From guidelines to real-world practice: clinical, biochemical, and genetic insights in a series of Moroccan patients with acid sphingomyelinase deficiency

Objectives Niemann–Pick disease types A and B (NPD-A, NPD-B) are lysosomal storage disorders caused by acid sphingomyelinase (ASM) deficiency, leading to sphingomyelin (SM) accumulation. NPD-A presents with rapidly progressive neurodegeneration in infancy, whereas NPD-B spares the nervous system. This study aimed to define the biochemical profile of Moroccan patients, delineate the SMPD1 mutation spectrum, and illustrate a practical diagnostic pathway suited to a resource-limited setting. Methods Genetic and biochemical investigations were performed to identify SMPD1 variants and evaluate sphingomyelin excretion. Molecular analysis was conducted using Sanger sequencing. Urinary lipid extracts were analyzed by thin-layer chromatography (TLC) as an orientation tool, and exploratory high-performance liquid chromatography–mass spectrometry (HPLC–MS/MS) was performed in two representative cases. Five genetically confirmed Moroccan patients are described in this cohort. Results Five patients were diagnosed with ASM deficiency (ASMD) using this integrated approach. TLC analysis revealed abnormal urinary sphingomyelin patterns, providing an early biochemical orientation toward the diagnosis. Enzymatic assays confirmed reduced ASM activity, and molecular analysis identified two pathogenic SMPD1 variants: the in-frame deletion NM_000543.4:c.1826_1828delGCC (p.Arg610del) in a patient with NPD-B and the nonsense mutation NM_000543.4:c.1624C>T (p.Arg542*) in patients with NPD-A. The exploratory HPLC-MS/MS analysis highlighted a marked signal for the SM(d18:1/16:0) isoform in urine. Conclusions This study proposes a practical diagnostic workflow adapted to a resource-limited setting and provides new insights into the SMPD1 mutation spectrum and urinary SM species in the Moroccan population. Future studies on larger cohorts are needed to better define biochemical variability and confirm genotype–phenotype associations.