Gragnaniello Vincenza, Cazzorla Chiara, Gueraldi Daniela, Loro Christian, Porcù Elena, Salviati Leonardo, Burlina Alessandro P, Burlina Alberto B
Division of Inherited Metabolic Diseases, Department of Women's and Children's Health, University Hospital of Padua, 35128 Padua, Italy.
Division of Inherited Metabolic Diseases, Department of Women's and Children's Health, University of Padua, 35128 Padua, Italy.
Int J Neonatal Screen. 2024 Dec 4;10(4):79. doi: 10.3390/ijns10040079.
Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disorder with a broad clinical spectrum. Early diagnosis and initiation of treatment are crucial for improving outcomes, yet the disease often goes undiagnosed due to its rarity and phenotypic heterogeneity. This study aims to evaluate the feasibility and disease incidence of newborn screening (NBS) for ASMD in Italy. Dried blood spot samples from 275,011 newborns were collected between 2015 and 2024 at the Regional Center for Expanded NBS in Padua. Acid sphingomyelinase activity was assayed using tandem mass spectrometry. Deidentified samples with reduced enzyme activity underwent second-tier testing with LysoSM quantification and gene analysis. Two samples were identified with reduced sphingomyelinase activity and elevated LysoSM levels. Both carried two variants, suggesting a diagnosis of ASMD. Molecular findings included novel and previously reported variants, some of uncertain significance. The overall incidence was 1 in 137,506 newborns and the PPV was 100%. This study demonstrates the feasibility of NBS for ASMD in Italy and provides evidence of a higher disease incidence than clinically reported, suggesting ASMD is an underdiagnosed condition. Optimized screening algorithms and second-tier biomarker testing can enhance the accuracy of NBS for ASMD. The long-term follow-up of identified cases is necessary for genotype-phenotype correlation and improving patient management.
酸性鞘磷脂酶缺乏症（ASMD）是一种罕见的溶酶体贮积病，临床谱广泛。早期诊断和开始治疗对于改善预后至关重要，但由于该病罕见且表型异质性，往往未被诊断出来。本研究旨在评估意大利新生儿筛查（NBS）ASMD的可行性和疾病发病率。2015年至2024年期间，在帕多瓦的区域扩大新生儿筛查中心收集了275,011名新生儿的干血斑样本。使用串联质谱法测定酸性鞘磷脂酶活性。酶活性降低的去识别样本进行了第二层检测，包括溶酶体鞘磷脂（LysoSM）定量和基因分析。鉴定出两个样本鞘磷脂酶活性降低且LysoSM水平升高。两者都携带两个变异，提示ASMD诊断。分子学发现包括新的和先前报道的变异，其中一些意义不确定。总体发病率为1/137,506新生儿，阳性预测值为100%。本研究证明了意大利NBS筛查ASMD的可行性，并提供了证据表明该病发病率高于临床报告，提示ASMD是一种诊断不足的疾病。优化的筛查算法和第二层生物标志物检测可以提高NBS筛查ASMD的准确性。对确诊病例进行长期随访对于基因型-表型相关性研究和改善患者管理是必要的。
