Binder Johannes, Hofmann Sabine, Kreisel Stefan, Wöhrle Johannes C, Bäzner Hansjörg, Krauss Joachim K, Hennerici Michael G, Bauer Matthias F
Department of Neurology, University Hospital Mannheim, University of Heidelberg, Germany.
Brain. 2003 Aug;126(Pt 8):1814-20. doi: 10.1093/brain/awg174. Epub 2003 Jun 4.
The Mohr-Tranebjaerg syndrome (MTS) is a rare neurodegenerative disorder characterized by early-onset deafness, dystonia and further neurological abnormalities such as cortical blindness, spasticity, dementia and mental retardation. Causative mutations were identified within the deafness-dystonia peptide (DDP1/TIMM8a) gene on the X-chromosome. The DDP1 protein is located in the intermembrane space of human mitochondria. Here, it acts in a complex together with its partner protein Tim13 in a chaperone-like manner to facilitate the import of nuclear-encoded precursor proteins into the mitochondrial inner membrane. Thus, MTS is a novel type of mitochondrial disorder. To obtain more insight into the pathophysiology of this neurodegenerative disorder, we performed for the first time a comprehensive clinical and functional characterization of a patient suffering from MTS. This patient exhibited a typical combination of deafness, dystonia and visual loss. Sequence analysis of the patient's DDP1 gene revealed a G to C transversion at nucleotide position 38 of the first exon. The mutation affects the ATG start codon, thereby changing methionine to isoleucine (M1I), and leads to a complete absence of the DDP1 protein. In addition, the partner protein Tim13 was found to be significantly reduced, suggesting that Tim13 requires the presence of DDP1 for its stabilization. The assessment of mitochondrial functions showed the enzyme activities of the mitochondrial energy-generating systems to be normal in the muscle biopsy. Structural abnormalities or aggregations of mitochondria were absent. Electron microscopy revealed only a mild neurogenic atrophy. Neurophysiological investigations showed cochlear dysfunction and disturbance of visual pathways. PET and MRI studies revealed a multifocal pattern of neurodegeneration with hypometabolic areas predominantly located over the right striatum and parietal cortex and marked atrophy of the occipital lobes. Although the visual loss is caused predominantly by neurodegeneration of the visual cortex, degeneration of the retina and the optic nerve contributes to the visual impairment. The pathological changes in basal ganglia and sensory cortex demonstrate the disintegration of subcortico-cortical circuits and correlate well with the clinical presentation of multifocal dystonia. The data presented here showed that, in contrast to most of the known mitochondrial disorders, MTS appears not to be associated with a functional defect of the energy generation system of the mitochondria. Whereas the specific mitochondrial dysfunction leading to neuronal loss in MTS remains to be clarified, the electrophysiological and neuroimaging findings allowed the multifocal manifestation of neurodegenerative lesions in MTS to be characterized specifically.
莫尔-特拉内耶尔格综合征（MTS）是一种罕见的神经退行性疾病，其特征为早发性耳聋、肌张力障碍以及其他神经异常，如皮质盲、痉挛、痴呆和智力迟钝。致病突变已在X染色体上的耳聋-肌张力障碍肽（DDP1/TIMM8a）基因中被鉴定出来。DDP1蛋白位于人类线粒体的膜间隙。在那里，它与其伴侣蛋白Tim13以伴侣样方式共同作用，促进核编码前体蛋白导入线粒体内膜。因此，MTS是一种新型的线粒体疾病。为了更深入了解这种神经退行性疾病的病理生理学，我们首次对一名患有MTS的患者进行了全面的临床和功能特征分析。该患者表现出耳聋、肌张力障碍和视力丧失的典型组合。对患者DDP1基因的序列分析显示，第一个外显子的第38位核苷酸发生了G到C的颠换。该突变影响ATG起始密码子，从而将甲硫氨酸变为异亮氨酸（M1I），并导致DDP1蛋白完全缺失。此外，发现伴侣蛋白Tim13显著减少，这表明Tim13需要DDP1的存在来维持其稳定性。线粒体功能评估显示，肌肉活检中线粒体能量产生系统的酶活性正常。线粒体不存在结构异常或聚集。电子显微镜检查仅发现轻度神经源性萎缩。神经生理学研究显示耳蜗功能障碍和视觉通路紊乱。PET和MRI研究显示神经退行性变呈多灶性模式，代谢减低区域主要位于右侧纹状体和顶叶皮质，枕叶明显萎缩。虽然视力丧失主要是由视觉皮质的神经退行性变引起的，但视网膜和视神经的退变也导致了视力损害。基底神经节和感觉皮质的病理变化表明皮质下-皮质回路的解体，与多灶性肌张力障碍的临床表现密切相关。此处呈现的数据表明，与大多数已知的线粒体疾病不同，MTS似乎与线粒体能量产生系统的功能缺陷无关。虽然导致MTS中神经元丢失的特定线粒体功能障碍仍有待阐明，但电生理和神经影像学研究结果使我们能够具体描述MTS中神经退行性病变的多灶性表现。
