Single large-scale rnitochondrial DNA deletion in a patient with mitochondria1 myopathy associated with multiple symmetric lipomatosis Y. Campos, MSc; M.A. Martin, PharmB; C. Navarro, MD; P. Gordo, MD; and J. Arenas, PhD Article abstract-In a nonalcoholic woman with multiple symmetric lipomatosis (MSL), muscle histochemistry showed ragged-red fibers and cytochrome c oxidase negative fibers. Southern blot analysis revealed a single deletion of mitochon- drial DNA (mtDNA). We suggest that MSL is an uncommon manifestation of the wide clinical spectrum of mitochondrial disorders, in particular of those associated with single mtDNA deletions. NEUROLOGY 1996;47:1012-1014 Multiple symmetric lipomatosis (MSL) (Launois- Bensaude syndrome, Madelung’s disease) is a rare disorder of middle life characterized by large nonen- capsulated lipomas distributed around the neck, shoulders, and other axial regions.’ Neurologic in- volvement, particularly peripheral neuropathy, is considered an integral part of the MSL syndrome.’ Alcoholism is frequently associated with MSL.I Re- cently, Berkovic et aL2 reported an association be- tween MSL and mitochondrial dysfunction. More- over, further recent reports documented that some patients with MSL harbor mutations in the mito- chondrial genome, in particular multiple mtDNA de- letion~,~~~ or the mutation at nucleotide position (np) 8344 in the tRNALy” gene of mtDNA.”-” Here, we present the first report of a patient with MSL har- boring a single large-scale mtDNA deletion. Case report. A 60-year-old nonalcoholic woman had a 28-year history of slowly progressive proximal muscle weakness and bilateral ptosis. She had neurosensory hear- ing loss and tension headache, but no other neurologic symptoms. At age 41 years, large confluent symmetric li- poma developed around the neck in a “horse-collar” distri- bution. Examination a t age 59 years revealed bilateral ptosis without diplopia, and symmetric proximal weakness without wasting, affecting muscles in her upper limbs and especially in her lower limbs. She had exercise intolerance and complained of muscle pain on repeated muscle testing. Deep tendon reflexes were normal. Cranial nerve examination was normal aside from hear- ing loss. Extraocular muscles were apparently uninvolved. Ophthalmoscopic examination was normal. Tibia1 and sural nerve conduction studies were normal, and needle electromyography showed a myopathic pattern. Electrocar- diographic studies showed right bundle branch block. Blood chemistry, including uric acid, and hematologic studies were normal. A recent clinical reevaluation revealed mild extraocular muscle weakness. Methods. Muscle biopsy and histochemistry. A muscle biopsy specimen was taken from the rectus femoris, frozen, and stored in liquid nitrogen until analysis. Serial frozen sections of muscle were tested with a battery of histologic stains and cytochemical reactions, including combined staining for cytochrome c oxidase (COX) and succinate de- hydrogenase (SDHhg The activities of NADH dehydro- genase, rotenone-sensitive NADH cytochrome c reductase, SDH, succinate cytochrome c reductase, COX, and citrate synthase were measured in muscle homogenates as de- scribed.’” The activity of each complex was normalized to that of citrate synthase for correcting to mitochondrial vof- ume. Total DNA was isolated from frozen muscle samples by phenol extraction. For Southern blot analysis, DNA was digested with Puu I1 or BamHI, separated by agarose gel electrophoresis (0.8%), and transferred onto nitrocellulose membranes as report- ed.“ The filters were hybridized with entire human mtDNA labelled with digoxigenin-alkaline phosphatase (Boehringer Mannheim). The deletion was mapped by PCR and restriction analysis as described. l1 To detect “the MERRF point mutation” (at np 8344 within the tRNALYS gene), we used a method described el~ewhere.~ Muscle biochemistry. Molecular genetic studies. Results. Sections stained with modified Gomori trichrome revealed ragged-red fibers (RRF). These fibers From the Centro de Investigacion (Drs. Campos, Martin, and Arenas), Hospital 12 de Octubre, Madrid; the Department of Pathology (Dr. Navarro), Hospital do Meixoeiro, Vigo; and the Department of Medicine (Dr. Gordo). Hospital da Costa Burela, Lugo, Spain. Supported by a grant from the Fondo de Investigacion Sanitaria (FIS) number 9510658, Ministerio de Sanidad, Spain. Y. Campos was supported by Sigma-Tau and M.A. Martin by FIS. Received October 9, 1995. Accepted in final form February 9, 1996. Address correspondence and reprint requests to Joaquin Arenas, Centro de Investigacion, Hospital 12 de Octubre, Avda de Cordoba Km 5.2, 28041; Madrid, Spain. 1012 Copyright 0 1996 by the American Academy of Neurology