Acid sphingomyelinase deficiency …

Marie T Vanier MD PhD

Neurogenetic Disorders

Updated 12.13.2024
Released 11.15.1997
Expires For CME 12.13.2027

Acid sphingomyelinase deficiency

Author: Marie T Vanier MD PhD

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Editor: Andrea Gropman MD

Acid sphingomyelinase deficiency

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Introduction

Overview

The term "acid sphingomyelinase deficiency” (ASMD) is now used to collectively designate the historical Niemann-Pick disease types A and B (as well as the intermediate type A/B). ASMD is a rare autosomal recessive lysosomal lipid storage disease due to biallelic pathogenic variants in the acid sphingomyelinase SMPD1 gene. This denomination clearly differentiates ASMD from Niemann-Pick disease type C, a distinct entity. In this article, the author includes updates on the natural history of the three clinical forms, methods for laboratory diagnosis, genotype/phenotype correlations, and progress in clinical management, including enzyme replacement therapy for noncentral nervous system manifestations.

Key points

	• Acid sphingomyelinase deficiency (ASMD) is a rare autosomal recessive lysosomal lipid storage disease corresponding to the historical Niemann-Pick disease types A, B, and A/B.
	• Infantile neurovisceral acid sphingomyelinase deficiency (classical type A) is a severe neurovisceral form associated with limited survival.
	• The more frequent chronic visceral form (type B) typically shows only visceral involvement (mainly spleen, liver, and lung) and may be diagnosed from infancy to late adulthood.
	• Chronic neurovisceral acid sphingomyelinase deficiency refers to rare intermediate forms with mild or late onset neurologic and neuropsychiatric involvement.
	• Two-year and longer-term results from clinical trials of enzyme replacement therapy by recombinant acid sphingomyelinase in adults and children with chronic ASMD have been published. Olipudase alfa is approved in the European Union, Japan, United States, and other countries for the treatment of noncentral nervous system manifestations in children and adults with ASMD.

Historical note and terminology

The eponym “Niemann-Pick disease” has historically been used to designate genetic disorders sharing the clinical and biochemical features of hepatosplenomegaly and varying degrees of sphingomyelin and cholesterol accumulation in tissues. This heterogeneous group is now divided into two distinct entities: ASMD and Niemann-Pick type C. Its recognition had its genesis in Albert Niemann's report of an 18-month-old girl who died of a neurodegenerative disorder accompanied by massive hepatosplenomegaly; pathological studies by Ludwig Pick followed (56; 62). In 1933, Klenk demonstrated that the predominant stored lipid in those patients was sphingomyelin. In 1946, Pfändler and Dusendschon described two adult brothers with similar pathologic findings, but distinct from Niemann’s patients by a later onset of disease symptoms and the lack of central nervous system (CNS) manifestations. In 1958, Crocker and Farber published a seminal paper on 18 cases of “Niemann-Pick disease,” showing that there was a wide variability in age of onset and clinical expression as well as in the level of sphingomyelin storage in tissues (09). This led Crocker to propose a classification of Niemann-Pick disease into four subgroups, A to D (08). Type A (corresponding to the original case of Albert Niemann) was characterized by severe, early CNS deterioration and massive visceral and cerebral sphingomyelin storage. Type B showed a chronic course with marked visceral involvement and massive sphingomyelin storage, but with a sparing of the nervous system. Types C and D were characterized by a subacute nervous system involvement with a moderate and slower course, as well as a milder visceral storage. In 1966, R Brady demonstrated a generalized deficiency in acid sphingomyelinase in tissues from patients with type A (03) soon extended to type B, but not to type C. A small number of patients intermediate between the A and B forms were then described (13; 59; 96; 54), indicating that the clinical spectrum of acid sphingomyelinase deficiency forms is a continuum, much like what is observed in Gaucher disease. In the 1980s, types C and D were defined as distinct entities characterized by alterations in cellular trafficking of endocytosed cholesterol (later shown to be due to pathogenic variants in NPC1 or NPC2 genes). The gene encoding acid sphingomyelinase, SMPD1, was identified in 1991 (78). Identification of the three pathogenic variants common in type A patients of Ashkenazi Jewish origin followed, allowing carrier genetic screening in this population.

The generic name "Niemann-Pick disease” is, thus, ambiguous, and the historical distinction of three types (A, B, C) further adds to the confusion. Therefore, the collective term “acid sphingomyelinase deficiency” (ASMD) was proposed to specifically designate primary sphingomyelinoses (ie, types A, B, and intermediate forms) (75), and it has gained general acceptance. In this nomenclature, the infantile neurovisceral form corresponds to the historical type A, the chronic neurovisceral form to type A/B (intermediate), and the chronic visceral form to the historical type B. The abbreviated ASMD types A, B, and AB are also used. Note that literature anterior to 2020 only uses the denomination Niemann-Pick disease, types A, B, and A/B (or intermediate) for ASMD, whereas searching “Niemann-Pick” as the keyword in PubMed will overlook important recent publications only indexed under “ASMD.”

Clinical manifestations

Presentation and course

	• All types of ASMD share involvement of the reticuloendothelial system.
	• They are distinguished by the presence (type A and intermediate) or absence (type B) of central nervous system involvement.
	• The finding of one copy of the SMPD1 p.Arg610del variant in a patient with proven acid sphingomyelinase deficiency is predictive of a chronic visceral form of the disease (type B).

Infantile neurovisceral ASMD (ASMD type A). Affected individuals show a clinical course quite similar to that described by Niemann (56), with some variations in the intensity of the visceral signs and in the age of onset of neurologic dysfunction. The natural history has been well described by McGovern and colleagues (44). The early neonatal period is often normal, with first symptoms of vomiting, diarrhea, or both, most commonly appearing in the first months of life. Failure to thrive often motivates a first consultation leading to the discovery of hepatosplenomegaly. Prominent and progressive hepatosplenomegaly and lymphadenopathy occur in most cases before 3 to 4 months of age. Growth delay is observed in 70% of cases. The facial appearance may be unremarkable or may show minor dysmorphy. A brownish pigmentation of the skin may be present. There is no clinical or x-ray evidence of bone abnormalities. Bone marrow contains foamy storage cells. Neurologic onset does not usually occur until 5 to 10 months of age. The first evidence of psychomotor regression may be overlooked due to the severity of visceral signs and poor general condition. The child generally shows hypotonia, progressive loss of acquired motor skills, loss of interest in the surroundings, and reduction in spontaneous movements. At examination, initial axial hypotonia is later combined with bilateral pyramidal signs. Slowed nerve conduction velocity is generally present. The cerebrospinal fluid is normal. Developmental age usually does not progress beyond 9 months for gross motor skills, and acquired skills are lost with progression. The disease progresses with a variable span of evolution towards spasticity and cerebral deterioration (and cachexia without proper nutrition and nursing care). Neurogenic impairment of swallowing is a common feature. Blindness is also frequent. Macular cherry-red spots are a typical feature but may not be present until an advanced stage of the neurologic disease. As the disease progresses, there is increasing tendency to rigidity. Seizures are uncommon but may occur in the later stages of the disease. Recurrent respiratory infections are a common complication. Death classically occurs between 1 and 3 years of age, most often from respiratory infection and failure (44; 79; 45). Cases with a slightly later onset of neurologic symptoms and slower course may occur, but this form is globally very homogenous.

Chronic visceral ASMD (ASMD type B). The prognosis of this form, which has a number of similarities with Gaucher disease type 1, completely differs from that of the infantile neurovisceral form. True type B patients do not have neurologic involvement, although ophthalmoscopic examination may reveal retinal macular halo or cherry red maculae (49), and some cases may display low deep tendon reflexes. The age of discovery is typically in late infancy or childhood but may occur from birth until late adulthood, with about 30% of the patients diagnosed in adulthood. In a large majority (close to 80%) of patients, the presenting sign is splenomegaly or hepatosplenomegaly (49; 45; 46). Splenomegaly is usually less pronounced than in Gaucher disease; thus, mechanical complications are less severe. Hypersplenism (or spleen rupture) may occur in a small proportion of patients, but splenectomy is seldom necessary (and should be avoided). Some adult patients may have a very mild splenomegaly. Bleeding episodes, which may result from thrombocytopenia due to splenic sequestration, most often involve recurrent epistaxis. In cases presenting in infancy or childhood, stunted body growth, particularly in regard to height, is a common finding between the ages of 6 and 16 years (105; 49). Skeletal age and puberty are often delayed. A later catch-up of growth usually takes place. Apart from liver or spleen enlargement, or both, radiographic abnormalities of the lung (diffuse, reticulonodular infiltrations) with a variable degree of interstitial lung disease are observed in a large majority of patients and are associated with a widely variable impairment of respiratory function (51; 83). Pulmonary involvement is common in affected individuals of all ages and can also be severe in children (51; 22; 93; 48). In adults, this may be the presenting sign (49; 39), usually leading to the discovery of a yet unnoticed enlarged spleen. The functional tolerance is often better than the radiologic findings would suggest, but a variable degree of decreased pulmonary diffusion due to alveolar infiltration is very common (51). In adult patients with a long follow-up, pulmonary involvement was in general the main source of symptoms, ranging from dyspnea on exertion (frequent) to oxygen dependency. In general, alterations of liver function are mild (45), but possibly underestimated (87); a few patients have been described in whom liver cirrhosis and intrahepatic block developed and led to fatal liver failure (34; 38). Hyperlipemia with low HDL-cholesterol, elevation of LDL-cholesterol, and of triglycerides is common, even in children (98; 49). Early coronary disease has been identified in some adults (47). Other features associated with the disease are joint/limb pain, bruising, headaches, abdominal pain, or diarrhea (49). A majority of patients have a decreased bone mineral density, and some have a history of spontaneous fractures (92; 49; 101). Studies of psychosocial aspects and impact of the disease show limited physical activity and negative impact on social function and relationships as important stressors (25; 63). Longitudinal studies indicate that a majority of patients survive into late adulthood (49; 48; 27; 39; 40; 15). Some patients, including children, however, may have a very severe systemic disease, eventually leading to premature death (34; 98; 59; 05). Causes of morbidity and mortality in type B patients mostly involve respiratory insufficiency and liver disease (47; 05). A histopathologic study of liver impact in 17 adult patients found a variable degree of fibrosis in nearly all patients. Two individuals progressed to cirrhosis despite a lack of clinical symptoms of liver failure; there was also a wide variability in the degree of sphingomyelin accumulation, which did not correlate with the grade of fibrosis (87).

Chronic neurovisceral ASMD (ASMD type AB). There is a continuum between types A and B. The small number of affected individuals classified as "intermediate" or "subacute" or “type A/B” constitute a particularly heterogeneous category, even with the same genotype. This includes phenotypes with a variable visceral involvement and a late infantile, juvenile, or even adult neurologic onset, with a generally slow progression (23; 59; 96; 54; 48). Most of these patients present a bilateral macular cherry red spot. Genotype/phenotype correlations have been described. Patients who carry two or even one SMPD1 p.Gln294Lys variant allele typically present a chronic neurovisceral form (23; 59; 96; 02). The neurologic findings can include cerebellar ataxia, extrapyramidal involvement, or psychiatric disorders. Another recurrent SMPD1 variant, p.Trp393Gly, is also frequently but inconsistently associated with a chronic neurovisceral form (54), which can also manifest as intellectual and learning disabilities without specific neurologic signs at examination. Finally, in the past, some patients have been included in this intermediate category even though they had a typical type B clinical course with only very minimal nervous system involvement: mild peripheral neuropathy or mild intellectual disability (98; 96; 27). A significant proportion of individuals with true chronic neurovisceral ASMD have an early death (47; 52; 66).

Prognosis and complications

Infantile neurovisceral ASMD (ASMD type A). The disease invariably leads to death, with a median age of around 1.5 years, and almost always before 3 to 4 years of age. Swallowing problems, cachexia, and recurrent pulmonary infections are the most common complications. Survival may be prolonged through improved nutritional status, control of fluid retention, supplemental oxygen or noninvasive positive pressure ventilation, and spasticity management. Early involvement of palliative care is recommended (97).

Chronic neurovisceral ASMD (ASMD type AB). Individuals with chronic neurovisceral forms show a wide range of variability regarding the age of onset and disease progression (59; 96; 54; 47). The systemic involvement is very variable, with eventual complications similar to those described below for type B. The global prognosis may be partly related to the severity of the systemic involvement and partly to that of the neurologic disease. Some patients die in childhood, and others survive until adulthood. The number of reported cases with an individual detailed longitudinal study is, thus far, limited. Survival studies indicate a poor prognosis (42; 52; 66).

Chronic visceral ASMD (ASMD type B). There is a wide range of severity within the manifestations of ASMD type B, from mild to severe (45; 48). The burden of illness can be substantial (07). Splenomegaly can be massive in some patients (particularly in young children) and lead to thrombocytopenia and leukocytopenia, hence, frequent bruising and nosebleeds. Spontaneous splenic rupture has been described in rare cases. Total splenectomy should be avoided. Some degree of liver disease is usually present, with mild elevation of transaminases (ALT, AST) and total bilirubin, and an evolution toward fibrosis is common. Some patients may progress to frank cirrhosis (with or without symptoms), and a few of them may progress to liver failure, both in childhood and in adulthood (34; 87; 47; 38; 19). Pulmonary involvement, mainly interstitial lung disease, is frequent and may be diagnosed in infancy to the late 40s; it may precede diagnosis or develop during follow-up. About half of the patients describe shortness of breath at diagnosis (49). Common respiratory symptoms are recurrent cough, dyspnea on exertion, and recurrent respiratory infections. However, a number of patients may become oxygen-dependent, and cases progressing to lung failure have been reported. In a retrospective study of 85 cases, liver and lung disease were equally reported as the most common primary causes of death (27.7%) in chronic ASMD (05). In an earlier survey of 103 patients (1 to 72 years), three died from liver failure, four from oxygen-dependent pulmonary disease, and three from valvular heart disease; four suffered from coronary artery disease (47). Among other complications, bone mineral density is commonly decreased, and most adults are osteopenic or osteoporotic at one or more sites (101). Spontaneous bone fractures have been reported (92). Of note, growth development is often impaired in children; height may be below the third percentile in children aged 6 to 12 years, and puberty is usually delayed (105). In a survey of adult patients, monoclonal gammopathy of undetermined significance was a frequent (5/28 cases) observation (39). Multiple myeloma has been described in one patient (65). The prevalence of cancer appeared to be strikingly elevated (16.1%) in a cohort of 31 patients, with a median age of 48.7 years (43). The latter aspects need further investigation. Finally, data in a large Ashkenazi Jewish population suggest that the p.Leu304Pro variant (carrier frequency of about 1 in 1000 in this population) appears as a risk factor (odds ratio: 9.4) for Parkinson disease (18). Thus far, in reference to the situation with the "N370S" variant in Gaucher disease, no such study has been conducted in populations in which p.Arg610del is the most frequent mutation.

The mortality rate of ASMD type B has been investigated in three countries: the United States, Germany, and France. The two existing studies from the U.S. report a very significant impact on lifespan (33% of deaths for type B in the more recent cohort) (47; 66). Of note, in both reports, few patients had been diagnosed in adulthood, and follow-up of patients was short. Interestingly, parallel studies in the German type B cohort reported a mortality rate of only 17% of deaths (52), and in the French cohort, an even lower (11%) mortality rate (42). Differences might be explained by the larger proportion of patients diagnosed in adulthood and late adulthood in the latter studies, and possibly by different genotype profiles. Several natural history studies have shown that patients homozygous for the p.Arg610del variant, particularly frequent in Belgium and the Netherlands, France, and Spain, had a relatively mild disease (98; 70; 27; 39; 48). Long-term follow-up of patients from the Netherlands appears to corroborate this statement (15). A relatively slow progression has also been reported in a Polish cohort with another (p.Gly166Arg) common SMPD1 variant (40). Thus, the global prognosis of ASMD type B appears to be very variable and can be fairly good in some cases.

Clinical vignette

Infantile neurovisceral ASMD (ASMD type A). A male, born following an uncomplicated pregnancy, was noted to have failure to thrive, frequent vomiting, and rapidly increasing hepatosplenomegaly from the third month of life. The diagnosis was established at 4 months of age by demonstration of deficient activity of acid sphingomyelinase in leukocytes. At 6 months of age, hypotonia and slow motor development were apparent. The neurologic evaluation at 8 months of age showed marked delay in development. The child did not sit independently, truncal control was poor, and the parachute response was absent. He did not reach for objects or show interest in people or toys. Diffuse hypotonia was present but with preserved muscular strength. Deep tendon reflexes were diminished or absent. Fundoscopic examination was normal. Nerve conduction velocities were low. At the age of 10 months, his weight was 5.5 kg (0.1 percentile), and he could not sit independently. At 19 months, cachexia (5.1 kg, 69 cm), loss of head control, and frank pyramidal bilateral signs with severe spasticity were observed. Swallowing problems began at the age of 23 months, ascites developed at 26 months, and death occurred at 27 months. The patient was homozygous for the p.Arg447Serfs*28 SMPD1 variant.

Chronic visceral ASMD (ASMD type B). At the age of 4 years, severe hepatomegaly and moderate splenomegaly were discovered in a male born after an uncomplicated pregnancy. Neurologic examination and psychomotor development were normal. Chest x-ray showed bilateral reticulonodular infiltrations. Serum cholesterol was elevated (200 mg/dL). Diagnosis was made at that time based on liver pathology. It was confirmed by enzyme assay at the age of 12 years, at which age clinical examination was unchanged, except for height and weight of 3.5 and 3.1 standard deviations below the mean, respectively. Pulmonary function was normal despite severe infiltration. Serum cholesterol had increased to 490 mg/dl. He had delayed puberty and a further decline in height growth between 14 to 16 years of age, with a slow catch up from the age of 16 years (adult height: 1.63 m). At the age of 18 years, pulmonary function showed restrictive syndrome with reduced diffusion and hypoxia on exertion. At the age of 48 years and without the development of more severe symptoms, he only complains of dyspnea on exertion. He has a college level of education and runs a small business. The patient is compound heterozygous for the p.Arg610del and p.Gly496Arg SMPD1 variants.

Chronic neurovisceral ASMD (ASMD type AB). An 8-month-old boy was referred because of hepatosplenomegaly discovered at the age of 4 months. He also had a mildly dysmorphic face. Ophthalmologic examination revealed bilateral macular cherry red spots. Deficient activity of acid sphingomyelinase in leukocytes and SMPD1 gene analysis [p.Cys228Arg/ c.1263+8C>T] established the diagnosis of ASMD. The child had anemia, mild thrombocytopenia, and hypertransaminemia. A delay in normal developmental motor milestones occurred from the age of 1 year. At the age of 3 years, he could only sit independently, spoke only a few words, and had a dorso-lumbar kyphosis. At 5 to 6 years old, he had several spontaneous fractures that needed orthopedic intervention. By then, he could sit and pulled to stand, and he had very poor language skills. At the age of 7.5 years, hepatosplenomegaly was severe, he was no longer able to speak, and he could only maintain a sitting position. DEXA performed after an accidental tibial fracture showed a very decreased bone mineral density. At 10.5 years, he developed progressive liver failure, and his neurologic condition also worsened. He died at 11.5 years of age.

Biological basis

Etiology and pathogenesis

	• Biallelic pathogenic SMPD1 variants are the underlying cause of ASMD (primary deficiency of the lysosomal acid sphingomyelinase [E.C. 3.1.4.12]).
	• This deficiency leads to the progressive accumulation of sphingomyelin and other lipids.
	• Correlations between certain SMPD1 variants and a neuronopathic or nonneuronopathic phenotype have been made.

Biochemistry and enzymatic findings. The primary deficiency in lysosomal acid sphingomyelinase resulting from pathogenic variants on the SMPD1 gene leads to the progressive accumulation of sphingomyelin in systemic organs for all types of the disease, and in the brain for neuronopathic forms. More specially, there is a massive (up to 50-fold) accumulation of sphingomyelin in organs of the reticuloendothelial system, including the liver and spleen, with a lesser and secondary increase of unesterified cholesterol and other phospholipids, including bis(monoacylglycero)phosphate, and of glycosphingolipids (89). Cerebral storage of sphingomyelin is only present in neurovisceral types. The brain tissue of type A patients also shows pronounced alterations of the ganglioside profiles, with accumulation of the minor GM2 and GM3 gangliosides (69).

Most studies have been conducted in a sphingomyelinase knock out (ASMKO) transgenic mouse model (36; 17). Neuronal death is a prominent feature of the disease, and a patterned death of Purkinje cells has been described (74). Calcium homeostasis was further shown to be altered, with reduced rates of calcium uptake via SERCA (21). Sphingomyelin-induced inhibition of plasma membrane calcium ATPase could be involved in neurodegeneration (60). Increased levels of a potentially apoptotic metabolite, the lysoderivative of sphingomyelin, sphingosylphosphorylcholine (06), have been reported in the brains of individuals with type A (but not B), as well as in that of ASMKO mice (69). Sphingosylphosphorylcholine (or lysosphingomyelin) is greatly elevated in the liver and spleen of both types (A and B), and a significant increase has been documented in plasma (33; 61; 64; 10; 04) or dried blood spots (32) of patients with all types of ASMD.

Although the degree of sphingomyelin accumulation is variable in different organs and between type A or B patients, acid sphingomyelinase activity measured in vitro is uniformly deficient in all tissues. In situ hydrolysis of labeled sphingomyelin by living cultured fibroblasts, however, demonstrates a significant level of residual activity in typical type B patients, suggesting that the mutated enzyme has retained sufficient catalytic activity to limit brain sphingomyelin accumulation (91; 59). Interestingly, besides its essential function within the lysosomes, a secreted form of acid sphingomyelinase has also been shown to exert an important and complex role at the cell surface, including reorganization of ceramide-rich microdomain structures and activation of apoptotic signaling (84; 76).

Genetics. The disease demonstrates an autosomal recessive pattern of inheritance. The SMPD1 acid sphingomyelinase gene (GenBank NC_000011.10) localizes to chromosome 11p15.1 to 11p15.4 and consists of six exons. Relatively small (approximately 6 kb), it encodes a polypeptide of 631 amino acids with a 48 amino acid signal peptide. The two in frame ATG initiation sites are functional in vivo. It is located within an imprinted region of the human genome and has been shown to be preferentially expressed from the maternal chromosome (paternal imprinting) (82). Currently, 415 variants have been described in HGMD Professional 2023.4, among which over 300 have been classified as disease-associated. Zampieri and colleagues have compiled a list of mutations as well as corresponding references (106); more information can also be found at HGMD Professional 2023.4, which can be accessed at the following site:https://digitalinsights.qiagen.com. In order to comply with the guidelines for mutation nomenclature from the Human Genome Variation Society (HGVS), mutations identified early and located downstream of nucleotide 142 (codon 48) currently appear with a codon number = p.(n+2) compared to the original description. This is due to the fact that two different cDNA reference sequences (GeneBank accession numbers NM_000543.4 and M81780.1) have been used, which differed in the length of a highly polymorphic hexanucleotide sequence, GCTGGC (p.L37_A38), located in exon 1 within the region encoding the signal peptide. The current nomenclature (RefSeq NM 000543.5) has been used in this article, with the “historical” one given in parentheses.

Collectively, three variants, p.Arg498Leu (R496L), p.Leu304Pro (L302P), and p.Pro333Serfs*52 (P330fs), account for more than 90% of alleles in Ashkenazi Jewish patients with classic type A. A number of other type A-related variants have been described. In type B patients, Arg610del (R608del) is globally the most common variant (37; 90; 81; 70; 27; 48). It has so far always been correlated with a type B phenotype, even in the heteroallelic status, indicating that one copy of this variant is always associated with a chronic visceral form of acid sphingomyelinase deficiency (similar to the situation with the p.Asn409Ser (N370S) GBA1 mutation in Gaucher disease). Highly prevalent (greater than 90% of alleles) in North African individuals with ASMD type B (90), it is also very frequent in Spain (61% of alleles) (70), France (55%, but only 34% excluding patients of North African extraction) (Vanier unpublished data; 39), the Netherlands (52%) (27), and the United States (20% to 30%) (103). It has generally been considered as a variant associated with a “mild” phenotype. Among other type B variants, p.Arg476Trp (R474W) and p.Leu139Pro (L137P) seem to be associated with a less severe form, but p.His144Tyr (H142Y) and p.Lys578Asn (K576N), frequent in Saudi Arabia, are associated with a severe form. The p.Ala359Asp variant, associated with a moderate to severe type B phenotype, is highly prevalent in Chile (01). In China, Arg602H is the common type B variant (28). The variant p.Gln294Lys (Q292K), initially described in patients from Central Europe, is clearly associated with late-onset neurologic involvement (59). The variant p.Trp393Gly (W391G), with a demonstrated Rumanian Gipsy origin, is relatively common in patients originating from the Western Balkanic region. The mutated p.Trp393Gly protein and resulting phenotypes have been well studied. A clinical variability was described within patients homozygous for this variant; a majority had systemic symptoms only, but some developed a late-onset neurologic disease (16; 54). In India, a large study revealed a significant prevalence of p.Arg742* (R740*) (68). The SMPD1 variant spectrum has also been reported in a cohort of 118 Chinese patients with acid sphingomyelinase deficiency, with a study of genotype correlations with a neuronopathic or a non-neuronopathic phenotype (28).

Differential diagnosis

Confusing conditions

Infantile neurovisceral ASMD (ASMD type A). Other conditions with hepatosplenomegaly and failure to thrive or psychomotor regression must be considered. Among the lysosomal diseases, differential diagnoses of Wolman disease (severe form of acid lipase deficiency), Gaucher disease type 2 (distinguished by the presence of hypotonia in ASMD type A and hypertonia in Gaucher), and the neonatal hepatic form of Niemann-Pick disease type C, but also non/little-dysmorphic forms of GM1 gangliosidosis, need to be considered. Cholestatic jaundice in early infancy is not uncommon in ASMD type A, but the onset is generally slightly later than in Niemann-Pick disease type C (95).

Chronic visceral ASMD (ASMD type B). Apart from more general or common causes of spleno- or hepatosplenomegaly, differential diagnoses include lysosomal diseases, primarily Gaucher disease type 1, Niemann-Pick disease type C (before the onset of neurologic symptoms), acid lipase deficiency (chronic form, cholesterol ester storage disease), and glycogen storage disorders. Regarding similarities and differences between ASMD and Gaucher disease, hepatosplenomegaly is a shared feature. Cytopenia, bone complications, and chitotriosidase activity are generally more prominent in Gaucher disease, whereas pulmonary manifestations and atherogenic lipid profile are more common in ASMD. It is now recommended to conjointly assay the activities of beta-glucocerebrosidase and acid sphingomyelinase in samples referred for suspicion of Gaucher disease (46; 19). This has indeed led to the observation of significant underdiagnosis of ASMD (57). The concomitant assay of lyso-Gb1, lyso-SM, and lysoSM-509/PPCS biomarkers in plasma or deep brain stimulation is also helpful in the differential diagnosis of Gaucher disease, ASMD, and Niemann-Pick disease type C. The finding of foamy macrophages or sea-blue histiocytes in bone marrow can also give an orientation towards ASMD or Niemann-Pick disease type C, but such cells are not specific nor always present.

Chronic neurovisceral ASMD (ASMD type AB). Some cases with the (rare) intermediate forms may be confused with Niemann-Pick type C or Gaucher type 3.

Diagnostic workup

	• Acid sphingomyelinase activity (leukocytes, dried blood spots)
	• SMPD1 gene sequencing
	• For screening/follow-up: lysosphingomyelin and lysosphingomyelin-509/PPCS biomarkers (plasma)

A detailed algorithm for the laboratory diagnosis of ASMD has been published (19). The diagnosis of ASMD is established by demonstration of deficient acid sphingomyelinase activity in leukocytes (or lymphocytes), dried blood spots samples, or in cultured skin fibroblasts (from which a much higher level of activity can be demonstrated) (46). The choice of a specific substrate is critical. Sphingomyelin radioactively labeled on the choline moiety (natural substrate) remains the gold standard, but its use has almost disappeared. Methods using a short-chain fatty acid sphingomyelin analogue and detection by tandem mass spectrometry (allowing enzyme determination on dried blood spots) have a good specificity and are currently recommended (46; 19). Multiplex enzyme assays kits using this principle for simultaneous diagnosis of six lysosomal storage diseases are commercialized and can also be used for neonatal screening (26). The synthetic fluorogenic substrate 6-hexadecanoylamino-4MU-phosphorylcholine has a low sensitivity and is less reliable. Although patients with type B often show some residual activity, the in vitro assay does not reliably distinguish neuronopathic from non-neuronopathic phenotypes. The loading test in living fibroblasts was more informative but is no longer offered by diagnostic laboratories.

SMPD1 molecular genetic testing is increasingly becoming the preferred first-line test, but the diagnosis of ASMD can only be established if biallelic pathogenic variants have been identified. In other cases (ie, variants of uncertain significance, allele segregation not established), the functional test, namely demonstration of a deficient activity of acid sphingomyelinase, is required to confirm the diagnosis. Identification of mutations is essential for genetic counseling and heterozygote detection in blood relatives. Genotyping may also help to predict a phenotype when the diagnosis is made in a young child (46). Of note, for SMPD1, it is particularly important that reports of genetic tests include the reference sequence number used (more information can be found in the “genetics” section).

Several plasma biomarkers show abnormalities. They can constitute a first orientation test before measuring enzyme activity. Plasma chitotriosidase activity is generally moderately elevated (difference with Gaucher disease), but this finding is unspecific. Sensitive and more specific plasma biomarkers have been discovered in recent years. Lysosphingomyelin (lyso-SM) and “lysosphingomyelin-509”(lysoSM-509), now identified as N-palmitoyl-O-phosphocholine-serine (PPCS), are significantly elevated in acid sphingomyelinase deficiency (20; 33; 61; 64; 10; 94; 40; 80; 32), as well as the oxysterols cholestane-3β,5α,6β-triol (C-triol) and 7-ketocholesterol (7-KC) (31; 71), and the bile acid N-(3β,5α,6β-trihydroxycholan-24-oyl)glycine (TCG) (29). It is, however, important to remember that lysoSM-509/PPCS, C-triol, 7-KC, and TCG are also elevated in Niemann-Pick C (NPC) and C-triol or 7-KC in acid lipase deficiencies and some nonlysosomal diseases. The plasma biomarker most specific for ASMD to date is lyso-SM (the deacetylated form of sphingomyelin, also named sphingosyl-phosphorylcholine). A marked elevation of lyso-SM only occurs in acid sphingomyelinase deficiency (but not in Niemann-Pick C). Plasma lyso-SM levels (and lysoSM-509 / PPCS) are useful in follow-up of enzyme replacement therapy (11; 103; 104). A pilot study suggests that in untreated individuals, plasma lyso-SM levels are positively associated with the degree of clinical severity in patients (04). Multiplex MS/MS assays have been developed, which allow simultaneous measurement of lyso-SM, PPCS, lyso-Gb1 (best biomarker for Gaucher disease), lyso-Gb3, and other lyso-glycosphingolipids. Such panels have proven useful in screening of sphingolipidoses and Niemann-Pick C. Striking elevation of lyso-Gb1 allows quick differential diagnosis of Gaucher disease, whereas a marked elevation of both lyso-SM and PPCS is the signature of acid sphingomyelinase deficiency, but not that of Niemann-Pick C.

Systematic testing for ASMD should be considered for patients suspected of having Gaucher disease and for whom this diagnosis was excluded (46; 19; 57).

Although not needed nor recommended for the diagnosis of acid sphingomyelinase deficiency, a bone marrow biopsy/aspirate may be performed, due to the suspicion of a malignancy in a patient with unexplained splenomegaly. Typically, bone marrow of acid sphingomyelinase deficiency patients displays foamy macrophages (“Niemann-Pick cells”) or sea-blue histiocytes, but similar storage cells can be observed in other diseases, such as Niemann-Pick C, acid lipase deficiency, GM1-gangliosidosis. Besides, less experienced examiners may not make a difference between Gaucher cells and Niemann-Pick cells.

Routine laboratory workup may reveal a thrombocytopenia, a leukopenia, slightly abnormal liver function tests with moderate bilirubin or transaminases elevation, and often, clear abnormalities of the fasting lipid profile (high total cholesterol values with particularly low HDL-cholesterol and hypertriglyceridemia) (98; 49).

Besides precise assessment of spleen and liver volume, complementary evaluation following initial diagnosis should include an ophthalmologic examination, a comprehensive neurologic evaluation, a chest radiograph, and, in patients old enough to perform the test, pulmonary function testing. There is not always a strong correlation between radiologic findings and the results of pulmonary function tests. For correct evaluation, both are necessary, together with the clinical status of the patient. The most common findings in patients with functional pulmonary disease are low forced vital capacity and, above all, low diffusing capacity of the lung for carbon monoxide (51; 45). Transient elastography (FibroScan) for the assessment of liver fibrosis may also be performed. Laboratory tests should include blood cell count, clotting tests, liver transaminases (AST, ALT), and lipid profile (100; 41; 19; 15). Depending on the clinical status and the examination of the skeleton, a DEXA scan could also be considered (101). If not already done, baseline measurements of the plasma biomarkers lyso-SM and PPCS/lyso-SM509 are recommended.

Management

	• To date, management of the infantile neurovisceral form and central nervous system manifestations in the chronic neurovisceral form of ASMD remain symptomatic.
	• Clinical trials of enzyme replacement therapy using olipudase alfa and long-term extension studies have resulted in significant improvements in patients with the chronic visceral form (99; 103; 104; 11; 12). Olipudase alfa has been approved for non-central nervous system manifestations of ASMD by regulatory agencies in the European Union, Japan, the United States, and other countries.
	• Consensus guidelines of recommended routine clinical assessments necessary for monitoring the multisystemic manifestations across the spectrum of acid sphingomyelinase deficiency phenotypes, which also includes options for treatment, interventions, and lifestyle changes, have been published (97; 19).
	• Information and support to families can be obtained through nonprofit organizations devoted to inherited metabolic diseases or lysosomal storage diseases. Organizations specific to “Niemann-Pick diseases” exist in many countries around the world. More information can be accessed at the following site:https://www.inpda.org.
	• Genetic counseling should be made available to family members and to adult patients.

Symptomatic management. Management of infantile neurovisceral patients (type A) includes maintenance of nutritional status, control of fluid retention, treatment of respiratory disease (supplemental oxygen or noninvasive positive pressure ventilation) and infections, appropriate treatment of feeding difficulties and swallowing problems (including nasogastric tube-feeding or gastrostomy), physiotherapy to prevent contractures, and spasticity management.

Follow-up of type B patients should in particular include regular monitoring for hypersplenism and pulmonary function (including measurement of diffusing capacity of the lung for carbon monoxide for old enough patients), as well as liver function and fasting lipid profile. Guidelines of recommended routine clinical assessments have been proposed for all types of acid sphingomyelinase deficiency (97; 19), or specifically for general care and monitoring of type B (14; 15; 41). Attempts have also been made to define criteria leading to a stratification of patients with type B by degree of disease severity (41).

Thrombocytopenia may lead to bleeding. Total splenectomy should be a very last resort, as it has been shown to exacerbate the interstitial pulmonary disease and the liver disease, likely through increased accumulation of sphingomyelin and ancillary lipids.

In some patients, liver enlargement may evolve towards fibrosis and cirrhosis, with a highly variable rate of progression. Chronic liver disease must, therefore, be closely monitored because (rare) cases of fulminant liver failure have been reported. Successful liver transplantation has been reported in a few patients with advanced chronic liver disease.

Some patients with symptomatic pulmonary disease (including some children) may require various levels of oxygen therapy. Pulmonary lavage has been proposed in patients with severe respiratory disease but is controversial (75). It may have a temporary effect, but inflammatory cells are likely to repopulate the airways. Three patients (one of whom had a previous liver transplant) received a lung transplantation, with limited follow-up in the two surviving patients. A favorable 2-year follow-up was reported for two additional patients. From available reports, lung transplant in ASMD appears to be a risky procedure. There is reasonable hope that the institution of enzyme replacement therapy at an early enough stage might halt the progression of the pulmonary disease.

Many type B patients have an atherogenic lipid profile, and adults can be treated with concomitant monitoring of their hepatic function.

Disease-specific therapy

Enzyme replacement therapy. Patients with chronic visceral acid sphingomyelinase deficiency (type B) were appropriate candidates for enzyme replacement therapy, and the proof-of-concept was obtained early in ASMKO mice. It, however, took more than a decade before a phase 1 monocentric clinical trial with single increasing doses of olipudase alfa was completed in 11 (adult) patients; highest doses were associated with an increase of C-reactive protein, bilirubin, and ceramide, indicating a need for initial "debulking" (50). A phase 1b (using a within-patient dose escalation) in five adult patients provided further safety and efficacy data, including reduction in liver and spleen volumes, improved lung-diffusing capacities, and improvement in dyslipidemia, with results up to 6.5 years of treatment (102; 99; 86; 35). Two separate multicentric clinical trials were further conducted for 1 year, a placebo-controlled trial in adults (ASCEND) and an open-labeled trial in pediatric patients (ASCEND-Peds), and both were followed by an open extension phase. A well-documented (ADIS Q&A) review summarizing the rationale of treatment, the trials and their results (efficacy and safety), and warnings and precautions has been published (85).

ASCEND trial. This phase 2/3 trial in adults (NCT02004691) was a randomized (1/1), double-blind, ascending dose, placebo-controlled study involving 36 patients with chronic ASMD. At the 52-week primary analysis period, the two independent primary efficacy endpoints, diffusing capacity of the lung for carbon monoxide (DLCO) and spleen volume, were met (40% difference between olipudase alfa versus placebo for spleen volume, 19% difference for predicted DLCO) (103). Treatment outcomes also favored olipudase alfa for liver volume and platelet levels. All treatment-related adverse events were mild to moderate in severity. In a long-term extension study (NCT02004704), improvements in the cross-over group after 1 year paralleled those in the treated group from the primary analysis, and improvement continued for those receiving olipudase alfa for 2 years (104).

ASCEND-Peds trial. This phase 1/2 open-label, ascending dose trial was conducted in 20 children with chronic ASMD over a 64-week study period (NCT02292654). One-year results showed comprehensive improvements across a range of clinically relevant endpoints, including a 49% reduction in spleen size and a 33% increase of diffusing capacity of the lung for carbon monoxide (DLCO); improvements were maintained or augmented in the second year of treatment (30; 11; 12).

Treatment with olipudase alfa has now been approved by regulatory agencies in Japan, the European Union, the United States, and other countries. A compassionate use program (NCT04877132) is ongoing in some countries (41).

Hematopoietic stem cell transplantation. Hematopoietic stem cell transplantation has shown no evidence of neurologic improvement in patients with infantile neurovisceral acid sphingomyelinase deficiency (type A) or severe chronic neurovisceral acid sphingomyelinase deficiency (55; 53). Although it significantly improved the lipid storage in one patient with chronic visceral acid sphingomyelinase deficiency (type B), hematopoietic stem cell transplantation remains a theoretical option in such patients due to the risks and the limitation of matched donors.

Experimental studies towards future therapeutic directions. An extensive number of studies towards neural progenitor injections and gene therapy have also been conducted in the ASMKO mouse (75; 77). AAV-mediated hepatic expression of acid sphingomyelinase had a profound effect on the reticuloendothelial system organs, but not on the brain. However, by intracerebral or, better, intracerebroventricular gene transfer, a remarkable improvement of the cerebral pathology and of the mouse lifespan was observed. A first safety study of AAV2-mediated human acid sphingomyelinase (hASM) in the nonhuman primate brain revealed an inflammatory reaction. Encouraging data have, however, been obtained by cerebellomedullary cistern injection of AAV9-rhASM (73). Experimental data have suggested that low levels of enzyme activity in the brain could have a major impact on the neurologic disease, provided the delivery occurred prior to onset of neurologic symptoms, which is a major limitation.

Outcomes

Published outcomes of treatment with olipudase alfa thus far are mostly those described in this article. The investigators have concluded that the treatment is well tolerated and reduces systemic manifestations of chronic ASMD with sustained efficacy (104). A review has summarized the tolerability, immunogenicity, warnings, and precautions of the treatment (85). A specific and important difference of this treatment compared to other enzyme replacement therapies is the requirement to strictly observe the initial dose escalation regimen (longer for children than for adults) before reaching the final 3.0 mg/kg treatment dose. Further, a strict adherence to the 2-week infusion scheme, also at the steady-state dose, must be followed to avoid a potential need for a new dose escalation.

The first study of patient-reported outcomes has been published (67). The results highlight the positive impact of olipudase alfa in many domains. For ASMD type AB, there was benefit in the management of systemic symptoms, despite the unmet need to treat the neurologic manifestations. Because a significant number of patients have benefited from a compassionate use/early access program (NCT04877132) in different countries prior to olipudase alfa approval, more real-life data should soon become available (58; 88).

References

01: Acuna M, Martinez P, Moraga C, et al. Epidemiological, clinical and biochemical characterization of the p.(Ala359Asp) SMPD1 variant causing Niemann-Pick disease type B. Eur J Hum Genet 2016;24(2):208-13. PMID 25920558
02: Blumlein U, Mengel E, Amraoui Y. Acid sphingomyelinase deficiency: the clinical spectrum of two patients who carry the Q294K mutation and diagnostic challenges. Mol Genet Metab Rep 2022;32100900. PMID 36046391
03: Brady RO, Kanfer JN, Mock MB, Fredrickson DS. The metabolism of sphingomyelin. II. Evidence of an enzymatic deficiency in Niemann-Pick disease. Proc Natl Acad Sci U S A 1966;55(2)366-9. PMID 5220952
04: Breilyn MS, Zhang W, Yu C, Wasserstein MP. Plasma lyso-sphingomyelin levels are positively associated with clinical severity in acid sphingomyelinase deficiency. Mol Genet Metab Rep 2021;28:100780. PMID 34285875
05: Cassiman D, Packman S, Bembi B, et al. Cause of death in patients with chronic visceral and chronic neurovisceral acid sphingomyelinase deficiency (Niemann-Pick disease type B and B variant): Literature review and report of new cases. Mol Genet Metab 2016;118(3):206-13. PMID 27198631
06: Chiulli N, Codazzi F, Di Cesare A, et al. Sphingosylphosphocholine effects on cultured astrocytes reveal mechanisms potentially involved in neurotoxicity in Niemann-Pick type A disease. Eur J Neurosci 2007;26:875-81. PMID 17666077
07: Cox GF, Clarke LA, Giugliani R, McGovern MM. Burden of illness in acid sphingomyelinase deficiency: a retrospective chart review of 100 patients. JIMD Rep 2018; 41:119-29. PMID 29995201
08: Crocker AC. The cerebral defect in Tay-Sachs disease and Niemann-Pick disease. J Neurochem 1961;7:68-80. PMID 13696518
09: Crocker AC, Farber S. Niemann-Pick disease: a review of eighteen patients. Medicine 1958;37:1-98. PMID 13516139
10: Deodato F, Boenzi S, Taurisano R, et al. The impact of biomarkers analysis in the diagnosis of Niemann-Pick C disease and acid sphingomyelinase deficiency. Clin Chim Acta 2018;486:387-94. PMID 30153451
11: Diaz GA, Jones SA, Scarpa M, et al. One-year results of a clinical trial of olipudase alfa enzyme replacement therapy in pediatric patients with acid sphingomyelinase deficiency. Genet Med 2021;23(8):1543-50.** PMID 33875845
12: Diaz GA, Giugliani R, Guffon N, et al. Long-term safety and clinical outcomes of olipudase alfa enzyme replacement therapy in pediatric patients with acid sphingomyelinase deficiency: two-year results. Orphanet J Rare Dis 2022;17(1)437.** PMID 36517856
13: Elleder M, Cihula J. Niemann-Pick disease (variation in the sphingomyelinase deficient group). Neurovisceral phenotype (A) with an abnormally protracted clinical course and variable expression of neurological symptomatology in three siblings. Eur J Pediatr 1983;140(4)323-8. PMID 6628453
14: Eskes ECB, Sjouke B, Vaz FM, et al. Biochemical and imaging parameters in acid sphingomyelinase deficiency: potential utility as biomarkers. Mol Genet Metab 2020;130(1)16-26. PMID 32088119
15: Eskes ECB, van Dussen L, Brands M, et al. Natural disease course of chronic visceral acid sphingomyelinase deficiency in adults: a first step toward treatment criteria. J Inherit Metab Dis 2025;48(1):e12789. PMID 39177062
16: Ferlinz K, Hurwitz R, Weiler M, Suzuki K, Sandhoff K, Vanier MT. Molecular analysis of the acid sphingomyelinase deficiency in a family with an intermediate form of Niemann-Pick disease. Amer J Hum Genet 1995;56:1343-9. PMID 7762557
17: Gabande-Rodriguez E, Boya P, Labrador V, Dotti CG, Ledesma MD. High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A. Cell Death Differ 2014;21(6):864-75. PMID 24488099
18: Gan-Or Z, Ozelius LJ, Bar-Shira A, et al. The p.L302P mutation in the lysosomal enzyme gene SMPD1 is a risk factor for Parkinson disease. Neurology 2013;80(17):1606-10. PMID 23535491
19: Geberhiwot T, Wasserstein M, Wanninayake S, et al. Consensus clinical management guidelines for acid sphingomyelinase deficiency (Niemann-Pick disease types A, B and A/B). Orphanet J Rare Dis 2023;18(1)85.** PMID 37069638
20: Giese AK, Mascher H, Grittner U, et al. A novel, highly sensitive and specific biomarker for Niemann-Pick type C1 disease. Orphanet J Rare Dis 2015;10:78. PMID 26082315
21: Ginzburg L, Futerman AH. Defective calcium homeostasis in the cerebellum in a mouse model of Niemann-Pick A disease. J Neurochem 2005;95:1619-28. PMID 16277603
22: Guillemot N, Troadec C, de Villemeur TB, Clément A, Fauroux B. Lung disease in Niemann-Pick disease. Pediatr Pulmonol 2007;42(12):1207-14. PMID 17969000
23: Harzer K, Rolfs A, Bauer P, et al. Niemann-Pick disease type A and B are clinically but also enzymatically heterogeneous: pitfall in the laboratory diagnosis of sphingomyelinase deficiency associated with the mutation Q292 K. Neuropediatrics 2003;34:301-6. PMID 14681755
24: Hellani A, Schuchman EH, Al Odaib A, et al. Preimplantation genetic diagnosis for Niemann-Pick disease type B. Prenat Diagn 2004;24:943-8. PMID 15612058
25: Henderson SL, Packman W, Packman S. Psychosocial aspects of patients with Niemann-Pick disease, type B. Am J Med Genet A 2009;149A(11):2430-6. PMID 19877061
26: Hickey RE, Baker J. Newborn screening for acid sphingomyelinase deficiency in Illinois: a single center's experience. J Inherit Metab Dis 2024;47(6):1363-70. PMID 38992987
27: Hollak CE, de Sonnaville ES, Cassiman D, et al. Acid sphingomyelinase (Asm) deficiency patients in The Netherlands and Belgium: disease spectrum and natural course in attenuated patients. Mol Genet Metab 2012;107(3):526-33. PMID 22818240
28: Hu J, Maegawa GHB, Zhan X, et al. Clinical, biochemical, and genotype-phenotype correlations of 118 patients with Niemann-Pick disease types A/B. Hum Mutat 2021;42(5)614-25. PMID 33675270
29: Jiang X, Sidhu R, Dietzen DJ, et al. Improved diagnostics for Niemann-Pick disease type C based on a novel bile acid biomarker. Mol Genet Metab 2016;117(2):S62.
30: Jones SA, McGovern M, Lidove O, et al. Clinical relevance of endpoints in clinical trials for acid sphingomyelinase deficiency enzyme replacement therapy. Mol Genet Metab 2020;131(1-2)116-23. PMID 32616389
31: Klinke G, Rohrbach M, Giugliani R, et al. LC-MS/MS based assay and reference intervals in children and adolescents for oxysterols elevated in Niemann-Pick diseases. Clin Biochem 2015;48(9):596-602. PMID 25819840
32: Kubaski F, Burlina A, Pereira D, et al. Quantification of lysosphingomyelin and lysosphingomyelin-509 for the screening of acid sphingomyelinase deficiency. Orphanet J Rare Dis 2022;17(1)407. PMID 36348386
33: Kuchar L, Sikora J, Gulinello ME, et al. Quantitation of plasmatic lysosphingomyelin and lysosphingomyelin-509 for differential screening of Niemann-Pick A/B and C diseases. Anal Biochem 2017;525:73-7. PMID 28259515
34: Labrune P, Bedossa P, Huguet P, Roset F, Vanier MT, Odievre M. Fatal liver failure in two children with Niemann-Pick disease type B. J Pediatr Gastroenterol Nutr 1991; 13:104-9. PMID 1919942
35: Lachmann RH, Diaz GA, Wasserstein MP, et al. Olipudase alfa enzyme replacement therapy for acid sphingomyelinase deficiency (ASMD): sustained improvements in clinical outcomes after 6.5 years of treatment in adults. Orphanet J Rare Dis 2023;18(1)94. PMID 37098529
36: Ledesma MD, Prinetti A, Sonnino S, Schuchman EH. Brain pathology in Niemann Pick disease type A: insights from the acid sphingomyelinase knockout mice. J Neurochem 2011;116(5):779-88. PMID 21214563
37: Levran O, Desnick RJ, Schuchman EH. Niemann-Pick type-B disease-identification of a single codon deletion in the acid sphingomyelinase gene and genotype/phenotype correlations in type-A and type-B patients. J Clin Invest 1991;88:806-10. PMID 1885770
38: Lidove O, Sedel F, Charlotte F, Froissart R, Vanier MT. Cirrhosis and liver failure: expanding phenotype of Acid sphingomyelinase-deficient niemann-pick disease in adulthood. JIMD Rep 2015;15:117-21. PMID 24718843
39: Lidove O, Belmatoug N, Froissart R, et al. [Acid sphingomyelinase deficiency (Niemann-Pick disease type B) in adulthood: A retrospective multicentric study of 28 adult cases]. Rev Med Interne 2017;38(5):291-9. PMID 27884455
40: Lipinski P, Kuchar L, Zakharova EY, Baydakova GV, Lugowska A, Tylki-Szymanska A. Chronic visceral acid sphingomyelinase deficiency (Niemann-Pick disease type B) in 16 Polish patients: long-term follow-up. Orphanet J Rare Dis 2019;14(1):55. PMID 30795770
41: Mauhin W, Borie R, Dalbies F, et al. Sharing experience of disease monitoring and severity in France. J Clin Med 2022;11(4):920. PMID 35207195
42: Mauhin W, Guffon N, Vanier MT, et al. Acid sphingomyelinase deficiency in France: a retrospective survival study. Orphanet J Rare Dis 2024;19(1):289. PMID 39103853
43: Mauhin W, Levade T, Vanier MT, Froissart R, Lidove O. Prevalence of cancer in acid sphingomyelinase deficiency. J Clin Med 2021;10(21):5029. PMID 34768550
44: McGovern MM, Aron A, Brodie SE, Desnick RJ, Wasserstein MP. Natural history of Type A Niemann-Pick disease: possible endpoints for therapeutic trials. Neurology 2006;66:228-32. PMID 16434659
45: McGovern MM, Avetisyan R, Sanson BJ, Lidove O. Disease manifestations and burden of illness in patients with acid sphingomyelinase deficiency (ASMD). Orphanet J Rare Dis 2017a;12(1):41.** PMID 28228103
46: McGovern MM, Dionisi-Vici C, Giugliani R, et al. Consensus recommendation for a diagnostic guideline for acid sphingomyelinase deficiency. Genet Med 2017b;19(9):967-74. PMID 28406489
47: McGovern MM, Lippa N, Bagiella E, Schuchman EH, Desnick RJ, Wasserstein MP. Morbidity and mortality in type B Niemann-Pick disease. Genet Med 2013;15(8):618-23. PMID 23412609
48: McGovern MM, Wasserstein MP, Bembi B, et al. Prospective study of the natural history of chronic acid sphingomyelinase deficiency in children and adults: eleven years of observation. Orphanet J Rare Dis 2021;16(1):212.** PMID 33971920
49: McGovern MM, Wasserstein MP, Giugliani R, et al. A prospective, cross-sectional survey study of the natural history of Niemann-Pick disease type B. Pediatrics 2008;122:e341-9.** PMID 18625664
50: McGovern MM, Wasserstein MP, Kirmse B, et al. Novel first-dose adverse drug reactions during a phase I trial of olipudase alfa (recombinant human acid sphingomyelinase in adults with Niemann-Pick disease type B (acid sphingomyelinase deficiency). Genet Med 2016;18(1):34-40. PMID 25834946
51: Mendelson DS, Wasserstein MP, Desnick RJ, et al. Type B Niemann-Pick disease: findings at chest radiography, thin-section CT, and pulmonary function testing. Radiology 2006;238:339-45.** PMID 16304086
52: Mengel E, Muschol N, Weinhold N, et al. A retrospective study of morbidity and mortality of chronic acid sphingomyelinase deficiency in Germany. Orphanet J Rare Dis 2024;19(1):161. PMID 38615062
53: Mercati O, Pichard S, Ouachee M, et al. Limited benefits of presymptomatic cord blood transplantation in neurovisceral acid sphingomyelinase deficiency (ASMD) intermediate type. Eur J Paediatr Neurol 2017;21(6):907-11. PMID 28801223
54: Mihaylova V, Hantke J, Sinigerska CM, et al. Highly variable neural involvement in sphingomyelinase-deficient Niemann-pick disease caused by an ancestral Gypsy mutation. Brain 2007;130:1050-61. PMID 17360762
55: Morel CF, Gassas A, Doyle J, Clarke JT. Unsuccessful treatment attempt: cord blood stem cell transplantation in a patient with Niemann-Pick disease type A. J Inherit Metab Dis 2007;30:987. PMID 17960492
56: Niemann A. Ein unbenkanntes Krankheitsbild. Jahrb Kinderheilkd 1914;79:1-10.
57: Oliva P, Schwarz M, Mechtler TP, et al. Importance to include differential diagnostics for acid sphingomyelinase deficiency (ASMD) in patients suspected to have to Gaucher disease. Mol Genet Metab 2023;139(1):107563. PMID 37086570
58: Pan YW, Tsai MC, Yang CY, et al. Enzyme replacement therapy for children with acid sphingomyelinase deficiency in the real world: a single center experience in Taiwan. Mol Genet Metab Rep 2023;34:100957. PMID 24034926
59: Pavlu-Pereira H, Asfaw B, Poupetova H, et al. Acid sphingomyelinase deficiency: phenotype variability with prevalence of intermediate phenotype in a series of twenty-five Czech and Slovak patients. A multi-approach study. J Inherit Metab Dis 2005;28:203-27. PMID 15877209
60: Perez-Canamas A, Benvegnu S, Rueda CB, Rabano A, Satrustegui J, Ledesma MD. Sphingomyelin-induced inhibition of the plasma membrane calcium ATPase causes neurodegeneration in type A Niemann-Pick disease. Mol Psychiatry 2017;22(5):711-23. PMID 27620840
61: Pettazzoni M, Froissart R, Pagan C, et al. LC-MS/MS multiplex analysis of lysosphingolipids in plasma and amniotic fluid: A novel tool for the screening of sphingolipidoses and Niemann-Pick type C disease. PLoS One 2017;12(7):e0181700. PMID 28749998
62: Pick L. Uber die lipoidzellige splenohepatomegalie typus Niemann-Pick als stoffwechselkrankungen. Med Klin 1927;23:1431-8.
63: Pokrzywinski R, Hareendran A, Nalysnyk L, et al. Impact and burden of acid sphingomyelinase deficiency from a patient and caregiver perspective. Sci Rep 2021;11(1):20972.** PMID 34697402
64: Polo G, Burlina AP, Kolamunnage TB, et al. Diagnosis of sphingolipidoses: a new simultaneous measurement of lysosphingolipids by LC-MS/MS. Clin Chem Lab Med 2017;55(3):403-14. PMID 27533120
65: Portier E, Talbot A, Nguyen Y, et al. Multiple myeloma occurring in a case of Niemann-Pick disease Type B: a pathophysiological link? Br J Haematol 2022;197(4)e53-5. PMID 35141883
66: Pulikottil-Jacob R, Dehipawala S, Smith B, et al. Survival of patients with chronic acid sphingomyelinase deficiency (ASMD) in the United States: a retrospective chart review study. Mol Genet Metab Rep 2024;38:101040. PMID 38188692
67: Raebel EM, Wiseman S, Donnelly C, et al. Real-life impacts of olipudase alfa: the experience of patients and families taking an enzyme replacement therapy for acid sphingomyelinase deficiency. Orphanet J Rare Dis 2024;19(1)36. PMID 38303068
68: Ranganath P, Matta D, Bhavani GS, et al. Spectrum of SMPD1 mutations in Asian-Indian patients with acid sphingomyelinase (ASM)-deficient Niemann-Pick disease. Am J Med Genet A 2016;170(10):2719-30. PMID 27338287
69: Rodriguez-Lafrasse C, Vanier MT. Sphingosylphosphorylcholine in Niemann-Pick disease brain: accumulation in type A but not in type B. Neurochem Res 1999;24:199-205. PMID 9972865
70: Rodriguez-Pascau L, Gort L, Schuchman EH, Vilageliu L, Grinberg D, Chabas A. Identification and characterization of SMPD1 mutations causing Niemann-Pick types A and B in Spanish patients. Hum Mutat 2009;30:1117-22. PMID 19405096
71: Romanello M, Zampieri S, Bortolotti N, et al. Comprehensive evaluation of plasma 7-ketocholesterol and cholestan-3β,5α,6β-triol in an Italian cohort of patients affected by Niemann-Pick disease due to NPC1 and SMPD1 mutations. Clin Chim Acta 2016;455:39-45. PMID 26790753
72: Sako S, Oishi K, Ida H, Imagawa E. Allele frequency of pathogenic variants causing acid sphingomyelinase deficiency and Gaucher disease in the general Japanese population. Hum Genome Var 2024;11(1):24. PMID 38866761
73: Samaranch L, Perez-Canamas A, Soto-Huelin B, et al. Adeno-associated viral vector serotype 9-based gene therapy for Niemann-Pick disease type A. Sci Transl Med 2019;11(506). PMID 31434754
74: Sarna J, Miranda SR, Schuchman EH, Hawkes R. Patterned cerebellar Purkinje cell death in a transgenic mouse model of Niemann Pick type A/B disease. Eur J Neurosci 2001;13:1873-80. PMID 11403680
75: Schuchman EH. The pathogenesis and treatment of acid sphingomyelinase-deficient Niemann-Pick disease. J Inherit Metab Dis 2007;30:654-63. PMID 17632693
76: Schuchman EH. Acid sphingomyelinase, cell membranes and human disease: lessons from Niemann-Pick disease. FEBS Lett 2010;584(9):1895-900. PMID 19944693
77: Schuchman EH, Desnick RJ. Types A and B Niemann-Pick disease. Mol Genet Metab 2017;120(1-2):27-33.** PMID 28164782
78: Schuchman EH, Suchi M, Takahashi T, Sandhoff K, Desnick RJ. Human acid sphingomyelinase. Isolation, nucleotide sequence and expression of the full-length and alternatively spliced cDNAs. J Biol Chem 1991;266(13):8531-9. PMID 1840600
79: Schuchman EH, Wasserstein MP. Types A and B Niemann-Pick disease. Best Pract Res Clin Endocrinol Metab 2015;29(2):237-47.** PMID 25987176
80: Sidhu R, Mondjinou Y, Qian M, et al. N-acyl-O-phosphocholineserines: structures of a novel class of lipids that are biomarkers for Niemann-Pick C1 disease. J Lipid Res 2019;60(8):1410-24. PMID 31201291
81: Simonaro CM, Desnick RJ, McGovern MM, Wasserstein MP, Schuchman EH. The demographics and distribution of type B Niemann-Pick disease: novel mutations lead to new genotype/phenotype correlations. Am J Hum Genet 2002;71:1413-9. PMID 12369017
82: Simonaro CM, Park JH, Eliyahu E, Shtraizent N, McGovern MM, Schuchman EH. Imprinting at the SMPD1 locus: implications for acid sphingomyelinase-deficient Niemann-Pick disease. Am J Hum Genet 2006;78:865-70. PMID 16642440
83: Simpson WL Jr, Mendelson D, Wasserstein MP, McGovern MM. Imaging manifestations of Niemann-Pick disease type B. AJR Am J Roentgen 2010;194(1):W12-9. PMID 20028884
84: Smith EL, Schuchman EH. The unexpected role of acid sphingomyelinase in cell death and the pathophysiology of common diseases. FASEB J 2008;22:3419-31. PMID 18567738
85: Syed YY. Olipudase alfa in non-CNS manifestations of acid sphingomyelinase deficiency: a profile of its use. Clin Drug Invest 2023;43(5):369-77.** PMID 37133675
86: Thurberg BL, Diaz GA, Lachmann RH, et al. Long-term efficacy of olipudase alfa in adults with acid sphingomyelinase deficiency (ASMD): Further clearance of hepatic sphingomyelin is associated with additional improvements in pro- and anti-atherogenic lipid profiles after 42 months of treatment. Mol Genet Metab 2020;131(1-2):245-52. PMID 32620536
87: Thurberg BL, Wasserstein MP, Schiano T, et al. Liver and skin histopathology in adults with acid sphingomyelinase deficiency (Niemann-Pick disease type B). Am J Surg Pathol 2012;36(8):1234-46. PMID 22613999
88: Van Baelen A, Verhulst S, Eyskens F. Unexplained splenomegaly as a diagnostic marker for a rare but severe disease with an innovative and highly effective new treatment option: a case report. Mol Genet Metab Rep 2024;41:101144. PMID 39391364
89: Vanier MT. Biochemical studies in Niemann-Pick disease. I. Major sphingolipids of liver and spleen. Biochim Biophys Acta 1983;750:178-84. PMID 6824712
90: Vanier MT, Ferlinz K, Rousson R, et al. Deletion of arginine (608) in acid sphingomyelinase is the prevalent mutation among Niemann-Pick disease type B patients from northern Africa. Hum Genet 1993;92:325-30. PMID 8225311
91: Vanier MT, Rousson R, Garcia I, et al. Biochemical studies in Niemann-Pick disease III. In vitro and in vivo assays of sphingomyelin degradation in cultured skin fibroblasts and amniotic fluid cells for the diagnosis of the various forms of the disease. Clin Genet 1985;27:20-32. PMID 3978837
92: Volders P, Van Hove J, Lories RJ, et al. Niemann-Pick disease type B: an unusual clinical presentation with multiple vertebral fractures. Am J Med Genet 2002;109:42-51. PMID 11932991
93: von Ranke FM, Pereira Freitas HM, Mancano AD, et al. Pulmonary involvement in Niemann-Pick disease: a state-of-the-art review. Lung 2016;194(4):511-8. PMID 27164983
94: Voorink-Moret M, Goorden SMI, van Kuilenburg ABP, et al. Rapid screening for lipid storage disorders using biochemical markers. Expert center data and review of the literature. Mol Genet Metab 2018;123(2):76-84. PMID 29290526
95: Wang NL, Lin J, Chen L, et al. Neonatal cholestasis is an early liver manifestation of children with acid sphingomyelinase deficiency. BMC Gastroenterol 2022;22(1):227. PMID 35534800
96: Wasserstein MP, Aron A, Brodie SE, Simonaro C, Desnick RJ, McGovern MM. Acid sphingomyelinase deficiency: prevalence and characterization of an intermediate phenotype of Niemann-Pick disease. J Pediatr 2006;149:554-9. PMID 17011332
97: Wasserstein MP, Caggana M, Bailey SM, et al. The New York pilot newborn screening program for lysosomal storage diseases: report of the first 65,000 infants. Genet Med 2019a;21(3):631-40. PMID 30093709
98: Wasserstein MP, Desnick RJ, Schuchman EH, et al. The natural history of type B Niemann-Pick disease: results from a 10-year longitudinal study. Pediatrics 2004;114:e672-7.** PMID 15545621
99: Wasserstein MP, Diaz GA, Lachmann RH, et al. Olipudase alfa for treatment of acid sphingomyelinase deficiency (ASMD): safety and efficacy in adults treated for 30 months. J Inherit Metab Dis 2018;41(5):829-38.** PMID 29305734
100: Wasserstein M, Dionisi-Vici C, Giugliani R, et al. Recommendations for clinical monitoring of patients with acid sphingomyelinase deficiency (ASMD). Mol Genet Metab 2019b;126(2)98-105.** PMID 30514648
101: Wasserstein MP, Godbold J, McGovern MM. Skeletal manifestations in pediatric and adult patients with Niemann Pick disease type B. J Inherit Metab Dis 2013;36(1):123-7. PMID 22718274
102: Wasserstein MP, Jones SA, Soran H, et al. Successful within-patient dose escalation of olipudase alfa in acid sphingomyelinase deficiency. Mol Genet Metab 2015;116(1-2):88-97.** PMID 26049896
103: Wasserstein M, Lachmann R, Hollak C, et al. A randomized, placebo-controlled clinical trial evaluating olipudase alfa enzyme replacement therapy for chronic acid sphingomyelinase deficiency (ASMD) in adults: one-year results. Genet Med 2022;24(7):1425-36.** PMID 35471153
104: Wasserstein MP, Lachmann R, Hollak C, et al. Continued improvement in disease manifestations of acid sphingomyelinase deficiency for adults with up to 2 years of olipudase alfa treatment: open-label extension of the ASCEND trial. Orphanet J Rare Dis 2023;18(1):378. PMID 38042851
105: Wasserstein MP, Larkin AE, Glass RB, Schuchman EH, Desnick RJ, McGovern MM. Growth restriction in children with type B Niemann-Pick disease. J Pediatr 2003;142:424-8. PMID 12712061
106: Zampieri S, Filocamo M, Pianta A, et al. SMPD1 mutation update: database and comprehensive analysis of published and novel variants. Hum Mutat 2016;37(2):139-47. PMID 26499107

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Marie T Vanier MD PhD

Dr. Vanier, at Institut National de la Santé et de la Recherche Médicale received honorariums from Orchard Therapeutics and Sanofi Genzyme as a member of scientific advisory boards and consulting fees from Orchard Therapeutics.
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Editor

Andrea Gropman MD

Dr. Gropman of St. Jude Children's Research Hospital has no relevant financial relationships to disclose.
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Former Authors

Raphael Schiffmann MD
Erika Fullwood Augustine MD MS

Patient Profile

Age range of presentation: 0 month to >60 years
Sex preponderance: female=male
Heredity: heredity typical

heredity may be a factor

autosomal recessive
Population groups selectively affected: Ashkenazi Jews (type A)

Northern Africans (type B)
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: Niemann-Pick disease: E75.2
ICD-11: Other specified sphingolipidosis: 5C56.0Y
OMIM: Niemann-Pick disease, Type A: #257200

Niemann-Pick disease, Type B: #607616

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Acid sphingomyelinase deficiency

Differential Diagnosis

hepatosplenomegaly
failure to thrive
psychomotor regression
Wolman disease
Gaucher disease
- hepatic form of Niemann-Pick disease type C
- isolated splenomegaly
- cholesterol ester storage disease (acid lipase deficiency)

Acid sphingomyelinase deficiency …

Acid sphingomyelinase deficiency

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Disease-specific therapy

Outcomes

Special considerations

Pregnancy

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Leigh syndrome

Aminoacylase 1 deficiency

HMG-CoA lyase deficiency

Glutaric aciduria

Developmental delay in children: evaluation and management

GABA-transaminase deficiency

Porphyria

Carnitine palmitoyltransferase II deficiency

	• Acid sphingomyelinase deficiencies are inherited following an autosomal recessive mode. Appropriate genetic counseling should be provided to parents or patients and their relatives.
	• Prenatal diagnosis is possible by SMPD1 gene analysis (currently the preferred approach) provided that the variant alleles have been identified in the index case, and segregation is confirmed by a parental study or by measurement of acid sphingomyelinase activity. Both DNA and enzyme testing can be done on uncultured chorionic villus sampling, allowing a result at the 11th to 13th week of pregnancy, or performed on cultured chorionic villus or amniotic cells, with a result significantly later in pregnancy. For ASMD, one report of preimplantation diagnosis has been published. Heterozygote detection must be done by genetic testing, as enzymatic methods do not clearly discriminate carriers from healthy homozygotes.
	• In the Ashkenazi population, preventive carrier screening and prenatal diagnosis have resulted in a low birth incidence of individuals with acid sphingomyelinase deficiency.

Acid sphingomyelinase deficiency

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Disease-specific therapy

Outcomes

Special considerations

Pregnancy

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Leigh syndrome

Aminoacylase 1 deficiency

HMG-CoA lyase deficiency

Glutaric aciduria

Developmental delay in children: evaluation and management

GABA-transaminase deficiency

Porphyria

Carnitine palmitoyltransferase II deficiency

This is an article preview.
Start a Free Account
to access the full version.