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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 con ducted sequencing of coding exons of POLG, C10orf2 (Twinkle), and ANT1 and analy zed muscle mitochondrial DNA (mtDNA), including Southern blot analysis and long range PCR. Results: Ataxia occurred in combination with various CNS features,i ncluding myoclonus, epilepsy, cognitive decline, nystagmus, dysarthria, thalamic and cerebellar white matter lesions onMRI, and neuronal loss in discrete gray n uclei on autopsy. Gastrointestinal dysmotility, weight loss, cardiomyopathy, and valproate induced hepatotoxicity occurred less frequently. Two patients died w ithout preceding signs of progressive external ophthalmoplegia. In muscle, typic al findings of mitochondrial disease, such as ragged red fibers and Southern blo t mtDNA abnormalities, were absent. POLG mutations were present in eight patient s, including two isolated cases, and one Finnish and two unrelated Belgian famil ies contained in total six patients. All POLG mutations were recessive, occurrin g in a homozygous state in seven patients and in a compound heterozygous state i n one patient. The novel W748S mutation was identified in five patients from thr ee unrelated families. Conclusions: The clinical spectrum of recessive POLG muta tions is expanded by sensory ataxic neuropathy, combined with variable features of involvement of CNS and other organs. Progressive external ophthalmoplegia, my opathy, ragged red fibers, and Southern blot abnormalities of muscle mitochondri al DNA also are not mandatory features associated with POLG mutations.
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 con ducted sequencing of coding exons of POLG, C10orf2 (Twinkle ), and ANT1 and analy zed muscle mitochondrial DNA (mtDNA), including Southern blot analysis and long range PCR. Results: Ataxia occurred in combination with various CNS features, i ncluding myoclonus, epilepsy, cognitive decline, nystagmus, dysarthria, thalamic and cerebellar white matter lesions onMRI, and neuronal loss in discrete gray n uclei on autopsy. Gastrointestinal dysmotility, weight loss, cardiomyopathy, and valproate induced hepatotoxicity occurred less frequently. Two patients died w ithout preceding signs of progressive external ophthalmoplegia. In muscle, typic al findings of mitochondrial disease, such as ragged red fibers and Southern bloat mtDNA abnormalities, were absent. PO LG mutations were present in eight patients, including two isolated cases, and one Finnish and two unrelated Belgian famil ies contained in total six patients. All POLG mutations were recessive, occurrin g 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 thr ee unrelated families. Conclusions: The clinical spectrum of recessive POLG muta tions is expanded by sensory ataxic neuropathy, combined with variable features of involvement of CNS and other organs. Progressive external ophthalmoplegia, my opathy, ragged red fibers, and Southern blot abnormalities of muscle mitochondri DNA also are not mandatory features associated with POLG mutations.