The Invitae Medium Chain Acyl-CoA Dehydrogenase Deficiency Test analyzes the ACADM gene, which is associated with Medium Chain Acyl-CoA Dehydrogenase (MCAD) deficiency. Genetic testing of this gene may confirm a diagnosis and help guide treatment and management decisions. Identification of disease-causing variants would also determine carrier status and diagnosis of at-risk relatives.
The clinical presentation of MCAD deficiency can range from severe to mild, depending on the amount of residual enzyme activity. On the most severe end of the spectrum is the classic presentation, with onset of symptoms typically occuring within the first few months of life and before two years of age, though symptoms may not appear until adulthood. Patients typically present with vomiting, lethargy, seizures, and hepatomegaly; if untreated, they can progress to coma and death. Symptoms can be precipitated by prolonged fasting and intercurrent illness. Patients in metabolic crises will have hypoketotic hypoglycemia. They may have elevated liver enzymes, acidosis with increased anion gap, hyperuricemia, and hyperammonemia. In undiagnosed patients, the first metabolic crisis is often fatal and patients are at risk of sudden death. Patients can be mistaken as presenting with Reye syndrome. Females with MCAD deficiency who are pregnant with affected fetuses are at a greater risk of developing HELLP (Hemolysis, Elevated Liver enzymes, and Low Platelets) syndrome or acute fatty liver of pregnancy. Patients on the milder spectrum of MCAD deficiency remain at risk for acute metabolic crises.
Patients with MCAD deficiency can have elevations of C6, C8, and C10 on NBS or acylcarnitine analysis; C8 elevations are the most predominant. Patients may also have secondary carnitine deficiency. On urine organic acid analysis, patients can have characteristic dicarboxylic aciduria (adipic acid > suberic acid > sebacic acid) with elevations of hexanoylglycine, suberylglycine, and phenylpropionylglycine. Urine acylglycine analysis may be needed to detect the small elevations of hexanoylglycine, suberylglycine, and phenylpropionylglycine. Some patients may have normal urine organic acid analysis during asymptomatic periods. Fatty acid oxidation in vitro probe assays may show elevation of medium chain (C6-C10) acylcarnitine species; however, this assay typically requires a skin biopsy.
A low fat-high carbohydrate diet and avoidance of fasting have been used to treat patients with MCAD deficiency. Emergency protocols may also be implemented during times of intercurrent illness to avoid metabolic crisis. These therapies have been reported to successfully treat MCAD deficiency. Early diagnosis and detection may improve the long-term outcome of these patients.
For patients with biochemical features that are consistent with MCAD deficiency (elevated C6, C8, and C10 on acylcarnitines), approximately >96% will have two pathogenic variants in the ACADM gene.
MCAD deficiency is inherited in an autosomal recessive manner.
The overall prevalence of confirmed MCAD deficiency has been estimated at 1 in 19,000, but it can be as high as 1 in 7,500 in some ethnic populations (PMID: 22766612, 22166308, 21083904).
This test may be appropriate for patients:
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|