Familial cerebellar ataxia with muscle coenzyme Q10 deficiency O. Musumeci, MD; A. Naini, PhD; A.E. Slonim, MD; N. Skavin, PT; G.L. Hadjigeorgiou, MD; N. Krawiecki, MD; B.M. Weissman, MD; C.-Y. Tsao, MD; J.R. Mendell, MD; S. Shanske, PhD; D.C. De Vivo, MD; M. Hirano, MD; and S. DiMauro, MD Article abstract—Objective: To describe a clinical syndrome of cerebellar ataxia associated with muscle coenzyme Q10 (CoQ10) deficiency. Background: Muscle CoQ10 deficiency has been reported only in a few patients with a mitochondrial encephalomyopathy characterized by 1) recurrent myoglobinuria; 2) brain involvement (seizures, ataxia, mental retarda- tion), and 3) ragged-red fibers and lipid storage in the muscle biopsy. Methods: Having found decreased CoQ10 levels in muscle from a patient with unclassified familial cerebellar ataxia, the authors measured CoQ10 in muscle biopsies from other patients in whom cerebellar ataxia could not be attributed to known genetic causes. Results: The authors found muscle CoQ10 deficiency (26 to 35% of normal) in six patients with cerebellar ataxia, pyramidal signs, and seizures. All six patients responded to CoQ10 supplementation; strength increased, ataxia improved, and seizures became less frequent. Conclusions: Primary CoQ10 deficiency is a potentially important cause of familial ataxia and should be considered in the differential diagnosis of this condition because CoQ10 administration seems to improve the clinical picture. NEUROLOGY 2001;56:849 –855 In the past decade, mitochondrial encephalomyopa- thies due to mutations in mitochondrial DNA (mtDNA) have emerged as a major clinical group. Only recently has attention been directed to muta- tions in nuclear DNA that cause respiratory chain defects. However, in 1989, Ogasahara et al. 1 de- scribed a syndrome associated with coenzyme Q10 (CoQ10) deficiency in muscle, which was probably the first example of a mendelian defect in the respi- ratory chain. That syndrome, which was character- ized by the triad of recurrent myoglobinuria, brain involvement, and ragged-red fibers (RRF)/lipid stor- age in muscle, was confirmed in a few additional cases, 2,3 but the biochemical and molecular bases re- main to be defined. CoQ10, or ubiquinone, is a lipophilic component of the electron-transport chain, which transfers to com- plex III (ubiquinone-cytochrome c reductase) electrons derived from complex I (nicotinamide adenine dinucle- otide, reduced form [NADH]–CoQ reductase), complex II (succinate dehydrogenase), and from the oxidation of fatty acids and branched-chain amino acids via flavin- linked dehydrogenases. 4 CoQ10 also plays a role as an antioxidant and as a membrane stabilizer. 5,6 Decreased levels of muscle CoQ10 have been re- ported in patients with mitochondrial encephalo- myopathies due to mtDNA mutations, but these were inconsistent and probably secondary findings. 7 In 1997, we studied a 37-year-old woman who had severe muscle CoQ10 deficiency and a clinical pic- ture virtually identical to that of the patients de- scribed by Ogasahara et al. 3 To our surprise, one of 20 “disease control” muscle samples used in that study showed an extremely low level of CoQ10. The sample belonged to a 25-year-old man with heredi- tary ataxia, without RRF or lipid storage. This ser- endipitous finding prompted us to measure CoQ10 in muscle biopsies from other patients with unex- plained ataxia. Our interest in this association was bolstered by the report of a child with ataxia, cere- bellar atrophy, and generalized seizures, whose mus- cle biopsy showed complex III deficiency and severe CoQ10 deficiency. 8 Patients and methods. Case reports. Patient 1. An 11-year-old boy had a normal newborn period and early motor development, but at 1 year of age he was noted to be clumsy and to fall frequently. At age 3, he developed ataxia and myoclonus. A cranial MRI scan showed the Dandy–Walker variant with enlargement of the fourth ventricle, and a ventriculoperitoneal shunt was placed. However, his condition worsened steadily and at age 7 years he developed generalized tonic-clonic seizures, which were partially controlled with valproic acid. His parents were normal and nonconsanguineous, and his 9-year-old sister appeared healthy; his mother and sister had normal neurologic examinations. General physical examination was normal. Neurologically, he was alert, with normal oc- ular fundi. Eye movements had impaired smooth visual From the Department of Neurology (Drs. Musumeci, Naini, Shanske, De Vivo, Hirano, and DiMauro), Columbia University College of Physicians and Surgeons, New York, NY; Department of Pediatrics (Dr. Slonim and N. Skavin), North Shore University Hospital, Manhasset, NY; Department of Pediatrics (Drs. Krawiecki and Weissman), Emory University, Atlanta, GA; Children’s Hospital (Dr. Tsao), Columbus, OH; and Department of Neurology (Dr. Mendell), Ohio State University, Columbus. Supported by NIH grant NS11766 and by a grant from the Muscular Dystrophy Association. Also supported by a fellowship from the Telethon–Italy (O.M.). Received September 12, 2000. Accepted in final form January 22, 2001. Address correspondence and reprint requests to Dr. Salvatore DiMauro, 4-420 College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032; e-mail: sd12@columbia.edu Copyright © 2001 by AAN Enterprises, Inc. 849