NORMAL MITOCHONDRIAL-DNA AND RESPIRATORY-CHAIN ACTIVITY IN FAMILIAL DYSAUTONOMIA FIBROBLASTS

Familial dysautonomia (FD), an autosomal recessive disease mapped to c hromosome 9q31, is a sensory and autonomic neuropathy of unknown etiol ogy. We have previously reported light microscopic pleiomorphic change s in cells suggestive of altered plasma membranes, an increase in glob otriaosylceramide (Gb(3)), reflected by an increase in Gb(3) on the su rface of the plasma membrane, and a decrease in the rate and amount of ganglioside synthesized. In unrelated studies, we demonstrated that s torage of glycospingolipids (GSL) is deleterious to mitochondrial func tion. Recently, mitochondrial dysfunction has been associated with neu rodegenerative disease, superimposed on an autosomal inheritance patte rn. We have now probed Southern blots of total FD fibroblast DNA, dige sted with BamHI, EcoRII, and/or PvuII, with purified placental P-32-la beled mitochondrial DNA. The sizes of all FD mitochondrial DNAs were n ormal (16,569 bp), some containing previously identified BamHI polymor phisms. Lactate/pyruvate ratios, and activities of Complexes II and II I, matched those of control cells. Electron microscopy revealed morpho logically normal mitochondria, in conjunction with a normal oxidative state, determined using the redox dyes Mite Tracker CMXR and CMXR-H-2 and fluorescence microscopy. We conclude that mitochondrial dysfunctio n, due to GSL accumulation, changes in mitochondrial DNA, or mutation of a chromosome 9q gene involved in mitochondrial function, is neither a primary nor a secondary cause of FD, as determined by a study of FD fibroblasts. (C) 1996 Academic Press, Inc.