The mitochondrial oxidative phosphorylation and
fatty acid oxidation pathways have traditionally been considered independent major sources of cellular energy production; however, case reports of patients with specific enzymatic defects in either pathway have suggested the potential for a complex interference between the two. This study documents a new site of interference between the two pathways, a site in
respiratory complex II capable of producing clinical signs of a block in
fatty acid oxidation and reduced in vitro activity of
acyl-CoA dehydrogenases. The initial patient, and later her newborn sibling, had mildly dysmorphic features,
lactic acidosis and a defect in mitochondrial
respiratory complex II associated with many biochemical features of a block in
fatty acid oxidation. Results of in vitro probing of intact fibroblasts from both patients with methyl[2H3]
palmitate and
L-carnitine revealed greatly increased [2H3]
butyrylcarnitine; however, the ratio of
dehydrogenase activity with
butyryl-CoA with anti-MCAD inactivating antibody (used to reveal SCAD-specific activity) to that with
octanoyl-CoA was normal, excluding a selective SCAD or
MCAD deficiency.
Respiratory complex II was defective in both patients, with an absent
thenoyltrifluoroacetone-sensitive
succinate Q
reductase activity that was partially restored by supplementation with
duroquinone. Although secondary, the block in
fatty acid oxidation was a major management problem since attempts to provide
essential fatty acids precipitated acidotic decompensations. This study reinforces the need to pursue broadly the primary genetic defect within these two pathways, making full use of increasingly available functional and molecular diagnostic tools.