Multiple acyl-CoA dehydrogenase deficiency (MADD), which is also called glutaric aciduria type II (GAII), is an autosomal recessive disorder of mitochondrial fatty acid oxidation, amino acid, and choline metabolism . In most cases, this disorder is due to enzymatic defects of either electron transfer flavoprotein (ETF) or electron transfer flavoprotein dehydrogenase, both of which are required for electron transfer in the mitochondrial respiratory chain.
Three clinical phenotypes have been described . The neonatal onset with the congenital anomalies such as renal cystic dysplasia, facial dysmorphism, rocker bottom feet, and abnormalities of the external genitalia is categorized as type I. Patients with neonatal onset but without congenital abnormalities, are categorized as type II. Newborns (Type I and II) may present with hypotonia, hepatomegaly, hypoketotic hypoglycemia, metabolic acidosis, and hyperammonemia. Severe cardiomyopathy or symptoms of Reye syndrome-like decompensations have been reported . The remaining patients present with the late-onset form of the disease (Type III). They develop with heterogeneous symptoms such as intermittent episodes of vomiting, hypoglycemia, and metabolic acidosis, muscle weakness and progressive lipid storage myopathy . During acute decompensations, the late-onset patients have organic aciduria and increase of all chain length acylcarnitines. Some patients respond to the treatment with riboflavin.
Three genes have been shown to be involved in patients with MADD. ETFA (15q23-25) and ETFB (19q13.3) genes encode the two ETF subunits while the ETFDH (4q32) gene encodes the electron transfer flavoprotein dehydrogenase . Gene sequence analysis is available to test for mutations in the ETFA, ETFB, and ETFDH genes (GQ).
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- Confirmation of a clinical/biochemical diagnosis of MADD
- Carrier testing in adults with a family history of MADD
Prevalence: MADD is rare with incidence estimates of 1:250,000 live births .
Infants and Young Children (<2 years of age): 2-3 ml
Children > 2 years of age to 10 years old: 3-5 ml
Older Children & Adults: 5-10 ml
Autopsy: 2-3 ml unclotted cord or cardiac blood
Isolation using the Perkin Elmer™Chemagen™ Chemagen™ Automated Extraction method or Qiagen™ Puregene kit for DNA extraction is recommended.
- Biochemical tests for diagnosis of MADD include Urine Organic Acids (OA) and Plasma Acylcarnitine Profile (AR)
- Sequence analysis of the ETFA, ETFB, ETFDH genes is available and is required before deletion/duplication analysis.
- Prenatal testing is available to couples who are confirmed carriers of mutations. Please contact the laboratory genetic counselor to discuss appropriate testing prior to collecting a prenatal specimen.