Kumar Monica, Aguiar Mario, Jessel Andreas, Thurberg Beth L, Underhill Lisa, Wong Holly, George Kelly, Davidson Vanessa, Schuchman Edward H
Sanofi, Bridgewater, NJ.
Sanofi, Cambridge, MA.
Genet Med Open. 2024 Aug 23;2:101888. doi: 10.1016/j.gimo.2024.101888. eCollection 2024.
Acid sphingomyelinase deficiency (ASMD) is a rare progressive genetic disorder caused by pathogenic variants in the gene causing low or absent activity of the enzyme acid sphingomyelinase, resulting in subsequent accumulation of its substrate, sphingomyelin. Signs and symptoms of excessive lysosomal sphingomyelin storage, such as hepatosplenomegaly and pulmonary impairment, and in a subset of patients, progressive neurological manifestations, have long been recognized as hallmarks of the disease. Uncontrolled accumulation of sphingomyelin has important and complex downstream metabolic and immunologic consequences that contribute to the disease burden. This review article expounds on the complex and multifaceted role of sphingomyelin in the pathophysiology of ASMD and discusses the animal studies and human interventional trials demonstrating that sphingomyelin and its related metabolites are linked to ASMD clinical manifestations, disease burden, and response to treatment. The relationship between the diverse manifestations of ASMD and sphingomyelin accumulation and the connections between sphingomyelin clearance and reversal of the noncentral nervous system manifestations by olipudase alfa therapy also are described.
酸性鞘磷脂酶缺乏症（ASMD）是一种罕见的进行性遗传疾病，由该基因中的致病变异引起，导致酸性鞘磷脂酶活性降低或缺失，进而导致其底物鞘磷脂积累。溶酶体鞘磷脂过度储存的体征和症状，如肝脾肿大和肺部损害，以及部分患者的进行性神经学表现，长期以来一直被视为该疾病的标志。鞘磷脂的不受控制积累具有重要且复杂的下游代谢和免疫后果，这加重了疾病负担。这篇综述文章阐述了鞘磷脂在ASMD病理生理学中的复杂多面作用，并讨论了动物研究和人体干预试验，这些研究表明鞘磷脂及其相关代谢物与ASMD临床表现、疾病负担及治疗反应有关。还描述了ASMD多种表现与鞘磷脂积累之间的关系，以及通过olipudase alfa疗法清除鞘磷脂与逆转非中枢神经系统表现之间的联系。
