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From the Division of Neurology and the Neuromuscular Reference Center (Drs. Van Goethem, De Jonghe, and Martin), University Hospital, Antwerpen, Belgium; Department of Molecular Genetics (Drs. Van Goethem, De Jonghe, and Van Broeckhoven, A. Löfgren), Flanders Interuniversity Institute for Biotechnology (VIB8), Antwerpen, Belgium; Department of Neuropathology (Dr. Martin), Born-Bunge Foundation (BBS), Antwerpen, Belgium; University of Antwerpen (Drs. Van Goethem, De Jonghe, Martin, and Van Broeckhoven, A. Löfgren), Antwerpen, Belgium; Biomedicum-Helsinki, Program of Neurosciences and Department of Neurology (Dr. Suomalainen, P. Luoma), University of Helsinki and Helsinki University Central Hospital, Finland; Departments of Physical Medicine and Rehabilitation and Neurology (Dr. Rantamäki), Seinäjoki Central Hospital, Finland; Department of Neurology (Dr. Al Memar), Atkinson Morely’s Hospital, Wimbledon, London, UK; Department of Neurology (Dr. Kaakkola), Helsinki University Central Hospital, Finland; Folkhälsan Institute of Genetics (Drs. Hackman and Udd), Department of Medical Genetics, University of Helsinki, Finland; Section of Cancer Genetics, Department of Molecular Genetics (Dr. Krahe), University of Texas M.D. Anderson Cancer Center, Houston, TX; and Department of Neurology (Dr. Udd), Vaasa Central Hospital, Vaasa and Tampere University Hospital, Tampere, Finland.
Address correspondence and reprint requests to Dr. Gert Van Goethem, Department of Molecular Genetics VIB8, University of Antwerpen UA, Universiteitsplein 1, B-2610 Antwerpen, Belgium; e-mail: gert.vangoethem{at}ua.ac.be
Objective: To identify POLG mutations in patients with sensory ataxia and CNS features.
Methods: The authors characterized clinical, laboratory, and molecular genetic features in eight patients from five European families. The authors conducted sequencing of coding exons of POLG, C10orf2 (Twinkle), and ANT1 and analyzed muscle mitochondrial DNA (mtDNA), including Southern blot analysis and long-range PCR.
Results: Ataxia occurred in combination with various CNS features, including myoclonus, epilepsy, cognitive decline, nystagmus, dysarthria, thalamic and cerebellar white matter lesions on MRI, and neuronal loss in discrete gray nuclei on autopsy. Gastrointestinal dysmotility, weight loss, cardiomyopathy, and valproate-induced hepatotoxicity occurred less frequently. Two patients died without preceding signs of progressive external ophthalmoplegia. In muscle, typical findings of mitochondrial disease, such as ragged red fibers and Southern blot mtDNA abnormalities, were absent. POLG mutations were present in eight patients, including two isolated cases, and one Finnish and two unrelated Belgian families contained in total six patients. All POLG mutations were recessive, occurring in a homozygous state in seven patients and in a compound heterozygous state in one patient. The novel W748S mutation was identified in five patients from three unrelated families.
Conclusions: The clinical spectrum of recessive POLG mutations is expanded by sensory ataxic neuropathy, combined with variable features of involvement of CNS and other organs. Progressive external ophthalmoplegia, myopathy, ragged red fibers, and Southern blot abnormalities of muscle mitochondrial DNA also are not mandatory features associated with POLG mutations.
Received February 5, 2004. Accepted in final form May 10, 2004.
Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the October 12 issue to find the title link for this article.
*These authors contributed equally to this work as second authors.
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