PDF(Pubmed)
Abstract：
Pulmonary alveolar microlithiasis (PAM) is a rare autosomal recessive lung disease caused by variants in the SLC34A2 gene encoding the sodium-dependent phosphate transport protein 2B, NaPi-2b. PAM is characterized by deposition of calcium phosphate crystals in the alveoli. Onset and clinical course vary considerably; some patients remain asymptomatic while others develop severe respiratory failure with a significant symptom burden and compromised survival. It is likely that PAM is under-reported due to lack of recognition, misdiagnosis, and mild clinical presentation. Most patients are genetically uncharacterized as the diagnostic confirmation of PAM has traditionally not included a genetic analysis. Genetic testing may in the future be the preferred tool for diagnostics instead of invasive methods. This systematic review aims to provide an overview of the growing knowledge of PAM genetics. Rare variants in SLC34A2 are found in almost all genetically tested patients. So far, 34 allelic variants have been identified in at least 68 patients. A majority of these are present in the homozygous state; however, a few are found in the compound heterozygous form. Most of the allelic variants involve only a single nucleotide. Half of the variants are either nonsense or frameshifts, resulting in premature termination of the protein or decay of the mRNA. There is currently no cure for PAM, and the only effective treatment is lung transplantation. Management is mainly symptomatic, but an improved understanding of the underlying pathophysiology will hopefully result in development of targeted treatment options. More standardized data on PAM patients, including a genetic diagnosis covering larger international populations, would support the design and implementation of clinical studies to the benefit of patients. Further genetic characterization and understanding of how the molecular changes influence disease phenotype will hopefully allow earlier diagnosis and treatment of the disease in the future.
摘要：
肺泡微石症（PAM）是一种罕见的常染色体隐性遗传肺病，由编码钠依赖性磷酸盐转运蛋白2B的SLC34A2基因变异引起，NaPi-2b.PAM的特征在于磷酸钙晶体在肺泡中的沉积。发病和临床病程差异很大；一些患者无症状，而另一些患者则出现严重的呼吸衰竭，症状负担显着，生存率下降。由于缺乏认可，PAM很可能被低估了，误诊,和轻微的临床表现。大多数患者在遗传上没有表征,因为PAM的诊断确认传统上不包括遗传分析。将来，基因检测可能会成为诊断的首选工具，而不是侵入性方法。本系统综述旨在提供对PAM遗传学不断增长的知识的概述。在几乎所有经过基因测试的患者中都发现了SLC34A2的罕见变异。到目前为止,已经在至少68名患者中鉴定了34个等位基因变体。其中大多数以纯合状态存在；然而，在复合杂合形式中发现了一些。大多数等位基因变体仅涉及单个核苷酸。一半的变体要么是胡说八道，要么是移码，导致蛋白质的过早终止或mRNA的衰减。目前没有治疗PAM的方法,唯一有效的治疗方法是肺移植。管理主要是对症，但对潜在病理生理学的更好理解将有望导致靶向治疗方案的发展。关于PAM患者的更多标准化数据，包括覆盖更多国际人口的基因诊断，将支持临床研究的设计和实施，以使患者受益。进一步的遗传表征和对分子变化如何影响疾病表型的理解将有望在将来对疾病进行早期诊断和治疗。
