Acid Sphingomyelinase Deficiency

Acid Sphingomyelinase Deficiency – What is this condition?

Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disease which leads to accumulation of sphingomyelin in target organs with resulting damage to liver, spleen, lungs, bone marrow, and lymph nodes as well as neurons in severe disease⁽¹⁾
Autosomal recessive disorder with spectrum of clinical disease caused by pathogenic variants in the sphingomyelin phosphodiesterase 1 (SMPD1) gene leading to deficiency of lysosomal acid sphingomyelinase (ASM)⁽¹⁾

Types

acid sphingomyelinase deficiency (ASMD) includes 3 types^(1,2)
- infantile neurovisceral ASMD
  - most severe subtype with onset in infancy, rapid progression of disease, and death usually before age 3 years
  - characterized by little to no residual ASM activity
  - formerly called Niemann-Pick disease type A
- chronic neurovisceral ASMD
  - slower progression of neurologic symptoms than infantile form with progressive damage to organs
  - formerly called Niemann-Pick disease type A/B or ASMD intermediate form
- chronic visceral ASMD
  - variable onset from infancy to adulthood
  - slowly progressive multi-system disease without neurodegeneration
  - may have normal lifespan or early death due to complications from organ damage
  - formerly called Niemann-Pick disease type B
Niemann-Pick disease is a distinct disorder with different genetic and biochemical origins

Epidemiology

Who Is Most Affected

infantile neurovisceral acid sphingomyelinase deficiency (ASMD) is more common in patients of Ashkenazi Jewish descent, with estimated 2-3 cases per 100,000 births in this population⁽¹⁾

Incidence/Prevalence

reported estimated birth prevalence of 0.4 to 0.6 per 100,000⁽¹⁾
incidence of infantile neurovisceral and chronic neurovisceral ASMD about 1 per 110,000 births based on newborn screening and genetic analysis in the United States
- based on population-based cohort study in Illinois, United States
- 219,973 newborn infants screened for lysosomal storage disorders by mass spectrometry on dried blood spot specimens over 15 months
- incidence of infantile neurovisceral and chronic neurovisceral ASMD 1 per 109,897 births
- Reference – J Pediatr 2017 Nov;190:130

Associated Conditions

Hashimoto thyroiditis reported in several patients with acid sphingomyelinase deficiency⁽²⁾
some SMPD1 variants may be associated with Parkinson disease⁽²⁾

Etiology and Pathogenesis

Causes

acid sphingomyelinase deficiency (ASMD) due to pathogenic variants in SMPD1 gene located on chromosome 11p15.1-15.4^(1,3,4)
- inheritance pattern is autosomal recessive
- > 180 pathogenic variants have been identified, including point (missense and nonsense) mutations, small deletions, and splicing abnormalities
- 2 different reference sequences (GenBank Accession Numbers NM_000543.4 and M81780.1) are used to describe SMPD1 variants that differ by 2 amino acids due to a polymorphism in the length of SMPD1
in infantile neurovisceral ASMD reported variants include
- p.Leu302Pro
- p.Arg496Leu
- 1-BP del, Pro330fs
- above 3 variants account for 90% of infantile neurovisceral ASMD cases in Ashkenazi Jewish population
- 677delT variant identified in 12 Israeli Arab families with infantile neurovisceral acid sphingomyelinase deficiency (Hum Mutat 1998;12(2):136)
- Reference – ^1,3, Online Mendelian Inheritance in Man (OMIM) #607608
in chronic neurovisceral ASMD reported variants include
- p.Gln292Lys
- p.Trp391Gly
- Reference – ^(1,3), OMIM #607608
in chronic visceral ASMD reported variants
- p.Arg608del may account for up to 90% of pathogenic alleles in North African population and 20%-30% of pathogenic variants in the United States population
- homozygous p.Arg608del reported to result in milder clinical course
- p.Pro323Ala
- p.Pro330Arg
- p.Trp393Gly
- p.Ala359Asp
- p.Leu139Pro, p.Ala198Pro, p.Arg476Trp pathogenic variants reported to result in less severe disease
- Reference – ^(1,3), OMIM #607608

Pathogenesis

acid sphingomyelinase deficiency (ASMD) is caused by deficient activity of lysosomal enzyme acid sphingomyelinase (ASM) due to pathogenic variants of sphingomyelin phosphodiesterase 1 gene (SMPD1)
sphingomyelin (ceramide-phosphocholine) is a major component of cell membranes and a key component of the myelin sheath
ASM catalyzes the hydrolytic cleavage of sphingomyelin in the lysosomes, producing ceramide and phosphorylcholine
ASM interacts with other lipid hydrolases and maintains sphingolipid homeostasis and participates in membrane turnover
when cells are under stress, ASM translocates to the plasma membrane where it hydrolyzes sphingomyelin to ceramide, leading to reorganization of membrane lipid microdomains that stimulate downstream signaling events
deficiency of ASM results in multi-organ damage as sphingomyelin and other lipids progressively accumulate within tissues
- spleen – lipid laden macrophage infiltration leads to splenomegaly which can be massive and increases risk for bleeding, splenic rupture, and thrombocytopenia
- liver – infiltration by sphingomyelin laden hepatic macrophages and sphingomyelin accumulation in lysosomes of hepatocytes cause hepatomegaly and increase risk of cirrhosis and its complications
- lungs – accumulation of lipid laden macrophages in alveolar septa, bronchial walls, and pleura results in restrictive lung disease with decreased gas exchange as well as recurrent pulmonary infections
- large, lipid laden foam cells also accumulate in the lymph nodes, adrenal cortex, and bone marrow
- central nervous system – specifically in infantile neurovisceral ASMD, brain appears atrophic with swollen ganglion cells, pale and vacuolated cytoplasm, loss of cells in cerebral and cerebellar cortices, gliosis in gray and white matter, and some white matter demyelination along with foam cells in leptomeninges, tela choroidea, endothelium, and perivascular spaces of cerebral blood vessels which causes rapidly progressive neurodegeneration
- retinal ganglion cells (ophthalmologic) – infiltration leads to clinical finding of cherry-red spot
- sphingomyelin storage also found in dermal fibroblasts, macrophages, vascular endothelial cells, vascular smooth muscle cells, perineurium, and Schwann cells
References – ^1,2, Mol Genet Metab 2017 Jan ;120(1-2):27

History and Physical

Clinical Presentation

acid sphingomyelinase deficiency (ASMD) ranges from severe, rapidly progressive infantile neurovisceral disease to slowly progressive chronic neurovisceral and chronic visceral forms⁽¹⁾
infantile neurovisceral ASMD is the most severe form with symptom onset in early infancy, rapid systemic progression, and death prior to age 3 years^(1,3,4)
- healthy development for first 6 months of life, with development of hepatosplenomegaly at age 2-4 months
- in later infancy, development of progressive hypotonia with a developmental plateau followed by rapid deterioration of language, behavioral, gross, and fine motor skills
- macular cherry-red spots develop by age 12 months
- irritability and severe sleep disturbance starting around age 1 year, with failure to thrive, dysphagia, and vomiting, and progressive respiratory symptoms
chronic neurovisceral ASMD has onset in childhood and is characterized by combination of features of chronic visceral ASMD but also mild-to-severe neurological manifestations⁽¹⁾
- later onset than with infantile neurovisceral ASMD (usually between age 2-7 years) and slower progression
- neurologic manifestations characterized by
  - developmental delay
  - learning difficulties
  - ataxia
- similar to chronic visceral ASMD, clinical manifestations often include
  - abnormal linear growth
  - interstitial lung disease
  - hepatosplenomegaly
  - liver dysfunction which may lead to fibrosis, portal hypertension, and cirrhosis
  - delayed skeletal maturation
  - reduced bone density and pathologic fractures
  - dyslipidemia
  - thrombocytopenia
- coarse facial features may also be present in subset of patients
chronic visceral ASMD characterized by variable age at onset and progressive multisystem disease without neurodegeneration^(1,2,3)
- characterized by a wide range of disease manifestations and severity, and variable rates of disease progression
- growth delays including delayed bone age, short stature, and low weight
- interstitial lung disease with shortness of breath and pulmonary infections
- cardiac disease and hyperlipidemia
- hepatosplenomegaly (spleen size can be massive)
- liver dysfunction which may lead to cirrhosis and liver failure
- joint and/or limb pain
- bone disease including fracture, osteopenia, and osteoporosis
- thrombocytopenia and bleeding including bruising and epistaxis

History

History of Present Illness (HPI)

for infantile neurovisceral acid sphingomyelinase deficiency (ASMD), ask about
- loss of developmental milestones
- irritability
- history of respiratory infections
- poor feeding
- vomiting
- poor tone
- sleep disturbances
- Reference – ^1,3,4), Mol Genet Metab 2017 Jan ;120(1-2):27
for chronic neurovisceral ASMD, ask about signs or symptoms of^(1,3,4)
- learning disabilities
- back, limb, and joint pain
- peripheral neuropathy
- ataxia beginning in early childhood
- psychiatric illness
for chronic neurovisceral and chronic visceral ASMD, ask about^(1,4)
- growth restriction
- difficulties in performing daily activities or work
- fatigue
- shortness of breath
- abdominal pain, pressure, and/or early satiety
- diarrhea
- joint or limb pain
- history of bone fractures
- bleeding including bruising and nosebleeds
- headaches
- delayed puberty
- history of recurrent infections (ear and pulmonary)

Family History (FH)

ask about family history of
- acid sphingomyelinase deficiency
- hypersplenism or hepatomegaly

Physical

General

assess for failure to thrive and irritability, particularly in infantile neurovisceral acid sphingomyelinase deficiency (ASMD)^(1,2,3,4)
assess for regression of psychomotor development and loss of behavioral, language, gross and fine motor skills in children with infantile neurovisceral ASMD⁽⁴⁾
assess for decreased linear growth and delayed puberty, particularly in chronic visceral ASMD^(3,4)

HEENT

evaluate for cherry-red spot in macula or macular halo⁽⁴⁾
- detectable eventually in all infants and children with infantile neurovisceral ASMD
- may also be present in children or adults with chronic neurovisceral and chronic visceral ASMD
recurrent epistaxis may be observed, especially in chronic visceral ASMD⁽¹⁾
recurrent otitis media may be observed in chronic neurovisceral ASMD⁽⁴⁾

Cardiac

assess heart sounds for valve disease – severe mitral insufficiency and aortic stenosis reported in both children and adults with chronic forms of ASMD⁽²⁾

Lungs

findings of interstitial lung disease in chronic forms of ASMD, which may include⁽¹⁾
- dyspnea
- decreased breath sounds, crackles related to interstitial lung disease
- hypoxemia

Abdomen

hepatosplenomegaly evident in all types of ASMD; may be significant and contribute to^(1,2,3,4)
- abdominal pain
- abdominal pressure
- early satiety

Neuro

abnormal neurologic findings in patients with infantile neurovisceral and chronic neurovisceral ASMD may include^(1,4)
- hypotonia
- ataxia
  - consider ataxia-specific testing such as
    - tandem gait
    - International Cooperative Ataxia Rating Scale
    - Brief Ataxia Rating Scale
    - Reference – Mol Genet Metab 2012 Jul;106(3):330
- presence of tremor and abnormal fine motor function
- extrapyramidal signs
- delayed language skills, dysarthria
- dysphagia
- abnormal eye movements, vertical gaze palsy (VGPS)
- presence of seizures
- loss of deep tendon reflexes

Diagnosis

Making the Diagnosis

suspect infantile neurovisceral acid sphingomyelinase deficiency (ASMD) in infants with^(1,3)
- hepatosplenomegaly developing at age 2-4 months
- psychomotor development that plateaus between ages 6-15 months and then regresses
- recurrent respiratory infections and evidence of interstitial lung disease on x-ray
- cherry-red maculae on ophthalmologic examination
- failure to thrive in first year of life
- progressive hypotonia
suspect chronic neurovisceral ASMD in children and adults with similar systemic manifestations to visceral ASMD plus evidence of neurologic features including ataxia, developmental delay, or learning difficulties⁽¹⁾
suspect chronic visceral ASMD in children and adults with^(1,3,4)
- hepatosplenomegaly (spleen may be massive)
- recurrent lung infections and evidence of interstitial lung disease with decreased diffusing capacity
- hyperlipidemia (elevated serum triglycerides and low-density lipoprotein cholesterol [LDL-C])
- thrombocytopenia, anemia, and/or leukopenia
- reddish-brown halo surrounding maculae on ophthalmologic examination
additional findings that may support diagnosis (but are not diagnostic) include^(1,4)
- lipid-laden foam cells in liver, spleen, airways, and bone marrow on pathologic analysis
- thrombocytopenia
- mixed lipidemia (low high-density lipoprotein cholesterol [HDL-C] and high LDL-C and triglycerides)
testing to confirm diagnosis in patients with suspected ASMD^(1,4)
- perform ASM enzyme activity assay on peripheral blood lymphocytes or cultured skin fibroblasts as first step
- if ASM activity is diminished or absent, perform gene sequencing
  - if 2 pathogenic variants detected, diagnosis confirmed
  - for children from populations with commonly known SMPD1 pathogenic variants, targeted analysis may be performed for defined pathogenic variants

Differential Diagnosis

conditions causing hepatosplenomegaly⁽⁴⁾
- other lysosomal storage diseases including
  - Gaucher disease (major differential consideration and activity of glucocerebrosidase should be tested for at same time as activity of acid sphingomyelinase [ASM])
  - lysosomal acid lipase deficiency
  - Niemann-Pick disease type C
- liver malignancy
- primary hepatic disease such as autoimmune hepatitis or hepatitis B
other lysosomal storage diseases that typically have absent or milder hepatosplenomegaly⁽⁴⁾
- GM1 and GM2 gangliosidosis
- Farber disease
- mucopolysaccharidoses
- mevalonic aciduria
- lysinuric protein intolerance
- transaldolase deficiency
conditions causing abnormal pulmonary function⁽⁴⁾
- autoimmune disorders
- chronic respiratory diseases such as cystic fibrosis or interstitial lung disease
- drug and environmental exposures
- infectious diseases (tuberculosis)

Testing Overview

diagnostic algorithm for presentation in infancy and childhood⁽⁴⁾
- perform acid sphingomyelinase (ASM) enzyme assay in infant or child with splenomegaly and/or hepatomegaly plus ≥ 1 of
  - cherry-red maculae
  - developmental delay
  - hypotonia
  - low high-density lipoprotein cholesterol (HDL-C)
- test for glucocerebrosidase activity concurrently to assess for Gaucher disease
- if results of ASM testing equivocal, repeat with fibroblasts
- if ASM activity is low or nonexistent, perform SMPD1 gene sequencing to confirm genotype
  - suspect infantile neurovisceral acid sphingomyelinase deficiency (ASMD) if homoallelic for p.Arg496Leu, p.Leu302Pro, and 1-BP del, Pro330fs (account for 90% of variants in Ashkenazi Jewish population)
  - suspect chronic neurovisceral ASMD if p.Gln292Lys or p.Trp391Gly identified
  - suspect chronic visceral ASMD if homo- or heteroallelic for p.Arg608del, p.Pro323Ala, p.Pro330Arg, p.Trp393Gly
- if genotype unknown, determine phenotype with clinical assessment
diagnostic algorithm for presentation after childhood⁽⁴⁾
- perform ASM enzyme assay if splenomegaly and/or hepatomegaly plus ≥ 1 of
  - interstitial lung disease
  - pathogenic fractures
  - low HDL-C
- test for glucocerebrosidase activity concurrently to assess for Gaucher disease
- if results of ASM activity testing equivocal, repeat with fibroblasts
- if ASM activity is low or nonexistent, perform SMPD1 gene sequencing to confirm chronic visceral ASMD
for infantile neurovisceral ASMD, liver function, lung function, and hematology assessments are usually performed at time of diagnosis, but invasive testing is not necessary unless it may improve quality of life⁽²⁾
additional testing following diagnosis of chronic neurovisceral or chronic visceral ASMD
- blood tests including complete blood count, liver function tests, and lipid profile
- imaging tests including chest x-ray, echocardiogram, and electrocardiogram
- pulmonary function testing

Blood Tests

assay for acid sphingomyelinase (ASM) enzyme activity⁽⁴⁾
- assay may be performed with
  - isolated peripheral blood leukocytes
  - cultured skin fibroblasts
  - dried blood samples
- tandem mass spectrometry is recommended over fluorometric method for measuring enzyme activity as less false-negatives, no need for radiochemicals, and ability to test for multiple enzyme deficiencies on same sample
- missing or significantly diminished ASM enzyme activity leads to more severe disease with activity levels > 5% more likely to present as chronic visceral acid sphingomyelinase deficiency (ASMD)
- concurrent testing for Gaucher disease with assay of glucocerebrosidase activity recommended at time of ASM testing as conditions may have similar clinical presentation
- perform ASM enzyme activity testing prior to gene sequencing since most genetic variants are not pathogenic
baseline testing at time of diagnosis to identify ASMD-related disease manifestations^(1,2)
- liver function tests (although they commonly underestimate extent of liver disease and fibrosis)
  - transaminases aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
  - gamma glutamyl transferase (GGT)
- bilirubin
- albumin
- prothrombin time (PT) and INR
- fasting lipid profile – usually demonstrates low high-density lipoprotein cholesterol (HDL-C), high triglycerides, and high low-density lipoprotein cholesterol (LDL-C)
- complete blood count which may reveal anemia, thrombocytopenia, and leukopenia
- ferritin, iron saturation
- viral and autoimmune serology to rule out comorbidities
prenatal diagnosis is possible by testing for ASM enzyme activity⁽²⁾

Imaging Studies

in chronic neurovisceral and visceral acid sphingomyelinase deficiency (ASMD), baseline imaging includes⁽²⁾
- chest x-ray to assess for fibrosis
- ultrasound based-elastography to assess for liver stiffness and risk of portal hypertension, varices, and bleeding
- echocardiogram to assess for valvular disease
- skeletal x-rays in children to assess for bone fractures⁽¹⁾
- dual energy x-ray absorptiometry (DEXA) scan to measure bone mineral content and bone mineral density⁽¹⁾
upper endoscopy as indicated to screen for esophageal varices in patients with portal hypertension⁽²⁾

Electrocardiography (ECG)

perform baseline ECG⁽²⁾

Biopsy and Pathology

liver biopsy may be considered on an individual basis if there is deteriorating liver dysfunction and suspected fibrosis⁽²⁾

Genetic Testing

perform genetic testing to confirm genotype in children and adults with characteristic clinical presentation and low enzyme activity⁽³⁾
diagnosis confirmed with biallelic pathogenic variants on SMPD1 and residual acid sphingomyelinase enzyme activity < 10% of controls (in peripheral blood lymphocytes or cultured skin fibroblasts)⁽³⁾
genetic testing may include single gene or multigene panel⁽³⁾
- in populations with known SMPD1 pathogenic variants such as Ashkenazi Jewish persons
  - perform targeted analysis for pathogenic variants in single genes
  - if targeted analysis does not identify both pathogenic variants, sequence analysis of SMPD1 can be performed
carrier testing for at-risk relatives and prenatal diagnosis are possible if both SMPD1 pathogenic variants in family are identified⁽²⁾

Pulmonary Function Tests

obtain pulmonary function testing with diffusing capacity which may demonstrate a restrictive pattern with impaired gas exchange⁽²⁾

Other Diagnostic Testing

transjugular hepatic venous-portal vein pressure gradients in select patients to evaluate for portal hypertension⁽²⁾

Management

Management Overview

no curative treatments for acid sphingomyelinase deficiency (ASMD)^(1,2,3)
- management is directed at providing symptom relief with interventions and lifestyle modifications that reduce complications, decrease morbidity, and increase quality of life
- genetic counseling should be offered
- social services, family counseling, patient and disease support groups may be beneficial
following diagnosis, refer for following assessments to establish disease severity⁽³⁾
- ophthalmologic examination
- nutrition consult
- occupational and physical therapy evaluations
- genetic counseling
for infantile neurovisceral ASMD^(2,3)
- invasive and ongoing clinical and laboratory assessments are at discretion of clinician and are generally not necessary unless they may improve quality of life (such as assessing for a treatable infection)
- family counseling and early palliative care recommended to determine patient-centered approach to maximize quality of life
- interventions may include nutritional support, physical therapy, and spasticity management
for chronic neurovisceral and chronic visceral ASMD
- appropriate management should be carried out by a multidisciplinary team which typically includes metabolic disease specialists, hepatology/gastroenterology, pulmonology, hematology, and cardiology
- management of morbidities including progressive liver disease, restrictive lung disease, dyslipidemia, and cardiac disease may include
  - medications to manage symptoms
  - surgical intervention for massive splenomegaly or cardiac disease
  - hematopoietic stem cell transplant
- enzyme replacement therapy with olipudase alfa (recombinant human acid sphingomyelinase) is an FDA-approved therapy for treatment of non-neurologic manifestations of ASMD
- regular follow-up is recommended to monitor disease progression, severity, and to detect comorbid conditions

Diet

for liver disease, maintain nutrition and control fluid retention⁽²⁾

Activity

avoid contact sports due to splenomegaly and thrombocytopenia and associated risk of rupture and bleeding⁽¹⁾
maintain regular exercise as tolerated to prevent osteopenia⁽²⁾
nutrition support may be needed, including feeding tube⁽³⁾
physical therapy as needed for joint and limb pain⁽²⁾

Counseling and Psychotherapy

counseling to avoid alcohol and use of hepatotoxic medications⁽²⁾

Medications

medications for management of symptoms^(2,3)
- statins may be appropriate post puberty for dyslipidemia
- medications for management of valvular insufficiency should follow standard guidelines
- bronchodilators for symptomatic pulmonary disease
- nonselective beta-blockers for prevention of esophageal variceal hemorrhage in patients with varices
- medications to treat and manage hepatic encephalopathy from liver failure
- medications to prevent spontaneous bacterial peritonitis in patients with liver failure as appropriate
- sedation may be needed for sleep disturbances
enzyme replacement therapy with olipudase alfa (recombinant human acid sphingomyelinase)^(2,3)
- olipudase alfa-rpcp (Xenpozyme) FDA approved for treatment of noncentral nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in adults and pediatric patients
  - olipudase alfa is a hydrolytic lysosomal sphingomyelin-specific enzyme
  - efficacy based on 3 clinical trials
    - ASCEND trial in adults
    - ASCEND-Peds trial in children
    - extension trial (unpublished as of September 2, 2022) in 8 children aged 2 to < 12 years receiving olipudase for 2.5-3.2 years; continued improvement in percent predicted DLCO, platelet counts, and/or spleen and liver volume observed during 6-month extension
  - prior to treatment initiation, confirm negative pregnancy test in female patients of reproductive potential and obtain baseline transaminase levels
  - dosing and administration
    - given as weight-based IV infusion every 2 weeks (recommended starting dose in adults 0.1 mg/kg and 0.03 mg/kg in children)
    - dose is titrated every 2 weeks to recommended maintenance dose of 3 mg/kg IV every 2 weeks for adult and pediatric patients
    - see product information for recommended dose escalation and dose adjustments due to adverse effects
  - boxed warning includes hypersensitivity reactions, including anaphylaxis
    - consider pretreatment with antihistamines, antipyretics, and/or corticosteroids prior to infusion
    - if hypersensitivity reaction occurs
      - discontinue infusion and initiate medical treatment
      - consider desensitization procedure in patients with severe hypersensitivity reactions after considering risks and benefits of readministering
  - use in pregnancy: patients with the potential to get pregnant should use contraception during treatment and for 14 days after last dose
  - adverse effects in
    - adults (≥ 10%) include headache, cough, diarrhea, hypotension, and ocular hyperemia
    - children (≥ 20%) include pyrexia, cough, diarrhea, rhinitis, abdominal pain, vomiting, headache, urticaria, nausea, rash, arthralgia, pruritis, fatigue, and pharyngitis
  - elevated transaminases reported; see product information for additional information, including monitoring recommendations
  - References – FDA Press Release 2022 Aug 31, FDA DailyMed 2022 Aug 31
- olipudase alfa (Xenpozyme) authorized by European Commission for treatment of noncentral nervous system manifestations of ASMD in adults and pediatric patients with type A/B or type B (European Medicines Agency [EMA] Label 2022 Jul 27, EMA Public Assessment Report 2022 Jul 27)
- olipudase alfa may increase percent predicted lung diffusing capacity for carbon monoxide and decrease spleen volume in adults with acid sphingomyelinase deficiency (level 3 [lacking direct] evidence)
  - based on nonclinical outcomes in small randomized trial
  - 36 adults (mean age 34 years, 61% female, 89% White, 31% Hispanic or Latino) with acid sphingomyelinase deficiency were randomized to olipudase alfa IV vs. placebo every 2 weeks for 52 weeks
  - olipudase alfa dosing: 0.1 mg/kg starting dose, then increased every 2 weeks based on prespecified tolerability and toxicity criteria to maintenance dose of ≤ 3 mg/kg
  - exclusion criteria included mean platelet count < 60 × 10⁹ cells/L, alanine aminotransferase or aspartate aminotransferase > 250 units/L, and total bilirubin > 1.5 mg/dL
  - primary outcomes were changes in percent predicted lung diffusing capacity for carbon monoxide and in spleen volume from baseline to week 52
  - symptom burden of splenomegaly assessed using splenomegaly-related score (SRS) (score range 0-50 points, with higher scores indicating more severe symptoms)
  - baseline patient characteristics comparing olipudase alfa group vs. placebo group
    - mean percent predicted lung diffusing capacity for carbon monoxide 49.4% vs. 48.5%
    - mean spleen volume 11.7 vs. 11.2 multiples of normal
    - mean total SRS score 24.6 points vs. 28.1 points
  - 97% completed follow-up, 100% included in analysis
  - least squares mean changes from baseline to week 52 comparing olipudase alfa vs. placebo
    - percent predicted lung diffusing capacity for carbon monoxide +22% vs. +3% (p = 0.0004)
    - spleen volume -39.4% vs. +0.5% (p < 0.0001)
    - SRS total score -7.7 points vs. -9.3 points (not significant)
    - liver volume -28.1% vs. -1.5% (p < 0.0001)
    - percent predicted forced vital capacity +6.8% vs. +1.5% (p = 0.026)
    - platelet count +16.8% vs. +2.5% (p = 0.0185)
  - consistent results for change in percent predicted lung diffusing capacity for carbon monoxide, change in spleen volume, and SRS total score at week 26
  - treatment-emergent adverse events comparing olipudase alfa vs. placebo (no p values reported)
    - adverse event potentially related to study drug in 66.7% vs. 33.3%
    - severe adverse event in 5.6% vs. 33.3%
    - serious adverse event in 16.7% vs. 22.2%
  - most common adverse events in both groups were headache, nasopharyngitis, arthralgia, upper respiratory tract infection, and cough
  - no treatment-related serious adverse events or discontinuations due to adverse event reported
  - Reference – ASCEND trial (Genet Med 2022 Jul;24(7):1425 full-text)
- olipudase alfa reported to decrease liver and spleen volume and improve vertical growth in children with acid sphingomyelinase deficiency (level 3 [lacking direct] evidence)
  - based on uncontrolled trial
  - 20 children aged 1-17 years (mean age 8 years, 50% female, 85% White) with acid sphingomyelinase deficiency received olipudase alfa IV every 2 weeks for 64 weeks
    - olipudase alfa dosing: 0.03 mg/kg starting dose, then increased incrementally over 16 weeks to maintenance dose of 3 mg/kg
    - dosing schedules were adjusted per safety and protocol prespecified dose-limiting toxicity criteria
  - all patients had spleen volume ≥ 5 multiples of normal and height z-score ≤ -1
  - exclusion criteria included mean platelet count < 60 × 10⁹ cells/L, alanine aminotransferase or aspartate aminotransferase > 250 units/L, total bilirubin > 25.7 mcmol/L (1.5 mg/dL), or INR > 1.5
  - 60% had severe splenomegaly, and 100% had hepatomegaly
  - primary outcome was safety through week 64
  - all patients completed trial and were included in analysis
  - least squares mean changes from baseline to week 52
    - spleen volume -49.2% (p < 0.0001)
    - liver volume -40.6% (p < 0.0001)
    - height z-score +0.56 (p < 0.0001)
    - percent predicted lung diffusing capacity for carbon monoxide +33% (p = 0.0053) in analysis of 9 patients ≥ 5 years old
    - platelet count +34% (p = 0.0003)
  - safety outcomes at week 64
    - treatment-emergent adverse events
      - ≥ 1 adverse event in 100%
      - serious adverse event in 25%
      - severe adverse event in 15%
      - treatment-related adverse event in 56%
      - treatment-related serious adverse event in 15%, including anaphylactic reaction, transient asymptomatic alanine aminotransferase increase, urticaria, and rash
      - dose-limiting drug toxicity in 30%
    - infusion-associated reaction in 55%, including urticaria (20%), pyrexia (35%), vomiting (30%), and anaphylaxis (5%)
    - no adverse events leading to drug discontinuation reported
    - no clinically significant abnormalities in laboratory findings, vital signs, electrocardiograms, or echocardiograms reported
  - Reference – ASCEND-Peds trial (Genet Med 2021 Aug;23(8):1543 full-text)

Surgery and Procedures

splenectomy generally contraindicated due to risk of aggravating liver disease and increasing sphingomyelin accumulation in lungs causing progressive respiratory insufficiency⁽²⁾
partial splenectomy or splenic arterial embolization may be considered if⁽²⁾
- massive splenomegaly
- pressure symptoms
- severe unsustainable hypersplenism
surgical intervention may be needed to repair/replace heart valves⁽²⁾
stenting/coronary artery bypass graft may be indicated for coronary artery disease⁽²⁾
liver transplant may be needed for patients in fulminant liver failure^(1,2,3)

Hematopoietic Stem Cell Transplant (HSCT)

HSCT has been performed in children with variable results⁽³⁾
may improve blood counts and reduce hepato- and splenomegaly, but does not appear to stabilize neurologic disease⁽³⁾
not recommended due to unfavorable risk/benefit ratio and uncertain impact on short- and long-term outcomes and high risk of complications⁽¹⁾

Consultation and Referral

patients with acid sphingomyelinase deficiency (ASMD) should be managed by multi-disciplinary team which may include⁽²⁾
- metabolic disease specialist
- neurologist
- psychiatrist
- neuropsychologist
- neuro-ophthalmologist
- pulmonologist
- cardiologist
- speech and language therapist
- occupational and physical therapist
- orthopedic surgeon
- nutritionist/gastroenterologist
- social worker
- genetic counselor
- hematologist
- Reference – Orphanet J Rare Dis 2018 Apr 6;13(1):50, Orphanet J Rare Dis 2010 Jun 3;5:16
referral for genetic counseling to provide education on autosomal recessive inheritance, carrier status, and potential impact on siblings and offspring⁽²⁾
- discuss carrier testing
- discuss prenatal diagnostic testing with ASM enzyme activity

Follow-Up

monitoring in patients with chronic neurovisceral and chronic visceral acid sphingomyelinase deficiency (ASMD)
- following diagnosis, refer for the following assessments to establish disease severity^(1,2)
  - cognitive and developmental assessments in children
  - ophthalmologic examination
  - assess size of liver and spleen
- follow-up includes periodic assessments and supportive care including⁽²⁾
  - liver assessment every 6-12 months
    - liver panel including
      - bilirubin
      - prothrombin time/INR
      - gamma-glutamyltransferase (GGT)
      - albumin
      - aspartate transaminase (AST) and alanine transaminase (ALT)
    - ultrasound-based transient elastography to assess liver stiffness and monitor for fibrosis
    - esophagogastroduodenoscopy (EGD) to screen for esophageal varices in portal hypertension when liver elastography > 25 kilopascal (kPa) and platelets < 110,000/mm³
    - monitor for liver cirrhosis using Child-Pugh/MELD classifications although may not be accurate in ASMD as may underestimate disease severity
  - pulmonary assessments
    - annual assessments or as indicated by symptoms
      - assess exercise tolerance and dyspnea with modified Medical Research Council (mMRC) scale and 6-minute walk test
      - pulmonary function tests and diffusion capacity of lungs
      - oxygen saturation
    - chest x-ray or low radiation high-resolution computed tomography (HRCT) every 2-4 years
  - cardiovascular assessments, frequency may be based on symptoms
    - annual electrocardiogram (ECG)
    - coronary artery status assessed by HRCT or cardiac CT starting at age 18 years and then every 2-4 years (on same schedule as pulmonary imaging)
    - echocardiogram every 2-4 years
    - annual lipid profile
    - coronary catheterization as indicated
  - annual hematology assessments including complete blood count and coagulation profiles
  - skeletal and growth assessments
    - monitor growth and weight gain at least every 6-12 months (more frequently in infants and younger children)
    - consider monitoring hormone levels for delayed puberty although growth hormone therapy has not been systematically studied in ASMD
    - monitor skeletal health (including pathologic fractures) from infancy to adulthood
    - consider bone mineral content and bone mineral density assessments with dual energy x-ray absorptiometry (DEXA) every 2-4 years in those with low bone density (history of fractures)
  - neurologic assessments
    - annual neurologic and developmental assessments (may perform more frequently in younger children)
    - more frequent monitoring of children with Q292K (also known as Q294K) pathogenic variant due to known association with more severe neurologic abnormalities
    - neuropsychological testing in adults as needed
    - annual assessment for peripheral neuropathy

Complications

complications of infantile neurovisceral acid sphingomyelinase deficiency (ASMD) include^(1, 2,3)
- progressive neurological disease
- frequent respiratory infections, often leading to death
- inadequate nutrition and need for feeding by gastrostomy tube
- sleep disturbance
complications of chronic neurovisceral ASMD^(1, 2,3)
- hypotonia
- loss of motor function
- peripheral neuropathy
- loss of neurodevelopmental milestones and cognitive decline
complications of chronic neurovisceral and chronic visceral ASMD include^(1, 2,3)
- liver dysfunction progressing to liver failure and portal hypertension
- bleeding due to thrombocytopenia and rupture of esophageal varices
- spontaneous bacterial peritonitis and hepatic encephalopathy as complications of chronic liver disease
- chronic abdominal pain and pressure
- splenic rupture
- pulmonary infections including pneumonia
- progressive pulmonary disease requiring oxygen
- pathologic fractures
- osteopenia and osteoporosis
- hyperlipidemia
- early coronary artery disease and valvular disease
- growth delay

Prognosis

prognosis in infantile neurovisceral acid sphingomyelinase deficiency (ASMD) – death by 3 years usually from respiratory failure secondary to pulmonary infection^(1,4)
prognosis in chronic neurovisceral and chronic visceral ASMD⁽¹⁾
- liver failure is a common cause of death
  - liver dysfunction (elevated liver enzymes) reported in 88%
  - liver fibrosis reported in 88%
- respiratory disease is a leading cause of death due to progressive loss of pulmonary function (interstitial lung disease reported in 80%)
- bleeding reported as 3rd most common cause of death
- cardiac disease reported to account for > 7% of deaths
- neurologic morbidity reported in 30% of patients with chronic neurovisceral ASMD, and ranges from mild hypotonia to severe progressive abnormalities
- splenomegaly reported in 90%
  - may be a surrogate marker for disease severity
  - may increase risk of potentially fatal bleeding (rupture)
- life expectancy
  - children with chronic neurovisceral ASMD may survive early childhood and into adulthood
  - children with chronic visceral ASMD often survive into 2nd to 7th decade of life
hepatosplenomegaly, developmental delay, and need for surgical intervention are common in ASMD, and younger age at diagnosis of chronic visceral ASMD associated with higher morbidity
- based on retrospective cohort study
- medical records of 100 children and adults (63% female) with ASMD in the United States, Brazil, and Canada were reviewed over 25 year period
- 13% had infantile neurovisceral, 6% had chronic neurovisceral, and 81% had chronic visceral ASMD
- in infantile neurovisceral
  - 10 of 13 infants died, mean age at death 2.4 years
  - hepatosplenomegaly in 92%
  - ≥ 1 surgery in 54%
  - developmental delay in 92%
  - developmental regression in 63%
- in chronic neurovisceral
  - no mortality reported
  - hepatosplenomegaly in 83%
  - ≥ 1 surgery in 83%
  - developmental delay, developmental regression, and learning disabilities in 40%
- in chronic visceral
  - 2 of 81 patients died, 1 from hepatic failure at age 2 years and 1 from respiratory failure at age 42 years
  - factors associated with significant morbidity included
    - younger age at diagnosis (p = 0.0032)
    - younger gestational age (p = 0.044)
  - hepatosplenomegaly in 80%
  - ≥ 1 surgery in 52%
  - developmental delay in 21%
  - developmental regression in 2%
  - learning disabilities in 13%
- Reference – JIMD Rep 2018;41:119
respiratory and liver failure reported as most common causes of death in chronic forms of ASMD
- based on case series
- 85 patients with chronic neurovisceral or visceral ASMD (78 deceased and 7 liver transplants) were reviewed for symptom onset, diagnosis, and cause of death
- 68.2% had chronic visceral ASMD
- morbidities included
  - splenomegaly in 96.6%
  - hepatomegaly in 91.4%
  - liver dysfunction in 82.6%
  - pulmonary disease in 75%
- most common causes of death
  - overall
    - respiratory failure in 27.7%
    - liver failure in 27.7%
  - in chronic neurovisceral ASMD
    - respiratory disease in 23.1%
    - neurodegenerative disease in 23.1%
    - liver disease in 19.2%
  - in chronic visceral ASMD
    - respiratory in 30.9%
    - liver disease in 29.1%
- distribution of age at death by age at symptom onset
  - all patient deaths at < 40 years had symptom onset < 8 years of age
  - all patient deaths at > 40 years had symptom onset > 15 years of age
- Reference – Mol Genet Metab 2016 Jul;118(3):206
children < 21 years old with chronic forms of ASMD reported to have higher mortality than adults, with respiratory and liver failure reported as leading causes of death
- based on case series
- 103 children and adults with chronic neurovisceral and chronic visceral ASMD were followed at a single center from 1992 to 2012
- 59% were < 21 years old at study entry
- mortality
  - 18 deaths overall (17%)
  - mean age at death 25 years
  - 12 deaths in children (< 21 years old) (19%)
  - 6 deaths in adults ≥ 21 years old (14%)
- causes of death
  - pneumonia/respiratory failure in 5
  - liver failure in 3
  - complications following bone marrow transplant in 3
  - other causes, occurring in 1 each
    - postoperative bleeding
    - splenic vein tear
    - liver cancer
    - low-output heart failure
    - multi-organ failure
    - subdural bleed
    - unknown cause
- morbidity
  - neurologic disease in 13%
  - liver disease in 9%
  - cardiac disease in 9%
  - bleeding disorders in 7%
  - oxygen-dependent pulmonary disease in 4%
- Reference – Genet Med 2013 Aug;15(8):618

Prevention and Screening

Prevention

preimplantation genetic diagnosis may be possible if SMPD1 pathogenic variants have been identified in affected family member⁽³⁾

Screening

testing for acid sphingomyelinase deficiency (ASMD) on newborn screening⁽³⁾
- based on quantification of acid sphingomyelinase activity on dried blood spots
- ASMD not included in United States Recommended Uniform Screening Panel
- may be available in a limited number of states in the United States

Genetic Screening

prenatal screening for couples at risk⁽³⁾
- determine genetic risk, carrier status, and provide counseling prior to pregnancy
- prenatal diagnosis of at-risk pregnancies possible using biochemical testing of acid sphingomyelinase (ASM) activity in cultured amniocytes via amniocentesis at 15-18 weeks or chorionic villus sampling at 10-12 weeks gestation
risk in family of proband⁽³⁾
- parents and siblings of proband may have lipid abnormalities (low high-density lipoprotein) associated with acid sphingomyelinase deficiency
- siblings have 25% chance of being affected, 50% chance of being an asymptomatic carrier, and 25% chance of being unaffected and not a carrier
carrier detection⁽³⁾
- testing for at-risk relatives requires identification of SMPD1 pathogenic variants in family
- carrier identification by ASM activity is not reliable

Guidelines and Resources

Guidelines

International Guidelines

expert consensus recommendation on a diagnostic guideline for acid sphingomyelinase deficiency can be found in Genet Med 2017 Sep;19(9):967 full-text

United States Guidelines

American College of Medical Genetics and Genomics (ACMG) guideline on olipudase alfa approved for pediatric and adult patients with acid sphingomyelinase deficiency (ASMD) can be found at ACMG 2023 PDF

Review Articles

reviews can be found in
review of sphingolipid lysosomal storage diseases can be found in Lipids Health Dis 2021 May 3;20(1):44 full-text
review of causes of death from chronic forms of acid sphingomyelinase deficiency can be found in Mol Genet Metab 2016 Jul;118(3):206 full-text, correction can be found in Mol Genet Metab 2018 Dec;125(4):360

MEDLINE Search

to search MEDLINE for (Acid sphingomyelinase deficiency) with targeted search (Clinical Queries), click therapy, diagnosis, or prognosis

Patient Information

handout from National Organization for Rare Disorders

References

General References Used

The references listed below are used in this DynaMed topic primarily to support background information and for guidance where evidence summaries are not felt to be necessary. Most references are incorporated within the text along with the evidence summaries.

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. 2017 Feb 23;12(1):41 full-text.
Wasserstein M, Dionisi-Vici C, Giugliani R, et al. Recommendations for clinical monitoring of patients with acid sphingomyelinase deficiency (ASMD). Mol Genet Metab. 2019 Feb;126(2):98-105 full-text.
Wasserstein MP, Schuchman EH. Acid Sphingomyelinase Deficiency. GeneReviews 2021 Feb 25.
McGovern MM, Dionisi-Vici C, Giugliani R, et al. Consensus recommendation for a diagnostic guideline for acid sphingomyelinase deficiency. Genet Med. 2017 Sep;19(9):967-974 full-text.