Clinical, histological and genetic characterization of reducing body myopathy caused by mutations in FHL1
Clinical, histological and genetic characterization of reducing body myopathy caused by mutations in FHL1
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DOI：
10.1093/brain/awn325
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发表时间：
2009-02-01
期刊：
影响因子：
14.5
通讯作者：
Boennemann, Carsten G.
中科院分区：
文献类型：
--
作者：
Schessl, Joachim;Taratuto, Ana L.;Boennemann, Carsten G.
我们最近确定X染色体四条半LIM结构域基因FHL1是减少体肌病的致病基因，体肌病是一种以进行性虚弱和肌浆内聚集为特征的疾病，对甲奈酮硝基蓝四氮唑(NBT)具有还原活性。在FHL1中检测到的突变会影响第二个LIM结构域中高度保守的锌配位残基，并导致当导入细胞时形成聚集体。我们的目的是确定这种肌病的临床和形态表型，并评估FHL1突变在更大范围的患者队列中减少躯体肌病的突变谱。临床、组织学、超微结构和分子遗传学分析后，通过甲奈二酮-NBT染色的肌肉活检切片中还原小体的检测来确定患者。本研究共纳入9个家系的11例患者，包括7例散发性儿童早期起病患者和4例起病较晚的家族性患者。所有患者的虚弱都是进行性的，有时是迅速的。呼吸衰竭是常见的，一些患者有明显的脊柱侧弯和脊柱僵硬。肌肉活检分析证实，在所有活检组织中都存在FHL1阳性物质聚集体。在两名可以进行连续活组织检查的患者中，肌肉部分的总负荷似乎随着时间的推移而增加。超微结构分析表明，胞浆小体与还原小体呈规律性分布。检测到的突变仅限于FHL1的第二个LIM结构域，并在散发性和家族性减少性躯体肌病病例中发现。九个突变中有六个影响了关键的锌配位残基组氨酸123。该残基中的所有突变都是从头开始的，并与严重的临床病程有关，特别是在一名男性患者(H123Q)。锌配位残基半胱氨酸153的突变与较轻的表型有关，并且在男孩比他们的母亲受到更严重影响的家族性病例中可以看到。我们预计，这一光谱的温和端未来将大幅扩大。在严重的范围内，我们将减少性躯体肌病定义为早期但不一定是先天性起病的进行性疾病，将这种疾病与经典的基本上非进行性的先天性肌病区分开来。
We recently identified the X-chromosomal four and a half LIM domain gene FHL1 as the causative gene for reducing body myopathy, a disorder characterized by progressive weakness and intracytoplasmic aggregates in muscle that exert reducing activity on menadione nitro-blue-tetrazolium (NBT). The mutations detected in FHL1 affected highly conserved zinc coordinating residues within the second LIM domain and lead to the formation of aggregates when transfected into cells. Our aim was to define the clinical and morphological phenotype of this myopathy and to assess the mutational spectrum of FHL1 mutations in reducing body myopathy in a larger cohort of patients. Patients were ascertained via the detection of reducing bodies in muscle biopsy sections stained with menadione-NBT followed by clinical, histological, ultrastructural and molecular genetic analysis. A total of 11 patients from nine families were included in this study, including seven sporadic patients with early childhood onset disease and four familial cases with later onset. Weakness in all patients was progressive, sometimes rapidly so. Respiratory failure was common and scoliosis and spinal rigidity were significant in some of the patients. Analysis of muscle biopsies confirmed the presence of aggregates of FHL1 positive material in all biopsies. In two patients in whom sequential biopsies were available the aggregate load in muscle sections appeared to increase over time. Ultrastructural analysis revealed that cytoplasmic bodies were regularly seen in conjunction with the reducing bodies. The mutations detected were exclusive to the second LIM domain of FHL1 and were found in both sporadic as well as familial cases of reducing body myopathy. Six of the nine mutations affected the crucial zinc coordinating residue histidine 123. All mutations in this residue were de novo and were associated with a severe clinical course, in particular in one male patient (H123Q). Mutations in the zinc coordinating residue cysteine 153 were associated with a milder phenotype and were seen in the familial cases in which the boys were still more severely affected compared to their mothers. We expect the mild end of the spectrum to significantly expand in the future. On the severe end of the spectrum we define reducing body myopathy as a progressive disease with early, but not necessarily congenital onset, distinguishing this condition from the classic essentially non-progressive congenital myopathies.