The Invitae Multiple Acyl-CoA Dehydrogenase Deficiency Panel analyzes the three genes that are associated with multiple acyl-CoA dehydrogenase (MAD) deficiency. This test is useful for the diagnosis of patients in whom MAD deficiency is suspected due to clinical symptoms, abnormal newborn screening (NBS) results, or biochemical findings. This test may help distinguish MAD deficiency from other fatty acid oxidation disorders (FAODs) and riboflavin transporter deficiencies, which can have overlapping clinical and biochemical presentations. Knowing the underlying molecular cause of a patient’s MAD deficiency may also help inform management because some mutations are known to be responsive to riboflavin therapy.
ETFA ETFB ETFDH
ETFA ETFB ETFDH
MAD deficiency is an in inborn error of metabolism that interferes with the body’s ability to break down proteins and fats to produce energy. Incomplete breakdown of proteins and fats can cause blood and tissues to become acidotic, producing metabolic acidosis.
MAD deficiency is a fully penetrant disorder. Patients with MAD deficiency show a wide range of symptoms and severity. Patients with little or no enzyme activity typically have the severe neonatal presentation while patients with higher residual enzyme activity have the mild, late-onset form. Type I, the most severe form, can present in the neonatal period with life-threatening acidosis, vomiting, and seizures. Patients with the severe form may have physical abnormalities including facial dysmorphism, brain malformations, hypoglycemia, hypotonia, hepatomegaly, kidney cysts, and genital abnormalities. There may also be hepatomegaly, dilated cardiomyopathy, and sweaty-feet odor. Type I is typically fatal. Type II presents with similar symptoms but no physical abnormalities, and type III presents later, with intermittent episodes of hypoglycemia, metabolic acidosis, muscle weakness, and exercise-induced muscle pain. Some patients with the late-onset form remain asymptomatic despite the presence of biochemical abnormalities. Riboflavin has been shown to be an effective treatment for patients with late-onset MAD deficiency.
Patients with MAD deficiency typically show elevations of C4 and C5 in newborn screening. Upon plasma acylcarnitine analysis, patients can have elevations of C4, C5, and many other acylcarnitine species, which can lead to secondary carnitine deficiency. Severely affected patients can have elevations of 2-hydroxyglutaric acid, glutaric acid, ethylmalonic acid, and dicarboxylic aciduria during urine organic acids testing; patients with a milder form may only have elevations of ethylmalonic acid, adipic acid, ketones, and dicarboxylic acids. Isobutyrylglycine, isovalerylglycine, hexanoylglycine, and suberylglycine elevations may also be detected in urine. The organic aciduria can be normal in mildly affected patients, only manifest during times of metabolic stress.
For patients with a biochemical diagnosis of MAD deficiency (characteristic plasma acylcarnitines and urine organic acids, with or without enzyme analysis), >99% are expected to have pathogenic variants in ETFA, ETFB, or ETFDH. 93% of patients with late-onset disease carry pathogenic variants in ETFDH, 5% carry variants in ETFA, and 2% have variants in ETFB.
MAD deficiency is inherited in an autosomal recessive manner.
MAD deficiency is a very rare disorder with prevalence estimated at 1 in 200,000. There is great variation between countries and ethnicities. Incidence among the southern Chinese is approximately 1 in 22,500.
Testing for MAD deficiency should be considered in newborns and infants 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, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.
Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.
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