POLG mutations in neurodegenerative disorders with ataxia but no muscle involvement

共济失调 病理 线粒体DNA 小脑共济失调 粒线体疾病 肌病 医学 生物 遗传学 神经科学 基因
作者
Christine Van Broeckhoven,Petri Luoma,Maria Rantamäki,A. Al Memar,Seppo Kaakkola,Peter Hackman,Leena Peltonen,Ann Löfgren,J.J. Martin,Peter De Jonghe,Anu Suomalainen,Bjarne Udd,Christine Van Broeckhoven
出处
期刊:Neurology [Ovid Technologies (Wolters Kluwer)]
卷期号:63 (7): 1251-1257 被引量:260
标识
DOI:10.1212/01.wnl.0000140494.58732.83
摘要

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.

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