Inserm, U, Paris, France.
J Inherit Metab Dis. 2010 Feb;33(1):61-7. doi: 10.1007/s10545-009-9029-2.
Mucopolysaccharidoses are autosomal and recessive lysosomal storage disorders caused by the deficiency of a lysosomal enzyme involved in glycosaminoglycan catabolism. The Sanfilippo type A disease (MPS III A) results from sulfamidase deficiency, which leads to accumulation of heparan sulfate, whereas Sly disease (MPS VII) results from beta-glucuronidase deficiency, leading to accumulation of heparan, dermatan, and chondroitin sulfates. These syndromes are characterized by severe central nervous system degeneration, resulting in progressive mental retardation, and fatality occurs in severely affected children. To date, no effective treatment is available except for bone marrow transplantation in specific cases. Recently, the use of genistein, an isoflavone that inhibits glycosaminoglycans synthesis, has been tested as substrate reduction therapy for neuronopathic forms of these diseases.We tested five natural analogs to genistein in human fibroblasts from both Sanfilippo A and Sly patients. Four molecules were as efficient as genistein in decreasing glycosaminoglycan accumulation. Moreover, a combination of several isoflavones was more efficient than one single isoflavone, suggesting a synergistic effect. These preliminary data may offer new perspectives for treating Sly and Sanfilippo A diseases and could be relevant to other neurological forms of mucopolysaccharidoses.
黏多糖贮积症是一组由于溶酶体酶缺陷导致的常染色体隐性遗传代谢性疾病，引起氨基己糖（糖胺）多糖分解代谢障碍。黏多糖贮积症甲型（Sanfilippo 型 A 疾病，MPS III A）是由于芳基硫酸酯酶缺乏导致硫酸乙酰肝素蓄积，而黏多糖贮积症 VII 型（Sly 疾病，MPS VII）则是由于β-葡萄糖醛酸酶缺乏导致硫酸乙酰肝素、硫酸皮肤素和硫酸软骨素蓄积。这些综合征的特征是严重的中枢神经系统退行性变，导致进行性智力迟钝，严重受影响的儿童会死亡。迄今为止，除了在特定情况下进行骨髓移植外，尚无有效的治疗方法。最近，已经测试了染料木黄酮（一种抑制氨基己糖合成的异黄酮）作为这些疾病神经病变形式的底物减少治疗。
我们在来自 Sanfilippo A 和 Sly 患者的人成纤维细胞中测试了五种天然染料木黄酮类似物。四种分子在降低氨基己糖积累方面与染料木黄酮一样有效。此外，几种异黄酮的组合比一种异黄酮更有效，表明存在协同作用。这些初步数据可能为治疗 Sly 和 Sanfilippo A 疾病提供新的视角，并且可能与其他神经形式的黏多糖贮积症相关。
