We observed a deficiency of both the mitochondrial and cytosolic forms of
fumarase in a male infant with
mitochondrial encephalomyopathy who presented at one month of age with
failure to thrive, developmental delay,
hypotonia, cerebral
atrophy, lactic and pyruvic acidemia, and
fumaric aciduria. The patient died at eight months of age. Isolated skeletal-muscle mitochondria showed selective defects in the oxidation of
glutamate (31 ng atoms of
oxygen consumed per minute per milligram of
mitochondrial protein, as compared with 94 +/- 19 [mean +/- SD] in five controls) and of
succinate (18 vs. 145 +/- 18 ng atoms of
oxygen per minute per milligram of
protein), whereas isolated liver mitochondria oxidized these and other substrates normally.
Fumarase activity was virtually absent in both liver mitochondria (53 vs. 2878 +/- 248 nmol per minute per milligram of
protein [5 controls]) and skeletal-muscle mitochondria (23 vs. 1997 +/- 717 nmol per minute per milligram [12 controls]). Seventeen other mitochondrial
enzymes had normal activity in both liver and muscle mitochondrial extracts.
Fumarase activity was also significantly reduced in homogenates of liver tissue (less than 1 vs. 90 +/- 25 mumol per minute per gram of wet weight [five controls]) and skeletal muscle (less than 1 vs. 21 +/- 4 mumol per minute per gram [five controls]), indicating a deficiency of both mitochondrial and cytosolic fumarases. Organ differences in intramitochondrial accumulation of
fumarate may have accounted for the selective oxidative defects observed in the skeletal-muscle mitochondria but not liver mitochondria. All these findings are consistent with a profound combined
fumarase deficiency.