| Domain | Key details | Evidence/source (with year) |
|---|---|---|
| Disease name / classification | Niemann–Pick disease type A = infantile neurovisceral acid sphingomyelinase deficiency (ASMD); severe neuronopathic end of the ASMD spectrum | 2023 consensus guidelines; 2024 pediatric ASMD review (pqac-00000009, pqac-00000011, pqac-00000006) |
| Identifiers | MONDO: MONDO:0009756 (Niemann-Pick disease type A); OMIM numbers cited in 2023 guidelines header for ASMD/Niemann–Pick types A/B: 257200 and 607616 | Open Targets disease mapping; 2023 guidelines (pqac-00000000, pqac-00000009) |
| Causative gene | SMPD1 (sphingomyelin phosphodiesterase 1); loss-of-function variants cause acid sphingomyelinase deficiency | 2023 guidelines; 2017 review (pqac-00000011, pqac-00000007) |
| Inheritance | Autosomal recessive; biallelic pathogenic SMPD1 variants | 2023 guidelines; 2024 pediatric ASMD review (pqac-00000009, pqac-00000006) |
| Core biochemical defect | Deficient lysosomal acid sphingomyelinase (ASM) activity causes sphingomyelin accumulation with secondary lipid accumulation including cholesterol | 2023 guidelines; 2024 review (pqac-00000012, pqac-00000010) |
| Hallmark early visceral features | Hepatosplenomegaly in early infancy; often presents at 2–4 months; splenomegaly is a key clue | 2017 burden review; 2023 guidelines (pqac-00000001, pqac-00000012) |
| Hallmark neurologic course / onset | Development may be initially normal, then psychomotor delay/regression begins in the first year; neurologic symptoms median ~7 months; regression often noted in the second 6 months of life | 2017 burden review; 2024 pediatric ASMD review (pqac-00000001, pqac-00000006) |
| Other common features | Cherry-red macula often present by 12 months; hypotonia, growth failure/failure to thrive, rapidly progressive neurodegeneration, respiratory involvement | 2017 burden review; 2024 review (pqac-00000001, pqac-00000010) |
| Prognosis | Uniformly severe, rapidly progressive infantile disorder; patients rarely survive beyond 2–3 years | 2017 review; 2023 guidelines (pqac-00000007, pqac-00000011) |
| Survival statistics (French cohort, 2024) | Type A cohort n=15; median age at symptom onset 6.0 months (3.0–18.0), diagnosis 8.0 months (1.0–18.0), death 1 year (0–3.6); median survival from birth 2.0 years (95% CI 1.8–2.7); mortality 14/15 (93.3%) at study cut-off | Mauhin et al., Orphanet J Rare Dis 2024 (pqac-00000017, pqac-00000019) |
| Population genetics / founder effect | Ashkenazi Jewish carrier frequency reported around 1:100–1:200, with estimated disease prevalence 1:40,000–1:200,000 in that population | 2023 guidelines (pqac-00000012) |
| Diagnostic enzyme testing | ASM activity can be measured in peripheral blood leukocytes/lymphocytes, cultured skin fibroblasts, or dried blood spots; marked deficiency supports diagnosis | 2017 review; 2024 review/guidance (pqac-00000001, pqac-00000028) |
| Diagnostic molecular testing | Confirmatory SMPD1 sequencing; NGS/Sanger used, with MLPA/WGS considered if needed | 2017 review; 2024 review/guidance (pqac-00000001, pqac-00000030) |
| Biomarkers | Lyso-sphingomyelin (LysoSM) and LysoSM-509 are useful ASMD biomarkers; elevated in DBS and plasma and useful for screening/triage | 2024 Polish update; 2024 review/guidance (pqac-00000006, pqac-00000028) |
| Newborn screening algorithm (Italy) | First-tier DBS ASM activity by LC-MS/MS; monthly recalculated 0.2 MoM cutoff; second-tier LysoSM on same DBS; abnormal samples undergo SMPD1 genotyping | Gragnaniello et al., 2024 (pqac-00000021, pqac-00000024) |
| Newborn screening cutoff / abnormal biomarker | Italian NBS used LysoSM > 51.68 nmol/L as abnormal in second-tier testing | Gragnaniello et al., 2024 (pqac-00000021) |
| Newborn screening performance (Italy) | 275,011 newborns screened; 2 screen-positive/confirmed cases; estimated incidence 1:137,506; reported PPV 100% in study summary/table | Gragnaniello et al., 2024 (pqac-00000020, pqac-00000022) |
| 2023 care standard | First international consensus management guidelines published for ASMD, addressing diagnosis, multidisciplinary care, and standard-of-care gaps | Geberhiwot et al., 2023 (pqac-00000009) |
| Approved disease-modifying therapy | Olipudase alfa (Xenpozyme) is the first approved disease-modifying therapy for ASMD, but only for non-CNS manifestations; supportive care remains the mainstay for type A | 2024 review; 2023 guidelines; Mauhin 2024 reference summary (pqac-00000010, pqac-00000009, pqac-00000015) |
| Why olipudase alfa is limited in type A | Enzyme replacement improves visceral disease but is limited by lack of meaningful CNS penetration/blood–brain barrier barrier, so infantile neurovisceral type A is not adequately addressed | 2024 reviews (pqac-00000013, pqac-00000014) |
| Expanded access / real-world implementation | Compassionate-use olipudase alfa program for chronic ASMD: NCT04877132; excludes infantile-onset/genotype-compatible type A and includes type A/B or B patients with chronic disease | ClinicalTrials.gov expanded access (pqac-00000027) |
| Pivotal adult olipudase trial | ASCEND trial NCT02004691: phase 2/3 randomized placebo-controlled adult study; 36 participants; primary endpoints included spleen volume by MRI and DLCO | ClinicalTrials.gov; 2024 review (pqac-00000031, pqac-00000033) |
| Pediatric olipudase development | ASCEND-Peds / NCT02292654: phase 1/2 pediatric repeat-dose olipudase study; 20 participants | ClinicalTrials.gov registry summary (pqac-00000033) |
| Real-world early access study | OPERA France / NCT05359276: observational real-world cohort (n=40) evaluating lung, spleen, liver outcomes, safety, immunogenicity, biomarkers, and treatment-use patterns with olipudase alfa | ClinicalTrials.gov (pqac-00000029) |
| Infant/toddler post-approval study | NCT06192576: real-world long-term safety and immunogenicity study of olipudase alfa in pediatric patients <2 years with ASMD | ClinicalTrials.gov (pqac-00000032) |
| Research pipeline beyond ERT | Gene therapy is under active preclinical/early clinical investigation for ASMD because current ERT does not solve CNS disease in type A | 2024 reviews (pqac-00000003, pqac-00000014) |


*Table: This table summarizes the most actionable disease-characteristics facts for Niemann–Pick disease type A, including identifiers, genetics, phenotype, prognosis, diagnostics, and 2023–2024 therapeutic/screening developments. It is designed for rapid knowledge-base population with source-linked evidence.*