Acid sphingomyelinase deficiency

INTRODUCTION — 

Acid sphingomyelinase deficiency (ASMD) and Niemann-Pick disease type C (NPC) are autosomal recessive disorders associated with splenomegaly, variable neurologic deficits, and the storage of lipids including sphingomyelin and cholesterol.

This topic will review the classification, clinical manifestations, diagnosis, and treatment of ASMD. NPC and other lysosomal diseases are discussed separately:

●(See "Niemann-Pick type C disease".)

●(See "Fabry disease: Neurologic manifestations".)

●(See "Gaucher disease: Pathogenesis, clinical manifestations, and diagnosis".)

●(See "Krabbe disease".)

●(See "Metachromatic leukodystrophy".)

●(See "Mucopolysaccharidoses: Clinical features and diagnosis".)

CLASSIFICATION AND TERMINOLOGY — 

Historically, ASMD was classified as a form of Niemann-Pick disease, which encompassed a group of autosomal recessive disorders associated with splenomegaly, variable neurologic deficits, and the storage of lipids including sphingomyelin and cholesterol.

Niemann-Pick disease is now recognized to be two separate disorders (table 1):

●ASMD types A and B, previously known as Niemann-Pick disease types A and B [1-3].

•ASMD-A is the more severe type, and is also classified as the infantile neurovisceral type.

•ASMD-B is the less severe type, and is also classified as the chronic visceral type.

•ASMD-A/B is recognized by some experts as an intermediate phenotype, also classified as the chronic neurovisceral type [2,4,5].

●Niemann-Pick type C disease (NPC), which is caused by pathogenic variants of the NPC1 and NPC2 genes that result in impaired cellular processing and transport of low-density lipoprotein (LDL) cholesterol and other macromolecules, including glycosphingolipids. (See "Niemann-Pick type C disease", section on 'Clinical features'.)

PATHOGENESIS — 

ASMD-A and ASMD-B are allelic disorders caused by pathogenic variants in the sphingomyelin phosphodiesterase-1 (SMPD1) gene on chromosome 11p15 that encodes the enzyme acid sphingomyelinase. These disorders are characterized by a primary deficiency of acid sphingomyelinase activity [1].

Normally, acid sphingomyelinase catalyzes the hydrolysis of sphingomyelin to ceramide and phosphorylcholine [6]. When levels of acid sphingomyelinase are low or absent, the result is abnormal accumulation of sphingomyelin and lipids in multiple cell types, including macrophages and tissue-specific cells such as hepatocytes [7-11]. Large lipid-laden foam cells are seen in the reticuloendothelial system of the liver, lungs, spleen, bone marrow, lymph nodes, blood vessels, peripheral nerve Schwann cells, central nervous system, and retinal cells, and less commonly in mucosal and submucosal cells in the gastrointestinal tract [10,12,13]. Affected cells become dysfunctional and die, leading to the variable clinical symptoms and signs [11]. Electron microscopy reveals lysosomal and myelin inclusions in peripheral nerves, indicating a severe myelinopathy [14].

ASMD-A, the more severe type, is caused by pathogenic variants in the SMPD1 gene that result in complete absence of residual acid sphingomyelinase activity and subsequent lysosomal accumulation of sphingomyelin [7-9].

ASMD-A/B and ASMD-B, the less severe types, are associated with pathogenic variants of the SMPD1 gene that result in some residual activity of the acid sphingomyelinase enzyme [8,9,15]. In two studies, for example, acid sphingomyelinase activity in patients with ASMD-B was 4 percent of normal compared with undetectable activity in patients with ASMD-A [8,15].

EPIDEMIOLOGY — 

The incidence of ASMD-A is highest among Ashkenazi Jews, in whom the frequency of pathogenic variants is estimated to be between 1:80 and 1:100 [1]. The overall birth prevalence of ASMD (types A and B combined) is estimated to be 0.65:100,000, based on European data [16]. ASMD is pan-ethnic; pathogenic variants have been reported in patients from North Africa and the Middle East, Europe, North and South America, and Asia [17].

CLINICAL FEATURES

Disease spectrum — ASMD encompasses a continuum of disease phenotypes that ranges from the most severe, early-onset form (ASMD-A) through an intermediate phenotype (ASMD-A/B) to the least severe, later-onset form (ASMD-B) [1,2,4,5].

ASMD type A — Acid sphingomyelinase deficiency type A (ASMD-A) is the rapidly progressive acute neuronopathic form, also referred to as the neurovisceral infantile type.

●Manifestations – Affected patients present with hepatosplenomegaly, feeding difficulties, and loss of early motor skills in the first few months of life.

A peripheral neuropathy is manifest as hypotonia and absent reflexes [14,18].

Storage of sphingomyelin in pulmonary macrophages leads to interstitial lung disease, frequent respiratory infections, and often to respiratory failure [1].

Macular cherry-red spots (seen on funduscopic examination) are eventually present in all affected individuals (picture 1), although they may not be observed early in the course of the disease.

●Natural history – In a natural history study of 10 infants with ASMD-A, all had a normal neonatal course and early development [19]. The first detected sign of the disease was organomegaly, noted at a median of three months (range two to four). The median age at diagnosis was six months. A cherry-red spot was evident in all infants by 12 months of age but was absent in several on initial examination. No infant progressed beyond the gross motor milestone of sitting with support; none ever crawled on all fours or walked. Social smile was retained well into the disease course and was lost at a median age of 19 months.

Rapid, progressive, and profound loss of neurologic function leading to death occurs by two to three years of age. (See 'Prognosis' below.)

●Neuroimaging – In one series, all 10 infants with ASMD-A had brain ultrasound, which showed hydrocephalus in two [19]. Three infants had brain magnetic resonance imaging (MRI), which showed delayed myelination in all three.

●Laboratory – The laboratory findings in ASMD may include lipid abnormalities such as decreased high-density lipoprotein (HDL) cholesterol, hypertriglyceridemia, and increased low-density lipoprotein (LDL) cholesterol [20]. In one series, all 10 infants had low fasting HDL cholesterol values (mean 11.2 mg/dL [0.29 mmol/L]) from the earliest age at which they were obtained [19].

ASMD type B — Acid sphingomyelinase deficiency type B (ASMD-B) is later in onset and less severe than ASMD-A.

●Manifestations – ASMD-B is characterized by marked phenotypic variability. Hepatosplenomegaly develops during infancy or childhood. Most affected patients have thrombocytopenia secondary to hypersplenism. Liver involvement can be severe, with infiltration of foamy histiocytes, ballooning of hepatocytes, and fibrosis [21]. Other systemic manifestations include short stature with delayed skeletal maturation, interstitial lung disease, hyperlipidemia, and ocular abnormalities (macular halos and cherry-red maculae (picture 1)) [22-24].

Most patients with ASMD-B have no neurologic abnormalities. However, in those who survive early childhood, a minority of patients develop prolonged nerve conduction velocities, peripheral neuropathy, and varying degrees of central nervous system involvement, including cerebellar signs, nystagmus, extrapyramidal involvement, intellectual disability, and psychiatric disorders [1,4,25-28]. These patients with neurologic involvement are classified as ASMD-A/B by some experts. (See 'ASMD type A/B' below.)

In one series of 64 patients with ASMD-B, neurologic abnormalities were observed in 30 percent; these were minor and nonprogressive in 22 percent and global and progressive in 8 percent [4]. In the latter group, the onset of neurologic abnormalities occurred between the ages of two and seven years.

●Natural history – The natural history is one of progressive hypersplenism and gradual deterioration of pulmonary function [29,30].

Life expectancy among patients with ASMD-B is highly variable, but some reach adulthood. (See 'Prognosis' below.)

●Neuroimaging – Although data are limited, brain MRI may show pronounced cerebellar and mild supratentorial atrophy [28].

●Laboratory – Laboratory abnormalities may include liver dysfunction, decreased HDL cholesterol, hypertriglyceridemia, and increased LDL cholesterol [20]. The atherogenic lipid profile worsens over time, whereas the liver dysfunction remains stable [29].

Most patients have a mild thrombocytopenia, and some have anemia, neutropenia, or leukopenia [2].

ASMD type A/B — Also classified as the chronic neurovisceral type, ASMD-A/B represents an intermediate form that is less severe than ASMD-A but more severe than ASMD-B because of neurologic findings (eg, ataxia, developmental delay, peripheral neuropathy).

EVALUATION AND DIAGNOSIS

When to suspect the diagnosis — The diagnosis of ASMD-A is suggested by the following clinical features [1]:

●Hepatosplenomegaly

●Interstitial lung disease

●Macular cherry-red spot (picture 1)

●Failure to thrive

●Developmental delay

●Onset in infancy

The diagnosis of ASMD-B is suggested by the following clinical features [1]:

●Hepatosplenomegaly

●Thrombocytopenia

●Interstitial lung disease

●Hyperlipidemia

●Growth restriction

Because it is a rare disease with highly variable phenotype, ASMD is likely underdiagnosed, particularly in cases that lack organomegaly, which is not a universal feature [2]. In addition, common screening tests for metabolic diseases such as amino or organic acids are typically normal in ASMD and Niemann-Pick disease type C (NPC).

Confirming the diagnosis — The first step in confirming the diagnosis of ASMD is performing an enzyme assay for acid sphingomyelinase activity in peripheral leukocytes, cultured fibroblasts, and/or lymphoblasts [2,3,31]. Genetic testing is recommended to support the diagnosis in patients with low or absent acid sphingomyelinase activity. It is also useful for prenatal diagnosis.

●Acid sphingomyelinase assay – The diagnosis of ASMD is confirmed when residual acid sphingomyelinase activity in peripheral blood leukocytes or cultured skin fibroblasts is <10 percent of controls [1].

The choice of enzymatic substrate is important. Assays using a short-chain fatty acid sphingomyelin analog with detection by tandem mass spectrometry (rather than fluorometric assays) are the method of choice [31-33]. In rare cases, the use of a so-called "artificial" fluorometric substrate rather than the natural sphingomyelin substrate has led to falsely normal or enhanced laboratory determination of sphingomyelinase activity [34].

●Biomarker screening – Expert consensus guidelines suggest that the diagnostic evaluation for ASMD should include measurement of several plasma biomarkers simultaneously with the assay for acid sphingomyelinase activity [2]:

•Glucosylsphingosine (lysoGb1), which is highly elevated in Gaucher disease

•Lysosphingomyelin (lysoSM), which is elevated in ASMD but is normal or mildly elevated in NPC [35]

•N-palmitoyl-O-phosphocholineserine (PPCS), previously named lysoSM509, which is highly elevated in both ASMD and NPC [36]

Measuring these biomarkers can aid in distinguishing ASMD from other lysosomal disease [2]. (See 'Differential diagnosis' below.)

●Genetic testing – Genetic testing of the SMPD1 gene should be performed for patients with low or absent acid sphingomyelinase activity to support the diagnosis and allow for genetic counseling [2]. Genetic testing that identifies both disease-causing alleles in SMPD1 gene can confirm the diagnosis if performed before assessing acid sphingomyelinase activity.

If genetic testing is performed before the enzyme assay and identifies SMPD1 variants in one or two alleles that are not previously known as pathogenic (ie, variants of unknown significance), demonstration of reduced or absent acid sphingomyelinase activity is mandatory to confirm the diagnosis [2].

Three common SMPD1 pathogenic variants account for approximately 90 percent of ASMD-A cases among Ashkenazi Jews [37], and another common SMPD1 pathogenic variant accounts for approximately 90 percent of ASMD-B cases among patients of North African descent [38]. Thus, for patients of Ashkenazi Jewish or North African descent, targeted analysis for pathogenic variants is the preferred initial method of molecular genetic testing [1].

Sequence analysis of SMPD1 is appropriate if targeted analysis does not identify both pathogenic variants in patients with confirmed ASMD. In such patients, the pathogenic variant detection rate of sequence analysis is >95 percent [1].

Differential diagnosis

●NPC disease – NPC is an autosomal recessive disorder associated with splenomegaly, variable neurologic deficits, and sphingomyelin storage. NPC can present from the perinatal period until late adulthood, but usually in middle to late childhood.

Vertical supranuclear gaze palsy, cerebellar symptoms, and progressive dystonia, dysarthria, and dysphagia are common in NPC but not ASMD. Marked elevation in plasma lysoSM is characteristic of NPC, while PPCS is elevated in both ASMD and NPC.

The diagnosis of NPC is based upon abnormal biomarker screening for oxysterols and genetic confirmation of a pathogenic variant involving both alleles of NPC1 or NPC2. The genetics and clinical features of ASMD and NPC are summarized in the table (table 1). (See "Niemann-Pick type C disease".)

●Gaucher disease – Gaucher disease is the most common lysosomal disease. It is an autosomal recessive disorder caused by pathogenic variants in glucocerebrosidase 1 (GBA1). The presenting features of Gaucher disease are variable and may occur at any age (table 2).

The phenotype of Gaucher disease may be difficult to distinguish from ASMD, although interstitial lung disease is more prominent in ASMD, while skeletal manifestations are frequently present with Gaucher disease [2]. An elevated level of plasma lyso-Gb1 can also support the diagnosis of Gaucher disease.

The diagnosis of Gaucher disease is confirmed by the finding of reduced glucocerebrosidase activity in peripheral leukocytes; genetic testing can also confirm the diagnosis. (See "Gaucher disease: Pathogenesis, clinical manifestations, and diagnosis".)

●Lysosomal acid lipase deficiency – This is an autosomal recessive disorder caused by loss-of-function pathogenic variants in the LIPA gene. Onset during infancy is typically fatal within the first year of life. Later onset commonly presents with hepatosplenomegaly, dyslipidemia, fatty liver, and elevated liver transaminase levels [39,40]. The phenotype is highly variable and may overlap with ASMD-B. (See "Metabolic dysfunction-associated steatotic liver disease in children and adolescents", section on 'Tests to exclude other liver diseases' and "Overview of the evaluation of hepatomegaly in adults", section on 'Storage disorders'.)

●Hepatosplenomegaly associated with infection – Acute viral hepatitis, chronic Epstein-Barr virus infection, cytomegalovirus infection, and other infections may cause hepatosplenomegaly. (See "Overview of the evaluation of hepatomegaly in adults" and "Overview of cytomegalovirus (CMV) infections in children", section on 'Treatment'.)

●Hematologic malignancies – Hepatic or splenic enlargement may develop in patients with lymphoma or other malignancies [2]. (See "Overview of the evaluation of hepatomegaly in adults", section on 'Infiltrative diseases'.)

●Other causes of interstitial lung disease – Interstitial lung disease, also known as diffuse lung disease, has many causes in children and adults that include ASMD and other storage diseases, connective disease diseases, rheumatologic and inflammatory diseases, exposure to environmental agents, and infection. When present, associated hepatosplenomegaly can suggest the diagnosis of ASMD in patients with interstitial lung disease [1]. (See "Classification of diffuse lung disease (interstitial lung disease) in infants and children" and "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic testing".)

MANAGEMENT

Supportive care — Supportive care is the mainstay of management for ASMD. When possible, clinicians should refer patients diagnosed with ASMD to a center with expertise in this condition [2]. Multidisciplinary care is optimal given the protean manifestations of ASMD.

●ASMD-A – Infants with acid sphingomyelinase deficiency type A (ASMD-A) may temporarily benefit from physical and occupational therapy, periodic nutritional assessments, and possibly a feeding tube for nutrition. Sedatives may be helpful for sleep difficulty and irritability [1]. The family or other caregivers should be aware that lifespan is limited with ASMD-A and that most patients will succumb before the age of three years, regardless of interventions.

●Routine laboratory tests – Expert consensus guidelines recommend the following tests at baseline and regular intervals [2]:

•Complete blood count

•Liver transaminases (alanine transaminase [ALT], aspartate aminotransferase [AST])

•Clotting factors

•Albumin

•Lipid profile

•Vitamin D

•Enhanced Liver Fibrosis test (see "Noninvasive assessment of hepatic fibrosis: Overview of serologic tests and imaging examinations", section on 'Enhanced Liver Fibrosis test')

●Nutrition and growth – Suggested surveillance includes periodic assessment (every 6 to 12 months) of height and growth in children, weight in patients of all ages, and nutritional status. Children with neurologic involvement should have a formal swallowing assessment and dietary modification if required. Infants with ASMD-A may temporarily benefit from a feeding tube for nutrition.

●Liver and spleen – Most patients with ASMD develop hepatosplenomegaly and are at risk of progression to liver failure, which is a common cause of death in ASMD [2]. Monitoring includes imaging with ultrasound or MRI and routine monitoring of liver function and transaminases.

Avoidance of contact sports is suggested for patients with splenomegaly [1].

●Pulmonary – Most patients with ASMD develop interstitial lung disease. Evaluation includes chest x-ray, chest computed tomography (CT), and (for those who can cooperate) pulmonary function tests with diffusing capacity of the lungs for carbon monoxide (DLCO) [1,2]. This evaluation should be done at the time of diagnosis and periodically thereafter as required.

Patients with symptomatic pulmonary disease may benefit from supplemental oxygen. The risk of respiratory infection is increased for patients with pulmonary or neurologic disease, requiring vigilance and prompt treatment, along with recommended influenza, coronavirus disease 2019 (COVID-19), and streptococcal vaccinations.

●Hematologic – For patients with severe thrombocytopenia, hematology consultation is suggested [2]. Severe bleeding from thrombocytopenia can lead to the need for transfusion of blood products.

●Cardiovascular – For adults and hyperlipidemia, lipid-lowering therapy may be beneficial, but evidence is lacking for increased risk of premature cardiovascular events in patients with ASMD [2].

●Skeletal – Patients with ASMD are at risk for osteopenia and osteoporosis [2,41]. Evaluation of bone density with dual-energy x-ray absorptiometry (DXA) can be performed for patients with suspicion for low bone density or those with fractures [42]. Standard dietary and lifestyle interventions including weight-bearing exercise may be helpful as preventive measures. Bisphosphonates are not used because they inhibit acid sphingomyelinase activity [43].

●Neurodevelopmental – Developmental milestones (motor, cognitive, speech/language) should be assessed through routine screening; early intervention and support should be available for patients with delayed milestones [2].

●Advanced care planning – This is appropriate for patients with ASMD throughout their lifespan and should incorporate communication among patients, families, caregivers, and health care providers regarding disease management plans that address patient values and preferences [2]. Palliative care is appropriate for all patients with life-threatening illness, particularly for patients near the end of life. (See "Advance care planning and advance directives" and "Pediatric palliative care" and "Overview of comprehensive patient assessment in palliative care".)

Disease-modifying therapy

Olipudase alfa — For children and adults with acid sphingomyelinase deficiency type B (ASMD-B) or ASMD-A/B, we suggest treatment with olipudase alfa, an enzyme-replacement therapy that provides an exogenous source of acid sphingomyelinase. It was approved by the US Food and Drug Administration (FDA) in August 2022 for the treatment of non-central nervous system (CNS) manifestations of ASMD [44]. Olipudase alfa does not cross the blood-brain barrier and has no benefit for the neurologic manifestations of ASMD and, therefore, has no utility for treating patients with ASMD-A [45].

We advise patients that olipudase alfa significantly reduces liver and spleen volumes (size), improves lung function, and increases growth in children, with overall efficacy shown up to 6.5 years. The risks are manageable and include mainly infusion-associated reactions, rare hypersensitivity to the infused enzyme, including anaphylactic reactions, and occasional increases in liver enzymes.

Expert consensus guidelines for the management of ASMD support consideration of olipudase alfa for all patients with significant non-CNS manifestations of ASMD [2].

●Dose and administration – Olipudase alfa is given every two weeks by intravenous (IV) infusion. The starting dose for children is 0.03 mg/kg IV; the dose is gradually titrated up to the recommended maintenance dose of 3 mg/kg IV by the ninth dose (week 16). The starting dose for adults is 0.1 mg/kg IV, gradually titrated up to the recommended maintenance dose of 3 mg/kg by the eighth dose (week 14).

Details for the recommended dose escalation schedule and maintenance dosage, dosage modifications to reduce the risk of adverse reactions, and preparation and administration instructions are contained in the FDA prescribing label [46].

Before starting treatment, pregnancy status should be verified for females of reproductive potential, and baseline transaminase levels should be obtained [46]. Pretreatment with antihistamines, antipyretics, and/or glucocorticoids may be used to prevent infusion reactions.

●Efficacy – For patients with ASMD-B or ASMD-A/B, there is limited randomized trial and observational evidence that olipudase alfa treatment improves hepatosplenomegaly, lung function, and platelet counts in adults and children, and improves growth in children [47-52]. These effects may improve quality of life, but this outcome has not been optimally evaluated. There is no benefit for the neurologic manifestations of ASMD. The available data are short term and do not address life expectancy.

The ASCEND randomized controlled trial of 36 adults with ASMD randomly assigned participants in a 1:1 ratio to treatment with olipudase alfa or placebo. At one year, olipudase alfa treatment led to a greater increase in the mean percent predicted DLCO (22 percent versus 3 percent for the placebo) as well as a greater reduction in spleen volume (39 percent decrease versus 0.5 percent increase with placebo) and liver volume (28 versus 1.5 percent decrease) [48]. The ASCEND open-label extension study found that patients who crossed over to olipudase alfa treatment from the placebo group had similar improvements to those seen in the active treatment group during the randomized phase, while patients who completed two years of active treatment had continued clinical improvement [49].

The open-label ASCEND-Peds study included 20 pediatric patients with ASMD but excluded patients with acute or rapidly progressive neurologic abnormalities and/or with genotypes associated with ASMD-A [50]. One-year results showed that olipudase alfa treatment was associated with an increased mean percent predicted DLCO of 33 percent in patients able to perform the test, and with decreased mean spleen volume and liver volume of >40 percent each. All patients had growth retardation at enrollment, and olipudase alfa was associated with an improvement in mean height Z-scores of 0.56 at one year.

In the ASCEND-Peds open-label extension study, all 20 patients completed two years of olipudase alfa treatment [51,53]. Improvements noted in the first year of treatment, including decreased spleen and liver volume, increased mean predicted DLCO, and mean height Z-scores, were maintained or showed further improvement; no new safety issues were identified, and no patient discontinued treatment. One patient developed serious hypersensitivity reactions that resolved with medical treatment and temporary stopping of olipudase alfa infusions.

Although olipudase alfa-related treatment of visceral manifestations may improve quality of life, this outcome has not been optimally evaluated. However, results from a survey of 10 caregivers of pediatric patients with ASMD treated with olipudase alfa for at least 12 months suggest that treatment was associated with improvements in all non-neurologic manifestations of ASMD, including systemic symptoms and mental/emotional health [54]. These results are limited by several factors including small sample size and retrospective design.

●Adverse effects – Treatment is generally well-tolerated; infusion-related reactions (eg, headache, hypotension, fever, cough, pruritus, urticaria, nausea, arthralgias) are the most common and are generally mild [47]. In adult patients, the most common adverse effects are headache, cough, diarrhea, hypotension, and ocular hyperemia. In children, the most common adverse effects are pyrexia, cough, diarrhea, rhinitis, abdominal pain, vomiting, headache, urticaria, nausea, rash, arthralgia, pruritus, fatigue, and pharyngitis [46]. No patients discontinued treatment in the ASCEND and ASCEND-Peds clinical studies [47-51].

There is a boxed warning of severe hypersensitivity reactions, including anaphylaxis [46]. Other warnings include the risk of infusion reactions including acute phase reactions, elevated transaminases, and risk of fetal malformations with use during pregnancy.

Experimental therapies — There is a persistent search for new treatment approaches. Evaluation of novel therapies is ongoing and may offer some hope for the future. The following reports illustrate the range of experimental therapies for ASMD:

●Hematopoietic stem cell transplantation (HSCT) did not modify the neurologic course in an ASMD mouse model, although increased Purkinje cells were noted in the cerebellum and decreased sphingomyelin storage was noted in spinal cord neurons [55].

●In utero stem cell transplant has been shown to have only a transitory benefit [56]. Allogeneic or bone marrow treatment has generally not modified the neurologic course in patients [57,58]. However, there are rare case reports of successful HSCT in children with ASMD-B [58,59]. Transplant-related complications included chronic graft versus host disease of the skin and renal tubular dysfunction.

●Direct intracerebral transplant of neural progenitor cells into the mouse model of ASMD-A resulted in up to five times more acid sphingomyelinase activity and led to reversal of distended lysosomal pathology in transplanted cells in vivo [60].

Genetic counseling — ASMD is an autosomal recessive disorder. At the time of conception, siblings of an affected patient have a 25-percent chance of being affected with the disease, a 50-percent chance of being an unaffected carrier, and 25-percent chance of being unaffected and not a carrier. (See "Genetic counseling: Family history interpretation and risk assessment".)

Prenatal testing for pregnancies at 25-percent risk of ASMD-A or ASMD-B can be accomplished by measuring acid sphingomyelinase activity in amniotic fibroblasts [61,62] or by molecular genetic testing if both disease-causing SMPD1 gene alleles have been identified in an affected family member [1]. Additionally, screening for population-specific pathogenic variants is feasible for individuals of Ashkenazi Jewish descent and North African descent [1]. (See "Preconception and prenatal carrier screening for genetic disorders more common in people of Ashkenazi Jewish descent and others with a family history of these disorders", section on 'Niemann-Pick disease type A'.)

Support groups — Support groups for patients, families, and caregivers affected by ASMD or NPC include:

●International Niemann-Pick Disease Alliance

●National Niemann-Pick Disease Foundation

PROGNOSIS — 

Acid sphingomyelinase deficiency type A (ASMD-A) is a severe condition that leads to early death, typically before the age of three years [1]. In a natural history study of 10 patients with ASMD-A, death (from respiratory failure in nine patients and bleeding in one) occurred at a median age of 27 months (range 19 to 35) [19].

Survival among patients with acid sphingomyelinase deficiency type B (ASMD-B) or ASMD-A/B is highly variable [1,2]. In a natural history study of 103 patients with ASMD-B, there were 18 deaths during the follow-up period between 1992 and 2012; the median age at death was 17 years (range 2 to 72) [63]. The most common cause was pneumonia, followed by liver failure and complications following bone marrow transplant. Other causes in one patient each were heart failure, multiorgan failure, liver cancer, subdural hemorrhage, postoperative hemorrhage, splenic vein tear, and undetermined.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acid sphingomyelinase deficiency".)

SUMMARY AND RECOMMENDATIONS

●Classification and terminology – Historically, acid sphingomyelinase deficiency (ASMD) was classified as a subtype of Niemann-Pick disease, which encompassed a group of autosomal recessive disorders with splenomegaly, variable neurologic deficits, and lipid storage (table 1). Niemann-Pick disease is now recognized to be two separate disorders (see 'Classification and terminology' above):

•Acid sphingomyelinase deficiency (ASMD), with subtypes ranging from most severe (ASMD-A) to less severe (ASMD A/B and ASMD-B).

•Niemann-Pick type C disease (NPC), caused by pathogenic variants of the NPC1 and NPC2 genes. (See "Niemann-Pick type C disease".)

●Pathogenesis – Acid sphingomyelinase deficiency type A (ASMD-A) and type B (ASMD-B) are allelic disorders caused by pathogenic variants in SMPD1, which result in low or absent acid sphingomyelinase activity and abnormal accumulation of sphingomyelin and lipids in multiple cell types. (See 'Pathogenesis' above.)

●Epidemiology – ASMD is rare; the disorder is pan-ethnic, but the birth prevalence is highest in Ashkenazi Jews. (See 'Epidemiology' above.)

●Clinical features – ASMD encompasses a continuum of disease phenotypes that ranges from the most severe, early-onset form (ASMD-A) through an intermediate phenotype (ASMD-A/B) to the least severe, later-onset form (ASMD-B).

•ASMD-A – Affected patients present with hepatosplenomegaly, feeding difficulties, and loss of early motor skills in the first few months of life. Additional manifestations include peripheral neuropathy, hypotonia, loss of reflexes, and interstitial lung disease. Macular cherry-red spots are eventually present in all affected individuals (picture 1). Progressive loss of neurologic function leads to death by two to three years of age. (See 'ASMD type A' above.)

•ASMD-B – The onset of ASMD-B is generally later and less severe than that of ASMD-A. Hepatosplenomegaly develops during infancy or childhood. Other systemic manifestations include short stature with delayed skeletal maturation, interstitial lung disease, and hyperlipidemia. The natural history is one of progressive hypersplenism and gradual deterioration of pulmonary function. (See 'ASMD type B' above.)

•ASMD-A/B – ASMD-A/B represents an intermediate form that is less severe than ASMD-A but more severe than ASMD-B because of neurologic findings. (See 'ASMD type A/B' above.)

The main clinical features of ASMD-A and ASMD-B are summarized in the table (table 1). (See 'Clinical features' above.)

●Evaluation and diagnosis – ASMD-A is suggested when infants present with hepatosplenomegaly, interstitial lung disease, a macular cherry-red spot (picture 1), failure to thrive, and/or developmental delay. ASMD-B is suggested when onset occurs in older children, adolescents, or adults who develop hepatosplenomegaly, thrombocytopenia, interstitial lung disease, hyperlipidemia, and/or growth restriction.

The diagnosis of ASMD, including ASMD-A or ASMD-B depending on clinical context, is confirmed when residual acid sphingomyelinase activity in peripheral blood leukocytes or cultured skin fibroblasts is <10 percent of controls. Genetic testing of the SMPD1 gene should be performed for patients with low or absent acid sphingomyelinase activity to support the diagnosis and allow for genetic counseling. (See 'Evaluation and diagnosis' above.)

●Management – The management of ASMD is mainly supportive. The approach recommended by expert consensus guidelines is outlined above, including recommendations for laboratory monitoring, nutrition and growth, liver and splenic involvement, pulmonary disease, thrombocytopenia, osteopenia and osteoporosis, neurodevelopmental delay, and advanced care planning. (See 'Supportive care' above.)

●Disease-modifying therapy – For children and adults with ASMD-B or ASMD-A/B, we suggest treatment with olipudase alfa (Grade 2C). Small clinical trials have demonstrated that treatment reduces liver and spleen volume, improves lung function, and increases growth in children. Effects on quality of life and longevity have not been demonstrated but seem likely. Treatment does not appear to improve neurologic manifestations.

●Prognosis – With ASMD-A, the most severe form, death usually occurs at or before age three years. Survival among patients with ASMD-B is highly variable. (See 'Prognosis' above.)