4 weeks is required to culture fibroblasts before genetic testing can occur.
Specimen Type: Cultured fibroblast
Container/Tube: T-25 flask
Specimen Volume: 2 Flasks
Collection Instructions: Submit confluent cultured fibroblast cells from a skin biopsy from another laboratory. Cultured cells from a prenatal specimen will not be accepted.
Specimen Stability Information: Ambient (preferred)/Refrigerated (<24 hours)
Additional Information: A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing. An additional 3 to 4 weeks is required to culture fibroblasts before genetic testing can occur.
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 (formerly Ahlstrom 226) filter paper or blood spot collection card
Specimen Volume: 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 Dried Blood Spot Samples.
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.
Specimen Stability Information: Ambient (preferred)/Refrigerated
Additional Information:
1. Due to lower concentration of DNA yielded from blood spot, it is possible that additional specimen may be required to complete testing.
2. For collection instructions, see Blood Spot Collection Instructions
3. For collection instructions in Spanish, see Blood Spot Collection Card-Spanish Instructions (T777)
4. For collection instructions in Chinese, see Blood Spot Collection Card-Chinese Instructions (T800)
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: 1 Swab
Collection Instructions: Collect and send specimen per kit instructions.
Specimen Stability Information: Ambient 30 days
Additional Information: Due to lower concentration of DNA yielded from saliva, it is possible that additional specimen may be required to complete testing.
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.
Useful For
Follow up for abnormal biochemical results suggestive of a methylmalonic acidemia
Establishing a molecular diagnosis for patients with methylmalonic acidemia
Identifying variants within genes known to be associated with methylmalonic acidemia, allowing for predictive testing of at-risk family members
Genetics Test Information
This test utilizes next-generation sequencing to detect single nucleotide and copy number variants in 25 genes associated with methylmalonic aciduria: ABCD4, ACSF3, ALDH6A1, AMN, CD320, CUBN, CBLIF, HCFC1, LMBRD1, MCEE, MMAA, MMAB, MMACHC, MMADHC, MTHFR, MTR, MTRR, MMUT, PRDX1, SUCLA2, SUCLG1, TCN1, TCN2, THAP11, ZNF143. For additional details see Method Description or Targeted Genes and Methodology Details for Methylmalonic Aciduria Gene Panel.
Identification of a pathogenic variant may assist with diagnosis, prognosis, clinical management, familial screening, and genetic counseling for methylmalonic aciduria.
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 | Special Container |
|---|---|---|---|
| Varies | Varies | ||
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.
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;17(5):405-424
2. Fenton WA, Gravel RA, Rosenblatt DS. Disorders of propionate and methylmalonate metabolism. In: Valle D, Antonarakis S, Ballabio A, Beaudet A, Mitchell GA, eds. The Online Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill Education; 2019. Accessed March 8, 2024. Available at: http://ommbid.mhmedical.com/content.aspx?bookid=2709§ionid=225086103
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
Report Available
28 to 42 daysReflex Tests
| Test ID | Reporting Name | Available Separately | Always Performed |
|---|---|---|---|
| CULFB | Fibroblast Culture for Genetic Test | Yes | No |
Testing Algorithm
For skin biopsy or cultured fibroblast specimens, fibroblast culture testing will be performed at an additional charge. If viable cells are not obtained, the client will be notified.
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