Lipid storage in Fabry disease and Acid Sphingomyelinase deficiency

Fabry disease (FD) and Acid sphingomyelinase deficiency (ASMD) , also known as
Niemann Pick disease type B, are both inherited lysosomal storage diseases
where the inherited deficiency of lysosomal *-galactosidase and acid
sphingomyelinase leads to the accumulation globotriaosylceramide (Gb3) and
sphingomyelin (SM) respectively. Enzyme replacement therapy (ERT) is an
established treatment for FD , for ASMD therapy with recombinant human acid
sphingomyelinase is currently under clinical evaluation.
Cholesterol accumulation also plays an important role in both FD and ASMD . It
was recently shown that cholesterol accumulation can be alleviated by enhancing
ABCA1 mediated efflux in both Fabry disease and ASMD .
With these study we aim to further characterize the altered cholesterol
metabolism in these patients and asses whether objective is to assess whether
treatment of FD and ASMD fibroblasts with recombinant HDL can relieve the
intracellular accumulation of cholesterol.

The objective of this study is to further characterization the cholesterol
pathways leading to storage of not only globotriaosylceramide (Gb3) en
sphingomyelin (SM) in respectively Fabry disease and ASMD but also of storage
of cholesterol in these diseases. We will focus on plasma LCAT activity and
HDL composition; SREBP-signaling and LDL-receptor abundance and activity ;
lipid content of lysosomes and endosomes in fibroblasts.
Furthermore we aim to develop a new treatment strategy to break the vicious
cycle of GB3, sphingomyelin and cholesterol accumulation with recombinant high
density lipoprotein using a cellmodel of Fabry disease and ASMD: by using
cultured fibroblasts and treating these wit recombinant HDL the ABCA1-mediated
efflux of cholesterol if facilitated which leads to reduced lipid storage.

This is a single center cohort study to further characterize cholesterol
pathways and the effects of treatment with recombinant HDL in patients with FD
, ASMD and healthy subjects.

The risks of blood collection through venipuncture and skin biopsy are
considered minimal but may include soreness, bleeding or infection. In total
about 55,4 blood will be collected (2x 10 ml in EDTA-tube, 2x 10 ml in
HGEL-tube, 1x 10 ml in serum-tube, 2x 2,7 ml in citrate-tube)

In the participating FD and ASMD patients, blood sample collection and will
be performed during routine check-up visits. Patients will be asked to fast
overnight prior to their routine visit and study blood collection through
venipuncture will be combined with those as part of the routine visit.
Fibroblasts of participating FD and ASMD patients will be obtained from the AMC
biobank metabolic diseases. Patient will not directly benefit from
participation.

Healthy subjects that participate in this study will not benefit from
participation. They will be asked to fast overnight before study visit. The
single study visit consist of a blood draw through venipuncture and a skin
biopsy. Due to the extent of this study certain findings in healthy subjects
might call for further medical evaluation. Depending on the follow up may
require additional tests or medical procedures as indicated, and/or referral to
the general physician or a medical specialist.