Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disease. The most commonly affected organs are the spleen, the liver, and the lungs. Pulmonary involvement resembles interstitial lung disease and often leads to decreased diffusion capacity of the lungs for carbon monoxide (DLCO). An emerging technique in pulmonary research is the analysis of exhaled breath. The aim of this study was to investigate potential markers of pulmonary involvement in the exhaled breath of adult chronic visceral ASMD patients and to quantify findings on high-resolution computed tomography (HRCT) of the lungs in order to be able to correlate HRCT findings with (the potential) markers for pulmonary involvement. Fifteen adult, chronic visceral ASMD patients and 34 age-, sex-, and smoking habit-matched healthy controls were recruited and provided two different types of exhaled breath samples: exhaled air and exhaled condensate. Additionally, pulmonary function testing was performed for both patients and healthy controls, and HRCT of the lungs and biochemical markers were available for patients. Exhaled breath samples were analyzed using gas and liquid chromatography-mass spectrometry (GC-MS and LC-MS respectively). Fifteen compounds of interest were identified based on significant differences between ASMD patients and healthy controls, of which the most promising were 2-hydroperoxyhexane, 6-heptyn-2-one, and 4-pentenyl acetate. Other compounds have been described in the context of systemic sclerosis (i.e., acetophenone) or lung cancer (i.e., benzaldehyde and dodecane). Some markers were associated with the pathophysiological process of lipid peroxidation (i.e., decane, dodecane and 2-methylnonane). SPLSDA and AUROCC analyses showed that the model was better able to distinguish the patients with pulmonary involvement from their matched controls than all patients from all controls. Lastly, a quantitative HRCT score was performed and correlated with patients' DLCO (R = -0.74, p = 0.006). The most promising markers based on our analyses (i.e., 2-hydroperoxyhexane, 6-heptyn-2-one and 4-pentenyl acetate) have not been described in previous studies in the pulmonary field and might be ASMD-specific.

Acid sphingomyelinase deficiency (ASMD) is an ultra-rare lysosomal storage disease with a broad spectrum of manifestations ranging from severe neuropathic forms to attenuated, chronic visceral forms. Manifestations of the chronic visceral subtype are variable and encompass different degrees of hepatosplenomegaly, pulmonary disease and dyslipidemia. The aim of this study was to provide insights into the natural course of adult patients with the chronic visceral subtype. Based on these insights, we proposed tentative criteria for initiation and follow-up of enzyme replacement therapy (ERT). The data of 23 adult patients were collected in a prospective study. Clinical, genetic and demographic data, plasma measurements, abdominal imaging, pulmonary imaging, pulmonary function tests and quality of life questionnaires were collected. Stability of disease based on several clinical, biochemical and radiological markers (i.e., spleen volume, platelet levels, liver volume, alanine aminotransferase [ALT] levels, diffusion capacity of the lungs for carbon monoxide [DLCO] chitotriosidase activity and lysosphingomyelin [LSM]) was assessed. Cardiovascular risk was estimated based on sex, age, smoking, systolic blood pressure and lipid profile. Quality of life was evaluated with the 36-Item Short Form Health Survey and the Health Assessment Questionnaire. Median follow-up was 6.1 years (range 1.3-19.5 years). The most common manifestations were splenomegaly (100%), decreased high-density lipoprotein cholesterol (HDL-C) plasma levels (83%), (signs of) steatosis measured with transient elastography (82%), thrombocytopenia (64%), hepatomegaly (52%) and decreased diffusion capacity (45%). The majority of markers remained stable during follow-up. Twelve patients showed progression of disease: four for spleen volume, two for liver volume, three for DLCO, seven for chitotriosidase activity and three for LSM. One patient showed progression of disease based on four markers, although this patient did not report any problems at the last visit. Cardiovascular risk was estimated and was increased in half of the patients older than 40 years. Patient-reported quality of life did not differ from the general population, but differences in median 36-Item Short Form Health Survey (SF-36) scores of patients with severe pulmonary involvement and those of patients without pulmonary involvement were observed. Tentative criteria for initiation and effect of therapy were proposed. In conclusion, the chronic visceral subtype of ASMD showed a predominantly stable disease course in this cohort. We propose that ERT should be initiated on an individual basis and only in case of progression or symptomatic disease. Collection and analysis of real world data are necessary to refine start, stop and follow-up criteria in the future.

Hepatic involvement is one of the main visceral manifestations of Acid Sphingomyelinase Deficiency (ASMD). It can lead to liver fibrosis and liver failure in a subset of patients. Better understanding of the boundary between reversible and irreversible liver involvement is important to initiate enzyme replacement therapy at the right moment. Currently, liver enzymes and liver stiffness measured with transient elastography (TE) are used to assess liver involvement of ASMD. The aim of this study was to investigate whether magnetic resonance (MR) techniques such as MR spectroscopy (MRS) and MR elastography (MRE) are useful methods to measure liver involvement of ASMD and whether they are more useful than TE. Thirteen therapy-naïve adult ASMD patients with the chronic visceral subtype and eleven age-, sex- and body mass index-matched healthy controls were recruited. All participants underwent MRS and MRE scans and had blood drawn for the measurement of liver enzymes. For patients data of TE and biochemical plasma markers for ASMD were collected. Median fat fraction measured with MRS and median liver stiffness measured with MRE did not differ significantly between ASMD patients and healthy controls (respectively median PDFF 1.0 %, range 0.2-24.2 % for patients and median PDFF 0.7 %, range 0.2-8.4 % for healthy controls, p = 0.49 and median liver stiffness 1.2 m/s, range 0.9-1.4 m/s for patients and median liver stiffness 1.3 m/s, range 1.1-1.4 m/s for healthy controls, p = 0.86). A significant correlation was observed between liver stiffness measured with MRE and liver stiffness measured with TE (R = 0.74, p = 0.014). The MRS spectra showed no specific sphingomyelin peaks. At this moment, TE seems the best method to monitor liver stiffness for adult patients with chronic visceral ASMD.

The lysosomal storage diseases chronic visceral acid sphingomyelinase deficiency (ASMD) and Gaucher disease type 1 (GD1) are both macrophage storage disorders with overlapping clinical manifestations. We compared cross-sectional data on visceral, hematological, and biochemical manifestations of untreated adult patients with chronic visceral ASMD (n = 19) and GD1 (n = 85). Spleen volume, liver volume, and bone marrow fat fraction did not significantly differ between the two disease groups (p >0.05 for all). Chitotriosidase activity was higher in GD1 (GD1: median 30 940 nmol/(mL.h), range 513-201 352, ASMD: median 1693 nmol/(mL.h), range 326-6620, p <0.001), whereas platelet levels were lower (GD1: median 102 109/L, range 16-726, ASMD: median 154 109/L, range 86-484, p <0.010), as were hemoglobin levels (GD1: median 7.8 mmol/L, range 5.0-10.4, ASMD: median 9.0 mmol/L, range 7.0-10.4, p <0.001). No bone complications were reported for ASMD, compared to 33% in GD1 (p <0.005). In ASMD pulmonary disease was more severe as evidenced by a median diffusion capacity of the lungs for carbon monoxide of 73% of predicted (range 26-104), compared to 85% (range 53-126) in GD1 (p = 0.029). In conclusion, bone complications, hematological abnormalities, chitotriosidase activity, and CCL18 levels were more prominent in GD1, while pulmonary manifestations were more common in AMSD. Different secondary pathophysiological processes surrounding sphingomyelin and glucosylceramide accumulation might explain these differences.

Acid sphingomyelinase deficiency (ASMD) is a rare LSD characterized by lysosomal accumulation of sphingomyelin, primarily in macrophages. With the recent availability of enzyme replacement therapy, the need for biomarkers to assess severity of disease has increased. Glycoprotein non-metastatic protein B (GPNMB) plasma levels were demonstrated to be elevated in Gaucher disease. Given the similarities between Gaucher disease and ASMD, the hypothesis was that GPNMB might be a potential biochemical marker for ASMD as well. Plasma samples of ASMD patients were analyzed and GPNMB plasma levels were compared to those of healthy volunteers. Visceral disease severity was classified as severe when splenic, hepatic and pulmonary manifestations were all present and as mild to moderate if this was not the case. Median GPNMB levels in 67 samples of 19 ASMD patients were 185 ng/ml (range 70-811 ng/ml) and were increased compared to 10 healthy controls (median 36 ng/ml, range 9-175 ng/ml, p < 0.001). Median plasma GPNMB levels of ASMD patients with mild to moderate visceral disease compared to patients with severe visceral disease differed significantly and did not overlap (respectively 109 ng/ml, range 70-304 ng/ml and 325 ng/ml, range 165-811 ng/ml, p < 0.001). Correlations with other biochemical markers of ASMD (i.e. chitotriosidase activity, CCL18 and lysosphingomyelin, respectively R = 0.28, p = 0.270; R = 0.34, p = 0.180; R = 0.39, p = 0.100) and clinical parameters (i.e. spleen volume, liver volume, diffusion capacity and forced vital capacity, respectively R = 0.59, p = 0.061, R = 0.5, p = 0.100, R = 0.065, p = 0.810, R = -0.38, p = 0.160) could not be established within this study. The results of this study suggest that GPNMB might be suitable as a biomarker of visceral disease severity in ASMD. Correlations between GPNMB and biochemical or clinical markers of ASMD and response to therapy have to be studied in a larger cohort.