G.P.190: Multiple deletions in mitochondrial DNA in myofibrillar myopathy and centronuclear myopathy

Abstract

Multiple deletions in mitochondrial DNA (mtDNA) are associated with mutations in nuclear genes which encode proteins either directly or indirectly involved in the replication or maintenance of mtDNA. To date, mutations in twelve nuclear genes, POLG, POLG2, C10orf2, SLC25A4, RRM2B, TK2, MPV17, DGUOK, OPA1, MFN2, MGME1, and DNA2 have been identified in patients with multiple deletions in mtDNA, yet the genetic cause of multiple mtDNA deletions still remains undefined in a large number of patients. In addition to patients with a classic mitochondrial myopathy, multiple mtDNA deletions are also found in patients with myopathies such as sporadic IBM. Mitochondrial changes have also been identified in skeletal muscle from patients with myofibrillar myopathy, with histochemical changes such as rubbed out fibres observed with COX and NADH staining, and focal clustering and depletion of mitochondria. Mitochondrial pathology, including COX negative and ragged red fibres, and paracrystalline inclusions have also been described in patients with centronuclear myopathy due to mutations in DNM2, which encodes Dynamin 2, a GTPase which is involved in membrane trafficking. Here we describe our findings in two patients with multiple mtDNA deletions. In one patient, a 70 year old male who presented with a history of exercise induced muscle pain and distal myopathy we identified a novel pArg2364His mutation in the gene FLNC which encodes the actin binding protein filamin-C. In the second patient, a 40 year old male who presented at age 3 years with ataxia and later developed facial myopathy, proximal muscle weakness, and CPEO, histochemical investigation indicated centronuclear myopathy, and a p.Glu560Lys mutation in DNM2 was identified. Our findings suggest that FLNC and DNM2 should be added to the list of genes associated with multiple deletions in mtDNA.