**Background:** Acid Sphingomyelinase Deficiency (ASMD), historically known as Niemann-Pick disease types A, B, and A/B, is an ultra-rare autosomal recessive lysosomal storage disorder caused by pathogenic variants in the SMPD1 gene. The resulting deficiency of acid sphingomyelinase leads to accumulation of sphingomyelin and other lipids in lysosomes, particularly affecting cells of the monocyte/macrophage system. The disease presents along a clinical continuum: infantile neurovisceral ASMD (type A) is rapidly progressive with neurodegeneration and death typically by 3 years of age; chronic visceral ASMD (type B) involves hepatosplenomegaly, interstitial lung disease, thrombocytopenia, and atherogenic dyslipidemia without CNS involvement; chronic neurovisceral ASMD (type A/B) represents an intermediate phenotype with both visceral and slowly progressive neurological manifestations. Prior to these guidelines, no published national or international consensus existed for ASMD diagnosis and management. The rarity of the disease contributes to misdiagnosis, delayed diagnosis, and barriers to adequate care. With the recent regulatory approval of olipudase alfa (enzyme replacement therapy) in multiple countries, standardized care protocols have become essential.
**Methods:** The Guidelines Development Group (GDG) comprised international experts including paediatric and adult metabolic specialists, geneticists, neurologists, hepatologists, pulmonologists, epidemiologists, clinical biochemists, specialist nurses, and patient support group representatives from the International Niemann-Pick Disease Alliance (INPDA) and International Niemann-Pick Disease Registry (INPDR). A systematic literature review covering the last 20 years until December 2021 was conducted using Medline, Embase, and the Cochrane Library. The initial search identified 720 reference abstracts, of which 195 were accepted as relevant after first screen. The GDG adopted the AGREE II system as the methodological framework, though the guidelines did not completely meet 5 of the 23 AGREE II items. Evidence levels were classified using GRADE methodology (A = high quality, B = moderate quality, C = low quality), and recommendations were graded 1 (strong) or 2 (weak). A Delphi consensus process involving 24 international experts was conducted; after the first round, 5 statements required substantial revision. The guidelines were developed without external financial support from therapy manufacturers.
**Key Results:** The guidelines produced 39 conclusive statements with corresponding evidence levels, strength of recommendations, and expert consensus percentages. Key diagnostic recommendations include: enzyme assay for ASM activity in leukocytes or fibroblasts as the gold standard (Statement 10, Level A); tandem mass spectrometry using short-chain fatty acid sphingomyelin analogue as the method of choice (Statement 11, Level B); and genetic testing of SMPD1 to confirm diagnosis and enable genetic counselling (Statement 15, Level B). Plasma biomarkers, particularly lysosphingomyelin (lyso-SM) and N-palmitoyl-O-phosphocholine-serine (PPCS), are useful adjuncts (Statement 13, Level B). The guidelines report that ASMD has an estimated global prevalence of approximately 1:100,000–1,000,000 births, with higher frequency in certain populations (e.g., ~1:40,000 in Ashkenazi Jewish population). Over 250 SMPD1 variants have been described. Regarding disease-modifying therapy, olipudase alfa received regulatory approval in Brazil, Japan, Europe, and the United States. The pivotal Phase II/III ASCEND trial (NCT02004691) enrolled 36 adults randomized 1:1 to olipudase alfa or placebo. At 52 weeks, least square mean percent change from baseline favored olipudase alfa over placebo for: percent predicted DLCO (22% increase vs 3.0% increase, p=0.0004), spleen volume (39% decrease vs 0.5% increase, p<0.0001), and liver volume (28% decrease vs 1.5% decrease, p<0.0001). The ASCEND-Peds trial (NCT02292654) in 20 paediatric patients showed generally well-tolerated treatment with significant improvements across clinically relevant endpoints. The guidelines recommend multidisciplinary care (Statement 16, Level A) with specialists including metabolic physicians, neurologists, hepatologists, pulmonologists, haematologists, and others as needed. Comprehensive monitoring assessments are recommended at diagnosis and regular intervals, including growth parameters, pulmonary function testing (especially DLCO), liver and spleen imaging (MRI preferred), blood counts, lipid profiles, and developmental/cognitive assessments.
**Clinical Implications:** These guidelines establish the first standard of care for ASMD patients, addressing the full disease spectrum from infantile neurovisceral to chronic visceral forms. For patients with non-CNS manifestations, olipudase alfa ERT is recommended as disease-modifying therapy (Statement 25, Level A), with all confirmed ASMD patients having significant non-CNS manifestations considered for treatment on an individual basis (Statement 26, Level A). The guidelines emphasize that ERT does not cross the blood-brain barrier and will not prevent or impact CNS manifestations; families of infants with rapidly progressive neuronopathic forms should be counselled about risks, benefits, limitations, and long-term futility. Symptomatic management recommendations include: avoiding splenectomy due to risk of exacerbating liver and lung disease (Statement 29); encouraging vaccination against influenza, COVID-19, and Streptococcus pneumoniae (Statement 30); comprehensive swallowing assessment for children with neuronopathic forms (Statement 32); and awareness of increased prevalence of behavioural problems, anxiety, and depression with low threshold for psychological referral (Statement 35). The guidelines identify knowledge gaps including the need for better understanding of genotype-phenotype correlations, more accurate disease incidence data, and further research on cardiovascular risk, skeletal disease, and quality of life measures. The GDG commits to revising these guidelines every 3–5 years to incorporate new evidence.