Genetic deficiency of short-chain acyl-coenzyme A dehydrogenase in cultured fibroblasts from a patient with muscle carnitine deficiency and severe skeletal muscle weakness.

Abstract

Genetic deficiency of short-chain acyl-coenzyme A (CoA) dehydrogenase activity was demonstrated in cultured fibroblasts from a 2-yr-old female whose early postnatal life was complicated by poor feeding, emesis, and failure to thrive. She demonstrated progressive skeletal muscle weakness and developmental delay. Her plasma total carnitine level (35 nmol/ml) was low-normal, but was esterified to an abnormal degree (55% vs. controls of < 10%). Her skeletal muscle total carnitine level was low (7.6 nmol/mg protein vs. controls of 14±2 nmol/mg protein) and was 75% esterified. Mild lipid deposition was noted in type I muscle fibers. Fibroblasts from this patient had 50% of control levels of acyl-CoA dehydrogenase activity towards butyryl-CoA as substrate at a concentration of 50 ,M in a fluorometric assay based on the reduction of electron transfer flavoprotein. All of this residual activity was inhibited by an antibody against medium-chain acyl-CoA dehydrogenase. These data demonstrated that medium-chain acylCoA dehydrogenase accounted for 50% of the activity towards the short-chain substrate, butyryl-CoA, under these conditions, but that antibody against that enzyme could be used to unmask the specific and virtually complete deficiency of shortchain acyl-CoA dehydrogenase in this patient. Fibroblasts from her parents had intermediate levels of activity towards butyryl-CoA, consistent with the autosomal recessive inheritance of this metabolic defect.

Molecular cloning and nucleotide sequence of complementary DNAs encoding human short chain acyl-coenzyme A dehydrogenase and the study of the molecular basis of human short chain acyl-coenzyme A dehydrogenase deficiency.

“…The third patient had a history of progressive skeletal muscle weakness, developmental delay, and muscle carnitine deficiency. Butyryl-CeA dehydrogenating activity in the cultured fibroblasts from all three infants, assayed in the presence of anti-medium chain acyl-CoA dehydrogenase antibody, was found to be < 11% ofcontrols, indicating a specific SCAD deficiency (8,9).…”

“…The main clinical features in two of them were metabolic acidosis and ethylmalonic aciduria (8,9), with one patient dying in the neonatal period due to severe metabolic acidosis and hyperammonemia. The third patient had a history of progressive skeletal muscle weakness, developmental delay, and muscle carnitine deficiency.…”

“…As the first step in the study of the molecular basis of (8,9). Normal cell lines were obtained from the NIGMS Human Genetic Mutant Cell Repository (Camden, NJ).…”

Misfolding, Degradation, and Aggregation of Variant Proteins

“…Newly imported SCAD proteins are proteolytically processed, folded, and assembled into the biologically active homotetrameric form (168 kDa) containing one molecule of FAD per subunit (2). Hereditary deficiency of SCAD has been reported in 20 patients world-wide with a variety of clinical symptoms (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). The most frequent symptoms are chronic and episodic neuromuscular disabilities, including cognitive and muscular developmental delay, hypotonia, and seizures.…”

A Rare Case of Short-Chain Acyl-COA Dehydrogenase Deficiency: The Apparent Rarity of the Disorder Results in Under Diagnosis

“…Till date, 25 patients have been identified and 50 reported worldwide based upon reduced or absent SCAD activity in vitro [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. Genotype-phenotype correlations have been inconsistent [8,18].…”