Diagnostic Workup for Acid Sphingomyelinase Deficiency (ASMD)
The definitive diagnostic workup for suspected ASMD should begin with enzyme activity testing for acid sphingomyelinase (ASM), followed by genetic testing of the SMPD1 gene to confirm the diagnosis. 1
Initial Diagnostic Testing
- Enzyme activity testing should be performed first using tandem mass spectrometry (MS/MS), which is the preferred method due to enhanced analytical range and more accurate assessment of enzyme activity in the lower ranges of detection 1
- Simultaneous testing for glucocerebrosidase activity should be performed to distinguish ASMD from Gaucher disease, as they share similar clinical manifestations 1
- ASM enzyme activity can be measured using:
- Isolated peripheral blood leukocytes
- Fibroblasts
- Dried blood spots (DBS) - particularly useful when shipping liquid blood samples is difficult 1
- When using DBS, note any recent transfusions on the request form, as plasma transfusions may impact enzyme test results 1
Confirmatory Genetic Testing
- SMPD1 gene sequencing should be performed after confirmation of reduced ASM activity to identify specific mutations 1
- The SMPD1 gene is located on chromosome 11p15.1–15.4 with over 180 described mutations 1
- When reporting mutations, specify the reference sequence used (NM_000543.4 or M81780.1) as they differ in the signal peptide region 1
- Common mutations to look for include:
Biomarker Testing
- Lysosphingomyelin is increased in DBS and plasma from patients with chronic ASMD and may serve as a useful biomarker 1, 2
- Plasma chitotriosidase is elevated in ASMD and can be used as a biomarker of disease activity, though levels are not as high as in Gaucher disease 1
- Note that 6% of individuals have a recessively inherited chitotriosidase deficiency that may affect results 1
- CCL18 levels in plasma can be used as an alternative biomarker when patients have chitotriosidase deficiency 1
Additional Laboratory Assessments
- Complete blood count to assess for cytopenias, particularly thrombocytopenia 3, 4
- Liver function tests to evaluate hepatic involvement 3, 4
- Lipid profile to identify characteristic mixed dyslipidemia (low HDL cholesterol with elevated LDL cholesterol and triglycerides) 1, 3, 2
- Coagulation studies to identify normal prothrombin level discordant with low factor V, which can be seen in ASMD 4
- Immunoglobulin levels to detect polyclonal hypergammaglobulinemia or monoclonal gammopathy 4
Imaging Studies
- Abdominal ultrasound to assess liver and spleen morphology and detect signs of portal hypertension 3, 5
- Chest X-ray or CT scan to evaluate for interstitial lung disease, which is common in ASMD 3, 5
- Liver elastography to assess for fibrosis in patients with hepatosplenomegaly 3, 5
Specialized Testing
- Bone marrow biopsy may be considered to identify characteristic lipid-laden foam cells (Niemann-Pick cells) 1, 5
- Pulmonary function testing to evaluate for interstitial lung disease 3, 5
- Ophthalmologic examination to look for cherry-red spots, which can be present in some patients 2
Important Clinical Considerations
- Fluorometric assays for ASM activity should be avoided as they can result in high false-negative rates, particularly in patients with the p.Q294K mutation 1
- Cultured skin fibroblasts may be preferred for confirmation of enzyme activity in equivocal cases 1
- Residual enzyme activity should not be used as a predictor of phenotype; instead, positive enzyme testing should be used in concert with molecular and clinical assessments 1
- Early diagnosis is critical for appropriate management and to avoid inappropriate procedures such as splenectomy 4, 5
- Diagnosis is often delayed by 4+ years in young adults with ASMD due to its rarity 3, 4
By following this diagnostic algorithm, clinicians can efficiently diagnose ASMD and determine the specific phenotype, which is essential for appropriate patient management and family counseling 1, 6.