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  • Test code: 06141
  • 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
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Invitae Combined Methylmalonic Acidemia and Homocystinuria Panel

Test description

The Invitae Combined Methylmalonic Acidemia and Homocystinuria Panel analyzes 11 genes that are associated with methylmalonic acidemia and homocystinuria. This test is useful for the diagnosis of patients who are suspected to have a combined defect of cobalamin metabolism based on clinical symptoms, biochemical findings, or abnormal newborn-screening results.

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Primary panel (11 genes)

ABCD4 AMN CD320 CUBN GIF HCFC1 LMBRD1 MMACHC MMADHC TCN1 TCN2

Alternative tests to consider

For a broader analysis of the genetics of organic acidemias:

Gene Disorders
ABCD4 Cobalamin J deficiency
AMN Imerslund-Gräsbeck syndrome
CD320 Transcobalamin receptor deficiency
CUBN Imerslund-Gräsbeck syndrome
GIF Hereditary intrinsic factor deficiency
HCFC1 Cobalamin X deficiency
LMBRD1 Cobalamin F deficiency
MMACHC Cobalamin C deficiency
MMADHC Cobalamin D deficiency
TCN1 Haptocorrin (R binder) deficiency
TCN2 Transcobalamin deficiency

Defects in the absorption, transport, and some steps of intracellular metabolism of cobalamin cause combined methylmalonic acidemia and homocystinuria. Cobalamin (vitamin B12) is metabolized in cells to the active forms methylcobalamin and adenosylcobalamin, which are cofactors for methylmalonyl-CoA mutase and methionine synthase, respectively. Disorders which affect the metabolism of both of these cofactors lead to combined methylmalonic acidemia and homocystinuria.

Patients with a disorder affecting the transport or absorption of cobalamin typically start showing symptoms within the first few months of life or the first few years of life, depending on the underlying disorder. In some cases, onset may be into adolescence or adulthood. Symptoms typically include megaloblastic anemia and neurological symptoms such as developmental delay, neuropathy, myelopathy, spasticity, ataxia, and cerebral atrophy. Other features that may be present, depending on the underlying disorder, include failure to thrive, irritability, proteinuria, diarrhea, hepatosplenomegaly, and others.

Cobalamin C (cblC) deficiency is the most common disorder of intracellular cobalamin metabolism, affecting both adenosylcobalamin and methylcobalamin production. CblC displays wide clinical heterogeneity, with age of onset from prenatal to adulthood, but the infantile presentation is the most widely recognized. Infants often present with failure to thrive, macrocytic anemia, hypotonia, and developmental delay; some develop hemolytic uremic syndrome or acute metabolic encephalopathy that can be lethal if untreated. Additional findings may include congenital heart defects or cardiomyopathy and seizures. Long-term complications are primarily neurologic and also include progressive retinopathy without lens dislocation. Adolescent and adult presentations manifest predominantly with neurologic (cognitive decline) and neuropsychiatric symptoms. Treatment consists of normalizing abnormal methylmalonic acid and homocysteine levels with pharmacologic doses of hydroxocobalamin (also known as hydroxycobalamin), homocysteine-lowering medications, and aggressive intervention during metabolic crisis. Use of dietary amino acid restriction remains controversial. Patients with Cobalamin D, F, J, and X deficiencies have similar clinical features.

Patients with combined methylmalonic acidemia and homocystinuria typically have several biochemical laboratory findings in addition to elevated methylmalonic acid and homocysteine in blood and urine. These patients can 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 low methionine on plasma amino acid analysis.

For patients with combined methylmalonic acidemia and homocystinuria, it is estimated that greater than 95% will have two pathogenic variants in one of the genes tested in this panel.

Most forms of combined methylmalonic acidemia and homocystinuria are are inherited in an autosomal recessive manner. Cobalamin X deficiency is inherited in an X-linked manner.

Cobalamin C deficiency is the most common cause of combined methylmalonic acidemia and homocystinuria with an estimated incidence of 1 in 200,000, but US newborn screening programs have suggested that the incidence is approximately 1 in 100,000 in New York state and 1 in 37,000 among the California Hispanic population. The other causes of combined methylmalonic acidemia and homocystinuria are rare.

This test may be appropriate for patients with:

  • methylmalonic acidemia and homocystinuria with low plasma methionine
  • low serum cobalamin
  • symptoms including megaloblastic anemia with neurological findings
  • older patients with unexplained onset of neuropsychiatric findings

  1. Lerner-Ellis, JP, et al. Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype-phenotype correlations. Hum. Mutat. 2009; 30(7):1072-81. PMID: 19370762
  2. Fischer, S, et al. Clinical presentation and outcome in a series of 88 patients with the cblC defect. J. Inherit. Metab. Dis. 2014; 37(5):831-40. PMID: 24599607
  3. Carrillo-Carrasco, N, et al. Disorders of Intracellular Cobalamin Metabolism. 2008 Feb 25. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301503
  4. Feuchtbaum, L, et al. Birth prevalence of disorders detectable through newborn screening by race/ethnicity. Genet. Med. 2012; 14(11):937-45. PMID: 22766612
  5. Huemer, M, et al. Guidelines for diagnosis and management of the cobalamin-related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency. J. Inherit. Metab. Dis. 2017; 40(1):21-48. PMID: 27905001
  6. Yu, HC, et al. An X-linked cobalamin disorder caused by mutations in transcriptional coregulator HCFC1. Am. J. Hum. Genet. 2013; 93(3):506-14. PMID: 24011988
  7. Coelho, D, et al. Mutations in ABCD4 cause a new inborn error of vitamin B12 metabolism. Nat. Genet. 2012; 44(10):1152-5. PMID: 22922874
  8. Tanner, SM, et al. Inherited cobalamin malabsorption. Mutations in three genes reveal functional and ethnic patterns. Orphanet J Rare Dis. 2012; 7:56. PMID: 22929189
  9. Rutsch, F, et al. Identification of a putative lysosomal cobalamin exporter altered in the cblF defect of vitamin B12 metabolism. Nat. Genet. 2009; 41(2):234-9. PMID: 19136951
  10. Yildirim, ZK, et al. Seven Patients With Transcobalamin Deficiency Diagnosed Between 2010 and 2014: A Single-Center Experience. J. Pediatr. Hematol. Oncol. 2017; 39(1):38-41. PMID: 27824740
  11. Watkins D, Rosenblatt DS, Fowler B. Inborn metabolic diseases: diagnosis and treatment. 5th ed. Heidelberg: Springer; 2012. Chapter 28, Disorders of Cobalamin and Folate Transport and Metabolism; p. 385-402.

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 in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

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
AMN NM_030943.3
CD320 NM_016579.3
CUBN* NM_001081.3
GIF NM_005142.2
HCFC1 NM_005334.2
LMBRD1 NM_018368.3
MMACHC NM_015506.2
MMADHC NM_015702.2
TCN1 NM_001062.3
TCN2 NM_000355.3

CUBN: Analysis includes the intronic variant NM_001081.3: c.3330-439C>G.