| Topic | Key facts for chronic neurovisceral ASMD (Niemann-Pick A/B) | Key source | Year | URL |
|---|---|---|---|---|
| Disease definition / spectrum | Chronic neurovisceral ASMD is the intermediate phenotype on the ASMD continuum between infantile neurovisceral type A and chronic visceral type B; patients have visceral disease plus later-onset/slowly progressive neurologic involvement, and some may show developmental delay, ataxia, hyporeflexia, hypotonia, learning or behavioral abnormalities. ASMD is an ultra-rare multisystem lysosomal storage disorder caused by SMPD1 deficiency with sphingomyelin accumulation. (pqac-00000002, pqac-00000027, pqac-00000030) | Geberhiwot et al., *Orphanet J Rare Dis* | 2023 | https://doi.org/10.1186/s13023-023-02686-6 |
| Key identifiers / synonyms | Synonyms used in recent literature: acid sphingomyelinase deficiency (ASMD), Niemann-Pick disease type A/B, chronic neurovisceral ASMD, intermediate NPD. OMIM IDs explicitly cited in guideline text for ASMD/Niemann-Pick disease are 257200 and 607616; Orphanet prevalence cited in the guideline is 1–9 per 1,000,000 in Europe. (pqac-00000026, pqac-00000027) | Geberhiwot et al., *Orphanet J Rare Dis* | 2023 | https://doi.org/10.1186/s13023-023-02686-6 |
| Inheritance / epidemiology | Autosomal recessive, pan-ethnic disorder due to biallelic SMPD1 variants. Estimated birth prevalence in expert review: ~0.4–0.6 per 100,000; global prevalence in guideline: ~1:100,000–1,000,000 births, with some populations showing higher incidence due to founder effects/consanguinity. Ashkenazi Jewish carrier frequency for common type A variants estimated at ~1:100 to 1:200. (pqac-00000002, pqac-00000007, pqac-00000027) | Arslan et al., *Front Pediatr*; Geberhiwot et al., *Orphanet J Rare Dis* | 2023 | https://doi.org/10.3389/fped.2023.1113422 ; https://doi.org/10.1186/s13023-023-02686-6 |
| Causal gene / molecular basis | Causal gene: **SMPD1** (sphingomyelin phosphodiesterase 1), encoding acid sphingomyelinase (ASM). ASM deficiency impairs lysosomal hydrolysis of sphingomyelin to ceramide + phosphocholine, causing sphingomyelin, cholesterol and other lipid accumulation and downstream defects in autophagy, inflammation/apoptosis, and mitochondrial function. (pqac-00000025, pqac-00000027, pqac-00000031) | Tirelli et al., *Biomolecules*; Wang et al., *Hereditas* | 2024, 2023 | https://doi.org/10.3390/biom14020211 ; https://doi.org/10.1186/s41065-023-00272-1 |
| Diagnostic biomarkers / tests | Recommended workflow: DBS ASM assay as screening test, preferably **MS/MS or LC-MS/MS**, then confirmation with **leukocyte ASM activity** (gold standard), plus **SMPD1 sequencing**. **LysoSM** and **LysoSM-509** are useful adjunct biomarkers where available. DBS is convenient but may yield false positives/negatives and should be confirmed in leukocytes; fibroblasts can help in ambiguous cases. Clinical red flags include splenomegaly ± hepatomegaly, interstitial lung disease, elevated transaminases, dyslipidemia, low HDL-C, thrombocytopenia, and neuroregression. (pqac-00000008, pqac-00000013, pqac-00000014, pqac-00000030) | Arslan et al., *Front Pediatr*; Alagia et al. review | 2023, 2024 | https://doi.org/10.3389/fped.2023.1113422 |
| Newborn screening: Italy | Padua, Italy screened **275,011** newborn DBS samples (2015–2024) using LC-MS/MS; 2 newborns had low ASM and elevated LysoSM, giving **incidence 1:137,506** and **PPV 100%**. Primary cutoff was **0.2 MoM**; second-tier LysoSM cutoff **>51.68 nmol/L**. Positive cases had ASM activities ~0.52–0.53 µmol/L. (pqac-00000009, pqac-00000011, pqac-00000012, pqac-00000029) | Gragnaniello et al., *Int J Neonatal Screen* | 2024 | https://doi.org/10.3390/ijns10040079 |
| Newborn screening: Illinois / New York / Washington / Hungary | Illinois: **1,230,900** screened; **10** low ASM activity samples, all molecularly confirmed; **incidence 1:126,345**. Earlier Illinois example in expert review: **219,973** screened, **2** Niemann-Pick A/B cases. New York: **65,605** screened; 2 infants homozygous for previously undescribed VUSs. Washington pilot: ~**43,000** screened; 5 low ASM activity, 1 with two pathogenic SMPD1 variants. Hungary: **40,024** screened in one report with 5 low ASM activity and 2 molecular confirmations; larger summary cited **incidence ~1:20,012, PPV 40%**. (pqac-00000008, pqac-00000010, pqac-00000029) | Gragnaniello et al., *Int J Neonatal Screen*; Arslan et al., *Front Pediatr* | 2024, 2023 | https://doi.org/10.3390/ijns10040079 ; https://doi.org/10.3389/fped.2023.1113422 |
| Exemplar SMPD1 variants / genotype-phenotype | Expert review links **p.Q294K** and **p.W393G** to chronic neurovisceral ASMD (A/B); **p.R498L, p.L304P, p.P333Sfs*52** to infantile neurovisceral type A; and **ΔR610 (p.R608del/R610del), p.P323A, p.P330R, p.W393G** to chronic visceral type B. Newborn-screen positives included **p.Tyr369Cys + p.Arg591Cys** and **p.Glu411Serfs*14 + p.Ser510Phe**. Large mutation-landscape study notes severe deletions/insertions tend toward type A, milder missense variants toward type B; **p.Arg3AlafsX76** is prevalent in Chinese patients and **p.R608del** in Mediterranean countries. (pqac-00000008, pqac-00000012, pqac-00000031) | Arslan et al., *Front Pediatr*; Wang et al., *Hereditas*; Gragnaniello et al., *Int J Neonatal Screen* | 2023, 2023, 2024 | https://doi.org/10.3389/fped.2023.1113422 ; https://doi.org/10.1186/s41065-023-00272-1 ; https://doi.org/10.3390/ijns10040079 |
| Pediatric chronic ASMD cohort facts | In Polish pediatric chronic ASMD (n=7), **splenomegaly 7/7**, mild hepatomegaly **4/7**, hypercholesterolemia **6/7**, decreased HDL-C **all patients**, cherry-red spot **5/7** including 1 neurovisceral patient; missense variants comprised **71% of alleles**. Lyso-SM in DBS was elevated in all screened patients and higher in chronic neurovisceral than chronic visceral disease. (pqac-00000005, pqac-00000024) | Lipiński et al., *Adv Clin Exp Med* | 2024 | https://doi.org/10.17219/acem/193696 |
| Olipudase alfa: role / approvals | **Olipudase alfa (Xenpozyme)** is the first and currently only disease-modifying therapy for **non-CNS manifestations** of ASMD; it does **not cross the blood-brain barrier**. Review notes approval in **>35 countries** including EU, USA, and Japan; EMA approval timing is cited in other reviews as 2022, and Polish cohort notes availability in Poland from April 2024. Dose escalation is required to avoid toxicity from rapid sphingomyelin catabolism. (pqac-00000018, pqac-00000021, pqac-00000024) | Syed, *Clin Drug Investig*; Lipiński et al. | 2023, 2024 | https://doi.org/10.1007/s40261-023-01270-x ; https://doi.org/10.17219/acem/193696 |
| Olipudase alfa: adult ASCEND efficacy | In ASCEND (52-week randomized trial), baseline mean % predicted **DLCO ≈49%** and mean spleen volume **11–12 MN**. Olipudase alfa significantly improved DLCO and spleen volume vs placebo; **27.7% vs 0%** achieved **≥15% absolute increase in % predicted DLCO**, and **94.4% vs 0%** achieved **≥30% spleen-volume reduction**. Liver volume decreased and platelets increased; ALT **−36.5% vs −0.98%**, AST **−31.6% vs +2.0%**, total bilirubin **−29.9% vs +12.5%**. HRCT ILD and ground-glass scores also improved. (pqac-00000016, pqac-00000028) | Syed, *Clin Drug Investig* | 2023 | https://doi.org/10.1007/s40261-023-01270-x |
| Olipudase alfa: pediatric efficacy | In pediatric studies, % predicted **FVC increased from 77.5% to 85.7%** at 52 weeks; FEV1 from **76.5% to 81.7%**; TLC from **86.8% to 110.2%**; HRCT ILD scores decreased by **13% (adolescents), 23% (children), 24% (infant/early child)**. Six severe ILD cases improved to mild/moderate in five and resolved in one. Spleen and liver volumes decreased significantly by week 26 and 52 across age cohorts; all 10 severe hepatomegaly cases improved to moderate by week 52. Benefits were sustained or improved through **24 months**. (pqac-00000016, pqac-00000017) | Syed, *Clin Drug Investig* | 2023 | https://doi.org/10.1007/s40261-023-01270-x |
| Olipudase alfa: biomarker effects | In trials, olipudase alfa reduced **lyso-sphingomyelin by 78% in adults vs 6.1% with placebo**, and **87% in pediatric patients**; **chitotriosidase −54.7% in adults vs −12.3% placebo**; liver sphingomyelin fell **−92.7% at 52 weeks vs +10.9% placebo**. (pqac-00000018) | Syed, *Clin Drug Investig* | 2023 | https://doi.org/10.1007/s40261-023-01270-x |
| Olipudase alfa: dosing / safety | Within-patient escalation to **3 mg/kg every 2 weeks** is used to debulk sphingomyelin gradually; adult examples escalated 0.1 → 0.3 → 0.6 → 1 → 2 mg/kg before maintenance 3 mg/kg. Common AEs are mostly mild **infusion-associated reactions**; **headache 44.4% vs 16.7% placebo** in adults. **Transient transaminase elevations** can occur 24–48 h post-infusion. **ADAs** occurred in **25% of adults** and **60% of pediatric patients** (mostly low titer). One pediatric patient developed **IgG/IgE-associated anaphylaxis**; US labeling carries a boxed warning for severe hypersensitivity. (pqac-00000017, pqac-00000021) | Syed, *Clin Drug Investig* | 2023 | https://doi.org/10.1007/s40261-023-01270-x |


*Table: This table condenses the most actionable disease, diagnostic, genetic, screening, and treatment facts for chronic neurovisceral ASMD/Niemann-Pick A/B. It is useful as a quick-reference summary anchored to recent guideline, screening, and olipudase alfa evidence.*