Magnetic Resonance Spectroscopy in Acid Sphingomyelinase Deficiency (MONACO)

The goal of this study is to assess the ability of MRI techniques to detect early stages of lipid accumulation in the liver of ASMD patients with the chronic visceral subtype compared to healthy subjects. Participants will undergo an MRI with MR Spectroscopy (MRS) to measure lipid accumulation (steatosis) and MR Elastography (MRE) to measure liver stiffness (fibrosis).

Rationale: Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disorder caused by a deficiency of sphingomyelinase resulting in accumulation of the sphingolipid sphingomyelin (SM) in the liver, spleen and lungs. Accumulation of SM in the liver leads to liver fibrosis in a subset of ASMD patients. Enzyme replacement therapy (ERT, olipudase alfa, Sanofi Genzyme) is currently investigated in a phase 2/3 trial and recently received market authorization by the EMA and FDA. As ASMD is a slowly progressive disease, detection of early stages of SM storage in the liver might aid in identifying patients at risk for major complications who would benefit from therapy. Two magnetic resonance (MR) based techniques might be of interest: MR Spectroscopy (MRS) to measure lipid accumulation (steatosis) and MR Elastography (MRE) to measure liver stiffness (fibrosis). Objective: To assess the ability of MRI techniques to detect early stages of lipid accumulation in the liver of ASMD patients with the chronic visceral subtype compared to healthy subjects. Study design: Cross-sectional pilot study in which MRS and MRE measurements of ASMD patients will be compared to measurements in healthy subjects. All ASMD patients who participate will undergo an MRI during their yearly assessments. Patients eligible for therapy will also undergo an MRI after one year of treatment. Study population: All adult patients with ASMD visiting the outpatient clinic for metabolic disorders of the Amsterdam UMC will be invited to participate. Participating ASMD patients will be matched to healthy controls based on age, sex and BMI in a ratio of 1:1. Main study endpoint: Fat fraction in volume percentage (%) of liver tissue of ASMD patients measured with MRS compared to values of healthy subjects. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The MRI procedure yields no risk: at most patients might feel uncomfortable lying in the tight space. Patients and healthy subjects will not directly benefit from participation in the study. The results of the study may improve clinical care in the future.

Cross-sectional pilot study in which MRS and MRE measurements of ASMD patients will be compared to measurements in healthy subjects.

MR Elastography (MRE) with a device that induces shear waves in the body. This device is placed upon the abdomen of the subject and is hold in place by straps. The device will produce low-frequency vibrations (e.g. 30-60 Hz) which are not painful to the participant. A declaration of conformity and a safety document are provided in the study dossier.

Fat fraction in volume percentage measured with MRS-PDFF of ASMD patients compared to age-, sex, and BMI-matched healthy subjects.

Liver stiffness in kPa measured with MRE of ASMD patients compared to age-, sex, and BMI-matched healthy subjects.

Correlations between fat fraction and/or liver stiffness and liver parameters (i.e. liver stiffness measured with fibroscan, liver volume and plasma ALT and AST levels)

Correlations between fat fraction and/or liver stiffness and general disease parameters (i.e. spleen volume, CO diffusion capacity, plasma LSM, LSM-509 and chitotriosidase levels)

Inclusion Criteria: Patients: The patient has biochemically proven ASMD (preferably genetically confirmed) The patient is willing and able to provide written informed consent prior to the study-related procedure. The patient is ≥ 18 years of age Healthy controls: The individual is willing and able to provide written informed consent prior to the study-related procedure The individual is ≥ 18 years of age General good health as determined by medical history Exclusion Criteria: Patients and healthy controls: Inability to adhere to the study protocol Inability to undergo an MRI procedure

Research data will be submitted as articles to peer-reviewed journals. Also, an abstract of our research data reporting our findings will be submitted for presentations on scientific, public and/or patient organization meetings for (oral) presentation(s).