Test Code MPAGP Methylmalonic Aciduria-Propionic Aciduria Combined Gene Panel, Varies

Ordering Guidance

Additional recommended first-tier tests to screen for methylmalonic acidemia include plasma acylcarnitine profile (ACRN / Acylcarnitines, Quantitative, Plasma), quantitative plasma amino acids (AAQP / Amino Acids, Quantitative, Plasma), urine organic acids (OAU / Organic Acids Screen, 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)/Refrigerated

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)

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)

Useful For

Follow up for abnormal biochemical results suggestive of methylmalonic acidemia or propionic acidemia

Establishing a molecular diagnosis for patients with methylmalonic acidemia or propionic acidemia

Identifying variants within genes known to be associated with methylmalonic acidemia or propionic acidemia, allowing for predictive testing of at-risk family members

Special Instructions

Method Name

Sequence Capture and Targeted Next-Generation Sequencing followed by Polymerase Chain Reaction (PCR) and Sanger Sequencing.

Reporting Name

MMA PA Combined Gene Panel

Specimen Type

Varies

Specimen Minimum Volume

See Specimen Required

Specimen Stability Information

Specimen Type	Temperature	Time	Special Container
Varies	Varies

Reject Due To

All specimens will be evaluated at Mayo Clinic Laboratories for test suitability.

Clinical Information

Methylmalonic acidemia (MMA) and propionic acidemia (PA) are defects of propionate metabolism caused by deficiencies in methylmalonyl-CoA mutase and propionyl-CoA carboxylase, respectively. The clinical phenotype includes vomiting, hypotonia, lethargy, apnea, hypothermia, and coma. The biochemical phenotype for MMA includes elevations of propionyl carnitine, methylmalonic acid, and methylcitric acid. Patients with PA will have elevations of propionyl carnitine and methylcitric acid with normal methylmalonic acid concentrations as the enzymatic defect is upstream of methylmalonic-CoA mutase. All known disorders of MMA and PA metabolism are inherited in an autosomal recessive manner.

Newborn screening for inborn errors of propionic acid metabolism relies on elevations of methionine and propionyl carnitine, which are reported as an elevation of C3. These analytes are not specific for this condition and are prone to false-positive results, leading to increased cost, stress, and anxiety for families who are subjected to follow-up testing. Homocysteine, methylmalonic acid, and methylcitric acid are more specific markers for inborn errors of propionic acid metabolism (HCMM / Homocysteine [Total], Methylmalonic Acid, and Methylcitric Acid, Blood Spot).

For MMA, the preferred biochemical screening tests include plasma acylcarnitine profile (ACRN / Acylcarnitines, Quantitative, Plasma), quantitative plasma amino acids (AAQP / Amino Acids, Quantitative, Plasma), urine organic acids (OAU / Organic Acids Screen, Urine), and homocysteine (HCYSP / Homocysteine, Total, Plasma or HCYSS / Homocysteine, Total, Serum).

Molecular genetic testing can be used to confirm a biochemical diagnosis for MMA or PA.

Treatment is most effective when tailored to the specific type of MMA or PA. For example, intramuscular injections of hydroxocobalamin are critical in the treatment of Cbl C, whereas oral cyanocobalamin is effective for MMA mutase subtypes as well as other cobalamin subtypes. Acute treatment for MMA and PA is similar, consisting 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 used with success in treating some patients with MMA or PA.

Reference Values

An interpretive report will be provided.

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)

Day(s) Performed