Department of Medical Genetics and the Child and Family Research Institute, University of British Columbia, Vancouver, Canada.
Mol Genet Metab. 2012 May;106(1):99-103. doi: 10.1016/j.ymgme.2012.02.004. Epub 2012 Feb 8.
Galactosialidosis is a lysosomal storage disorder caused by loss of function of protective protein cathepsin A, which leads to secondary deficiencies of β-galactosidase and neuraminidase-1. Emphysema has not been previously reported as a possible complication of this disorder, but we now describe this condition in a 41-year-old, non-smoking male. Our patient did not display deficiency in α-1-antitrypsin, the most common cause of emphysema in non-smokers, which brings about disseminated elastolysis. We therefore hypothesized that loss of cathepsin A activity was responsible because of previously published evidence showing it is prerequisite for normal elastogenesis. We now present experimental evidence to support this theory by demonstrating impaired primary elastogenesis in cultures of dermal fibroblasts from our patient. The obtained data further endorse our previous finding that functional integrity of the cell surface-targeted molecular complex of cathepsin A, neuraminidase-1 and the elastin-binding protein (spliced variant of β-galactosidase) is prerequisite for the normal assembly of elastic fibers. Importantly, we also found that elastic fiber production was increased after exposure either to losartan, spironolactone, or dexamethasone. Of immediate clinical relevance, our data suggest that surviving patients with galactosialidosis should have periodic assessment of their pulmonary function. We also encourage further experimental exploration of therapeutic potential of the afore-mentioned elastogenesis-stimulating drugs for the alleviation of pathological processes in galactosialidosis that could be mechanistically linked to impaired deposition of elastic fibers.
半乳糖脑苷脂贮积症是一种溶酶体贮积病，由保护性蛋白组织蛋白酶 A 功能丧失引起，导致β-半乳糖苷酶和神经氨酸酶-1 的继发缺乏。肺气肿以前从未被报道为这种疾病的可能并发症，但我们现在描述了一位 41 岁不吸烟男性的这种情况。我们的患者α-1-抗胰蛋白酶不缺乏，α-1-抗胰蛋白酶是不吸烟人群肺气肿的最常见原因，会导致弥散性弹性纤维溶解。因此，我们假设组织蛋白酶 A 活性丧失是导致这种情况的原因，因为之前有证据表明它是正常弹性生成的必要条件。我们现在通过证明我们患者的皮肤成纤维细胞培养物中初级弹性生成受损提供了实验证据来支持这一理论。获得的数据进一步支持了我们之前的发现，即组织蛋白酶 A、神经氨酸酶-1 和弹性蛋白结合蛋白（β-半乳糖苷酶的剪接变体）的细胞表面靶向分子复合物的功能完整性是正常弹性纤维组装的必要条件。重要的是，我们还发现，暴露于氯沙坦、螺内酯或地塞米松后，弹性纤维的产生增加。立即具有临床意义的是，我们的数据表明，幸存的半乳糖脑苷脂贮积症患者应定期评估其肺功能。我们还鼓励进一步探索上述弹性生成刺激药物的治疗潜力，以减轻与弹性纤维沉积受损相关的半乳糖脑苷脂贮积症的病理过程。
