We report a multiplex family with extended multisystem neurological phenotype associated with a CRYAB variant. Two affected siblings were evaluated with whole exome sequencing, muscle biopsy, laser microdissection, and mass spectrometry-based proteomic analysis. Both patients and their mother manifested a combination of early-onset cataracts, cardiomyopathy, cerebellar ataxia, optic atrophy, cognitive impairment, and myopathy. Whole exome sequencing identified a heterozygous c.458C>T variant mapped to the C-terminal extension domain of the Alpha-crystallin B chain, disrupting its function as a molecular chaperone and its ability to suppress protein aggregation. In accordance with the molecular findings, muscle biopsies revealed subsarcolemmal deposits that appeared dark with H&E and trichrome staining were negative for the other routine histochemical staining and for amyloid with the Congo-red stain. Electron microscopy demonstrated that the deposits were composed of numerous parallel fibrils. Laser microdissection and mass spectrometry-based proteomic analysis revealed that the inclusions are almost exclusively composed of crystallized chaperones/heat shock proteins. Moreover, a structural model suggests that Ser153 could be involved in monomer stabilization, dimer association, and possible binding of partner proteins. We propose that our report potentially expands the complex phenotypic spectrum of alpha B-crystallinopathies with possible effect of a CRYAB variant on the central nervous system.

我们报告了一个与CRYAB相关的具有扩展多系统神经表型的多重家族变体。对两个受影响的兄弟姐妹进行了全外显子组测序、肌肉活检、激光显微切割和基于质谱的蛋白质组学分析。患者和他们的母亲都表现出早发性白内障、心肌病、小脑共济失调、视神经萎缩、认知障碍和肌病。全外显子组测序鉴定了一个杂合的 c.458C>T 变体，映射到 α-晶状体蛋白 B 链的 C 末端延伸结构域，破坏了其作为分子伴侣的功能及其抑制蛋白质聚集的能力。根据分子发现，肌肉活检显示肌膜下沉积物在 H&E 下呈黑色，三色染色对其他常规组织化学染色和刚果红染色对淀粉样蛋白呈阴性。电子显微镜显示沉积物由许多平行的原纤维组成。激光显微切割和基于质谱的蛋白质组学分析表明，内含物几乎完全由结晶的伴侣/热休克蛋白组成。此外，结构模型表明 Ser153 可能参与单体稳定、二聚体结合和可能的伴侣蛋白结合。我们建议，我们的报告可能会扩展 α B 晶体病的复杂表型谱，并可能影响 一个结构模型表明 Ser153 可能参与单体稳定、二聚体结合和可能的伴侣蛋白结合。我们建议，我们的报告可能会扩展 α B 晶体病的复杂表型谱，并可能影响 一个结构模型表明 Ser153 可能参与单体稳定、二聚体结合和可能的伴侣蛋白结合。我们建议，我们的报告可能会扩展 α B 晶体病的复杂表型谱，并可能影响中枢神经系统上的CRYAB变体。