Sphingomyelinase Deficiency Workup

Updated: May 29, 2020
  • Author: Jaimin M Patel, MD, MBBS, MS; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG  more...
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Approach Considerations

During infancy, patients presenting with hepatosplenomegaly and one or more features suggestive of ASMD, such as cherry-red macules, developmental delay and/or regression, hypotonia, and/or low HDL-C, should be evaluated for ASM activity. In patients with hepatosplenomegaly without other features of ASMD, infections and hematologic-oncologic etiology should first be ruled out, followed by assessment of ASM activity.

When lysosomal storage disease is suspected, enzyme assays for ASM can be performed, along with evaluation of glucocerebrosidase activity, to distinguish between ASMD and Gaucher disease.

For diagnosis of ASMD, enzyme assay is preferred over gene sequencing. There are a wide variety of mutations, leading to different combinations of alleles and resulting in varying levels of enzyme activity; hence, genetic mutation results are difficult to interpret unless two known pathogenic mutations are present. For assessment of ASM activity, tandem mass spectrometry is considered the method of choice. [4]

A diagnostic algorithm for the infantile neurovisceral form of ASMD and for ASMD presenting after childhood has been developed. [4]


Acid Sphingomyelinase


The diagnosis of Niemann-Pick disease (NPD) is confirmed with measurement of enzyme activity in peripheral white blood cells or in cultured fibroblasts.

Mutation analysis

Targeted mutation analysis for 4 common SMPD1 mutations is available in clinical laboratories. Three common type A mutations (L302P, R496L, fsP330) predict the severe infantile form of the disease common in the Ashkenazi Jewish population. One common type B allele (delta R608) is associated with the non-neuronopathic, milder form of disease. Individuals with the Gln294Lys mutation, often associated with NPD type B with progressive neurologic findings, may have apparently normal enzymatic activity when artificial substrate is used. [14]

Sequence and deletion/duplication analysis of SMPD1 are available in clinical laboratories and permit identification of rare and private gene mutations. This information is useful for genotype-phenotype correlation. In addition, genotype information allows identification of carriers among at-risk family members and permits prenatal diagnosis using fetal DNA analysis.


Histologic Findings

The pathologic hallmark in Niemann-Pick disease (NPD) types A and B is the histochemically characteristic lipid-laden foam cell, often termed the Niemann-Pick cell, on bone marrow examination.

These cells, which can be readily distinguished from Gaucher cells by histologic and histochemical characteristics, are not pathognomonic for NPD. Histologically similar lipid-laden foam cells are found in patients with Wolman disease, cholesterol ester storage disease, lipoprotein lipase deficiency, NPD type C, and, in some patients, GM1 gangliosidosis type 2.

Bone marrow examination is not necessary for the diagnosis of NPD.


Laboratory Studies

Complete blood count (CBC)

Pancytopenia may be present secondary to the enlarged spleen in patients with Niemann-Pick disease (NPD).

Serum chemistry

Transaminase levels may be elevated.


Reduced HDL-C fraction is common in NPD type B. In most patients, this is accompanied by elevated total cholesterol and low-density–lipoprotein cholesterol (LDL-C) levels.


Most patients with NPD type B and low serum HDL-C levels also have hypertriglyceridemia.


Imaging Studies


Chest radiography in Niemann-Pick disease (NPD) type B reveals a typical reticulonodular pattern of infiltration, even in patients with no overt pulmonary symptoms. Calcified pulmonary nodules may be seen.

Skeletal imaging in NPD type B often shows delayed bone age. Indeed, bone age can lag on average 2.5 years behind chronologic age. [15] Many patients have significant osteopenia, which can be quantified using dual-energy x-ray absorptiometry (DEXA) scanning. In adults with NPD type B, DEXA Z-scores are often in the osteopenic or osteoporotic ranges.

CT scanning and MRI

Computed tomography (CT) scanning of the lungs in NPD type B may reveal a reticulonodular pattern of pulmonary involvement, with interlobular septal thickening, ground-glass density, and, sometimes, calcified nodules (which are usually less than a centimeter in diameter). These findings are typically located initially in the lung bases and may appear cranially in the lungs over time. [5, 16, 17]

CT scanning or magnetic resonance imaging (MRI) in NPD type B can be used to quantify liver and spleen volumes. Splenic masses are often detected, representing accumulated storage material. These masses are echogenic on ultrasonography and low resolution on CT scan. [5, 17, 18]

MRI of the brain in NPD type A may be normal or may show signs of white matter involvement, as evidenced by hyperintensity on T2-weighted imaging. It may also reveal cerebral or cerebellar atrophy. [5]


Other Tests

Pulmonary function testing

Testing typically reveals decreased oxygen diffusion, restrictive lung disease, and decreased maximal exercise tolerance.

Echocardiogram (ECHO)

ECHO may reveal valve dysfunction in patients with valvular heart disease and myocardial dysfunction in those with underlying coronary artery disease.

Electrocardiography (ECG) and stress testing

Testing may be abnormal in patients with hyperlipidemia and evidence of coronary artery disease.

Biomarkers for ASMD

Once ASMD has been diagnosed, a biomarker assay may be useful to monitor disease progression. The following biomarkers have been under investigation. [4]

Plasma chitotriosidase

This is a biomarker of macrophage activation and is markedly increased in several lysosomal storage diseases, including Gaucher disease and chronic ASMD. In up to 6% patients who may have inherited deficiency in chitotriosidase, plasma chemokine ligand 18 (CCL18) may serve as surrogate marker for disease activity. [4]

Plasma lysosphingolipids

Plasma lysosphingolipids, such as lysosphingomyelin, are increased in patients with ASMD and may serve as biomarkers to monitor disease activity. Additional studies are needed, however. [4]