Invitae Methylmalonic Acidemia Panel


Test description

The Invitae Methylmalonic Acidemia Panel analyzes five 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.

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Primary panel (5 genes)


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
Isolated methylmalonic acidemia Methylmalonyl-CoA mutase deficiency; Cobalamin A deficiency; Cobalamin B deficiency; Cobalamin D deficiency
Combined methylmalonic acidemia with homocystinuria Cobalamin C deficiency; Cobalamin D deficiency

Clinical subtypes:

  • Vitamin B12-responsive methylmalonic acidemia
  • Vitamin B12-unresponsive methylmalonic acidemia

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 elevated 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. Patients with deficiencies of both adenosylcobalamin and methylcobalamin (Cobalamin C deficiency and some forms of Cobalamin D deficiency), will also have low methionine in plasma with elevated total plasma homocysteine.

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 four genes tested in this panel. MUT is the most commonly mutated gene in isolated methylmalonic acidemia patients (60%), followed by MMAA (25%), MMAB (12%), and MMADHC (rare).

MMACHC is the most common cause of combined methylmalonic acidemia and homocystinuria and is therefore included in this panel as a differential.

Methylmalonic acidemia is 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.. 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, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
MMAA NM_172250.2
MMAB NM_052845.3
MMACHC NM_015506.2
MMADHC NM_015702.2
MUT NM_000255.3