Methylmalonic Acidemia Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
10295 ACSF3 81479,81479 Order Options and Pricing
ALDH6A1 81479,81479
CD320 81479,81479
MCEE 81479,81479
MLYCD 81479,81479
MMAA 81405,81479
MMAB 81405,81479
MMADHC 81479,81479
MMUT 81406,81479
SUCLA2 81479,81479
SUCLG1 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
10295Genes x (11)81479 81405, 81406, 81479 $930 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our PGxome Custom Panel tool.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

For Reflex to PGxome pricing click here.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View more about turnaround times here.

Targeted Testing

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

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Methylmalonic acidemia (MMA) 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 experience neurological and renal complications. Milder forms of the disease are also known. Today, many cases are detected through routine neonatal screening with tandem mass spectrometry (Fenton et al. 2014; Watkins and Rosenblatt 2014; Manoli et al. 2016).

The MMADHC, MMAA, MMAB, MCEE, MMUT and CD320 genes encode proteins directly related to cobalamin transport or metabolism, or methylmalonyl-CoA metabolism. Defects in these genes have been shown to lead to the development of isolated MMA. Defects in each gene are associated with a specific type of MMA disorder (cblD, cblA, cblB, MCEE, MUT or CD320 deficiency, respectively). The majority of MMA patients have defects in the MMUT gene, followed by the MMAA and then MMAB genes (Manoli et al. 2016). Defects in the MMADHC, MCEE and CD320 genes are rare, having only been reported in a small number of families (Bikker et al. 2006; Dobson et al 2006; Carrillo et al. 2013; Manoli et al. 2016). It should be noted that pathogenic variants in the CD320 gene lead to transient methylmalonic aciduria and/or homocystinuria, which has not been associated with the neurological or hematological symptoms of the cblD, cblA, cblB, mcee or mut deficiency disorders. However, CD320 deficient individuals may be detected via newborn screening (Quadros et al. 2010; Karth et al. 2012; Watkins and Rosenblatt 2014).

This sequencing panel also includes coverage for several genes that do not encode proteins directly involved in cobalamin or methylmalonyl-CoA metabolism. Defects in the ALDH6A1 gene lead to methylmalonate semialdehyde dehydrogenase deficiency (MMSDH), which is an inborn error of valine and thymine metabolism (Chambliss et al. 2000; Marcadier et al. 2013). Defects in the ACSF3 and MLYCD genes lead to combined malonic and methylmalonic aciduria (CMAMMA) (FitzPatrick et al. 1999; Alfares et al. 2011; Sloan et al. 2011; Baertling et al. 2014). Defects in the SUCLA2 and SUCLG1 genes lead to mitochondrial DNA depletion syndromes (MDSs) (Elpeleg et al. 2005; Carrozzo et al. 2007; Ostergaard et al. 2007; Carrozzo et al. 2016). These five genes are included in this panel as defects in all of them have been shown to result in methylmalonic acidemia in at least some patients. Phenotypically, these disorders may be similar or quite different from the cblD, cblA, cblB, mcee or mut types of methylmalonic acidemia.

More details regarding each disorder are available on individual gene test pages.

Genetics

Isolated methylmalonic acidemia (MMA) can result from pathogenic variants in at least six different genes directly associated with inborn errors of cobalamin metabolism or transport, or methylmalonyl-CoA metabolism (MMADHC, MMAA, MMAB, MCEE, MMUT and CD320). In addition, defects in an additional five genes (ACSF3, ALDH6A1, MLYCD, SUCLA2 and SUCLG1) may also lead to methylmalonic acidemia, although these genes are not directly related to cobalamin metabolism or transport or methylmalonyl-CoA metabolism. All of these disorders are inherited in an autosomal recessive manner.

Massively parallel sequencing plus Sanger confirmation will detect the vast majority of sequence variants in the MMADHC, MMAA, MMAB, MCEE, MMUT, CD320, ACSF3, ALDH6A1, MLYCD, SUCLA2 and SUCLG1 genes. It should be noted that large deletions that may not be detectable via sequencing have been reported in the MMAA, MMUT, ACSF3 and SUCLA2 genes (Human Gene Mutation Database).

See individual gene test descriptions for information on molecular biology of gene products.

Clinical Sensitivity - Sequencing with CNV PGxome

The overall clinical sensitivity of this sequencing panel is expected to be high. Based on enzymatic studies of patients with isolated methylmalonic acidemia, Hörster et al. (2007) reported that ~63% of patients can be classified as mut0 or mut -, ~24% as cblA type, and ~13% as cblB type. Two molecular studies of patients diagnosed biochemically, enzymatically and via complementation analysis with isolated methylmalonic acidemia have been fairly consistent with these results. First, Martinez et al. (2005) evaluated 25 MMA patients and found MMUT pathogenic variants in 13 (52%), MMAA pathogenic variants in 7 (28%), and MMAB pathogenic variants in 2 (8%). Merinero et al. (2008) studied 32 patients with isolated MMA and found MMUT causative variants in 19 (59%), MMAA causative variants in 9 (28%), and MMAB causative variants in 4 (13%).

Pathogenic variants in the MMADHC, MCEE, ACSF3, ALDH6A1, CD320, SUCLA2, SUCLG1 and MLYCD genes are expected to make up some fraction of the remaining patients. In one recent study of 131 methylmalonic acidemia/aciduria patients without a diagnosis based on testing of the more commonly involved genes, 8 patients were found to have pathogenic variants in less commonly mutated genes (2 patients with SUCLG1 variants and 5 patients with ACSF3 variants) (Pupavac et al. 2016). Of note, the ALDH6A1 and MLYCD genes were not included in this study.

Nearly all reported pathogenic variants in the eleven genes in this panel (MMUT, MMAA, MMAB, MMADHC, MCEE, ACSF3, ALDH6A1, CD320, MLYCD, SUCLA2 and SUCLG1) are detectable via direct sequencing, so the analytical sensitivity of this sequencing panel is expected to be high.

To date, no gross deletions or insertions have been reported in the MMAB, MMADHC or SUCLG1 genes, and only 1-2 gross deletions have been reported in the MMAA and ACSF3 genes (Nizon et al. 2013; Pupavac et al. 2016). Deletions and duplications appear to be somewhat more common in the MMUT and SUCLA2 genes (Acquaviva et al. 2005; Chu et al. 2016; Forny et al. 2016), though it is difficult to precisely estimate the fraction of patients carrying such large copy number variants. In summary, the sensitivity of duplication/deletion testing for these rare disorders, although not precisely known, is low.

Testing Strategy

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes 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 coverage as ≥20X NGS reads or Sanger sequencing.

In addition to the regions described above, this testing includes coverage of the following deep intronic variant: MCEE c.379-644A>G.

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

Patients with biochemical and/or clinical symptoms suggestive of isolated methylmalonic acidemia (MMA) are good candidates for this test.

Genes

Official Gene Symbol OMIM ID
ACSF3 614245
ALDH6A1 603178
CD320 606475
MCEE 608419
MLYCD 606761
MMAA 607481
MMAB 607568
MMADHC 611935
MMUT 609058
SUCLA2 603921
SUCLG1 611224
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
PGxome®

Citations

  • Acquaviva C. et al. 2005. Human Mutation. 25: 167-76. PubMed ID: 15643616
  • Alfares A. et al. 2011. Journal of Medical Genetics. 48:602-5. PubMed ID: 21785126
  • Baertling F. et al. 2014. European Journal of Pediatrics. 173: 1719-22. PubMed ID: 25233985
  • Bikker H. et al. 2006. Human Mutation. 27: 640-3. PubMed ID: 16752391
  • Carrillo N. et al. 2013. Disorders of Intracellular Cobalamin Metabolism. 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: 20301503
  • Carrozzo R. et al. 2007. Brain 130: 862–74. PubMed ID: 17301081
  • Carrozzo R. et al. 2016. Journal of Inherited Metabolic Disease. 39:243-52 PubMed ID: 26475597
  • Chambliss K.L. et al. 2000. Journal of Inherited Metabolic Disease. 23: 497-504. PubMed ID: 10947204
  • Chu J. et al. 2016. Molecular Genetics and Metabolism. 118: 264-71. PubMed ID: 27233228
  • Dobson C.M. et al. 2006. Molecular Genetics and Metabolism. 88: 327-33. PubMed ID: 16697227
  • Elpeleg O. et al. 2005. American Journal of Human Genetics. 76: 1081-6. PubMed ID: 15877282
  • 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.
  • FitzPatrick D.R. et al. 1999. American Journal of Human Genetics. 65: 318-26. PubMed ID: 10417274
  • Forny P. et al. 2016. Human Mutation. 37: 745-54. PubMed ID: 27167370
  • Hörster F. et al. 2007. Pediatric Research. 62: 225-30. PubMed ID: 17597648
  • Human Gene Mutation Database (Bio-base).
  • Karth et al. 2012. PubMed ID: 22819238
  • 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
  • Marcadier J.L. et al. 2013. Orphanet Journal of Rare Diseases. 8: 98. PubMed ID: 23835272
  • Martínez M.A. et al. 2005. Molecular Genetics and Metabolism. 84: 317-25. PubMed ID: 15781192
  • Merinero B. et al. 2008. Journal of Inherited Metabolic Disease. 31: 55-66. PubMed ID: 17957493
  • Nizon M. et al. 2013. Orphanet Journal of Rare Diseases. 8: 148. PubMed ID: 24059531
  • Ostergaard E. et al. 2007. Brain. 130: 853-61. PubMed ID: 17287286
  • Pupavac et al. 2016. PubMed ID: 26827111
  • Quadros et al. 2010. PubMed ID: 20524213
  • Sloan J.L. et al. 2011. Nature Genetics. 43:883-6. PubMed ID: 21841779
  • Watkins and Rosenblatt. 2014. Inherited Disorders of Folate and Cobalamin Transport and Metabolism. In: Valle D, Beaudet A.L., Vogelstein B, et al., editors. New York, NY: McGraw-Hill. OMMBID.

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

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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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