Newborn Screening for Acid Sphingomyelinase Deficiency: Prevalence and Genotypic Findings in Italy

Area of Science:

• Biochemistry
• Genetics
• Pediatrics
• Rare Diseases

Background:

• Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disorder with diverse clinical presentations.
• Delayed diagnosis of ASMD hinders timely treatment and impacts patient outcomes due to its rarity and heterogeneous symptoms.
• Newborn screening (NBS) is vital for early detection of genetic disorders, but its feasibility for ASMD requires evaluation.

Purpose of the Study:

• To assess the feasibility of implementing newborn screening for ASMD in Italy.
• To determine the incidence of ASMD in newborns through a pilot screening program.
• To evaluate the effectiveness of tandem mass spectrometry and genetic analysis in ASMD screening.

Main Methods:

• Analyzed 275,011 dried blood spot samples from newborns in Italy (2015-2024) for acid sphingomyelinase activity using tandem mass spectrometry.
• Conducted second-tier testing, including LysoSM quantification and SMPD1 gene sequencing, for samples with reduced enzyme activity.
• Identified ASMD cases based on enzyme activity, biomarker levels, and molecular genetic findings.

Main Results:

• Identified two newborns with ASMD, yielding an incidence of 1 in 137,506 live births.
• Confirmed diagnoses through elevated LysoSM levels and the presence of two SMPD1 variants, including novel and known mutations.
• Achieved a 100% positive predictive value (PPV) for the screening protocol.

Conclusions:

• Newborn screening for ASMD is feasible in Italy, revealing an underdiagnosed incidence compared to clinical reports.
• Optimized screening algorithms and second-tier biomarker testing improve the accuracy of ASMD detection in newborns.
• Further research, including long-term follow-up, is essential for genotype-phenotype correlations and refining patient management strategies.