POLG mutations in neurodegenerative disorders with ataxia but no muscle involvement

被引:200
作者
Van Goethem, G
Luoma, P
Rantamäki, M
Al Memar, A
Kaakkola, S
Hackman, P
Krahe, R
Löfgren, A
Martin, JJ
De Jonghe, P
Suomalainen, A
Udd, B
Van Broeckhoven, C
机构
[1] Univ Instelling Antwerp, Dept Mol Genet, B-2610 Antwerp, Belgium
[2] Univ Antwerp Hosp, Div Neurol, Antwerp, Belgium
[3] Univ Antwerp Hosp, Neuromuscular Reference Ctr, Antwerp, Belgium
[4] Flanders Interuniv Inst Biotechnol VIB8, Dept Mol Genet, Antwerp, Belgium
[5] Born Bunge Fdn, Dept Neuropathol, Antwerp, Belgium
[6] Univ Helsinki, Program Neurosci, Helsinki, Finland
[7] Univ Helsinki, Dept Neurol, Helsinki, Finland
[8] Univ Helsinki, Cent Hosp, Dept Neurol, Helsinki, Finland
[9] Seinajoki Cent Hosp, Dept Phys Med, Seinajoki, Finland
[10] Seinajoki Cent Hosp, Dept Rehabil & Neurol, Seinajoki, Finland
[11] Atkinson Morelys Hosp, Dept Neurol, London, England
[12] Univ Helsinki, Dept Med Genet, Folkhalsan Inst Genet, Helsinki, Finland
[13] Univ Texas, MD Anderson Canc Ctr, Sect Canc Genet, Dept Mol Genet, Houston, TX 77030 USA
[14] Vaasa Cent Hosp, Vaasa, Finland
[15] Tampere Univ Hosp, Tampere, Finland
关键词
D O I
10.1212/01.WNL.0000140494.58732.83
中图分类号
R74 [神经病学与精神病学];
学科分类号
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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页码:1251 / 1257
页数:7
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