Methylmalonic Acidemia via the MMUT/MUT Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
9707 MMUT 81406 81406,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
9707MMUT81406 81406, 81479 $890 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

For Reflex to PGxome pricing click here.

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

Turnaround Time

18 days on average

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Methylmalonic acidemia is caused by a deficiency in the activity of the enzyme methylmalonyl-CoA mutase. Methylmalonyl-CoA mutase catalyzes the last step in the breakdown of certain amino acids (met, ile, thr, val), odd-numbered chain length fatty acids, and propionic acid from gut flora (Fenton et al. 2014). Methylmalonic acidemia is typically a severe disease with onset in infancy. Patients may present with lethargy, vomiting, hepatomegaly, acidosis, hypoglycemia and neutropenia. Many patients die in childhood; those that survive often have neurological and renal complications. Milder forms of the disease are also known (Fenton et al. 2014; Manoli et al. 2016). Today, many cases are detected through routine neonatal screening with tandem mass spectrometry.

Genetics

Methylmalonic acidemia is an autosomal recessive disease. The MMUT/MUT gene on chromosome 6 encodes the methylmalonyl-CoA mutase enzyme. Over 250 causative MMUT sequence variants have been reported to date (Acquaviva et al. 2005; Worgan et al. 2006; Human Gene Mutation Database). Of these, nearly 60% are missense, ~20% frameshift, ~15% nonsense, and ~10% splicing. Although founder mutations are known in specific populations, no pathogenic variants are common in the mixed American population.

Methylmalonyl-CoA mutase requires adenosylcobalamin (a vitamin B12 derivative) as a cofactor. Methylmalonic acidemia can be caused pathogenic variants in the MMUT, MMAA, MMAB, MMADHC or MCEE genes, as well as by vitamin B12 deficiency, or by defects in vitamin B12 metabolism. Two types of MUT deficiency are known to exist, and are termed complete (mut0) or partial (mut -) enzyme deficiency based on the amount of detectable residual methylmalonyl-CoA mutase activity (Fenton et al. 2014; Manoli et al. 2016).

Clinical Sensitivity - Sequencing with CNV PGxome

Lempp et al. (2007) detected by genomic DNA sequencing 97% of possible MMUT pathogenic variants in 32 mutase apoenzyme-deficient patients. Similarly, Worgan et al. (2006) detected 96% of pathogenic variants in 160 patients. The fraction of patients with isolated methylmalonic acidemia due to sequence variants in the MMUT gene is estimated to be approximately 60% (Worgan et al. 2006; Hörster et al. 2007; Manoli et al. 2016).

It is difficult to estimate the clinical sensitivity of CNV detection as to date, only one gross deletion has been reported in the MMUT gene (Acquaviva et al. 2005), and no gross insertions have been reported. However, the clinical sensitivity appears to be relatively low.

Testing Strategy

This test provides full coverage of all coding exons of the MMUT gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Indications for Test

Individuals with elevated serum methylmalonic acid are good candidates for this test. Family members of patients known to have MMUT variants are also good candidates, and we will also sequence the MMUT gene to determine carrier status.

Gene

Official Gene Symbol OMIM ID
MMUT 609058
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
Methylmalonic Acidemia Panel

Citations

  • Acquaviva C. et al. 2005. Human Mutation. 25: 167-76. PubMed ID: 15643616
  • Fenton W.A. et al. 2014. Disorders of Propionate and Methylmalonate Metabolism. In: Valle D, Beaudet A.L., Vogelstein B, et al., editors. New York, NY: McGraw-Hill. OMMBID.
  • Hörster F. et al. 2007. Pediatric Research. 62: 225-30. PubMed ID: 17597648
  • Human Gene Mutation Database (Bio-base).
  • Lempp T.J. et al. 2007. Molecular Genetics and Metabolism. 90: 284-90. PubMed ID: 17113806
  • Manoli I. et al. 2016. Isolated Methylmalonic Acidemia. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle PubMed ID: 20301409
  • Worgan L.C. et al. 2006. Human Mutation. 27: 31-43. PubMed ID: 16281286

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

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