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.
ABCD4 AMN CD320 CUBN GIF HCFC1 LMBRD1 MMACHC MMADHC TCN1 TCN2
ABCD4 AMN CD320 CUBN GIF HCFC1 LMBRD1 MMACHC MMADHC TCN1 TCN2
For a broader analysis of the genetics of organic acidemias:
|ABCD4||Cobalamin J deficiency|
|CD320||Transcobalamin receptor deficiency|
|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|
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:
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|
AMN: Deletion/duplication analysis is not offered for exon 1.