Secondary pathophysiology in Fabry disease, Gaucher disease and ASMD

In Fabry disease (FD), Gaucher disease (GD) and Acid Sphingomyelinase Deficiency (ASMD), primary lysosomal storage due to specific enzyme deficiencies leads to accumulation of macromolecules. Emerging evidence suggests that this storage leads to general lysosomal dysfunction. This phenomenon may have many more consequences throughout the cells and the clinical features of patients, which is currently poorly understood.


As our understanding of lysosomal function evolves and expands, so does our understanding of the impact of lysosomal dysfunction at a cellular and organism level. In diseases caused by primary lysosomal storage leading to lysosomal dysfunction, such as FD, GD and ASMD, this means a shift towards investigating a broad spectrum of pathophysiological mechanisms that may occur secondary to this lysosomal dysfunction. Additionally, separate from the storage disorders, there is compelling evidence that lysosomal dysfunction contributes to the many features of aging. Similar features that could be attributed to aging can be seen in FD, GD and ASMD. Deeper insights into these secondary pathophysiological mechanisms have the potential to (partially) explain the broad spectrum of clinical presentations and reaction to therapy within these patient groups, differences between FD, GD and ASMD. In addition, new avenues for additional therapy options for symptoms persisting despite enzyme replacement therapy may be uncovered. Therefore, we are investigating the secondary pathophysiological mechanisms present in FD, GD and ASMD, as well as links these mechanisms and clinical symptoms provide between sphingolipidoses and aging.


This study will be initiated using two approaches: Firstly, transcriptomics, metabolomics and lipidomics will be performed in parallel in multiple disease models (skin biopsy derived fibroblasts derived and PBMCs of patients with FD, GD and ASMD, a macrophage model of GD and a kidney cell model of FD). Secondly, a literature review of possible parallels and overlap between FD, GD and ASMD at a cellular and organism level will be performed. Based on the outcome of both approaches, further in-depth studies will be performed to elucidate the details of secondary pathophysiological mechanisms, the interplay between these mechanisms, differences and similarities between the diseases and links to aging mechanisms.

Start date/expected completion

Start date: 01-2020


E.M. Corazolla, MD/PhD Candidate
Dept. of Internal Medicine, div. of Endocrinology and Metabolism
Laboratory Genetic Metabolic Disease (F0-115-2)
Academic Medical Center
Meibergdreef 9, 1105 AZ Amsterdam