| Historical label | Modern mapping / status | Gene(s) / biochemical defect | Representative clinical features | Hallmark diagnostics | Key source |
|---|---|---|---|---|---|
| Niemann-Pick type A | Now grouped under **acid sphingomyelinase deficiency (ASMD)**; infantile neurovisceral end of ASMD spectrum | **SMPD1**; deficient **acid sphingomyelinase (ASM)** activity causing sphingomyelin storage | Infantile onset, massive hepatosplenomegaly, profound CNS involvement, death usually by 2–3 years | Low ASM activity in leukocytes/fibroblasts; **SMPD1** molecular testing | Schuchman & Desnick, 2017, Mol Genet Metab, doi:10.1016/j.ymgme.2016.12.008, https://doi.org/10.1016/j.ymgme.2016.12.008 (pqac-00000006, pqac-00000016) |
| Niemann-Pick type B | Now grouped under **ASMD**; chronic visceral end of ASMD spectrum | **SMPD1**; deficient ASM activity | Hepatosplenomegaly, lung disease/pulmonary insufficiency, usually no CNS signs, survival into adulthood common | Low ASM activity; **SMPD1** testing; newer screening biomarkers include **lyso-sphingomyelin in DBS** | Geberhiwot et al., 2023, Orphanet J Rare Dis, doi:10.1186/s13023-023-02686-6, https://doi.org/10.1186/s13023-023-02686-6; Lipiński et al., 2024, Adv Clin Exp Med, doi:10.17219/acem/193696, https://doi.org/10.17219/acem/193696 (pqac-00000003, pqac-00000005, pqac-00000014) |
| Niemann-Pick type A/B (intermediate) | Modern **ASMD** continuum includes chronic neurovisceral/intermediate forms rather than a strict separate legacy subtype | **SMPD1**; partial ASM deficiency | Visceral disease with variable neurologic involvement | ASM assay plus **SMPD1** sequencing | Geberhiwot et al., 2023, doi:10.1186/s13023-023-02686-6, https://doi.org/10.1186/s13023-023-02686-6 (pqac-00000003, pqac-00000005) |
| Niemann-Pick type C | Separate entity: **Niemann-Pick disease type C (NPC)**, not ASMD | **NPC1** (~95% of families) or **NPC2**; defective intracellular cholesterol trafficking / cholesterol esterification abnormalities | Progressive neurovisceral disease; splenomegaly, ataxia, dysarthria, dysphagia, cognitive decline, vertical supranuclear gaze palsy; adult-onset forms occur | **Filipin staining** of cultured fibroblasts showing unesterified cholesterol accumulation; **NPC1/NPC2** genotyping | Vanier, 2010, Orphanet J Rare Dis, doi:10.1186/1750-1172-5-16, https://doi.org/10.1186/1750-1172-5-16; Bolton et al., 2022, doi:10.1186/s13023-022-02200-4, https://doi.org/10.1186/s13023-022-02200-4 (pqac-00000010, pqac-00000002) |
| Niemann-Pick type D | **Obsolete historical label**; patients now recognized within **NPC** | Historically separated geographically/clinically; molecularly falls within **NPC1/NPC2-related cholesterol trafficking disease** | NPC-like neurovisceral phenotype | Same as NPC: filipin testing and **NPC1/NPC2** testing | Schuchman & Desnick, 2017, doi:10.1016/j.ymgme.2016.12.008, https://doi.org/10.1016/j.ymgme.2016.12.008 (pqac-00000006, pqac-00000016) |
| Niemann-Pick type E | **Historical/ill-defined and obsolete label**; used for rare adult patients with splenomegaly/sea-blue histiocytosis or mixed features; modern sources indicate D/E nosology is no longer used, and older D/E/C cases were later split into **ASMD (SMPD1)** vs **NPC (NPC1/NPC2)** based on biochemistry/genetics | No single validated molecular basis for the legacy label; older reports described **normal leukocyte ASM** in some putative type E cases, underscoring heterogeneity | Adult onset; variable hepatosplenomegaly/splenomegaly, sometimes preserved cognition, occasionally neurologic or multisystem involvement; very rare renal involvement reported | Historically bone marrow Niemann-Pick/foam cells and exclusion of classic A/B; today recommended workup is **ASM enzyme assay + SMPD1 testing**, and if not ASMD, **NPC biochemical/genetic testing** | Schuchman & Desnick, 2017, doi:10.1016/j.ymgme.2016.12.008, https://doi.org/10.1016/j.ymgme.2016.12.008; Zheng et al., 2016, case report/lit review, URL not available in provided context (pqac-00000000, pqac-00000001, pqac-00000006, pqac-00000016) |


*Table: This table summarizes how historical Niemann-Pick subtype labels map to current molecularly defined entities. It is especially useful for clarifying why the legacy 'type E' designation is now considered obsolete and how modern diagnosis distinguishes ASMD from NPC.*