PARTIAL DEPLETION AND MULTIPLE DELETIONS OF MUSCLE MTDNA IN FAMILIAL MNGIE SYNDROME

Objective: To describe the unique combination of partial depletion and multiple deletions of mitochondrial DNA (mtDNA) on muscle DNA analysi s of three siblings with mitochondrial neurogastrointestinal encephalo myopathy (MNGIE). Background: MNGIE is a relatively homogeneous autoso mal recessive disorder characterized by gastrointestinal dysmobility, ophthalmoparesis, peripheral neuropathy, mitochondrial myopathy, and a ltered white matter signal at brain imaging. Muscle multiple mtDNA del etions have been found in about half of the described cases. Methods: We studied three affected siblings (two were monozygotic twins) born t o nonconsanguineous parents. Muscle mtDNA was investigated by quantita tive Southern and Slot blot techniques and by PCR analysis. Morphologi c confirmation in the muscle tissue was achieved by using in situ hybr idization with a mtDNA probe complementary to an undeleted region and by DNA immunohistochemistry. Results: Al three patients showed ragged red (RRF) and cytochrome c oxidase-negative fibers, as well as partial . deficiency of complexes I and TV. Southern and Slot blot analyses sh owed mtDNA depletion in all patients. Multiple mtDNA deletions were al so detected by PCR analysis. In situ hybridization demonstrated an ove rall signal weaker than controls, with a relatively higher signal in R RF. Antibodies against DNA showed a decreased cytoplasmic network. Con clusions: The muscle histopathology and respiratory chain enzyme defec ts may be accounted for by the decreased mtDNA amount and by the prese nce of mtDNA deleted molecules; however, relative levels of mtDNA seem to correlate with life span in these patients. The combination of par tial depletion and multiple deletions of mtDNA might indicate the dera ngement of a common genetic mechanism controlling mtDNA copy number an d integrity.