• Test code: 06196
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit

Invitae Methylmalonic Acidemia Panel

Test description

The Invitae Methylmalonic Acidemia Panel analyzes up to 18 genes that are associated with methylmalonic acidemia. This test is useful for the diagnosis of patients who are suspected to have methylmalonic acidemia according to clinical symptoms, biochemical findings, or abnormal newborn-screening results. This test can help distinguish patients with methylmalonyl-CoA mutase deficiency from those with defects of intracellular cobalamin metabolism.

Order test

Primary panel (7 genes)


Add-on Combined Malonic and Methylmalonic Acidemia Gene (1 gene)

Pathogenic variants in ACSF3 cause combined malonic and methylmalonic acidemia. In these patients, elevations of methylmalonic acid are usually much greater than malonic acid. Given the biochemical overlap between this disorder and disorders that cause isolated methylmalonic acidemia, this gene can be included at no additional charge.


Add-on Combined Methylmalonic Acidemia and Homocystinuria Genes (10 genes)

Disorders of cobalamin absorption and transport and well as some disorders of intracellular cobalamin metabolism can cause combined methylmalonic acidemia and homocystinuria. Given the biochemical overlap between these disorders and disorders that cause isolated methylmalonic acidemia, these genes can be included at no additional charge.


Alternative tests to consider

The Invitae Organic Acidemias Panel and the Invitae Elevated C3 Panel have been designed to provide a broad genetic analysis of this class of disorders. Depending on the individual’s clinical and family history, one of these broader panels may be appropriate. They can be ordered at no additional cost.

Condition Disorders tested
Primary panel
isolated methylmalonic acidemia methylmalonyl-CoA mutase deficiency
methylmalonyl-CoA epimerase deficiency
cobalamin A deficiency
cobalamin B deficiency
cobalamin D deficiency
succinate-CoA ligase deficiency
Add-on disorders
combined methylmalonic acidemia with homocystinuriacobalamin C deficiency
cobalamin D deficiency
cobalamin F deficiency
cobalamin J deficiency
cobalamin X deficiency
haptocorrin (R binder) deficiency
hereditary intrinsic factor deficiency
Imerslund Gräsbeck syndrome
transcobalamin deficiency
transcobalamin receptor deficiency
combined malonic and methylmalonic acidemiacombined malonic and methylmalonic acidemia

Clinical subtypes:

  • vitamin B12-responsive methylmalonic acidemia
  • vitamin B12-unresponsive methylmalonic acidemia

Isolated methylmalonic acidemia is an inherited biochemical disorder in which certain proteins and fats are not properly broken down and used by the body. Symptoms in patients with methylmalonic acidemia can vary from mild to severe, with severe being the most common presentation. Patients with severe methylmalonic acidemia accumulate toxic levels of methylmalonic acid in the body, which can be detected in the blood and urine, causing metabolic acidosis with an increased anion gap. Other symptoms may include neonatal encephalopathy, poor feeding, failure to thrive, lethargy, vomiting that can lead to seizures, hyperammonemia, coma, and (if untreated in the severe form) death. These patients can also have hypotonia, hepatomegaly, liver dysfunction, and neutropenia, thrombocytopenia, or pancytopenia due to secondary bone-marrow suppression. Others can present with Reye-like syndrome. Milder forms have been reported, such as an acute-intermittent form, where the patient is typically well between attacks of acute metabolic decompensation. Long-term complications may include developmental delay, intellectual disability, extrapyramidal movement disorder, renal tubular acidosis leading to renal failure, and recurrent pancreatitis.

Patients with methylmalonic acidemia typically have several biochemical laboratory findings in addition to elevated methylmalonic acid in blood and urine. These patients will have elevated propionylcarnitine (C3) on newborn screening or plasma acylcarnitine analysis, and they can have elevations of propionate metabolites (3-hydroxypropionic acid, propionylglycine, methylcitric acid, and 3-hydroxyisovaleric acid) in urine. They also have elevated lactate in the blood and urine, ketosis/ketonuria, and elevated glycine on plasma amino acid analysis. These patients will not have the increased CSF:plasma glycine ratio that is seen in patients with glycine encephalopathy.

Methylmalonic acidemia is treatable by lifetime dietary restriction of the amino acids isoleucine, valine, methionine, and threonine and by aggressive intervention during metabolic crises. Dietary therapy must be managed by a nutritionist to prevent malnutrition. Some cases are responsive to pharmacologic doses of vitamin B12. Vitamin B12 treatment does not eliminate the need for dietary intervention, but it reduces the degree of restriction. Some affected individuals have been treated by liver transplant or combined liver/kidney transplant. Determining the underlying molecular cause of methylmalonic acidemia is of great importance because the severity of the mutation (e.g., MUT- vs. MUT0) and vitamin B12-responsiveness can help determine treatment and predict clinical severity.

For patients with isolated methylmalonic acidemia, approximately 97% will have two pathogenic variants in one of seven genes tested in this panel. MUT is the most commonly mutated gene in isolated methylmalonic acidemia patients (60%), followed by MMAA (25%), and MMAB (12%). Pathogenic changes in MMADHC, MCEE, SUCLA2, and SUCLG1 are rare causes of isolated methylmalonic acidemia.

All forms of isolated methylmalonic acidemia are inherited in an autosomal recessive manner.

The general prevalence for isolated methylmalonic acidemia is unknown, but it is estimated at 1 in 60,000 and may be as high as 1 in 11,000 in certain ethnic populations in the U.S. (PMID:22766612). The birth incidence in several subpopulations has been estimated as follows:

  • Mainland China: 1 in 26,000
  • Eastern Saudi Arabia: 1 in 13,000
  • Tunisia: 1 in 16,000
  • Southern Italy: 1 in 45,500

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
ABCD4 NM_005050.3
ACSF3 NM_174917.4
AMN* NM_030943.3
CD320 NM_016579.3
CUBN NM_001081.3
GIF NM_005142.2
HCFC1 NM_005334.2
LMBRD1 NM_018368.3
MCEE NM_032601.3
MMAA NM_172250.2
MMAB NM_052845.3
MMACHC NM_015506.2
MMADHC NM_015702.2
MUT NM_000255.3
SUCLA2 NM_003850.2
SUCLG1 NM_003849.3
TCN1 NM_001062.3
TCN2 NM_000355.3

AMN: Deletion/duplication analysis is not offered for exon 1.