Diagnostic Approach to Acid Sphingomyelinase Deficiency (ASMD)
When ASMD is suspected, immediately order an enzyme assay for acid sphingomyelinase (ASM) activity using tandem mass spectrometry (MS/MS), followed by SMPD1 gene sequencing only after biochemical confirmation. 1
Critical First Step: Enzyme Activity Testing
Tandem mass spectrometry (MS/MS) is the mandatory method for measuring ASM activity—do not use fluorometric assays. 1, 2 Fluorometric assays produce high false-negative rates, particularly in patients with the p.Q294K mutation, which yields anomalously high enzyme activity readings despite the presence of disease. 1
Sample Collection Options
- Isolated peripheral blood leukocytes (preferred) 2
- Dried blood spots (DBS) when shipping liquid blood samples is difficult 2
- Cultured skin fibroblasts 1
Simultaneous Testing Required
Order glucocerebrosidase activity testing at the same time to distinguish ASMD from Gaucher disease, as both conditions share overlapping clinical manifestations including hepatosplenomegaly, thrombocytopenia, and lipid abnormalities. 1, 2
Second Step: Genetic Confirmation
Proceed to SMPD1 gene sequencing only after confirming reduced ASM enzyme activity. 1 Gene sequencing should never be the first diagnostic approach because:
- Most genetic variants are not pathogenic 1
- Sequencing typically takes longer than enzyme assays 1
- It may delay definitive diagnosis if the patient has a different lysosomal storage disorder 1
Key Mutations to Identify
In Ashkenazi Jewish populations, look for p.R498L, p.L304P, and p.P333Sfs*52, which account for >90% of infantile neurovisceral ASMD cases. 2 The SMPD1 gene is located on chromosome 11p15.1-15.4 with over 180 described mutations. 2
Clinical Recognition Patterns
Infantile Neurovisceral ASMD (NPD Type A)
Suspect this phenotype when you observe: 1
- Hepatosplenomegaly presenting at 3-4 months of age
- Failure to thrive with gastroesophageal reflux
- Elevated liver transaminases
- Hypotonia with poor head control
- Progressive neurologic deterioration
- Eastern European Jewish ancestry (though pan-ethnic occurrence exists) 1
This form is uniformly fatal, typically by age 3 years from respiratory failure. 3
Chronic Visceral ASMD (NPD Type B)
Suspect this phenotype when you observe: 1
- Isolated splenomegaly discovered incidentally at routine visits
- Thrombocytopenia with bleeding tendencies (severe nosebleeds)
- Persistently elevated transaminases
- Mixed dyslipidemia (low HDL, high LDL and triglycerides) 1
- Interstitial lung disease on chest imaging 1
- Normal neurodevelopmental milestones
Chronic Neurovisceral ASMD (Intermediate Phenotype)
Suspect this phenotype when you observe: 1
- Marked abdominal distension and hepatosplenomegaly at 6 months
- Chronic diarrhea and failure to thrive
- Developmental delay (but not regression like infantile form)
- Recurrent respiratory infections
- Ground-glass appearance on lung imaging
Supporting Laboratory Assessments
Lipid Profile
Order a complete lipid panel looking for the characteristic pattern of severely decreased HDL cholesterol with elevated LDL cholesterol, VLDL cholesterol, and triglycerides. 1, 2 This mixed dyslipidemia pattern is much more severe in ASMD than in other conditions like Gaucher disease or lysosomal acid lipase deficiency. 1
Biomarker Testing (After Diagnosis)
Once ASMD is confirmed, these biomarkers help monitor disease severity: 2
- Lysosphingomyelin in DBS or plasma (increased in chronic ASMD)
- Plasma chitotriosidase (markedly elevated, though not as high as Gaucher disease)
- Plasma CCL18 (useful when chitotriosidase deficiency is present, which occurs in 6% of individuals) 1
Additional Findings Suggestive but Not Diagnostic
The presence of lipid-laden foam cells in liver, spleen, airways, or bone marrow biopsies, along with thrombocytopenia, are highly suggestive but never substitute for confirmatory enzyme testing. 1
Critical Pitfalls to Avoid
Do not use residual enzyme activity levels to predict phenotype severity. 1, 2 Enzyme activity must be interpreted alongside molecular findings and clinical assessments, as unknown modifiers (secondary lipid accumulation, modifier genes, environmental factors) influence disease severity independent of measured enzyme activity. 1
Do not delay enzyme testing to wait for genetic results. 1 The consensus is unequivocal: biochemical diagnosis must come first.
Do not rely on genotype alone to predict clinical course when mutations of unknown pathogenicity are identified. 1 Clinical assessment over time determines phenotype in these cases.
Differential Diagnosis Considerations
When evaluating for ASMD, particularly in adults with isolated pulmonary involvement, expand your differential to include: 1
- Drug and environmental exposures
- Autoimmune disorders
- Chronic respiratory diseases (cystic fibrosis)
- Infectious etiologies (tuberculosis)
- Other lysosomal storage disorders (Gaucher disease, lysosomal acid lipase deficiency)
The restrictive pattern on pulmonary function testing with low diffusing capacity and interstitial lung disease on imaging can occur even without overt respiratory symptoms. 1
Laboratory Quality Standards
Ensure testing is performed at centers of excellence with ISO 15189 or similar accreditation, processing a minimum number of tests per month, and having access to physicians involved in patient care. 1 This standardization ensures diagnostic accuracy and appropriate interpretation of borderline results.
Timing and Prognosis Implications
Early diagnosis is critical for appropriate management and family counseling. 1 While infantile neurovisceral ASMD is uniformly fatal in early childhood, patients with chronic forms benefit from regular multisystem assessments and symptom management. 1, 4 Enzyme replacement therapy (olipudase alfa) is in clinical development for non-neurologic manifestations. 1, 4
The median age of earliest known ASD diagnosis varies significantly by region (36-69.5 months), highlighting the importance of clinical suspicion and prompt testing when characteristic features are present. 1