Acid Sphingomyelinase Deficiency (Niemann–Pick Disease Types A, A/B and B)

Autosomal recessive lysosomal disease caused by biallelic variants in SMPD1, with a continuous spectrum ranging from the infantile neurovisceral form (type A) to the chronic visceral form (type B), through the intermediate chronic neurovisceral form (type A/B). Niemann-Pick disease type C, caused by NPC1 or NPC2, is a different entity.

Literature and regulatory information updated: 10 October 2026.

0. Initial Reference Table

1. Introduction

1.1. From Niemann's Description to the Separation of Sphingomyelinase Deficiency and Type C

In 1914, the German paediatrician Albert Niemann described an infant with hepatosplenomegaly, progressive neurological deterioration and death at 18 months, whose liver and spleen were infiltrated by large foamy cells [3, 21]. Between 1922 and 1933, the pathologist Ludwig Pick characterised these cells and distinguished them from Gaucher disease cells, and the disease came to bear both names [3, 21]. In 1934, Klenk identified sphingomyelin as the stored lipid [21]. Recognition that the disease was not uniform emerged in 1946, when Pfändler and Dusendschon described two adult siblings with similar pathology, late onset and no central nervous system (CNS) involvement; in 1958, Crocker and Farber reviewed 18 cases and demonstrated variability in age at onset, clinical expression and degree of storage [3].

In 1961, Alan Crocker proposed the classification into four types: type A, with early CNS deterioration and visceral and cerebral storage; type B, with a chronic visceral course without CNS involvement; and types C and D, the latter described in patients from Nova Scotia, with subacute neurological involvement and less visceral storage [3]. In 1966, Brady, Kanfer, Mock and Fredrickson demonstrated severe deficiency of acid (lysosomal) sphingomyelinase (EC 3.1.4.12) in tissues from patients with type A [3, 22], and the deficiency was documented shortly afterwards in a patient with type B (Schneider and Kennedy, 1967) [21]. The discovery of the enzyme deficiency made it possible to separate patients without sphingomyelinase deficiency, who corresponded to types C and D. These are now recognised as a different disease, caused by variants in NPC1 or NPC2 (Niemann-Pick disease type C, NPC) [3, 21]. Since the early 1980s, the “Niemann-Pick” group has thus been divided into two distinct entities: Niemann-Pick disease due to acid sphingomyelinase deficiency and Niemann-Pick disease type C [14].

1.2. Milestones in Molecular Genetics

Somatic cell hybridisation studies (Besley, 1980) showed that types A and B were allelic variants of a single gene and that type C involved a different gene [21]. In 1989, Quintern and colleagues purified the enzyme from human urine, microsequenced 12 tryptic peptides and isolated the first complementary DNA (cDNA) clones, already observing alternatively spliced transcripts [23]. In 1991, Schuchman and colleagues obtained the full-length cDNA, with a reading frame of 1890 base pairs encoding 629 amino acids and a signal peptide cleaved after alanine 46, and showed that only the type 1 transcript encodes an active enzyme [24]. In 1992, the same group described the complete structure of SMPD1, with six exons and five introns, and an unusually large exon 2 encoding approximately 44% of the mature polypeptide, localising it to 11p15.1–p15.4 [25].

The first frequent pathogenic variant, R496L in historical numbering (= NM_000543.5:c.1493G>T p.(Arg498Leu)), was described in 1991 in Ashkenazi patients with type A [26]. In the same year, the single-codon deletion ΔR608 was identified in Ashkenazi patients with type B, constituting the first genotype-phenotype correlation of the disease: the presence of ΔR608 predicted the type B phenotype even when the other allele was a type A variant [27]. L302P (historical numbering, = NM_000543.5:c.911T>C p.(Leu304Pro)) followed in 1992 and the frameshift variant fsP330 in 1993, which, together with R496L, account for about 90% of type A alleles in Ashkenazi Jews [6, 28, 29].

1.3. Current Nomenclature and Definition of the Entities Covered

The designation “acid sphingomyelinase deficiency” (ASMD) emphasises the shared mechanism and distinguishes the disease from Niemann–Pick type C [3]. The phenotype is continuous, and the classical A/B classification has been considered artificial since the first series were genotyped, because “A” and “B” alleles combine in compound heterozygosity to produce intermediate phenotypes [21]. The nomenclature used by GeneReviews, Orphanet and the 2023 international guideline recognises three presentations [3, 6, 8]. Infantile neurovisceral ASMD (type A; ORPHA:77292) begins in infancy, with severe visceral involvement, rapidly progressive neurodegeneration and death usually before age 3 years [1, 3]. Chronic neurovisceral ASMD (type A/B, intermediate form; ORPHA:618891) combines visceral manifestations similar to those of type B with later-onset, slowly progressive CNS manifestations, such as ataxia, developmental delay, peripheral neuropathy or psychiatric disorder, with survival beyond childhood [2, 3]. Chronic visceral ASMD (type B; ORPHA:77293) is a multisystem disease without neurodegeneration, ranging from stable paucisymptomatic forms to progressive forms with premature death from respiratory or liver disease [3, 4]. All three forms belong to the ORPHA:618899 group [5].

The historical literature also describes clinical variants within this spectrum. The “Lewis variant” refers to adults or adolescents with type B, incidentally discovered splenomegaly and sea-blue histiocytes in the bone marrow [21]. The “Saudi variant” is a severe early-onset form, historically included in type B, associated with p.His423Tyr and p.Lys578Asn; Simonaro's original article (2002) describes it as earlier-onset, more severe type B, and GeneReviews places it within the intermediate chronic neurovisceral phenotype, not type A [6, 30]. Sea-blue histiocytes, described as a separate disease by Bloom in 1925–1928, are now recognised as a finding in sphingomyelinase deficiency and other diseases [21].

The approval of olipudase alfa in 2022 provided ASMD with its first therapy targeting non-neurological manifestations and altered the natural history of treated chronic forms [6, 12, 16]. Unless otherwise stated, natural history data concern untreated patients.

2. Molecular Genetics and Pathophysiology

2.1. The SMPD1 Gene and Acid Sphingomyelinase

SMPD1 spans approximately 5 kb at 11p15.4, has six exons and behaves as a constitutively expressed (housekeeping) gene [3, 7, 25]. It encodes acid sphingomyelinase (ASM; EC 3.1.4.12), a lysosomal enzyme with an optimum pH near 4.5 and a molecular mass of approximately 70 kDa; the cDNA predicts a 64-kDa monomer, reaching 72–74 kDa if all six potential glycosylation sites are occupied [21]. The enzyme hydrolyses sphingomyelin into ceramide and phosphorylcholine [6]. Sphingomyelin consists of an 18-carbon sphingosine base joined by an amide bond to a long-chain fatty acid (ceramide), to which phosphorylcholine is attached [21]. Sphingomyelinase activator proteins exist but do not appear essential for activity [21].

A single precursor is directed along two pathways, producing a lysosomal and a secreted form. Under cellular stress, lysosomal exocytosis may become the main source of the secreted form, which remodels the plasma membrane in host defence and membrane repair. The lysosomal form also promotes cholesterol export from intra-endolysosomal membranes, and the protein has additional phospholipase C activity [7].

The gene has two in-frame ATG initiation codons, separated by 32 codons, and HGVS (Human Genome Variation Society) nomenclature counts from the first ATG [3]. The two historically used reference sequences, NM_000543 and M81780.1, differ in the length of a polymorphic GCTGGC hexanucleotide (p.L37_A38) in exon 1, in the signal peptide region. This difference explains the two-amino-acid discrepancy between historical numbering (for example, R496L, L302P, ΔR608, Q292K) and current numbering (p.Arg498Leu, p.Leu304Pro, p.Arg610del, p.Gln294Lys). Reports should therefore always state the transcript [3, 6]. In the current reference protein sequence (NP_000534.3), counted from the first ATG, the precursor has 631 amino acids, whereas the cDNA described in 1991 predicted 629 [10, 24]. Paternal imprinting of SMPD1, with preferential expression of the maternal allele, has been described, but without a demonstrated impact on phenotype [3, 14, 31].

2.2. Molecular, Cellular and Tissue Mechanisms

Loss-of-function SMPD1 variants reduce sphingomyelin hydrolysis, leading to progressive accumulation in lysosomes of systemic organs in all types and in the brain in neuronopathic forms [6, 14]. Primary accumulation triggers secondary accumulation of unesterified cholesterol, ceramide and derivatives (sphingosine), lysosphingomyelin (sphingosylphosphorylcholine), glycosphingolipids and bis(monoacylglycero)phosphate, with alterations in membrane signalling (inflammation, apoptosis), mitochondrial function and nuclear transport [3, 14]. All cells except mature erythrocytes may be affected, but the monocyte–macrophage system is most affected. Lipid-laden macrophages form in the liver, spleen and lungs, in both alveoli and interstitium. The heart, skeleton, lymphatic and haematopoietic systems and, in some patients, glia and neurons are also involved [3]. Lysosphingomyelin is increased in systemic organs in all types and in the brain in type A, and probably participates in the pathogenic cascade. In chronic forms, cerebral storage is minimal or absent [14, 21].

In vitro, all patients have marked ASM deficiency, but sphingomyelin hydrolysis in living cells demonstrates significant residual activity in typical type B patients, possibly sufficient to protect the brain [14, 21]. Residual activity measured in the in vitro assay is not, however, a reliable indicator of severity or subtype [3, 6]. Rapid metabolism of accumulated sphingomyelin when the enzyme is replaced generates proinflammatory products, such as ceramide, explaining infusion-associated reactions and transient transaminase elevation during olipudase alfa dose escalation (section 7) [12].

2.3. Inheritance, Penetrance and Expressivity

All forms are autosomal recessive; heterozygotes are clinically normal, although some have intermediate enzyme activity and low HDL, and heterozygotes with splenomegaly or foamy cells in the marrow have been described [3, 6, 21]. Penetrance of pathogenic biallelic genotypes is complete for the biochemical deficiency, but clinical expressivity is highly variable. Patients with the same genotype, including siblings, may differ in severity, particularly in type B. Individuals homozygous for p.Arg610del span a spectrum from asymptomatic forms in adulthood to moderate disease [3, 6]. Proposed modifier genes and environmental factors have not been demonstrated [8].

2.4. Variant Spectrum and Genotype–Phenotype Correlations

More than 346 variants in SMPD1 have been described, 295 of them classified as disease-associated in the HGMD (Human Gene Mutation Database) Professional 2022.1; GeneReviews reports more than 150 published pathogenic variants, Saudubray more than 250 and the 2024 French PNDS more than 290, figures reflecting different periods and criteria [3, 6, 10, 14]. Missense variants predominate, followed by nonsense variants, frameshifts, small insertions and deletions and splicing variants; only three large rearrangements have been described [3]. Most variants are private and found in compound heterozygosity [3, 32].

The general correlation rule is functional. Nonsense variants, frameshifts, large deletions or splicing defects in both alleles produce little or no activity and the severe neurovisceral phenotype. The presence of at least one allele producing partially active ASM, such as a missense variant or an in-frame codon deletion with significant residual activity, is associated with the chronic visceral phenotype [3, 8]. Documented exceptions exist. p.Trp32Ter, common in Italy, is associated with a non-neurological phenotype, possibly through translation initiation at the second ATG, producing a protein lacking the first 32 residues but retaining partial activity. p.Arg3AlafsTer76 is frequent in Chinese patients with type B, even in homozygosity [3].

The following table presents the variants of greatest clinical relevance. The c. and p. descriptions on the MANE transcript NM_000543.5 were validated using VariantValidator and, for the specified variants, ClinVar. Correspondence with historical nomenclature comes from primary sources rather than manual conversion [3, 6, 33, 34].

Two nomenclature corrections have practical consequences. The first concerns p.Gln294Lys, corresponding to NM_000543.5:c.880C>A. The description “c.874C>A” circulating in some lists combines historical c. numbering with the protein in the new numbering; on NM_000543.5, c.874C>A is another variant, p.(Gln292Lys) (VCV000203426), without a ClinVar classification [33, 34]. The second concerns some variants described in older series, such as A482E (c.1445C>A) in Rodríguez-Pascau's Spanish series (2009), which cannot be normalised on the current transcript: the reference nucleotide at that position does not match, so the description should be retained as explicitly historical nomenclature [21, 33]. Variants such as S379P, R441X, F480L, fsP189 and L549P appear only in the historical numbering of Simonaro's article (2002) [30].

There are six particularly well-established genotype–phenotype correlations [3, 6, 8]. First, any combination of p.Arg498Leu, p.Leu304Pro or p.Phe333SerfsTer52 results in type A. Second, p.Arg610del is neuroprotective: patients with at least one copy do not develop neurological manifestations and have type B. Homozygotes have less severe disease than compound heterozygotes with a severe variant, with generally normal height and weight, less hepatosplenomegaly, less delayed bone age and normal insulin-like growth factor 1 (IGF-1), although dyslipidaemia occurs with all genotypes [6, 39]. Third, p.Gln294Lys, in homozygosity or heterozygosity, is associated with the intermediate phenotype with late-onset neurological disease; in the review of 64 patients initially classified as type B, all five with global progressive neurological disease carried this variant [6, 40]. Fourth, p.Leu139Pro, p.Ala198Pro and p.Arg476Trp are associated with less severe type B, and in the 10-year longitudinal study homozygosity for p.Arg610del, p.Pro325Ala or p.Pro332Arg was associated with attenuated disease [8, 30, 39]. Fifth, p.His423Tyr and p.Lys578Asn are associated with a severe early-onset form, with pulmonary involvement and death in early childhood. The GeneReviews text places it within the intermediate phenotype, the original article within severe type B and the GeneReviews variant table within severe type A; this divergence reflects the artificiality of the categories rather than the presence of type A neurodegeneration [6, 21, 30]. Sixth, p.Trp393Gly is associated with a visceral phenotype with a macular halo; in a series of 20 Roma patients, some developed cognitive impairment, psychiatric disorder, ataxia or peripheral neuropathy [3].

In expression studies in COS cells (a monkey kidney cell line), ΔR608 and other mild B phenotype variants retain considerable catalytic activity, whereas variants with a premature stop codon express no activity [21]. In the United States, approximately two-thirds of newly diagnosed patients have a unique genotype, limiting phenotype prediction from genotype [6]. In Illinois newborn screening, 7 of the 9 genotype combinations had never been described [9]. In populations with frequent variants, correlations support counselling of parents of newly diagnosed patients [21].

2.5. Founder Variants and Population Spectrum

Variant distribution reflects founder effects. In Ashkenazi Jews, the three type A variants account for approximately 90% of alleles [6]. In Levran's series, R496L accounted for 32% (10/31) of Ashkenazi type A alleles versus 5.6% (2/36) of non-Jewish type A alleles. L302P accounted for 23.5% (8/34) of Ashkenazi type A alleles and was not found in non-Jewish alleles [26, 28]. p.Arg610del is the most frequent variant worldwide. It accounts for more than 90% of alleles in patients from the Maghreb (Tunisia, Algeria, Morocco), 100% on Gran Canaria, 61.5% of Spanish patients with type B, 15–20% of North American and Western European patients (20–30% of type B alleles in the USA according to GeneReviews) and approximately 12% of alleles in a worldwide sample; it is rarer in Italy and Poland and has not been described in China [3, 6, 8, 21, 30, 35].

In Simonaro's worldwide sample (2002), with 394 type B patients (designations in historical numbering; NM_000543.5 equivalents in the table above: L137P = c.416T>C p.(Leu139Pro), H421Y = c.1267C>T p.(His423Tyr), K576N = c.1734G>C p.(Lys578Asn), R474W = c.1426C>T p.(Arg476Trp), A196P = c.592G>C p.(Ala198Pro)), the variants L137P, fsP189 and L549P accounted for about 75% of Turkish alleles; H421Y and K576N about 85% of Saudi alleles; S379P, R441X, R474W and F480L about 55% of alleles in Portuguese and Brazilian patients; and A196P about 42% of Scottish and English alleles [30]. In Chile, p.(Ala359Asp) has a conserved 280 kb haplotype compatible with a common ancestor of Amerindian origin, and the expressed protein retains 4.2% of normal activity [36]. In Czechia and Slovakia, p.Gln294Lys is frequent, and in a series of 25 patients most had intermediate phenotypes [3, 41]. Recent series have broadened the spectrum. In Taiwan, c.1497_1498inv p.(Tyr500His) is associated with the chronic neurovisceral form and c.995C>G p.(Pro332Arg) with the chronic visceral form, and the latter is frequent in carriers [42]. In Iraq (47 patients, 98% consanguinity), the most common variants were p.(Tyr519Cys), p.(Gly247AlafsTer10), p.(Ser323Arg) and p.(His423Tyr) [37]. In Morocco, p.(Arg610del) predominates in type B and p.(Arg542Ter) was found in type A [38].

2.6. Allelic Diseases and Modifiers

No other Mendelian phenotypes associated with germline pathogenic SMPD1 variants are known [6]. Some SMPD1 variants have been associated with increased Parkinson disease risk, without a clarified pathogenic relationship; one, p.Arg591Cys, classified as a variant of uncertain significance (VUS), was found in compound heterozygosity in a newborn from Italian screening [43, 44]. Hashimoto thyroiditis has been described in several patients, without an established mechanism [43]. Secondary accumulation of sphingosine, ceramide and cholesterol is the most likely pathophysiological modifier of severity [8].

3. Clinical Spectrum and Manifestations by System

3.1. A Phenotypic Continuum

The 2023 international guideline states, with a strong recommendation and level B evidence, that manifestations and life expectancy vary by subtype along a phenotypic continuum [3]. The table compares the presence of the main manifestations in the three forms.

Source: tables 2 and 3 of the guideline by Geberhiwot and colleagues [3].

3.2. Infantile Neurovisceral ASMD (Type A)

The neonatal period is generally normal, although some infants have neonatal oedema. Hydrops fetalis may occur, and lipid storage has been documented before birth in the liver, brain, kidney and placenta, whose enlargement is visible on ultrasonography and may cause fetal loss [21]. Vomiting or diarrhoea in the first weeks and poor weight gain often prompt the first consultation [14]. Hepatosplenomegaly appears at 2–4 months: in McGovern's prospective series (2006), involving 10 infants (6 boys and 4 girls) enrolled at 3–6 months, it was the first sign in all [3, 15]. The liver is disproportionately larger than the spleen, unlike in Gaucher disease; the abdomen becomes protuberant and lymphadenopathy is present [14, 21]. Transaminases are persistently elevated, alkaline phosphatase generally increased, and prolonged neonatal jaundice or episodes of jaundice may occur, with presentations resembling acute hepatitis; some liver biopsies have been interpreted as steatosis or glycogen storage disease [6, 21]. Without treatment, hepatomegaly becomes massive and progresses to liver failure with coagulopathy and ascites; hypersplenism alters the blood count, with microcytic hypochromic anaemia and subsequently thrombocytopenia and granulocytopenia [6, 21].

Feeding problems are severe. They begin with early satiety from gastric compression by organomegaly and, with neurological decline, are compounded by loss of suck–swallow coordination, frequent vomiting, constipation or diarrhoea and abdominal discomfort, contributing to irritability and sleep disturbance [6]. Linear growth is normal during the first year while weight declines, giving the child a cachectic appearance, with wasting in approximately 70% of cases [6, 14, 21].

Pulmonary involvement results from storage in macrophages of the alveolar septa, bronchi and pleura. Radiographs show reticular or finely nodular interstitial infiltrates. From 6 months, episodes of respiratory distress occur, some infectious and others non-infectious, together with aspiration-related infections; low pO2 is generally a late finding [3, 6, 21].

The neurological examination is normal or shows only mild hypotonia at presentation. Neurological symptoms appear at a median of 7 months, development plateaus at around 10 months and relentless regression follows [3]. The French PNDS places the plateau phase between 6 and 15 months, with hypotonia, reduced interaction and hypomobility, and states that most children never achieve sitting [10]. In the McGovern series, developmental age never exceeded 10 months for adaptive behaviour, 12 months for expressive language, 9 months for gross motor skills and 10 months for fine motor skills [6, 15]. Hypotonia is progressive, with loss of deep tendon reflexes and relative sparing of the cranial nerves [3, 6]. Sources diverge on the late phase: the Atlas describes brisk reflexes and progression to a rigid, spastic state, and Saudubray describes the later addition of bilateral pyramidal signs to axial hypotonia [14, 21]. The most likely reconciliation is chronological, with hypotonia and areflexia, linked also to peripheral neuropathy (nerve conduction velocity is reduced), followed by spasticity in the advanced phase [14]. Seizures are rare and the electroencephalogram is usually normal [14, 21]. Pathology shows storage in neurons and axons, cerebral atrophy and neuroaxonal dystrophy [21].

The cherry-red spot results from lipids in retinal ganglion cells forming a whitish ring around the fovea, which lacks ganglion cells. Depending on the ring's opacity and diameter, it appears as a macular halo or a cherry-red spot [6]. It may be absent in the first months. The Atlas reports it in approximately 50% of patients, but in Elleder's series (1983) and McGovern's series (2006) it was present in all by 12 months, and GeneReviews states that it develops in all untreated children [6, 15, 21]. The skin may show yellowish-brown pigmentation and xanthomas, and most patients develop osteoporosis [14, 21]. Death generally occurs between 1.5 and 3 years [14]. In McGovern's series, median time from diagnosis to death was 21 months, with respiratory failure in 9 infants and haemorrhage in 1 as the causes [15]. In France, median survival from birth in type A was 2.0 years (95% confidence interval, CI, 1.8–2.7) [13]. Cases with milder systemic involvement, somewhat later neurological onset and a slower course occur [14].

3.3. Chronic Neurovisceral ASMD (Type A/B)

The intermediate form is heterogeneous. Some patients resemble type A, with neurological onset in late childhood, adolescence or adulthood and slowly progressive disease, which may include cerebellar ataxia, nystagmus, extrapyramidal involvement, intellectual disability or psychiatric disorders. Others resemble type B, with minimal nervous system involvement, frequently peripheral neuropathy, and/or mild intellectual disability [6, 14, 45]. The 2023 guideline describes a neurological spectrum ranging from mild hypotonia and hyporeflexia to ataxia, spasticity and cognitive decline [3]. Visceral involvement is variable, as in type B: mild to massive hepatosplenomegaly, elevated transaminases and fibrosis or cirrhosis, hypersplenism with thrombocytopenia and splenic infarction, interstitial lung disease that may lead to oxygen dependence, dyslipidaemia, osteopenia and coarse facial features in a subset of patients [6, 46].

In the review of 64 patients initially classified as type B (Wasserstein, 2006), 19 (30%) had neurological abnormalities: 14 (22%) with minor non-progressive abnormalities (hypotonia, ataxia, hyporeflexia) and 5 (8%) with global progressive disease [6, 40, 43]. These five were diagnosed before age 5 years, had normal milestones at 2 years, began regressing between 3 and 7 years, all had retinal abnormalities and peripheral neuropathy, and all carried one or two copies of p.Gln294Lys [43]. In the Czech and Slovak series of 25 patients without a classical A phenotype, 16 (64%) had neurological symptoms, 12 of the 16 with p.Gln294Lys, 10 of them with a prolonged neurovisceral phenotype [3, 41]. The Atlas adds historical descriptions: extrapyramidal signs in three siblings with a protracted course (Elleder and Cihula, 1981), intellectual disability at ages 9 and 18 years in unrelated patients (Sogawa, 1978), and asymptomatic neural storage in two sisters with inclusions in axons and Schwann cells on rectal biopsy (Takada, 1987). Some of these cases with ataxia may have been NPC [21].

The Saudi variant, associated with p.His423Tyr and p.Lys578Asn, illustrates the severe early-onset form. It presents with early growth failure and abdominal distension, an enormous spleen, an equally large or larger liver, a cherry-red spot in all patients, hypotonia and developmental delay, cachexia and miliary pulmonary infiltration [21]. Most died by age 3 years from haemorrhage, thrombocytopenia (sometimes requiring daily platelet transfusions) or liver failure. In the Saudi series, 5 patients died between 18 and 36 months, and two survivors who underwent bone marrow transplantation developed white matter abnormalities and neurological manifestations [21].

In chronic neurovisceral ASMD, median age at death was 8 years in Cassiman's review [47]. In France, median age at death was 8.5 years (n=6), and median survival from birth was 11.4 years (95% CI 5.5–18.5) [13]. Most patients nevertheless reach adulthood even without treatment, according to GeneReviews [6]. Olipudase alfa neither improves nor prevents neurological manifestations [6, 12].

The boundary between types B and A/B is not always clear-cut. The French PNDS describes a grey zone of classification when the only finding is a mild neurocognitive change, a psychiatric disorder or an isolated peripheral neuropathy. In adults, the A/B form is a minority and may present only with cognitive impairment or psychiatric disorder, sometimes isolated, ataxia or an extrapyramidal syndrome, and the cherry-red spot is frequent in the neurovisceral forms of children and adults [10].

3.4. Chronic Visceral ASMD (Type B): Manifestations by System

The typical presentation is splenomegaly or hepatosplenomegaly discovered in late infancy or childhood, but disease may manifest at any age, from birth to late adulthood [3, 14]. The “classical” patient in the Atlas is an adult or adolescent with incidentally discovered splenomegaly. One example is a 39-year-old man with the Lewis variant, a spleen palpable 6 cm below the costal margin and fibroblast enzyme activity at 18% of control [21]. Heterogeneity ranges from asymptomatic to polysymptomatic patients, and attenuated forms may remain stable for years [3]. Reported complaints include bleeding, dyspnoea, joint and limb pain, bruising, headaches, abdominal pain, diarrhoea and fractures [3, 14].

Spleen and blood. Splenomegaly is one of the most common manifestations and often the first sign; in McGovern's cross-sectional survey (2008), splenomegaly (78%) and hepatomegaly (73%) were the most frequent findings at presentation [3, 48]. It may be massive and serves as a marker of severity, as it correlates with the other parameters [3]. In Wasserstein's 10-year longitudinal study (2004), with 29 patients, all those with an intact spleen had splenomegaly, with a mean of 12.7 multiples of normal (MN; range 4.5–27.3) [39]. Thrombocytopenia increased from 39% to 54% and leucopenia from 3% to 34% between the initial and final visits, with a mean annual fall of 7×10³/mm³ in platelets and 0.2×10³/mm³ in leucocytes [39]. Thrombocytopenia is the most common haematological abnormality, usually mild; anaemia and leucopenia are variable [3]. Bleeding occurred in 49% of 59 patients in a cross-sectional study. The most common is recurrent epistaxis, sometimes requiring cauterisation, but subdural haematoma, haematemesis, haemoptysis, haemothorax, bleeding after tonsillectomy, adenoidectomy or dental surgery and menorrhagia requiring hysterectomy have been described [3, 43]. Bleeding correlates with the degree of splenomegaly but not strictly with the platelet count, suggesting platelet dysfunction and other coagulation factors not yet systematically studied [3, 43, 49]. Splenic infarction with acute abdominal pain and splenic rupture have been described [6, 21]. The French PNDS, based on paediatric series, reports splenomegaly in more than 90% of children, sometimes painful and with reduced food intake, and bleeding, mainly epistaxis, in about one third, due to thrombocytopenia and/or coagulation factor deficiency. In adults, a spleen with nodules remains compatible with the diagnosis, and management of splenic rupture should be conservative whenever possible [10].

Liver. Hepatomegaly is present in almost all patients; in the 10-year study, all but one had it, with a mean of 1.91 MN (0.93–3.21) [39]. Transaminases and bilirubin are raised in many patients but remained stable throughout the study [39]. Histology in type B adults shows fibrosis in most and cirrhosis in some, even without signs of liver failure [3, 46]. Almost all of the 17 adults assessed for a phase 1 trial had some degree of fibrosis [43]. The disease may progress in the third or fourth decade to cirrhosis with portal hypertension, oesophageal varices, ascites and encephalopathy, and some patients have required liver transplantation [3, 50]. Homozygotes for p.(Ala359Asp), in Chile, have a high incidence of clinically relevant progressive cirrhosis [3, 36]. Focal liver lesions are common, and rapid enlargement of the spleen should suggest portal hypertension [8, 43]. The French PNDS stresses that the transaminase elevation, usual from diagnosis, is relatively stable and does not correlate with liver severity; that fibrosis, cirrhosis and even fulminant liver failure have been described as early as childhood; and that, in adults, steatohepatitis and cirrhosis may provide the background for hepatocellular carcinoma [10].

Lungs. More than 90% of patients with the chronic visceral form have radiological pulmonary infiltration with a reticulonodular or ground-glass pattern, even without symptoms [43, 51]. Disease is interstitial, with a restrictive pattern and impaired gas exchange; diffusing capacity for carbon monoxide (DLCO) was low in 69% of patients at the initial visit of the 10-year study, and more than one-third had low forced expiratory volume in one second (FEV1), forced vital capacity (FVC) or FEV1/FVC ratio, with gradual deterioration in all tests [39]. Radiological extent correlates poorly with symptoms and pulmonary function, so imaging alone is insufficient to assess disease [3, 6]. In adults with long follow-up, pulmonary disease is often the main complaint, ranging from exertional dyspnoea to oxygen dependence, with bronchopneumonia and cor pulmonale described [14, 21, 52]. Calcified pulmonary nodules have been described in untreated patients [6]. Adults with exclusively pulmonary involvement, without organomegaly, have been described [43]. Respiratory disease is one of the main causes of death in type B [3].

The French PNDS brings together complementary pulmonary data from French series and the literature [10]. In children, about half of patients have dyspnoea and respiratory infections, FVC is reduced in 42% and DLCO in 75%. In adults, interstitial lung disease may be diagnosed from birth to 50 years of age, preceding the diagnosis of ASMD or appearing during follow-up, with generally mild symptoms (cough, dyspnoea, recurrent infections), but with cases of progression to respiratory failure and death. The high-resolution CT findings, in the Mendelson series (2006), are ground-glass opacities (100%), interlobular septal thickening (100%) and intralobular lines (90–100%); the superimposition of ground glass and septal thickening (crazy paving pattern) occurs in about 40%. Ground glass is usually focal (75%) and may predominate in the upper zones, whereas reticulation predominates at the bases; cysts, nodules, bronchiectasis and emphysema are rare, and involvement is bilateral and symmetrical [10, 51]. In the French series of Guillemot (2007), half of patients had a restrictive ventilatory defect, with a mean FVC of 82% of predicted, about 75% had reduced DLCO (mean 60% of predicted) and resting hypoxaemia reached up to 85%. Progression is slow: the mean annual declines described are 1.6% in FEV1, 0.1% in FVC and 0.4% in DLCO [10]. Bronchoalveolar lavage usually confirms the involvement, with increased cellularity (median 1.5 × 10⁶/mL) and large multivacuolated histiocytes with dark blue granules (Niemann-Pick cells or sea-blue histiocytes), which are also seen in bronchial biopsies. Lung biopsy is not necessary; when performed, it shows foamy macrophages in the alveoli and thickened septa, without inflammation, sometimes with moderate interstitial fibrosis [10].

Lipids and heart. Dyslipidaemia is constant and early, with low HDL cholesterol and elevated triglycerides and LDL (low-density lipoprotein) cholesterol [6, 53]. In a paediatric study of 10 children with type A and 30 with type B, all had an abnormal fasting lipid profile [3, 53]. The profile worsens with age [39]. In an electron-beam tomography assessment of 18 patients with type B, 10 had a positive coronary calcium score (1.4–34.5), suggesting early atherosclerosis even before age 18 years [3]. In a cross-sectional study of 59 patients, the electrocardiogram was abnormal in 28% and the echocardiogram in 50%. Among 103 patients with chronic disease, 9% had valvular disease, with severe mitral regurgitation and aortic stenosis described, and medial and intimal hypertrophy of distal coronary branches is present [43]. There is no strong evidence of primary myocardial involvement [3].

Growth and puberty. Growth restriction is common and most marked in adolescence, with delayed bone age and puberty [3]. In Wasserstein's US series (2003), the mean Z-score was −1.24 for height and −0.75 for weight; 39% were below the fifth percentile for height and 21% for weight, and bone age was delayed by an average of 2.5 years. These deficits correlated with large organ volumes and low IGF-1 [6, 21, 54]. Most adults have stature at the lower limit of normal, suggesting catch-up growth in late adolescence [3]. In McGovern's prospective study (2021), growth deficits persisted into adulthood [55].

Skeleton. In children, the lumbar spine Z-score ranged from 0.061 to −4.879. Most untreated adults have osteopenia or osteoporosis at at least one site according to World Health Organization (WHO) criteria [6, 56]. In studies with 59 and 46 patients, fractures were reported by 25% of children and 53% of adults, some with minimal or no trauma [43]. Joint and limb pain is frequent [43]. The French PNDS quantifies bone and/or joint pain, mainly in the lower limbs and sometimes in the spine, in about 60% of children, and notes that bone involvement is less frequent than in Gaucher disease type 1, although osteopenia may progress to osteoporosis with early fractures [10].

Eyes. Up to one-third of patients with type B have a macular halo or cherry-red spot, without consequences for visual function. This finding does not predict neurodegeneration absolutely, and many adults with type B have it [6, 57].

Nervous system. True type B patients have no neurological involvement and normal intellectual function [14]. Identification of neurological signs, even minor ones, reclassifies the patient within the A/B spectrum (subsection 3.3).

Other organs and quality of life. Adrenal calcifications without known clinical consequence have been described [6]. The French PNDS reports adrenal changes (hypertrophy and nodules) that are very frequent in adults, whose endocrine impact is under evaluation, and includes chronic diarrhoea and sensory peripheral neuropathy among the manifestations of adults with the visceral form [10]. An excess risk of cancer and monoclonal gammopathies is also described: in the French cohort, half of type B deaths were due to cancer (lung in two patients, bladder, head and neck and unknown origin), and by analogy with Gaucher disease cases of gammopathy progressing to multiple myeloma have been described [10, 13]. The PNDS sets as a biochemical reference an HDL cholesterol usually below 0.3 g/L; the equivalence of “1 mmol/L” given in the same text is not exact, because 0.3 g/L corresponds to about 0.78 mmol/L [10]. Chronic pain and fatigue affect most patients at some point [3]. Behavioural problems, anxiety and depression are more frequent, linked to social isolation, peer rejection and living with a potentially fatal disease; some adults have required antidepressants or antipsychotics [3]. On the CHQ-PF50 and SF-36 questionnaires, a subgroup had reduced quality of life in physical function, mental health, general health perception and emotional well-being [3].

3.5. Natural History Cohorts of Chronic Forms

McGovern's multinational prospective study (2021) followed 59 patients from five countries (31 male and 28 female; aged 7–64 years) with A/B and B forms and at least two symptoms for 4.5–11 years [55]. Moderate or severe splenomegaly was present in 86% at baseline, 83% after one year and 90% at the end, with volumes of 4–29 MN. Interstitial lung disease increased from 66% (39/59) to 78% (25/32), and median DLCO fell by more than 10%. Nine patients (15%) died, 8 from disease-related causes, mainly pneumonia. Five of those eight deaths (63%) occurred in patients with onset before age 2 years, six of the nine deaths occurred before age 50 and three before age 20. Severe splenomegaly or previous splenectomy was associated with a 10-fold greater likelihood of death (odds ratio, OR 10.29; 95% CI 1.7–62.7) [55]. The wide confidence interval reflects the small number of deaths.

Cassiman's review (2016) analysed 85 patients who had died or undergone liver transplantation, 27 reported by treating physicians and 58 from the literature [47]. Before death, 96.6% had splenomegaly, 91.4% hepatomegaly, 82.6% liver dysfunction and 75.0% pulmonary disease. The main causes of death were respiratory failure and liver failure, each accounting for 27.7%, at any age. In the chronic neurovisceral form (31.8% of cases), the main causes were neurodegenerative progression and respiratory disease (23.1% each) and liver disease (19.2%). Median age at death was 8 years in the chronic neurovisceral form and 23.5 years in the chronic visceral form [47]. The 2023 guideline attributes the 27.7% respiratory mortality to type A while citing this study, but Cassiman's series concerns chronic forms [3, 47].

In France, the retrospective cohort of Mauhin (2024) brought together 118 patients from 27 hospitals between 1990 and 2020: 94 with type B, 15 with type A and 9 with type A/B [13]. The median age at diagnosis was 8.0 months in type A, 1.0 year in A/B and 5.5 years in B (0–73). There were 30 deaths, with a median age at death of 1 year in type A (n=14), 8.5 years in A/B (n=6) and 57.6 years in B (n=10). In type B, the standardised mortality ratio relative to the French population was 3.5 (1.6–5.9). The recorded causes were progressive neurodegeneration in type A (16.7%), cancer in type B (16.7%) and unspecified cause in 33.3% [13]. These percentages refer to the 30 deaths. Within type B, mortality was 10.6% (10 of 94), 80% of deaths occurred in adults, with a median age at death of 58.5 years in that subgroup, and cancer accounted for 5 of the 10 deaths; there were also two deaths from complications after liver transplantation and one cardiovascular death [10, 13]. In type B, 60.9% of patients were diagnosed before 10 years of age, 2.2% between 10 and 18 and 37.0% in adulthood [13]. The French PNDS, which uses this cohort, gives 9 years as the median age at diagnosis in type B; in the article, 9 years is the median given for the subgroup of adult patients, and the overall median for type B is 5.5 years [10, 13]. The Brazilian series of Giugliani (2026) and the Argentine, Iraqi and Egyptian series are described in section 9 [11, 37, 58, 59].

3.6. Natural History and Treated Disease

The data in subsections 3.2 to 3.5 describe untreated patients. With olipudase alfa, spleen and liver volumes, DLCO, platelets, lipid profile, transaminases, growth and bone density improve in types B and A/B (section 7). There is no effect on neurological disease, and reversal of pre-existing fibrosis or cirrhosis is not expected [6, 60, 61]. The effect of therapy on fractures, coronary disease, calcified pulmonary nodules and survival has not been studied [6].

4. Clinical Recognition and Warning Signs

4.1. When to Suspect the Disease, by Age and Context

ASMD cannot be diagnosed on clinical criteria alone, but combinations of findings should prompt enzyme measurement [6]. In infants, hepatosplenomegaly at 2–4 months, with appropriate acquisition of skills until approximately 6 months and neurological deterioration during the first year, particularly with a cherry-red spot, should raise suspicion of type A. This is a strong recommendation with level B evidence [3]. Suggestive findings listed by GeneReviews are hepatosplenomegaly, developmental delay, interstitial disease on chest radiography, a cherry-red spot, growth failure and presentation before age 3 years [6]. Metabolic disease textbooks include type A among the causes of hepatosplenomegaly with storage signs in infants aged 1–12 months, alongside GM1 gangliosidosis, sialidosis type II, I-cell disease, mucopolysaccharidosis VII, galactosialidosis, prosaposin deficiency and Wolman disease. Shared presenting signs are growth failure, anorexia, poor feeding, severe diarrhoea, hypotonia, hypothermia and frequent infections [62]. In prolonged neonatal jaundice, ethnic origin, neurological abnormalities and hepatosplenomegaly should be sought as clues to Niemann–Pick disease [63].

In children and adults, the combination of splenomegaly (often the first sign), hepatomegaly, thrombocytopenia, interstitial lung disease and low HDL points to chronic forms [3, 6]. For type A/B, GeneReviews lists hepatosplenomegaly, interstitial lung disease, dyslipidaemia, CNS manifestations (learning difficulties, ataxia, developmental delay), thrombocytopenia and, in a subset, coarse facial features. For type B, it lists the same findings without CNS involvement, with growth restriction in children [6]. Hepatosplenomegaly may be the only sign of type B, possibly accompanied by asymptomatic interstitial pneumonia [62]. In adults, splenomegaly is highly suggestive of forms B and C, Gaucher disease and Tangier disease [64]. Coexisting hepatosplenomegaly and interstitial lung disease point to a multiorgan disease such as ASMD [3].

The patient pathway explains diagnostic delay. Initial contact is often with hepatology or gastroenterology because of elevated transaminases, or haematology because of splenomegaly leading to bone marrow biopsy. Mixed dyslipidaemia is sometimes detected on routine testing, and some adults present only with pulmonary disease [8]. Diagnostic delay was approximately 8 years in Brazil and 7.5 years in Argentina [11, 58]. In Lyon, 8 of 56 ASMD diagnoses (14.3%) were made in patients referred for suspected Gaucher disease, and in Argentina two patients were initially diagnosed with Gaucher disease [58, 65]. Investigation for Gaucher disease, lysosomal acid lipase deficiency and NPC should systematically include ASMD [3].

Screening for ASMD in unselected adults with interstitial lung disease is not justified. In Belgium, dried blood spot screening of 250 consecutive adults (median age 73 years, idiopathic pulmonary fibrosis in 73%) identified 16 with low or borderline activity or elevated lysosphingomyelin, but no ASMD case; only three VUS heterozygotes were found [66]. The authors recommend testing patients with interstitial disease associated with hepatosplenomegaly, thrombocytopenia, low HDL or unexplained liver disease [66].

4.2. Warning Signs and Emergencies

The table summarises situations requiring urgent assessment in a patient with known or suspected ASMD.

Patients with splenomegaly should avoid contact sports, and emergency cards, proposed by patient organisations and by the Orphanet emergency guidelines, are recommended [6, 43]. In France, the PNDS (National Diagnosis and Care Protocol) requires that, at the time the diagnosis is disclosed, an ASMD-specific emergency card be issued and explained, provided by the reference or competence centre in the common format of the rare disease filières (credit-card format, personal and covered by medical confidentiality, available from the G2M filière). The card identifies the contacts of the patient, the physicians and the centre and flags the three risks to bear in mind in an emergency: bleeding, splenic rupture and interstitial lung disease [10].

4.3. Newborn Screening

ASMD newborn screening measures ASM activity in dried blood spots, usually by tandem mass spectrometry (MS/MS) in multiplex lysosomal disease panels, with biochemical and molecular confirmation of positive results [3, 6, 67]. At the latest GeneReviews update (2023), ASMD was not included in the US Recommended Uniform Screening Panel (RUSP), and only a limited number of states screened for it [6]. According to Gragnaniello (2024), approximately 4% of US states screened for ASMD, compared with 64% for Pompe disease and 60% for MPS I [44]. The sources consulted do not include the current official Health Resources and Services Administration (HRSA) document on ASMD status in the RUSP.

In Illinois, eight infants were predicted to have type B and two were indeterminate, and their age did not allow exclusion of type A/B [9]. Lysosphingomyelin was normal in the neonatal period in the six tested, potentially predicting type B, although the cohort contained no type A case. With follow-up from 6 months to 9 years and 10 months, only two siblings with the p.Gln294Lys/p.Arg610del genotype were recommended to start enzyme replacement therapy (ERT) [9]. At least two carrier siblings had negative screening results, demonstrating that screening does not reliably identify carriers [9]. In Italy, lysosphingomyelin was already elevated at birth in both cases, and the 100% positive predictive value could not be confirmed because follow-up was unavailable in an anonymous study [44]. The Japanese experience suggests that hospitalised newborns require specific reference ranges and repeat sampling after maturation [68].

Newborn screening has clinical and ethical limitations. Most genotypes are new, and the phenotype (A, A/B or B) is often unpredictable during the first year, generating parental anxiety and requiring close neurological surveillance [9, 44]. Screening creates “patients-in-waiting” who might remain asymptomatic until adulthood [44]. Moreover, olipudase alfa does not cross the blood–brain barrier, so early diagnosis of type A does not alter the neurological course [12, 44]. Fluorogenic substrates yield false negatives with p.Gln294Lys, making MS/MS the preferred method [3, 44]. Arguments in favour include evidence that earlier ERT preserves growth and limits irreversible splenic fibrosis (section 7) [60, 69]. In New York, ScreenPlus includes ASMD in multidisease newborn screening of 100,000 newborns (2021–2029) [70].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic Criterion

GeneReviews defines diagnosis by identification of biallelic pathogenic or likely pathogenic SMPD1 variants and residual ASM activity below 10% of controls in peripheral blood lymphocytes or cultured fibroblasts [6]. Molecular testing is increasingly used first, but demonstration of low activity is necessary for confirmation. Two VUS, or one pathogenic variant and one VUS, neither establish nor exclude diagnosis [6]. The 2023 guideline establishes, with a strong recommendation and level A evidence, that diagnosis rests on deficient or markedly reduced activity in leucocytes or fibroblasts. If sequencing comes first and the variants are not known to be pathogenic, demonstration of enzyme deficiency is mandatory [3]. Enzyme testing is required rather than merely accepted, and absolute values should be interpreted against the laboratory's own controls [7, 71].

5.2. Algorithm

The 2017 diagnostic recommendations propose measuring ASM activity first and only then sequencing SMPD1 [8]. Sequencing is slower, many variants found are not pathogenic, and starting with it would delay the diagnosis of another disease. Glucocerebrosidase should be measured at the same time, in multiplex by MS/MS or in parallel, to include Gaucher disease [8]. These recommendations result from expert opinion gathered in an international panel, were published in Genetics in Medicine without representing American College of Medical Genetics and Genomics (ACMG) policy and were supported by Sanofi Genzyme [8]. The 2023 guideline adds the use of plasma biomarkers as first line or in combination and the investigation of variants not detected by sequencing when the molecular result is incomplete [3]. The 2024 French PNDS (National Diagnosis and Care Protocol) (annex 2) proposes an algorithm with two entry points. With clinical suspicion, with or without cytological findings, ASM activity is measured in a dried blood spot; in parallel or beforehand, plasma (or dried blood spot) biomarkers can be measured, and an abnormal profile (raised lysosphingomyelin, PPCS and cholestane-triol) leads to enzyme measurement, whereas normal biomarkers make the diagnosis unlikely. Deficient activity establishes the diagnosis of ASMD and leads to SMPD1 sequencing; intermediate activity requires biomarkers, if not already done, and sequencing; normal activity rules out the diagnosis and points to the differential. A pathogenic variant on each allele confirms the diagnosis. A single identified allele, a VUS or no variant, with activity confirmed as deficient, require further molecular analyses and discussion at an RCP with genetic counselling [10]. The PNDS also recommends asking for the patient's consent for inclusion in the national registry at diagnosis [10]. GeneReviews, from the perspective of the genetics laboratory, accepts in symptomatic patients a multigene panel with SMPD1 and the genes of the differential, or an exome or genome when the phenotype cannot be distinguished from other diseases [6].

The practical algorithm combines these sources in five steps [3, 6, 8]. First, when clinical suspicion arises, ASM and glucocerebrosidase activity are measured in dried blood spots by MS/MS or in leucocytes and, when available, the lysosphingolipid profile (lysosphingomyelin, N-palmitoyl-O-phosphocholine-serine or PPCS, and glucosylsphingosine). Second, low dried blood spot activity is confirmed in leucocytes or fibroblasts, or by identification of biallelic pathogenic variants. Third, SMPD1 is sequenced (exons and flanking intronic regions), and parental segregation is studied. Fourth, if only one variant is found, if homozygosity is not confirmed in the parents, or if no variant is found despite enzyme deficiency, copy number variants (CNVs) are investigated by multiplex ligation-dependent probe amplification (MLPA), and deep intronic variants by ribonucleic acid (RNA) analysis. Fifth, VUS are classified according to ACMG and Association for Molecular Pathology (ACMG/AMP) criteria and, if necessary, functional studies. Figure 1 of the 2023 guideline depicts this laboratory algorithm, and figures 1 and 2 of McGovern (2017) separate presentations in infancy and after infancy [3, 8]. The figures were not consulted, only the captions and text.

5.3. Enzyme Assay

The dried blood spot has specific limitations. Activity is influenced by anaemia, leucopenia, recent transfusions, heat and humidity, and there are more false negatives than in leucocytes [3]. The request should state the type of transfusion and the time elapsed since the last one, because plasma may affect the result more than red cells [8]. With strong clinical suspicion and a normal dried blood spot result, the test is repeated in leucocytes or fibroblasts [3]. Measurement of glucocerebrosidase by fluorometry in dried blood spots is not reliable, and measurement of acid lipase in the same MS/MS panel is suggested because lysosomal acid lipase deficiency also has an ERT [8]. The 2017 recommendations propose reference laboratories with a minimum monthly volume and ISO 15189 accreditation [8]. In France, the PNDS reserves activity measurement to reference medical biology laboratories (Toulouse, Rouen, Lyon, Grenoble and Necker, in Paris), which perform it on dried blood spots by MS/MS with a sphingomyelin analogue in a multiplex kit, allowing Gaucher disease to be tested in the same sample. Measurement in leucocytes, fibroblasts or other cells with radiolabelled natural substrate is no longer performed in the country. The PNDS insists on expert interpretation, particularly of dried blood spots, and on confirmation of any abnormal or doubtful result by complementary analyses [10]. The turnaround times given in annex 3 range from 10 days to 6 weeks for the enzyme and from 4 weeks to 6 months for SMPD1 analysis, depending on the laboratory [10].

5.4. Biomarkers

Simultaneous multiplex measurement of lysosphingomyelin, PPCS and glucosylsphingosine guides the differential. Markedly raised glucosylsphingosine indicates Gaucher disease; markedly raised lysosphingomyelin and PPCS form the ASMD signature; raised PPCS with normal or slightly raised lysosphingomyelin indicates NPC. This recommendation is weak, with grade B evidence [3]. The oxysterols (cholestane-3β,5α,6β-triol and 7-ketocholesterol), the bile acid 3β,5α,6β-trihydroxycholanoyl-glycine and PPCS are raised in almost all patients with NPC, but also in ASMD; the distinction is made by lysosphingomyelin, markedly raised only in ASMD [14]. Biomarkers are not sufficient for diagnosis and serve mainly to support the suspicion, assess severity and monitor therapy [3, 8]. The French PNDS adds practical details [10]. Biomarkers can serve as a first orienting test and help when residual enzyme activity is not collapsed. Lysosphingomyelin is always increased in ASMD, and a pilot study associated it positively with clinical severity. PPCS is always raised in ASMD, but also in NPC and, non-specifically, in other lysosomal diseases (very moderate elevation in Gaucher disease, acid lipase deficiency) and in dyslipidaemias. Both can be measured in dried blood spots. Oxysterols cannot be measured in dried blood spots, owing to instability, and 7-ketocholesterol, more than the triol, also rises in acid lipase deficiency, cerebrotendinous xanthomatosis and some dyslipidaemias. Chitotriosidase, measured by fluorimetry in plasma, is moderately increased in many patients, but also in other lysosomal diseases (NPC, GM1 gangliosidosis, Krabbe and Fabry diseases) and in macrophage activation (sarcoidosis, leishmaniasis); about 30% of people have partial and 8% complete deficiency of the enzyme, which prevents it from serving as a diagnostic marker. On ERT, lysosphingomyelin and chitotriosidase fall and can be used in parallel for monitoring [10]. In the olipudase alfa trials, baseline plasma lysosphingomyelin was about 40 times the upper limit of normal (10 µg/L) in adults and more than 60 times in children [60, 61].

5.5. General Laboratory Tests, Imaging and Bone Marrow

The full blood count shows mild thrombocytopenia, anaemia and leucopenia or neutropenia; the lipid profile shows increased triglycerides and total cholesterol and low HDL [3]. Ultrasonography assesses liver and spleen volume and echogenicity, but accurate measurement uses computed tomography (CT) or, preferably, magnetic resonance imaging (MRI); interstitial disease may be suspected on radiography and characterised on CT [3].

Bone marrow aspiration or biopsy is neither necessary nor recommended for diagnosis. It is nevertheless frequent in adults with unexplained splenomegaly, because of suspected malignancy [3, 6]. It shows foamy macrophages (“Niemann-Pick cells”), 20–90 µm in size, with honeycomb cytoplasm and positive lipid staining, and/or sea-blue histiocytes [14, 21]. Electron microscopy shows membrane-bound lucent areas and lamellar material [21]. These cells are not specific and are also found in NPC, acid lipase deficiency, GM1 gangliosidosis, Tangier disease and lysinuric protein intolerance; Gaucher cells may be confused with them by less experienced observers [3, 73]. The marrow finding therefore requires enzymatic confirmation and does not replace it [8]. The French PNDS also advises against bone marrow aspiration for diagnosis and points out that bronchoalveolar lavage cytology and the peripheral blood smear may reveal storage cells; in all these cases the diagnosis requires enzymatic and molecular confirmation [10].

5.6. Molecular Testing: Methods and Limitations

These percentages refer to the proportion of pathogenic variants each method can identify, not clinical test sensitivity. A targeted panel with 90% detection in a founder population has a much lower yield in a patient of another ancestry [6]. Sequencing does not detect deep intronic variants or most rearrangements, and gene structure, with two ATGs and a polymorphic repeat in exon 1, may generate annotation errors when the transcript is unspecified [3]. A Turkish report from 2026 describes an adult with unexplained splenomegaly and an ASMD diagnosis despite negative SMPD1 sequencing; only the title and record were consulted [75]. A negative molecular result does not exclude disease if enzyme activity is deficient; in that case, investigation continues with MLPA, RNA analysis or genome sequencing [3]. Conversely, carriers of p.Gln294Lys may have normal activity in older fluorogenic assays [3].

Molecular reports should state the gene, versioned transcript (NM_000543.5), HGVS c. and p. descriptions and equivalence with historical nomenclature when relevant, zygosity confirmed by parental testing, and the ACMG/AMP class of each variant [3, 76]. For p.Arg610del, the normalised notation is c.1829_1831del p.(Arg610del); descriptions such as “c.1826GCC” or “c.1826_1828delGCC” refer to the same deletion in repeat notation or earlier transcript versions [33, 34]. ClinGen has no actionability assertion or dosage curation for SMPD1 [7].

5.7. Prenatal and Preimplantation Diagnosis

Prenatal diagnosis preferably uses molecular testing for familial variants in chorionic villi or amniotic fluid. Alternatively, ASM activity is measured in chorionic villi or cultured amniocytes [3, 6]. Enzyme diagnosis in chorionic villi at 12 weeks was described by Vanier in 1985 [21]. Preimplantation genetic testing requires prior identification of both variants [6]. Section 8 addresses indications and counselling.

6. Differential Diagnosis

6.1. Comparative Table

In the table, AR means autosomal recessive.

Sources for the table: GeneReviews table 2 and the 2017 and 2023 guidelines, supplemented by the metabolic disease textbooks and the French PNDS [3, 6, 8, 10, 62, 64, 73, 77].

6.2. Main Differential Diagnoses

Gaucher disease is the differential diagnosis most often leading to error. Clinical overlap is extensive (splenomegaly, thrombocytopenia, hepatomegaly, foamy marrow cells), and ASMD patients have been identified among individuals with hepatosplenomegaly and normal Gaucher tests [6]. In a selective study of suspected Gaucher cases, one ASMD case was found for every four Gaucher cases [44]. In Lyon, 14.3% of ASMD cases were diagnosed incidentally in patients referred for suspected Gaucher disease [65]. Pulmonary infiltration and very low HDL, present very early in ASMD, distinguish it from Gaucher disease, in which HDL is also low but less markedly [6, 8]. Glucocerebrosidase and ASM should therefore be measured together [8, 65].

NPC shares the historical name, the foam cells in the marrow and the elevation of oxysterols and PPCS. It is distinguished by its own neurology and by normal or slightly raised lysosphingomyelin [3, 14]. Some patients formerly classified as “type B with cerebellar ataxia” may have had NPC [21].

Lysosomal acid lipase deficiency produces similar dyslipidaemia and foamy cells closely resembling Niemann–Pick cells. Some patients described as having Niemann–Pick disease with adrenal calcifications probably had Wolman disease [8, 77]. Because it has its own ERT, it should be excluded in the same panel [8].

In infants, the cherry-red spot links ASMD to gangliosidoses and sialidosis, but massive hepatosplenomegaly and interstitial lung disease are rare in Tay–Sachs and Sandhoff diseases [6, 78]. Type A diagnosis is sometimes delayed by investigations for EBV or CMV infection, and presentation as acute hepatitis or a liver biopsy interpreted as steatosis or glycogen storage disease also diverts diagnosis [6, 21]. In gangliosidoses, Farber disease, mucopolysaccharidoses, lysinuric protein intolerance, mevalonic aciduria and transaldolase deficiency, hepatosplenomegaly is absent or milder [8].

In adults, haematological malignancies are the differential diagnosis prompting marrow biopsy. Coexisting interstitial lung disease and dyslipidaemia point towards ASMD [6]. When involvement is exclusively pulmonary, the differential includes drug or environmental exposures, infections such as tuberculosis, autoimmune diseases and chronic respiratory diseases such as cystic fibrosis [8]. Hepatosplenomegaly distinguishes ASMD from other interstitial diseases [3, 6].

The French PNDS (National Diagnosis and Care Protocol) organises the differential by presentation [10]. In children with isolated hepatomegaly and/or splenomegaly, once infection has been excluded, it proposes Gaucher disease, NPC, Wolman disease and haematological diseases, recalling that ASMD may mimic leukaemia through hepatosplenomegaly with cytopenia, without blasts on the smear and with storage cells on the marrow aspirate. In children with interstitial lung disease, it considers systemic diseases (connective tissue diseases), infections and NPC. In severe persistent neonatal cholestasis, in addition to hepatic causes, it includes NPC, Gaucher disease, mevalonate kinase deficiency, cerebrotendinous xanthomatosis and transaldolase deficiency. In children with neurological disease and splenomegaly, it includes Gaucher disease types 2 (in infants) and 3, NPC and, very rarely, histiocytoses and neurosarcoidosis. In adults with hepatosplenomegaly and interstitial lung disease, it includes sarcoidosis, Gaucher disease, NPC, rheumatoid arthritis, histiocytoses and, exceptionally, lysinuric protein intolerance; with isolated hepatomegaly or splenomegaly, haematological diseases, chronic haemolysis, infections, chronic liver diseases, sarcoidosis and Gaucher disease. With interstitial lung disease with a ground-glass predominance, the pulmonary differential covers acute causes (infection, heart failure, alveolar haemorrhage), non-specific interstitial pneumonia (idiopathic or associated with connective tissue disease), lymphocytic interstitial pneumonia, sarcoidosis and granulomatoses, desquamative interstitial pneumonia and hypersensitivity pneumonitis [10].

Neutral sphingomyelinase 3 deficiency (SMPD3 gene) is a distinct entity and should not be confused with lysosomal enzyme deficiency [14].

7. Treatments and Risk Management Strategies

7.1. General Principles

ASMD is not curable but is treatable [3, 6]. Management rests on a multidisciplinary team at an experienced centre, treatment of complications and symptoms and, for non-neurological manifestations, ERT with olipudase alfa [3]. Before starting ERT, disease burden is assessed and individualised therapeutic goals agreed with the patient and family, with periodic reassessment. During treatment, tolerability, adherence and comorbidities are monitored [3]. GeneReviews table 3 lists recommended assessments after diagnosis, which form the basis of this decision and are incorporated into the surveillance table in section 11 [6].

7.2. Olipudase Alfa (Xenpozyme®)

Mechanism. Olipudase alfa is a recombinant human acid sphingomyelinase, with ATC (Anatomical Therapeutic Chemical classification) code A16AB25, taken up by cells to reduce sphingomyelin accumulation in the lungs, liver, spleen and other organs outside the CNS [6, 12]. It is not expected to cross the blood–brain barrier or modify CNS manifestations [12, 79]. Rapid degradation of accumulated sphingomyelin at treatment initiation releases proinflammatory metabolites such as ceramide. Treatment therefore always starts with progressive dose escalation, differing between adults and children [12].

Presentation and preparation. The drug is a white to off-white lyophilised powder in 4-mg and 20-mg single-dose vials [16]. It is reconstituted with 1.1 mL (4-mg vial) or 5.1 mL (20-mg vial) of water for injections, yielding 4 mg/mL, and diluted in 0.9% sodium chloride [16]. The reconstituted solution can be stored for up to 24 hours at 2–8 °C or 6 hours at 20–25 °C. The diluted solution can be stored for up to 24 hours at 2–8 °C or 12 hours at room temperature, including infusion time. It must not be frozen [16]. Each vial contains 0.60 mg (4 mg) or 3.02 mg (20 mg) of sodium [12].

Before the first infusion. Transaminases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), are measured within the month before initiation, and women of reproductive potential are checked for pregnancy [12, 16]. Premedication with antihistamines, antipyretics and/or corticosteroids may be considered, and cardiopulmonary resuscitation equipment should be available [16]. Treatment is supervised by a professional experienced in ASMD or inherited metabolic diseases [12]. The dose is calculated using actual weight if body mass index (BMI) is ≤30 kg/m². If BMI is >30 kg/m², adjusted weight is used, equal to 30 × (height in metres)². In the European summary of product characteristics (SmPC) example, a patient weighing 110 kg and measuring 1.7 m (BMI 38) receives a dose calculated for 86.7 kg [12, 16]. No adjustment is required for age >65 years or hepatic or renal impairment [12].

Escalation and maintenance. Intravenous infusion is given every 2 weeks. FDA and EU regimens are identical [12, 16].

The EPAR summary states that the maintenance dose is usually reached after 14 to 16 weeks [12]. In ASCEND-Peds, the median time to reach 3 mg/kg was 18 weeks, and in the FDA label 7 of 8 children reached the dose within 22 weeks [16, 60]. GeneReviews describes the same starting and maintenance doses and states that, in the maintenance phase, infusions last 3.5–4 hours [6]. The French PNDS (National Diagnosis and Care Protocol) reproduces the two escalation schedules of the labels (eight steps in adults and nine in children) and organises them in practice: escalation takes place in a day hospital over about 4 months and only then is transfer to home allowed. Each infusion lasts on average 3 hours and 40 minutes, except the first, and the patient is monitored for 2 hours after the end of the infusion during escalation, an interval that may be reduced to 1 hour once tolerance is established. There is no experience with shortening infusion duration and no oral treatment is available [10].

Infusion rate. In adults, the 0.1 mg/kg dose is infused at 20 mL/h for 20 minutes and then 60 mL/h for 15 minutes (approximately 35 minutes). Doses from 0.3 to 3 mg/kg are infused at 3.33 mL/h, 10 mL/h and 20 mL/h for 20 minutes each, followed by 33.33 mL/h for 160 minutes (approximately 220 minutes) [12, 16]. In children, the rate is expressed in mg/kg/h. The 0.03 mg/kg dose is infused at 0.1 mg/kg/h throughout (approximately 18 minutes). Subsequent doses increase in steps every 20 minutes (0.1, 0.3, 0.6 and 1 mg/kg/h), with durations of approximately 35 minutes (0.1 mg/kg), 60 (0.3), 80 (0.6), 100 (1), 160 (2) and 220 minutes (3 mg/kg) [12, 16]. The rate is increased only if no reaction occurs. At the end, the line is flushed with 0.9% sodium chloride at the final rate [12, 16]. Total volumes depend on weight. In adults, these are 20 mL for 0.1 mg/kg and 100 mL for 0.3 to 3 mg/kg. In children weighing <10 kg (0.03 and 0.1 mg/kg doses) and 10–20 kg (0.03 mg/kg dose), small doses are prepared in a syringe at a fixed concentration of 0.1 mg/mL [16].

Missed doses. A dose is considered missed if not administered within 3 days of the scheduled date [16]. The two labels differ in points with practical consequences [12, 16].

The French PNDS deals only with missed doses after escalation has been completed and gives practical examples (tonsillitis, bronchitis, transport that did not arrive, holidays). Its rules coincide with the European label, but restarting at 0.1 mg/kg after three missed doses is formulated for adults; in children, the first step of the label is 0.03 mg/kg [10, 12]. The consequence is that, after an interruption of 6 weeks or more during maintenance, the European label requires complete re-escalation, over 14 to 16 weeks, whereas the US label allows restarting at an intermediate level. Both justify caution by the possible reaccumulation of sphingomyelin [12, 16]. In the 5-year extension of ASCEND, 14 participants had interruptions of 3 or more consecutive infusions, with a mean duration of the first of 3.8 ± 2.6 months. In 6 participants, 7 to 25 consecutive missed doses were associated with clinically relevant worsening of lung function or organ volumes, in combination with non-consecutive missed doses, dose reduction or respiratory infection [61].

Transaminase monitoring. During escalation, transaminases rose 24–48 hours after infusion in 4 adults (13%) and 1 child (13%), reaching 3–14 times the upper limit of normal (ULN), and generally normalised by the next infusion [16]. They are measured within the month before initiation and within 72 hours before each escalation infusion, including the first 3 mg/kg dose, and before the next infusion on resuming after a missed dose. If baseline or preinfusion values are >2 times ULN, testing is repeated within 72 hours after the infusion ends. During maintenance, monitoring is part of routine management [12, 16]. If transaminases are above baseline and >2 times ULN before the next infusion, the previous dose is repeated or reduced, or treatment is suspended until levels return to baseline [16]. In the long term, transaminases decrease. At 52 weeks, mean ALT decreased by 46.9% and AST by 40.2%, and in adults ALT normalised in 16 of 16 with elevated baseline values and AST in 10 of 12 [12].

Infusion-associated reactions and hypersensitivity. The FDA label carries a boxed warning for hypersensitivity reactions, including anaphylaxis. It requires appropriate medical monitoring and available cardiopulmonary resuscitation equipment, and mandates immediate discontinuation in a severe reaction; it allows a desensitisation procedure [16]. The European SmPC contraindicates the drug in life-threatening hypersensitivity (anaphylactic reaction) to olipudase alfa or an excipient, whereas the FDA lists no contraindications [12, 16]. In pooled European data involving 60 patients (40 adults and 20 children), infusion-associated reactions occurred in 57.5% of adults and 65% of children, and hypersensitivity reactions in 22.5% and 45% [12]. In the US label, involving 38 patients, infusion-associated reactions occurred in approximately 50% of adults and 75% of children, and mild to moderate hypersensitivity in 10 adults (33%) and 4 children (50%), with urticaria, pruritus, erythema, rash, eczema, angioedema and, in adults, erythema nodosum [16]. Anaphylaxis occurred in an 18-month-old child at the sixth escalation infusion. Another child, aged 16 months, with type A, treated with olipudase from a different manufacturing process and previously subjected to immune tolerance induction, experienced two anaphylactic reactions at the fifth and sixth infusions. Both had IgE and IgG (immunoglobulins E and G) antidrug antibodies [16]. An acute-phase reaction has been described, with increased C-reactive protein (CRP), calcitonin and interleukin 6 (IL-6), decreased serum iron, fever, vomiting and diarrhoea, particularly approximately 48 hours after infusion during escalation [12, 16].

Desensitisation allowed prolonged treatment to be maintained in some children, but in others it failed and treatment was stopped before the maintenance dose [12]. The 18-month-old child resumed treatment 4 months later, with diluted solution and desensitisation, and in ASCEND-Peds a young child with anaphylaxis in the 2nd month resumed after individualised desensitisation [16, 60]. In 2026, the first report of omalizumab in ASMD, a single case, was published. An Italian child with chronic neurovisceral ASMD had three IgE-mediated anaphylactic reactions, at 3 mg/kg and then during two desensitisation protocols, with anti-olipudase IgE of 8.34 kUA/L [80]. The child received omalizumab 75 mg subcutaneously every 2 weeks, off-label for age and for clinical indication, with authorisation from the Lombardy rare disease network, as an adjunct to a 10-step desensitisation protocol with dilutions down to 1:100,000. The child reached 2.5 mg/kg without further reactions, and anti-olipudase IgE fell to <0.35 kUA/L after 8 months [80]. This is a case report and not a recommendation. The French PNDS cites an earlier report from the same group (Fiori, 2024) of anaphylaxis in a child with the chronic neurovisceral form, with reintroduction of olipudase alfa after a desensitisation protocol [10].

Immunogenicity. In European data, 19 of 40 adults (47.5%) and 15 of 20 children (75%) developed antidrug antibodies, with median seroconversion at approximately 52 and 12 weeks. Most had low titres (≤400) or reverted. Neutralising antibodies occurred in 8 of 19 adults and 9 of 15 children with antibodies, persisting in 2 adults and 3 children, without a demonstrated effect on pharmacokinetics or efficacy [12]. Infusion-associated reactions were more frequent in antibody-positive patients (70.6% versus 46.2% in the EU; 73% versus 44% with antidrug IgG in ASCEND according to the FDA) [12, 16].

Other adverse effects. In pooled European data, the most frequent effects were headache (31.7%), urticaria (26.7%), fever (25%), nausea (20%), abdominal pain (16.7%), vomiting (16.7%), pruritus (13.3%), myalgia (13.3%), rash (11.7%), increased CRP (11.7%), upper abdominal pain (10%) and erythema (10%) [12]. Serious effects included extrasystoles in an adult with pre-existing cardiomyopathy (2.5%) and, in one child each (5%), anaphylaxis, urticaria, rash, hypersensitivity and increased ALT. One adult discontinued treatment because of recurrent rash [12]. With a median exposure of 4.95 years in adults and 6.15 years in children, the profile remained similar to that of the first year [12]. Hypotension may slightly affect driving ability [12].

In the 8 children in the US label, the most frequent effects were fever (100%), cough, diarrhoea and rhinitis (75% each), abdominal pain (63%), vomiting, headache and urticaria (50% each), and nausea, rash and arthralgia (38% each) [16].

Overdose. In children during escalation, higher-than-recommended starting doses caused severe reactions within the following 24 hours, including death. Presentations included fever, hypotension, gastrointestinal haemorrhage, markedly elevated liver tests, metabolic acidosis, respiratory failure and vomiting. A 2-year-old child died 24 hours after a higher-than-recommended starting dose. There is no antidote [12, 16]. Calculation and double-checking of the paediatric escalation dose are therefore critical safety points.

Pharmacokinetics and pharmacodynamics. In adults receiving 3 mg/kg every 2 weeks, Cmax is 30 (5) µg/mL and AUC 607 (120) µg·h/mL, proportional to dose between 0.1 and 3 mg/kg. Distribution volume is 13 L, clearance 0.33 L/h and half-life 32–38 hours [12, 16]. In children aged 1.5–17.5 years, Cmax is 24.3 µg/mL and AUC 449 µg·h/mL [16]. Plasma ceramide rises transiently after each infusion, and preinfusion values decrease during maintenance. Preinfusion lysosphingomyelin decreased from 379 to 99 µg/L in adults and from 625 to 80 µg/L in children at week 52. Histological hepatic sphingomyelin decreased by 92.0% with olipudase and increased by 10.3% with placebo [12, 16].

Home infusion. The European SmPC allows home infusion only after escalation, in patients on maintenance who tolerate infusions well, under the supervision of a healthcare professional trained in emergency management and with the same dose and rate as in hospital. After missed or delayed doses, a return to the supervised setting may be necessary. The EU requires an educational programme for professionals, patients and carers [12]. The US label does not address home infusion in the sections consulted [16]. In ASCEND, 18 adults moved to home infusion during the pandemic, with 113 adverse events in 15 of 18 (83.3%) versus 708 in 35 (100%) in hospital. There were serious events in 1 patient (5.6%; COVID-19) at home and in 6 (17.1%) in hospital [61]. In ASCEND-Peds, 70% of children received home infusions [60]. In France, the PNDS provides for transfer to home after hospital escalation, with essentially clinical monitoring by the attending physician [10].

Interactions and efficacy monitoring according to the French PNDS. Some psychotropic drugs interfere with acid sphingomyelinase, but there are only in vitro data, and the PNDS does not restrict olipudase alfa in patients taking these drugs. Bisphosphonates, potent inhibitors of the enzyme, should be avoided in the treatment of osteoporosis [10]. Efficacy is monitored through liver and spleen volumes, DLCO, haematological parameters, lipid profile and blood biomarkers [10].

7.3. Regulatory Status

Table sources: FDA label, EMA SmPC and EPAR, and ACMG therapeutics bulletin [12, 16, 79].

The ACMG therapeutic bulletin (2023), of voluntary adherence, stresses that approval was based on ASCEND and ASCEND-Peds, which included only patients with types B and A/B. Benefit in type A has not been documented and safety in pregnancy has not been established [79]. The 2023 international guideline also reports approvals in Brazil and Japan [3, 11]. The dates of these approvals were not consulted in the official sources of ANVISA and PMDA. In France, the Haute Autorité de Santé (HAS) granted early access authorisation on 17/03/2022, renewed on 27/04/2023, and issued favourable opinions on reimbursement on 23/11/2022 and 19/07/2023 [81]. The November 2024 PNDS (National Diagnosis and Care Protocol) states that treatment is covered by social security, with the price still being set, and that more than 40 patients, mostly adults, were being treated in France [10]. In Portugal, the case published in 2026 describes treatment in an early access programme between July 2023 and January 2024 and resumption in May 2024 after special authorisation [82]. The sources consulted do not include INFARMED information on reimbursement, and the European post-authorisation variations were not read in detail. The international non-proprietary name is olipudase alfa, with the brand name Xenpozyme® in the USA and the EU [12, 16].

7.4. Clinical Trials

The US label presents different numbers for the same trials. It includes only 13 olipudase-treated patients in ASCEND, with DLCO +23.9% versus +3.0% (difference 20.9; 95% CI 10.6–31.2; p=0.0003) and spleen −38.9% versus +0.5% (difference −39.4; 95% CI −47.6 to −31.2; p<0.0001). In ASCEND-Peds, it includes only 8 children aged 1–10 years (spleen −46.7%; 95% CI −55.5 to −37.9) [16]. The FDA label mentions patients treated with olipudase from another manufacturing process, but the exact reason for exclusion was not read in a primary FDA source. Numbers from each label should not be mixed [12, 16].

Source: Wasserstein and colleagues, 2026 [61]. At the end, no patient had severe splenomegaly: of the 23 with moderate and 8 with severe splenomegaly at baseline, 19 moved to mild and 12 to moderate. Of the 15 with moderate DLCO impairment, 14 moved to mild or normal. Of the four with severe impairment, the three younger patients improved and the oldest, aged 60 years, remained severely impaired [61]. Triglycerides and LDL normalised at 6 months, HDL at 2 years [61]. All 35 patients experienced adverse events, 98% mild or moderate, and there were 23 serious events in 13 patients, one related to treatment (extrasystoles with pre-existing cardiomyopathy). There were no acute-phase reactions or deaths [61].

In the paediatric extension, spleen status changed from severe splenomegaly in 12 children and moderate in 8 to mild or absent in 12 and moderate in 8. The liver normalised or remained slightly enlarged in 19 of the 20 children [60]. The proportion with platelets <150×10⁹/L fell from 75% to 35%. HDL, below the lower limit of normal in all at baseline (16.9 mg/dL), rose to 45.4 mg/dL. No child remained short (Z-score ≤ −2), compared with 10 of 20 at baseline, and 4 of the 5 who reached adulthood attained skeletal maturity [60]. Serious treatment-related events occurred in 4 children (20%), all during the first two years, including one anaphylactic reaction. Infusion-associated reactions peaked at 3–6 months. Antidrug antibodies developed in 14 children, without antibodies neutralising cellular uptake or an effect on efficacy [60].

Evidence limitations. The only randomised controlled trial is ASCEND, with 36 adults and a 52-week controlled period; the remaining data come from open-label extensions without a long-term comparison group, with losses to follow-up and interference from the COVID-19 pandemic in assessments [60, 61]. Outcomes are surrogates (DLCO, organ volumes, platelets, lipids). During the controlled period, quality of life and patient-reported outcomes did not differ from placebo, and there are no data on mortality, liver transplantation, cardiovascular events or fractures [6, 61]. Percentage changes should be read alongside absolute values. For example, a 36% increase in DLCO corresponds on average to moving from 50% to 66% predicted, leaving mild impairment [61]. The 2025 meta-analysis, with 3 studies and 46 patients, including one randomised study, estimated at 2 years DLCO +34.63% (95% CI 26.09–43.18), liver volume −37.76% and spleen volume −49.46%, but mainly pools open-label data from the same programmes [89]. Entry criteria (DLCO ≤70%, spleen ≥6 MN, absence of p.Arg610del homozygosity in ASCEND-Peds) make the study populations more severely affected than many patients in clinical practice [12, 60, 61]. No negative trials or suspensions for safety reasons were identified. The single-dose study was registered as “terminated”, without a reason described in the sources consulted [70].

7.5. Olipudase Alfa in Type A and Severe Neurovisceral Forms

The 2023 guideline recommends considering for olipudase alfa, case by case, all patients with a confirmed diagnosis and significant non-neurological manifestations. This is a strong recommendation, with grade A evidence and 65% full agreement [3]. Patients with acute or rapidly progressive neurological disease were excluded from the trials. Early access programmes nevertheless treated some patients with visceral and neurological manifestations, with the aim of controlling visceral symptoms [3]. In a patient organisation survey, parents of children treated for at least 12 months were satisfied with visceral control; this is weak evidence, from a manuscript then submitted [3]. The French PNDS follows the European label: ERT is intended for types B and A/B, is not indicated in type A, because it does not cross the blood-brain barrier, and there is no specific treatment for the infantile neurovisceral form [10]. In countries with broader indications, such as the USA, it is possible to treat infants with type A. In such cases, the guideline recommends informing about risks, benefits, limitations and long-term futility, providing for the option of stopping treatment when neurodegeneration progresses and discussing alternatives such as supportive care, family counselling and palliative care [3].

An Italian compassionate-use report illustrates the problem of early classification. An 8-month-old infant with hepatosplenomegaly, elevated transaminases and normal development was initially considered to have chronic neurovisceral disease and treated for 2 years with escalation from 0.03 to 3 mg/kg, which was well tolerated [90]. Spleen and liver size decreased, liver tests normalised, oxysterols normalised and lysosphingomyelin decreased without normalising. The child subsequently developed neurocognitive regression consistent with type A. ERT did not alter neurological progression but improved visceral symptoms [90]. In the USA, an observational study (NCT06192576) assesses long-term safety and immunogenicity in children younger than 2 years with types A/B or B and in type A patients without an age limit, with 10 participants planned through 2029 [70].

French criteria for indication and prioritisation. In France, ERT is not systematic: each initial prescription is validated case by case at a multidisciplinary consultation meeting (RCP) of the CETLv, the CRML or a reference or competence centre for inherited metabolic diseases. The RCP brings together specialists from several disciplines, records the decision and explains it to the patient, and may address the diagnostic strategy, validation of the diagnosis, the initial or subsequent treatment plan and palliative decisions [10]. At the start of early access, the CETLv defined priority groups, published by Mauhin and colleagues (2022), which the PNDS retains as a reference [10].

Source: HAS PNDS, chapter X.2 [10].

In children, faltering of the growth curve is considered a potential indication. The PNDS also mentions a Dutch proposal of treatment criteria based on the natural history of adults with the chronic visceral form (Eskes, 2024) [10]. The same text lists the open questions: the best time to start ERT, decided at an RCP and in shared decision-making with the patient; the possible existence of a point of no return in liver fibrosis or fibrosing interstitial lung disease, not demonstrated; temporary interruption or stopping treatment after several years, to be discussed at an RCP; and the appropriateness of starting ERT in patients older than 65 years with a mild phenotype, already discussed case by case [10]. Data from patients treated in early access should be collected in the national registry, to complement those from the trials [10].

7.6. Haematopoietic Cell and Organ Transplantation

Bone marrow transplantation had no effect on the neurological picture in type A, although it may reduce the liver and spleen [14, 21]. In type B, there are reports of steady reduction of the organs and radiological pulmonary improvement after transplantation, with follow-up of up to 16 years [21]. Shah and colleagues (2005) described successful haematopoietic stem cell transplantation (HSCT) in a child, with correction of the metabolic defect, improvement in the blood count and reduction of liver and spleen volumes [6, 91]. The 2023 guideline classifies HSCT as an option with variable results, with morbidity (graft-versus-host disease, infection, renal tubular dysfunction) and mortality that limit its use. It does not treat neurological disease, reversal of growth delay is uncertain and, in clinically evident neurological disease, it should be considered experimental (weak recommendation, grade C evidence) [3]. GeneReviews considers it probably obsolete since the advent of ERT [6]. The Atlas presented it as advantageous in type B, from a pre-ERT perspective [21]. The French PNDS (National Diagnosis and Care Protocol) is more restrictive: it recalls the high mortality of HSCT in the visceral form (5 of 6 patients in the cited Cassiman series) and no longer considers it a therapeutic option [10].

Liver transplantation has been performed in several type B patients with progressive liver dysfunction, with improvement in liver function and dyslipidaemia and, in some cases, improvements in lung disease and paediatric growth [3, 6, 50]. Lung transplantation has not shown additional benefit, with variable results in four type B patients [3]. The French PNDS details the experience with liver transplantation in adults and children with the chronic visceral form: it restores liver function, corrects dyslipidaemia and allows catch-up in height and weight in children, without recurrence of the disease in the graft. It may improve or completely correct respiratory disease, clinically, functionally and radiologically, especially in children, probably because the transplanted hepatocytes secrete the enzyme into the plasma. Follow-up is too short to assess the effect on the neurology of the neurovisceral forms. With ERT, liver transplantation has lost ground, but it remains indicated in decompensated cirrhosis and liver failure, with good results [10]. For lung transplantation, the PNDS reports several cases, with complications linked to the pathophysiology of the disease itself [10].

7.7. Organ-Specific Supportive Treatment

Many of these measures apply to patients without ERT, those who do not improve with it, and all neurological manifestations [6].

The French PNDS (National Diagnosis and Care Protocol) adds supportive measures for the chronic visceral and chronic neurovisceral forms [10]. Growth is monitored and nutritional support is introduced if there is faltering. Vaccination should be complete and include hepatitis A and B, encapsulated bacteria (pneumococcus and meningococcus), COVID-19, particularly in adults, and influenza. Calcium and vitamin D3 intake should be sufficient, with supplementation if necessary to keep 25-hydroxyvitamin D above 30 ng/mL, together with regular physical activity. To protect the liver, excessive sugar intake, particularly in soft drinks, and alcohol are discouraged. Non-steroidal anti-inflammatory drugs and antiplatelet agents should be avoided, with case-by-case decisions, when portal hypertension is possible or confirmed, because of the bleeding risk. In severe liver disease, the patient is assessed at a reference centre to discuss follow-up and transplantation. Violent and contact sports are discouraged, but other sports are possible and recommended. Splenectomy is generally considered contraindicated, because of the risk of respiratory deterioration after surgery, and, when performed, requires vaccination and antibiotic prophylaxis. Long-term oxygen therapy may be necessary in severe hypoxaemia, and smoking is strongly discouraged, also because of the excess cancer risk. Statins and other lipid-lowering drugs have no demonstrated benefit in children; in adults they may be considered, although no study has demonstrated their value [10].

For types A and A/B, annex 5 of the PNDS describes multidisciplinary symptomatic treatment, with no drug contraindication in principle related to the deficiency and with each drug used within its authorisation [10]. The table summarises the measures by problem.

Source: annex 5 of the HAS PNDS [10]. The same annex stresses that palliative care, including support for parents and carers, accompanies the whole pathway and is not the same as end-of-life care [10].

7.8. Agents and Situations to Avoid

Total splenectomy is the intervention most to be avoided. In the McGovern cohort (2021), previous splenectomy or severe splenomegaly was associated with a 10-fold higher probability of death [3, 6, 55]. Contact sports, alcohol, tobacco and electronic cigarettes should also be avoided [6, 43]. Hepatotoxic drugs, such as statins, require more frequent monitoring of liver function [6, 43]. Bisphosphonates have not been studied in the disease, because they inhibit ASM [43]; the French PNDS goes further and recommends avoiding them in osteoporosis, as they are potent inhibitors of the enzyme in vitro [10]. The same PNDS advises against non-steroidal anti-inflammatory drugs and antiplatelet agents in the presence of portal hypertension and, in types A and A/B, flags the drugs that may worsen hypotonia (benzodiazepines, cervical botulinum toxin), dystonia (neuroleptics, valproate) or poorly controlled epilepsy (amitriptyline, baclofen) [10]. With olipudase alfa, dosing errors during paediatric escalation, which have already caused deaths, and restarting at the maintenance dose after a prolonged interruption are critical [12, 16].

7.9. Perioperative Care and Procedures

Severe bleeding after tonsillectomy, adenoidectomy and dental surgery has been described [3, 43]. Before a procedure, the blood count and coagulation are assessed, haemostasis is planned and the availability of blood products is ensured [6, 43]. The sources consulted contain no specific anaesthetic recommendations; interstitial lung disease, portal hypertension with varices and, in the neuronopathic forms, the risk of aspiration are the factors to consider in planning [3, 43]. Liver biopsy and portal pressure measurement are reserved for selected cases [43]. The French PNDS likewise formulates no disease-specific anaesthetic recommendations: indications, risks and techniques are assessed case by case, with attention to haemostasis and the platelet count before any surgical procedure [10].

7.10. Pregnancy, Contraception and Breastfeeding

Women with chronic visceral ASMD, even with significant pulmonary disease and hepatosplenomegaly, appear mostly to have normal pregnancies and deliveries and healthy newborns. This finding comes from observation of 17 monitored pregnancies in untreated women, communicated personally by McGovern, and is low-level evidence [6, 43]. Hepatosplenomegaly generally does not compromise fetal growth. Oesophageal varices increase bleeding risk as pregnancy advances and during the peripartum period, and high-risk obstetric follow-up with pulmonary and haematological surveillance is recommended [6, 14, 43].

For olipudase alfa, the FDA label advises against initiating or escalating the dose at any time during pregnancy because increased sphingomyelin metabolites may raise the risk of fetal malformations. Maintenance during pregnancy is decided by weighing maternal need, fetal risk and the risk of untreated maternal disease [16]. The European SmPC does not recommend the drug during pregnancy or in women of reproductive potential without effective contraception unless maternal benefit outweighs risk, including fetal risk [12]. In mice, exencephaly occurred at 10 and 30 mg/kg/day. The no-adverse-effect dose (3 mg/kg) corresponded to 0.14 times human exposure at the maximum dose, and no toxicity occurred in rabbits. There are no data in pregnant women or evidence of human placental transfer [16]. Effective contraception is recommended during treatment and for 14 days after the last dose if treatment is discontinued [12, 16]. Whether the drug passes into human milk is unknown; it was detected in mouse milk. A decision must be made whether to discontinue breastfeeding or the drug [12]. There are no human fertility data [12]. In ASCEND, one participant discontinued treatment because of pregnancy, which was uncomplicated, with a healthy baby [61].

The French PNDS (National Diagnosis and Care Protocol) devotes a chapter to pregnancy [10]. The literature contains only four published pregnancies in women with type B, between 1982 and 2022. They went well, with one case of fetal growth restriction from 32 weeks, but the postpartum period was complicated by haemorrhage after caesarean section in two cases, one of them fatal, and by non-serious infections in two, including one pyelonephritis. The experience of French teams and of personal series is reassuring, but pregnancy may worsen some manifestations and should be planned. The organ assessment is updated at the preconception consultation, according to the follow-up table, by a team bringing together the ASMD reference physician, the respiratory physician, the hepatologist, the haemostasis specialist, the obstetrician and the anaesthetist, to define and explain the maternal and fetal risk [10]. The points of surveillance by system are as follows:

Source: HAS PNDS, chapter XI [10].

Delivery should take place in a level III maternity unit. Vaginal delivery is not contraindicated, and epidural or spinal anaesthesia, if haemostasis and platelets allow, carries less respiratory risk than general anaesthesia. The risk of postpartum haemorrhage requires close monitoring, and antibiotic prophylaxis may be proposed [10]. With regard to olipudase alfa, the PNDS adopts the wording of the European SmPC (not recommended in pregnancy unless the maternal benefit outweighs the risk) and records the absence of pregnancies on treatment in the literature and in pharmacovigilance databases [10, 12].

For contraception, the PNDS considers oestrogens classically contraindicated, because of liver disease and dyslipidaemia. Oral or subcutaneous implant progestogens, barrier methods, spermicides and other non-hormonal local methods are accepted. The levonorgestrel intrauterine device is preferred, because it tends to reduce blood loss, and the copper device is discouraged because of the risk of bleeding; insertion of any intrauterine device is decided case by case with gynaecology and haemostasis, according to the history of bleeding [10]. The international sources consulted contain no ASMD-specific contraception recommendations.

7.11. Transition and Palliative Care

Most children with chronic visceral ASMD reach adulthood. The guideline recommends, with strong strength and grade A evidence, an early and gradual transition to adult services, with communication between teams and community services and assessment of barriers to independence [3]. At all stages, an updated advance care plan is recommended, with a designated point of contact and information flow between teams [3]. The French PNDS describes transition as an intentional, progressive and coordinated process, started at the beginning of adolescence and explained to the patient, parents and professionals, as it is a period of risk of deterioration in health and quality of life. The elements considered essential are explanatory documents, transfer of the record to the adult service or provision of a copy to the patient, designation of a transition coordinator, a prior visit to the adult service, identification of the care network and contacts in adult medicine, and one or more joint consultations of paediatricians and adult physicians, first in the paediatric unit and then in the adult unit. The timing of transfer depends on the patient's maturity, and the G2M filière provides transition guides and therapeutic education programmes [10]. In type A, invasive assessments are unnecessary unless they improve quality of life. Measuring head circumference is recommended, because a rapid increase suggests hydrocephalus. Palliative care should be early, with symptom control, respite for the carer and psychological and spiritual support [3, 43].

7.12. Developments in the Last 12 Months and Research

Between October 2025 and October 2026, new evidence consists mainly of follow-up publications and clinical series, without a new authorisation or label change identified in the official sources consulted [12, 16].

Research into neurological disease remains preclinical. In non-human primates and ASM-deficient mice, injection of AAV9 carrying human ASM into the cerebellomedullary cistern produced widespread expression in the brain and spinal cord without toxicity [100]. In mice, it prevented motor and memory deficits, sphingomyelin accumulation and neuronal death, and the authors propose clinical trials in type A [100]. An earlier study with AAV2 injected into the brainstem and thalami of primates showed motor deficits and inflammation at the high dose [101]. In the search performed on 10 October 2026, ClinicalTrials.gov had no registered gene therapy trial for ASMD. This negative search does not prove the absence of trials in other registries, which were not consulted [70]. Observational studies are ongoing or planned: the French national natural history cohort FASMD (NCT06985212; 200 patients, 2025–2035) and the safety study in young children (NCT06192576). A French study maintaining treatment for three trial patients until national reimbursement ended in 2025 (NCT06949358) [70].

7.13. Guideline Recommendations and Differences

The 2023 international consensus guideline, promoted by the International Niemann-Pick Disease Alliance (INPDA) with the International Niemann-Pick Disease Registry (INPDR), is the main reference [3]. It is based on a systematic review covering 20 years up to December 2021, AGREE II methodology, the GRADE system and a Delphi process with 24 experts, and contains 39 statements, without industry funding and with review planned every 3–5 years [3]. The 2019 monitoring recommendations (expert consensus supported by Sanofi Genzyme, written before olipudase alfa approval) and 2017 diagnostic recommendations complement it [8, 43]. The 2023 ACMG therapeutics bulletin provides the US perspective on olipudase alfa [79]. A 2023 Italian Delphi consensus on unmet needs and the patient pathway also exists, of which only the abstract was read [102].

Differences between sources are as follows. For the olipudase alfa indication, the FDA covers all subtypes and the EU only A/B and B [12, 16]. The guideline allows type A treatment where the indication permits, with counselling on futility, and the ACMG emphasises that benefit in type A is undocumented [3, 79]. In the diagnostic algorithm, the 2017 recommendation to start with enzyme testing coexists with the growing practice, described in GeneReviews, of starting with molecular testing, provided activity is subsequently confirmed [6, 8]. Ashkenazi carrier frequency is 1:80–1:100 in GeneReviews and 1:100–1:200 in the 2023 guideline [3, 6]. The guideline attributes respiratory mortality of 27.7% to type A, whereas the original source refers to chronic forms [3, 47]. Cardiac surveillance intervals also differ: echocardiography every 2–4 years in 2019 and GeneReviews, adult cardiac assessment every 3–5 years in the 2023 guideline. Section 11 addresses this difference [3, 6, 43].

The French PNDS (National Diagnosis and Care Protocol) of November 2024, developed by the CETLv at the request of the CRML according to the HAS and G2M filière method, is the most recent national guideline [10]. It agrees with the international sources on the doses and escalation of olipudase alfa, on the indication restricted to types B and A/B (as in the EU), on the requirement for enzymatic and molecular confirmation and on the rejection of splenectomy. The divergences are as follows [10].

The guidelines serve as the reference and the labels as comparison; in patients followed in France, the PNDS criteria and intervals apply.

8. Reproductive Options and Family Counselling

8.1. Inheritance and Recurrence Risks

All ASMD forms are autosomal recessive [6]. Parents of an affected individual are obligate heterozygotes, and parental molecular testing is recommended to confirm heterozygosity and permit reliable risk assessment [3, 6]. If the variant is found in only one parent, a de novo variant in the proband or uniparental isodisomy of chromosome 11 carrying the variant should be considered [6, 103].

8.2. Cascade Testing and Presymptomatic Diagnosis

Once familial variants have been identified, the guideline makes a strong recommendation, with level A evidence, to test all at-risk relatives for early diagnosis and treatment. Siblings should be tested at any age, by variant testing or ASM activity measurement [3, 6]. In a newborn sibling of an affected individual without prenatal diagnosis, testing is performed alongside newborn screening [6]. Presymptomatic patients are referred to specialist centres for surveillance [3]. Comparison of two siblings with the same genotype, treated at ages 3 and 7 years, showed that the younger maintained normal growth and had less persistent organomegaly. This supports early diagnosis in siblings, although it rests on only two patients [69].

8.3. Carriers and Carrier Screening

Carrier detection by enzyme activity is not reliable, because heterozygote values overlap with the normal range. Carrier testing is molecular and requires prior identification of the familial variants [6, 21]. Newborn screening also does not identify carriers, as shown by two carrier siblings with a negative result in Illinois [9]. In Ashkenazi Jews, carrier screening is based on the three type A variants, which account for about 90% of alleles in this population [6, 26, 28, 104]. The carrier frequency is 1:80–1:100 according to GeneReviews and 1:100–1:200 according to the 2023 guideline, and the difference results from the sources and periods used by each [3, 6]. Carrier screening and prenatal diagnosis programmes have reduced the birth incidence of type A in this population, so the current incidence underestimates the allele frequency [6, 7]. In Chile, the carrier frequency of p.(Ala359Asp) was 1:105.7 in 1691 healthy adults [36]. Some heterozygotes have low HDL, but carriers are clinically normal [3, 6]. The French PNDS (National Diagnosis and Care Protocol) recommends, after diagnosis, a genetics clinic appointment to screen siblings (25% risk) and allow early treatment, to discuss heterozygosity testing in ascendants, collateral relatives and adult descendants, and to test the partner, particularly in the case of consanguinity or common ethnic origin [10].

8.4. Prenatal Diagnosis and Preimplantation Genetic Testing

Prenatal diagnosis should be offered to all couples at risk, according to local protocols and laws (weak recommendation, grade B evidence) [3]. The French PNDS offers prenatal or preimplantation diagnosis to couples at risk of having a child with a severe form, mainly types A and A/B, by testing for the SMPD1 variants identified in the index case and the parents [10]. The most common method is molecular testing for the familial variants in chorionic villi or amniotic fluid. The biochemical alternative is measurement of ASM activity in villi or cultured amniocytes, which is useful when the variants are not known [3, 6, 43]. Preimplantation genetic testing is possible when both variants have been identified [6]. On fetal ultrasound, placental enlargement and hydrops may be signs of type A [21].

Risk and reproductive options should be discussed before pregnancy, and counselling offered to young adults who are affected, carriers or at risk of being carriers [3, 6]. For probands without molecular confirmation, DNA banking for future studies is recommended [6, 105].

8.5. Counselling After Diagnosis and Newborn Screening

Counselling should be provided by genetics professionals and explain inheritance, carrier status, implications for siblings and offspring, phenotypic variability and the limits of genotype-based prediction [3, 43]. In populations with common variants, genotype-phenotype correlations guide the parents of newly diagnosed patients. The presence of p.Arg610del, for example, predicts the absence of neurodegeneration, and the combination of two of the Ashkenazi type A variants predicts type A [6, 21]. Carriers of p.Gln294Lys, in one or two copies, should be monitored more frequently in childhood, because of the risk of late-onset neurological disease [43]. In France, the disclosure consultation informs about the type of ASMD, follow-up and therapeutic options, offers a genetics clinic appointment, where consent for genetic testing is obtained, and psychological and social support, and informs the attending physician, who is considered an essential partner [10].

After newborn screening, most genotypes are new and phenotype is often unpredictable during the first year, requiring close neurological surveillance during this period and generating parental anxiety [9, 44]. Families should be informed that some children may remain asymptomatic for years and that available ERT does not treat neurological disease [12, 44]. In asymptomatic minors, testing at-risk siblings is justified by the clinical benefit of early diagnosis and treatment [3, 6]. The sources consulted do not provide specific recommendations on carrier status testing in minors.

8.6. Women with ASMD Planning Pregnancy

Pregnancy is not contraindicated in women with ASMD but requires monitoring of bleeding, pulmonary function and oesophageal varices [14, 43]. Women receiving olipudase alfa should undergo pregnancy testing before initiation and use effective contraception during treatment and for up to 14 days after the last dose. Pregnancy planning includes the decision about continuing ERT, expressed differently in the US and European labels (subsection 7.10) [12, 16].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and What Each Figure Measures

ASMD frequency estimates measure different things and should not be directly compared.

Laboratory estimates underestimate true frequency because they depend on clinical diagnosis and referral. Attenuated type B forms may go unnoticed, and the number of living patients worldwide is roughly estimated at “several thousand” [3, 6]. Newborn screening data measure risk genotypes rather than clinical disease: in Illinois, incidence assumes all will become symptomatic, and in Taiwan, where no cases were detected among 59,123 newborns, the frequency of p.(Pro332Arg) in the Taiwan Biobank suggests underdiagnosis of the mild form [9, 42]. The proportion of subtypes depends on population. The Atlas stated that phenotype A accounted for approximately three-quarters of patients [21], but recent series show type B to be most frequent outside Ashkenazi populations: 94 of 118 patients in France and 12 of 19 in Argentina, while type A represents approximately 30% of cases according to the Brazilian series [11, 13, 58].

9.2. Geography, Ancestry and Founder Effects

United States. Type A is more frequent in Ashkenazi Jews, in whom type B is rare (5 of 394 patients in Simonaro's worldwide sample) [6, 21, 30]. p.Arg610del accounts for 20–30% of type B alleles [6]. In Illinois, genotypes detected by screening were almost all new [9]. In a retrospective US cohort of 110 patients cited in the Brazilian study, median age at onset was 3.9 years [11].

Europe. Type B appears more frequent in southern than in northern Europe [14]. In France, the cohort of 118 patients (1990–2020) showed a standardised mortality ratio of 3.5 in type B [13]. The French PNDS (National Diagnosis and Care Protocol), based on this cohort, attributes to type B about 80% of the diagnoses made in the country between 1990 and 2020, to type A 12% and to type A/B 8%, and estimates that 30% of diagnoses are made in adulthood; the proportion of type B among living patients is even higher, given its better prognosis. p.Arg610del is particularly frequent in France, Spain and above all North Africa [10]. The PNDS contrasts French type B mortality (10.6%, mainly in adults) with Anglo-Saxon series, with a bleaker prognosis, mortality of 19% below 21 years of age and a mean age at death of 25 years (deaths between 2 and 72 years). In these series, respiratory disease accounts for about 25% of deaths in the visceral form, 44% in patients diagnosed as adults, mainly from respiratory failure (82%), with associated infectious pneumonia in 30% and pulmonary embolism in 4%; liver disease accounts for another 25% [10]. p.Arg610del is frequent in Spain and France, rarer in Italy and Poland, and reaches 100% of alleles in Gran Canaria [3, 6]. In Italy p.Trp32Ter is common, with a non-neurological phenotype [3]. In Czechia and Slovakia, p.Gln294Lys determines a high proportion of intermediate phenotypes [3, 41]. In the Western Balkans and in the Sinti and Roma population, p.Trp393Gly accounts for 100% of alleles [3]. Patients of Scottish and English ancestry frequently have A196P (p.Ala198Pro), associated with mild disease [30]. In Germany, the median age at onset was 2.0 years in a series of 33 patients cited in the Brazilian study [11].

Portugal. The sources consulted include two Portuguese references. The first is Simonaro's worldwide sample (2002), in which type B occurred more frequently in Portuguese and Brazilian patients, with S379P, R441X, R474W and F480L accounting for approximately 55% of alleles [21, 30]. The second is the case published in 2026 of a man followed at the Inherited Metabolic Diseases Reference Centre of the Santo António Local Health Unit in Porto, homozygous for p.Arg610del and treated with olipudase alfa (section 10) [82]. The sources consulted do not include Portuguese prevalence estimates.

Brazil. A Brazilian reference laboratory recorded 0.33 diagnoses per 100,000 live births between 2000 and 2013 [11]. Giugliani's retrospective multicentre study (2026) included 124 patients diagnosed between 1986 and 2021, of whom 94 (75.8%) had type B and 30 (24.2%) type A/B, with 50.4% female [11]. Median age at diagnosis was 10.0 years (interquartile range 3.6–19.9). The highest absolute number of diagnoses was recorded in São Paulo (31), and the highest diagnosis rates in 2021 in Ceará (0.12/100,000) and the Federal District (0.13/100,000). These rates represent diagnoses recorded at a reference laboratory, not population prevalence [11].

In the subcohort of 24 patients with clinical records (21 with type B and 3 with A/B), median age at onset was 0.9 years and at diagnosis 6.7 years, with a delay of approximately 8 years, exceeding 11 years in 4 patients [11]. Hepatobiliary and splenic manifestations increased from 75.0% and 70.8% at presentation to 83.3% at last follow-up. At last follow-up, HDL was abnormal in 86.4% and the height Z-score in those younger than 18 years was −2.6. No patient underwent splenectomy. Two patients with type A/B (8.3%) died at a mean age of 2.7 years, one from respiratory disease, over a median follow-up of 11.3 years [11]. Study limitations include absent genotypes, the small sample and unavailable records for deceased patients [11]. No case was detected in newborn screening of 20,066 Brazilian newborns [44]. McGovern's prospective study included 13 Brazilian patients among the 59 [11, 55].

Other founder populations. Type B appears more frequent in North Africa, Turkey, the Arabian Peninsula and Chile than in northern Europe [14]. In the Maghreb, p.Arg610del accounts for about 90% of alleles and was found in about 90% of North African Arabs with splenomegaly [6, 21]. In Saudi Arabia, p.His423Tyr and p.Lys578Asn account for about 85% of alleles, and a series from King Faisal Hospital included 35 patients [21, 30]. In Turkey, L137P, fsP189 and L549P account for about 75% of alleles [30]. In Chile, p.(Ala359Asp) is of Amerindian origin, and all 13 homozygotes identified had moderate to severe type B [36]. In Iraq, a single-centre series of 47 patients had consanguinity in 98%, a family history in 66%, hepatosplenomegaly in 100%, anaemia in 79%, thrombocytopenia in 44% and dysmorphic features in 23% [37]. In Argentina, 19 patients from 7 centres had a mean onset at 3.9 years and diagnosis at 11.4 years, with hepatosplenomegaly in 100% and anaemia, pulmonary involvement and thrombocytopenia in 79% [58]. In Egypt, forms A and A/B presented earlier, with greater severity and mortality [59]. In Chinese patients, p.Arg3AlafsTer76 is frequent in type B, and p.Arg610del has not been described [3]; the French PNDS adds that p.(Arg602His) (NM_000543.5:c.1805G>A) accounts for 9.3% of alleles in China [10]. The Oxford Desk Reference reports a higher frequency in the Pakistani population, owing to consanguinity [63].

9.3. Special Populations

Young children are at greatest risk of olipudase alfa anaphylaxis and have the longest escalation regimen, and dosing errors at this age have been fatal [12, 16]. In newborns in intensive care, enzyme activity is influenced by gestational age, weight and haematocrit [68]. Treatment data in older people are scarce: the US label includes one adult aged 65–74 years and none aged 75 or older [16]. The Portuguese case shows pulmonary benefit at ages 67–68 years [82]. Pregnancy is addressed in subsection 7.10. In resource-limited settings, urinary sphingomyelin chromatography has been used for guidance, as in the Moroccan series [38].

9.4. Reference Networks and Patient Associations

In Europe, the relevant reference network is MetabERN (European Reference Network for Hereditary Metabolic Disorders) [17]. In Portugal, the published case was followed at a national inherited metabolic disease reference centre [82]. Patient organisations include the International Niemann-Pick Disease Alliance (INPDA), promoter of the 2023 guideline, the International Niemann-Pick Disease Registry (INPDR), a global registry, Niemann-Pick UK (NPUK), the National Niemann-Pick Disease Foundation (USA), Metabolic Support UK and the National Tay-Sachs and Allied Diseases Association [3, 6, 18–20]. Patient organisations propose emergency cards [43].

Organisation in France. The 2024 PNDS (National Diagnosis and Care Protocol) describes a structured national pathway [10]. Follow-up is multidisciplinary, coordinated by an ASMD specialist with the attending physician and with the CETLv, the reference centre for lysosomal diseases (CRML) or a reference or competence centre for inherited metabolic diseases. The CRML has a coordinating centre at Armand Trousseau Hospital in Paris, constituent centres (Necker-Enfants Malades, Beaujon, Croix Saint-Simon, Pitié-Salpêtrière, Rouen and Raymond Poincaré) and regional competence centres; the inherited metabolic disease network has its coordinating centre in Marseille and constituent and competence centres throughout the country. These centres belong to the G2M rare disease health filière, accredited in 2014 and renewed in 2019. Enzymatic, molecular and biomarker diagnosis is performed in reference medical biology laboratories (Toulouse, Rouen, Lyon, Grenoble, Necker and, for biomarkers, Pitié-Salpêtrière) [10].

ASMD is recognised as a long-term condition (ALD 17), with exemption from co-payment and 100% coverage of disease-related care, subject to a care protocol from the attending physician approved by the health insurance medical adviser; the patient still needs basic and complementary cover for expenses not included. Transport to a reference or competence centre more than 150 km away is reimbursed with prior approval, and the centre should be the one closest to home [10]. Parents may take parental presence leave, compensated by the allocation journalière de présence parentale (up to 310 days over a maximum period of 3 years, not exceeding 22 days per month), and carers the allocation journalière de proche aidant (up to 3 months, divisible and renewable up to 1 year). The Maison départementale des personnes handicapées (MDPH) awards the education allowance for a disabled child and the disabled adult allowance, the disability compensation benefit, the carte mobilité inclusion (from 80% disability) and recognition as a disabled worker, and guides schooling (personalised schooling plan, individualised reception plan, school support assistant, early medico-social action centres before 6 years, special education and home care services or medico-educational institutes) and working life (workstation adaptation, adapted companies, sheltered work establishments) [10].

The patient association Vaincre les Maladies Lysosomales (VML), recognised as being of public utility, has a group dedicated to Niemann-Pick disease and is a member of INPDA. The PNDS recommends informing patients about the association, offering therapeutic education programmes and asking for consent for the French ASMD registry (FASMD cohort, sponsored by Groupe Hospitalier Diaconesses Croix Saint-Simon, to describe natural history, quality of life and the effect of treatments) and for the Banque nationale de données maladies rares (BAMARA) [10].

10. Illustrative Clinical Case

10.1. Severe Interstitial Lung Disease in an Asplenic Patient with Late-Diagnosed ASMD Type B (Porto, Portugal)

In 2026, Guimas and Martins published the case of a man diagnosed with ASMD type B in 2009, at age 53 years [82]. Diagnosis followed spontaneous splenic rupture, described in the article as “spontaneous (traumatic)”, requiring emergency splenectomy. Suspicion arose from histological findings and was confirmed by acid sphingomyelinase activity of 0.0 nmol/h/mg protein (reference 0.840–3.36) [82]. Molecular testing identified SMPD1 homozygosity, described in the article as “c.1826GCC (p.Arg610del)”. In normalised HGVS notation on the MANE transcript, this corresponds to NM_000543.5:c.1829_1831del, NP_000534.3:p.(Arg610del), the historical variant ΔR608 [33, 34, 82]. The patient had been followed since 2015 at the National Inherited Metabolic Diseases Reference Centre of the Santo António Local Health Unit in Porto and was 68 years old in 2024 [82].

He had no neurological or psychiatric symptoms, and ophthalmological assessment was normal, consistent with the neuroprotective effect of p.Arg610del [6, 82]. He had no hepatomegaly (only mild steatosis), chronic liver disease or cytopenias. Dyslipidaemia was controlled with simvastatin 20 mg and fenofibrate 145 mg, echocardiography was normal without pulmonary hypertension, and bone density was normal [82]. The lungs were the most affected organ. The patient had severe interstitial lung disease, grade 2 dyspnoea on the modified Medical Research Council (mMRC) scale and chronic type 1 respiratory failure (arterial oxygen partial pressure to inspired oxygen fraction ratio, PaO2/FiO2, of 298 at rest). CT showed diffuse bilateral increased attenuation with basal predominance from non-specific ground-glass opacities, and smooth interlobular septal thickening more marked in the lower lobes, without fibrosis. Ventilation was preserved, but the DLCO/alveolar volume ratio was 57.9% predicted. On the 6-minute walk test, he covered 348 m (<70% predicted), with one stop and a recovery time of 100 seconds and minimum saturation of 84% [82].

Pulmonary rehabilitation, oxygen and bronchodilators brought partial improvement. The patient received olipudase alfa every 2 weeks through an early access programme from July 2023 to January 2024 (15 infusions, approximately 7 months). He resumed it in May 2024 following special authorisation and continued treatment [82]. In both courses, escalation was from 0.1 to 3 mg/kg, reaching the maximum dose at 14 weeks, as in the adult label regimen. Premedication consisted of paracetamol 1 g and desloratadine 5 mg, without adverse events [12, 82].

Source: table 1 of Guimas and Martins [82].

After 17 months of continuous treatment (35 infusions, 28 of them over 14 months at 3 mg/kg), the patient no longer had dyspnoea (mMRC 0) and discontinued daytime oxygen, without significant exertional desaturation. Nocturnal desaturation persisted (below 80% and above 75%), treated with nocturnal oxygen at 1–2 L/min [82]. Figure 1 of the article compares pulmonary CT before (left) and after olipudase alfa (right): https://pmc.ncbi.nlm.nih.gov/articles/PMC13393298/figure/f0005/. The authors describe CT disease as stable during ERT and consider the interstitial disease likely to have been aggravated by asplenia [82]. The work received funding and writing support from Sanofi, the marketing authorisation holder [82].

10.2. Lessons from the Case

The case brings together several points discussed in the preceding sections. Diagnosis was made only after a splenic complication at age 53 years, although ASMD type B can manifest from childhood [3, 82]. p.Arg610del homozygosity was associated with absence of neurodegeneration and relatively attenuated visceral disease outside the lungs [3, 6]. Asplenia, although not elective, was accompanied by severe pulmonary disease, consistent with guideline recommendations to avoid splenectomy and the association between splenectomy and mortality described by McGovern (2021) [3, 55]. Biomarkers and functional parameters improved even with late ERT initiation, although DLCO rose less than the ASCEND average and nocturnal desaturation persisted [61, 82]. The patient treated dyslipidaemia with a statin and fibrate, an option allowed by guidelines according to overall cardiovascular risk, with more frequent liver monitoring [3, 43]. An isolated case does not establish efficacy, and the observed benefit should be read alongside trial results (subsection 7.4).

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis Without Treatment

In type A, most untreated children die before age 3 years [6, 14]. In McGovern's series (2006), median time from diagnosis to death was 21 months, and 9 of the 10 infants died from respiratory failure [15]. In France, median survival from birth was 2.0 years (95% CI 1.8–2.7) [13]. The most common immediate cause of death is respiratory infection [6].

In type A/B, median age at death was 8 years in Cassiman's review and 8.5 years in France, where median survival from birth was 11.4 years (95% CI 5.5–18.5) [13, 47]. These figures come from series containing deceased patients, and GeneReviews notes that most survive into adulthood even without treatment [6]. Causes of death are neurodegenerative progression, respiratory disease and liver disease [47]. In Brazil, 2 of the 3 A/B patients in the subcohort died at a mean age of 2.7 years [11].

In type B, the most common phenotype is a moderately severe disease compatible with an essentially normal life expectancy [14]. Mortality is nevertheless increased. In France, the standardised mortality ratio was 3.5 (1.6–5.9) and the median age at death 57.6 years [13]. In the Cassiman review, the median age at death was 23.5 years, with respiratory and liver failure as the main causes (27.7% each) [47]. In the prospective study of McGovern (2021), 15% of patients died over 4.5–11 years, and severe splenomegaly or previous splenectomy was associated with an approximately 10-fold higher risk of death (OR 10.29; 95% CI 1.7–62.7) [55]. Liver failure is the second cause of death in type B [3]. A post hoc analysis suggested lower mortality with DLCO ≥60%, without statistical significance [94]. The markers of worse prognosis described are onset before 2 years of age, severe splenomegaly, splenectomy, liver fibrosis or cirrhosis and low DLCO. Genotypes with homozygous p.Arg610del, p.Leu139Pro, p.Ala198Pro or p.Arg476Trp are associated with milder disease [3, 6, 55]. The French PNDS (National Diagnosis and Care Protocol), citing the same McGovern cohort, specifies the thresholds: DLCO <50% of predicted and splenomegaly greater than 15 times normal, together with splenectomy, as predictors of mortality [10]. In France, type B mortality was 10.6%, with 80% of deaths in adults, half of them from cancer, and the causes of death in the A/B form were mostly unknown [10, 13].

11.2. Prognosis with Treatment

With olipudase alfa, adults and children with types B and A/B maintain reductions in spleen and liver volumes and improvements in DLCO, platelets and lipid profile for up to 5 years and more than 8 years, respectively. In children, height normalises (subsection 7.4) [60, 61]. Moderate or severe baseline splenomegaly may not normalise because of early irreversible fibrosis, supporting early treatment [60]. There are no data on the effects of ERT on survival, liver transplantation, cardiovascular events or fractures, or on reversal of pre-existing fibrosis or cirrhosis [6, 61]. Neurological disease in types A and A/B does not respond to ERT [6, 90].

11.3. Organisation of Follow-Up

Follow-up should be multidisciplinary and take place at an experienced centre (strong recommendation, grade A evidence) [3]. All patients should have a primary care physician, a metabolic disease specialist, a neurologist and a genetic counsellor. As needed, a hepatologist, haematologist, respiratory physician, lipidologist or cardiologist, psychiatrist or psychologist, speech and language therapist, occupational therapist, physiotherapist or physiatrist, dietitian, social worker and developmental paediatrician are added [3]. Newly diagnosed children without an established type need periodic detailed neurological examination, because the course defines the prognosis [3, 8]. The 2019 surveillance recommendations predate ERT but also apply to treated patients, to assess response and detect new manifestations [6]. The French PNDS (National Diagnosis and Care Protocol) adds to specialist follow-up the attending physician, who manages intercurrent problems in liaison with the specialist and, in patients on home infusion, carries out mainly clinical monitoring. In its summary, it proposes clinical examination and laboratory tests with biomarkers once or twice a year when targets are met, and imaging (MRI or hepatosplenic ultrasound) and respiratory tests with DLCO every 2–4 years.

11.4. Surveillance Table

The French PNDS (National Diagnosis and Care Protocol) organises follow-up into four time points: initial assessment, at 6 months (M6, relevant mainly after starting ERT), at 12 months (M12) and then at 24 months and annually. The following table summarises the schedule, to be adapted to each patient's condition; some investigations are specific to types A and A/B [10].

Source: table in chapter IX of the HAS PNDS [10]. Compared with the 2019 recommendations and GeneReviews, the PNDS adds protein electrophoresis, proteinuria, ferritin, quality of life and serology, considers elastography not validated and spaces out chest CT and densitometry (subsection 7.13). In pregnancy, respiratory surveillance becomes quarterly or more frequent (subsection 7.10) [10].

In type A, surveillance is simplified. Laboratory tests and abdominal imaging are performed only when they help decisions or improve quality of life, with priority given to nutrition, swallowing, comfort and palliative care [3, 43]. Liver biopsy, portal pressure measurement and coronary catheterisation are reserved for selected cases [43].

12. Summary and Final Considerations

Acid sphingomyelinase deficiency is an autosomal recessive lysosomal disease, caused by biallelic variants in SMPD1, that accumulates sphingomyelin mainly in macrophages of the liver, spleen, lung and bone marrow and, in the neuronopathic forms, in the brain [3, 6]. The former designations Niemann-Pick types A and B, and the intermediate A/B form, correspond to points on a continuum: the infantile neurovisceral form, with death usually before 3 years of age; the chronic neurovisceral form, with slowly progressive neurology; and the chronic visceral form, without neurodegeneration but with increased morbidity and mortality from lung and liver disease [3, 13, 47]. Niemann-Pick disease type C is a different entity.

Clinical suspicion arises in an infant with hepatosplenomegaly and regression from 6 months, or in a child or adult with splenomegaly, thrombocytopenia, interstitial lung disease and low HDL [3]. Diagnosis requires demonstration of deficient enzyme activity, ideally by tandem mass spectrometry and in parallel with glucocerebrosidase, and identification of biallelic SMPD1 variants, in a report specifying transcript NM_000543.5 and equivalence with historical nomenclature [3, 6, 8]. Plasma lysosphingomyelin is the most specific biomarker. Negative sequencing does not exclude disease when enzyme activity is deficient, and older fluorogenic assays fail with p.Gln294Lys [3]. Founder variants guide counselling: the three Ashkenazi variants predict type A, p.Arg610del protects the nervous system and p.Gln294Lys is associated with the intermediate phenotype [3, 6].

Olipudase alfa (Xenpozyme®), approved in 2022 in the EU and the USA, reduces organomegaly and improves DLCO, platelets, lipids and growth in types B and A/B. The effects are maintained for up to 5 years in adults and more than 8 years in children [12, 16, 60, 61]. Olipudase alfa does not treat neurological disease. The European indication excludes type A, unlike the US indication. Dose escalation is mandatory, and hypersensitivity reactions, anaphylaxis in young children and paediatric dosing errors require rigorous monitoring [12, 16]. Controlled evidence is limited to one trial of 36 adults with surrogate endpoints, and survival and quality-of-life data are lacking [61]. Total splenectomy should be avoided, and hepatic, pulmonary, cardiovascular, bone and neurological surveillance follows intervals defined by the 2019 and 2023 guidelines [3, 43]. Gene therapy for type A remains preclinical [70, 100]. In France, the 2024 PNDS (National Diagnosis and Care Protocol) adds explicit criteria for prioritising ERT by DLCO and platelets, validation at an RCP, its own follow-up schedule and recommendations for pregnancy, delivery and contraception [10]. Newborn screening, already in use in Illinois and studied in Italy, Taiwan and Japan, brings the diagnosis forward but confronts families with novel genotypes and uncertainty about the phenotype [9, 44].

13. References

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