Department of Laboratory Medicine, University of Gothenburg, Gothenburg, Sweden.
Neuromuscular Centre, Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden.
Acta Neuropathol. 2024 Nov 26;148(1):73. doi: 10.1007/s00401-024-02830-x.
Lipid storage myopathies are considered inborn errors of metabolism affecting the fatty acid metabolism and leading to accumulation of lipid droplets in the cytoplasm of muscle fibers. Specific diagnosis is based on investigation of organic aids in urine, acylcarnitines in blood and genetic testing. An acquired lipid storage myopathy in patients treated with the antidepressant drug sertraline, a serotonin reuptake inhibitor, has recently emerged as a new tentative differential diagnosis. We analyzed the muscle biopsy tissue in a group of 11 adult patients with muscle weakness and lipid storage myopathy which developed at a time when they were on sertraline treatment. This group comprise most patients with lipid storage myopathies in western Sweden during the recent nine-year period. By enzyme histochemistry, electron microscopy, quantitative proteomics, immunofluorescence of the respiratory chain subunits, western blot and genetic analyses we demonstrate that muscle tissue in this group of patients exhibit a characteristic morphological and proteomic profile. The patients also showed an acylcarnitine profile in blood suggestive of multiple acyl-coenzyme A dehydrogenase deficiency, but no genetic explanation was found by whole genome or exome sequencing. By proteomic analysis the muscle tissue revealed a profound loss of Complex I subunits from the respiratory chain and to some extent also deficiency of Complex II and IV. Most other components of the respiratory chain as well as the fatty acid oxidation and citric acid cycle were upregulated in accordance with the massive mitochondrial proliferation. The respiratory chain deficiency was verified by immunofluorescence analysis, western blot analysis and enzyme histochemistry. The typical ultrastructural changes of the mitochondria included pleomorphism, dark matrix and frequent round osmiophilic inclusions. Our results show that lipid storage myopathy associated with sertraline treatment is a mitochondrial disorder with respiratory chain deficiency and is an important differential diagnosis with characteristic features.
脂质贮积肌病被认为是影响脂肪酸代谢并导致肌肉纤维细胞质中脂质滴积累的先天性代谢错误。特定的诊断基于尿液中的有机辅助物、血液中的酰基肉碱和基因检测。最近，一种在接受抗抑郁药舍曲林（一种 5-羟色胺再摄取抑制剂）治疗的患者中出现的获得性脂质贮积肌病，已成为新的暂定鉴别诊断。我们分析了一组 11 名肌肉无力和脂质贮积肌病患者的肌肉活检组织，这些患者在服用舍曲林治疗时出现了这种疾病。这组患者构成了瑞典西部最近九年来大多数脂质贮积肌病患者。通过酶组织化学、电子显微镜、定量蛋白质组学、呼吸链亚基免疫荧光、western blot 和基因分析，我们证明了该组患者的肌肉组织具有特征性的形态和蛋白质组学特征。这些患者的血液酰基肉碱谱也提示存在多种酰基辅酶 A 脱氢酶缺乏症，但通过全基因组或外显子组测序未发现遗传解释。通过蛋白质组学分析，肌肉组织显示呼吸链中复合物 I 亚基明显缺失，在某种程度上复合物 II 和 IV 也缺乏。其他大多数呼吸链成分以及脂肪酸氧化和柠檬酸循环都被上调，与大量线粒体增殖一致。呼吸链缺陷通过免疫荧光分析、western blot 分析和酶组织化学得到验证。线粒体的典型超微结构变化包括多形性、暗基质和频繁的圆形亲脂性内含物。我们的结果表明，与舍曲林治疗相关的脂质贮积肌病是一种线粒体疾病，存在呼吸链缺陷，是一种具有特征性表现的重要鉴别诊断。
