6730: Lysosomal Disease Network Longitudinal Study of Fabry Disease

About Fabry Disease

Fabry disease is a rare inherited disorder of glycosphingolipid (fat) metabolism resulting from the absent or markedly deficient activity of the lysosomal enzyme, α-galactosidase A (α-Gal A). This enzymatic deficiency is caused by alterations (mutations) in the α-galactosidase A (GLA) gene that instructs cells to make the α-galactosidase A (α-Gal A) enzyme. The GLA gene is located on the X-chromosome and therefore, Fabry disease is inherited as an X-linked disorder. Enzymes within lysosomes break down or digest particular compounds within the cell. α-Gal A functions to break down big sugar-lipid molecules called glycolipids, specifically, globotriaosylceramide (GL-3 or Gb3). The enzyme deficiency causes a continuous build-up of GL-3/Gb3 and related glycolipids in the body’s cells, resulting in problems within cells and organs, particularly the small blood vessels, heart, and kidneys.

Currently Fabry disease is treated with enzyme replacement therapy (ERT) which reduces serious clinical events, but residual risks remain, specifically for the kidney and heart. While cardiovascular complications are the most common causes of death in Fabry disease, the natural history of the effects of Fabry disease on the cells that lead to Fabry-related cardiac and renal disease are not well understood.

About This Study

The goal of this study is to collect data on the natural history of the impact of Fabry disease on renal and cardiac function and to measure the effect of ERT on these two organ systems by using imaging, tissue biopsy, and cardiac function tests in comparison with each other. These studies will substantially improve our understanding of the biology of Fabry heart and kidney complications and can introduce new approaches to measure treatment response in the heart, blood vessels, and kidneys, with the potential to change how Fabry disease is treated.

In this study, we want to:

  1. Study the natural history of of GL3 accumulation in heart muscle cells (cardiomyocytes – “CM”) and to correlate these with CM cell death, fibrosis of the heart tissue, left ventricular ejection fraction, and heart muscle size. Direct measurement of GL3 inclusions will tell us if inclusions increase with age, and directly correlate with heart disease.
  2. Study the effect of ERT on GL3 content in heart cells. We will compare GL3 content in heart tissue biopsies from Fabry patients obtained pre- and post-ERT. We will study effects of age, sex, ERT dose and duration on GL3 inclusion.
  3. Determine the natural history of heart and kidney arterial smooth muscle cell (ASMC) GL3 accumulation and development of lesions within the arteries of these organs across Fabry patients of all ages and describe their relationships with heart and kidney function.
  4. Study the effects of long-term ERT on kidney and heart ASMC GL3 accumulation in Fabry patients. We will compare GL3 accumulation and severity of arterial lesions in pre- and post-ERT heart and kidney biopsies from Fabry patients.
  5. Determine if skin ASMC lesions correlate with kidney ASMC lesions. If true, a less invasive skin biopsy would provide valuable information about kidney GL3 accumulation and responsiveness to ERT.
  6. Utilize heart rate/blood pressure variability and electrocardiogram (ECG) changes between lay-flat and tilted positions as markers of dysautonomia in Fabry patients and their relationship to development of heart disease.