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Acylated coenzyme A (acyl-CoA) dehydrogenases are a
family of mitochondrial enzymes that catalyze the first dehydrogenation step
in the beta oxidation of fatty acyl-CoA derivatives. Fatty acids provide
important respiratory fuel for many tissues, including heart, brain,
skeletal muscle, pancreas, placenta, brown adipose tissue, kidney, and
liver. The disorder is inherited as an autosomal recessive trait. Metabolic
acidosis, severe hypoglycemia without ketosis, and coma are frequent
features of all types of acyl-CoA dehydrogenase deficiency syndrome. It also
occurs during adulthood. Large amounts of glutaric acid in the blood and
urine are caused by deficiency of the enzyme “multiple acyl-CoA dehydrogenase".
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The family of acyl-CoA dehydrogenase deficiency
syndromes contains eight members. The most frequent are the following five:
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Short-chain acyl-CoA dehydrogenase deficiency (SCAD)
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Medium-chain acyl-CoA dehydrogenase deficiency (MCAD)
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Long-chain acyl-CoA dehydrogenase deficiency (LCAD)
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Very-long-chain acyl-CoA dehydrogenase deficiency (VLCAD)
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Multiple acyl-CoA dehydrogenase deficiency (MADD)(Synonym: Glutaric
Acidemia Type II)
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All types are inherited as
either autosomal dominant or recessive pattern.
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All acyl-CoA dehydrogenase deficiencies catalyze
the same initial dehydrogenation of the substrate at the beta-carbon atom
and require electron transfer flavoprotein as an electron acceptor. They
differ distinctly from each other with regard to the length and
configuration of the hydrocarbon chain of their respective substrates and
have accordingly received appropriate names. They are nuclear encoded and
are synthesized as precursor proteins in the cytosol with an N-terminal
leader peptide, which is cleaved off upon import to the mitochondria,
producing a mature monomer. It has been genetically mapped on the 11q25.
Analysis using a Northern blot system detected an approximately 2.1-kb ACAD8
transcript in all tissues examined, namely, heart, lung, brain, skeletal
muscle, pancreas, placenta, liver, and kidney.
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Short-chain acyl-CoA dehydrogenase deficiency (SCAD) is an extremely
rare inherited disorder of fat metabolism often
recognized as an organic acidemia disorder. All reported cases have occurred
in females. A pattern of occurrence has not been defined. Severe metabolic
acidosis and hyperammonemia are principal features of the disorder. There
are two distinct types of SCAD. A congenital form is characterized
by progressive hypotonia and organic acidemia. The clinical symptoms in infants
associated with organic acidemia include poor feeding, frequent vomiting, failure
to thrive, progressive muscle weakness, hypotonia, growth retardation, impaired mental
development, and lethargy. Other features may include hypoglycemia,
accumulation of excessive amounts of fatty acids in muscle and/or liver
tissue, and severe hyperammonemia. Unusually low levels of carnitine in
muscle tissue (secondary carnitine deficiency) may occur. In some infants
the presence of cerebral edema and raised intracranial pressure,
hepatosplenomegaly, liver steatosis, biliary cholestasis, and focal
hepatocellular necrosis have been reported. It often is considered
life-threatening. The milder adult onset form of this disorder
affects the skeletal muscles and is characterized by severe muscle weakness.
Muscle weakness probably is the result of accumulation of fatty acids leading
to lipid storage myopathy. An abnormally low levels of the amino acid ...