Le Ber Isabelle, Martinez Maria, Campion Dominique, Laquerrière Annie, Bétard Christine, Bassez Guillaume, Girard Carol, Saugier-Veber Pascale, Raux Gregory, Sergeant Nicolas, Magnier Patrick, Maisonobe Thierry, Eymard Bruno, Duyckaerts Charles, Delacourte André, Frebourg Thierry, Hannequin Didier
Département de Neurologie, Centre Hospitalo-Universitaire Charles Nicolle, Rouen, France.
Brain. 2004 Sep;127(Pt 9):1979-92. doi: 10.1093/brain/awh216. Epub 2004 Jun 23.
The majority of proximal myotonic myopathy syndromes reported so far have been related to the myotonic dystrophy (DM) type 2 (DM2) mutation, an expanded (CCTG)n repeat in the ZNF9 gene. Here, we describe the phenotype and the histological features in muscle and brain of the first large pedigree with a non-myotonic dystrophy type 1 (DM1) non-DM2 multisystem myotonic disorder associated with severe frontotemporal dementia. Thirty individuals from three generations underwent detailed neurological, neuropsychological, electrophysiological, brain imaging and molecular analyses. Ten of them had proximal muscle weakness at onset, clinical/electrical myotonia and DM-type cataracts. The mean age at onset was 46.7 +/- 12.6 years (range: 32-69). Dementia was observed later in the course of the disease. On muscle biopsies, rare nuclear clumps, rimmed vacuoles and small angulated type 1 and type 2 fibres were seen early in the disease. They were replaced by fibrous adipose tissue at later stages. Immunohistochemical analysis of myosin heavy chain isoforms showed no selective fibre type atrophy-both type 1 and type 2 fibres being affected. Cortical atrophy without white matter lesions was seen on brain MRI. A brain single photon emission computed tomography (SPECT) study revealed marked frontotemporal hypoperfusion. Post-mortem examination of the brains of two patients showing prominent frontotemporal spongiosis, neuronal loss and rare neuronal and glial tau inclusions suggested frontotemporal dementia. Western blot analyses of the tau protein showed a triplet of isoforms (60, 64 and 69 kDa) in neocortical areas, and a doublet (64 and 69 kDa) in subcortical areas that distinguish our myotonic disorder from other's myotonic dystrophies. Molecular analyses failed to detect a repeat expansion in the DMPK and ZNF9 genes excluding both DM1 and DM2, whereas a genome-wide linkage analysis strongly suggested a linkage to chromosome 15q21-24. This previously unreported multisystem myotonic disorder including findings resembling DM1, DM2 and frontotemporal dementia provides further evidence of the clinical and genetic heterogeneity of the myotonic dystrophies. We propose to designate this disease myotonic dystrophy type 3, DM3.
迄今为止报道的大多数近端强直性肌病综合征都与2型强直性肌营养不良（DM2）突变有关，即ZNF9基因中（CCTG）n重复序列的扩增。在此，我们描述了首个与严重额颞叶痴呆相关的非1型强直性肌营养不良（DM1）、非DM2多系统强直性疾病的大家系中肌肉和大脑的表型及组织学特征。来自三代的30人接受了详细的神经学、神经心理学、电生理学、脑成像及分子分析。其中10人起病时有近端肌无力、临床/电生理强直性肌阵挛及DM型白内障。平均起病年龄为46.7±12.6岁（范围：32 - 69岁）。痴呆在疾病后期出现。肌肉活检显示，疾病早期可见罕见的核团块、镶边空泡以及小的角形1型和2型纤维。后期它们被纤维脂肪组织取代。肌球蛋白重链同工型的免疫组化分析未显示选择性纤维类型萎缩——1型和2型纤维均受影响。脑MRI显示皮质萎缩但无白质病变。脑单光子发射计算机断层扫描（SPECT）研究显示额颞叶明显灌注不足。对两名患者的大脑进行尸检，发现显著的额颞叶海绵状改变、神经元丢失以及罕见的神经元和胶质tau包涵体，提示为额颞叶痴呆。tau蛋白的蛋白质印迹分析显示，新皮质区域有一组三联体同工型（60、64和69 kDa），皮质下区域有一组二联体同工型（64和69 kDa），这将我们的强直性疾病与其他强直性肌营养不良区分开来。分子分析未能在DMPK和ZNF9基因中检测到重复序列扩增，排除了DM1和DM2，而全基因组连锁分析强烈提示与15号染色体q21 - 24区域连锁。这种先前未报道的多系统强直性疾病，包括类似DM1、DM2和额颞叶痴呆的表现，为强直性肌营养不良的临床和遗传异质性提供了进一步证据。我们建议将这种疾病命名为3型强直性肌营养不良，即DM3。
