title: A novel mitochondrial DNA deletion producing progressive external ophthalmoplegia associated with multiple sclerosis.
abstract: We report a previously undescribed 7676 base pair mitochondrial (mt)DNA deletion involving genes of complex I, complex IV subunits 2 and 3 (cytochrome oxidase [Cox] II, III), adenosine triphosphatase 8 and 6, cytochrome b and 8 transfer (t)RNA genes producing myopathy and progressive external ophthalmoplegia (PEO) in a 44-year-old right-handed Caucasian man with features of multiple sclerosis (MS). We performed complete mtDNA sequencing and deletion analysis, spectrophotometric analysis of muscle and platelet respiratory chain activity, measurement of platelet mitochondrial membrane potential with the potentiometric dye JC-1 and magnetic resonance spectroscopy (MRS) and MRI studies of normal-appearing and lesional cerebral tissue. The deletion resulted in significant respiratory chain deficiency in muscle and blood and abnormalities of the platelet mitochondrial membrane potential. However, cerebrospinal fluid analysis, magnetic resonance spectroscopy and MRI features suggested inflammatory central nervous system demyelination rather than a primary respiratory chain disorder. We conclude that this novel mtDNA deletion causing myopathy and PEO is associated with severe muscle and platelet cellular energetic abnormalities. Furthermore, clinical and paraclinical features of multiple sclerosis were found. The potential pathomechanistic interaction between mtDNA variation and multiple sclerosis is reviewed.
authors.affiliation: Department of Human Physiology, Flinders University of South Australia, South Australia, Australia. mark.slee@flinders.edu.au
authors.forename: M
authors.initials: M
authors.lastname: Slee
authors.forename: J
authors.initials: J
authors.lastname: Finkemeyer
authors.forename: M
authors.initials: M
authors.lastname: Krupa
authors.forename: R
authors.initials: R
authors.lastname: Raghupathi
authors.forename: J
authors.initials: J
authors.lastname: Gardner
authors.forename: P
authors.initials: P
authors.lastname: Blumbergs
authors.forename: M
authors.initials: M
authors.lastname: Agzarian
authors.forename: D
authors.initials: D
authors.lastname: Thyagarajan
mesh_terms: D000328:Adult; D001483:Base Sequence; D004272:DNA, Mitochondrial / Q000235:genetics*; D017353:Gene Deletion; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D017246:Ophthalmoplegia, Chronic Progressive External / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D017354:Point Mutation / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial