VII. Female project

FEMALE FABRY PROJECT IN GERMANY

TITLE

Female Fabry patients in Germany - interdisciplinary medical care in German Fabry centers: when should ERT be started ?

BACKGROUND

Fabry disease (FD; OMIM #301500) is an X-linked (Xq22.1) inborn error of  glycosphingolipid catabolism resulting from deficient α-galactosidase A activity (GLA; 300644) due to mutations mainly in the GLA coding region. While former studies reported the incidence of FD to reach 1:40,000 to 1:120,000 [Ref. 1, 2], a recent newborn screening study in males revealed that the GLA mutation rate was ≈1:3,100 in their population [Ref. 3]. FD-specific manifestations result from the differential systemic accumulation of globotriaoslyceramide (Gb3) in the cellular lysosomes [Ref. 4]. Onset of first symptoms (acroparesthesias, angiokeratoma, abdominal pain, cornea verticillata and hypo- or hyperhidrosis) in affected hemizygous males with low or absent enzymatic GLA activity starts in early childhood. The persistent accumulation of Gb3/GL-3 in cells of different tissues comes along with an early onset of stroke, myocardial infarction, or renal failure, leading to a severely reduced life expectancy. Although X-chromosomal heredity and the X-lionization in females (mosaic pattern) can explain why FD-specific symptoms and manifestations are delayed and often milder in heterozygous affected females, lionization is not a sufficient model to explain observed bright variability of disease progression in females. Furthermore, it is unclear which affected females benefit from enzyme replacement therapy (ERT) and when ERT should be initiated. So far, large FD cohorts with well characterized phenotypes in clinical follow-ups are missing to validate the impact of ERT especially in affected females.

PROJECT RATIONALE, HYPOTHESIS AND GOAL

Due to the great variability in time and onset of disease progression in female Fabry patients it is currently still unclear, which female patient types would benefit from early ERT and when would be the optimal time to start therapy.

The hypothesis is that female Fabry patients are treated to late with ERT (“therapeutic nihilism”).

The project goal is to evaluate clinical symptoms and end-organ damage in a large cohort of untreated and treated female Fabry patients from 7 large Fabry centers in Germany to establish parameters which would allow and facilitate recommendation about adequate diagnostic and therapy start. Retrospective analysis and set up of a joint comprehensive data base is planned.

STUDY DESIGN

  • Multicenter study: German Fabry center network: Berlin, Hamburg, Koeln, Mainz, Muenster, Rostock, Wuerzburg
  • Observational non-interventional study approach
  • Retrospective data analysis of clinical phenotypes

DATABASE

  • The interdisciplinary Fabry-centers in MUENSTER (n~150), WUERZBURG (n~180), BERLIN – Charité, Campus Virchow-Klinikum (n~40), KOELN (n~43), HAMBURG (n~14), ROSTOCK (n~28) and MAINZ (n~240) take care of approximately 695 FD patients (~50-60% females, n~382 females) by nephrologists, cardiologists, and neurologists, yearly.
  • In the current project, it is envisaged to analyze the clinical phenotype of ~ 385 female Fabry patients.

DURATION OF THE STUDY

Start of study: July 2014
Study duration: one year, until June 2015

EXPECTED RESULTS

The retrospective, observational non-interventional study will give us the possibility to analyze clinical symptoms and end-organ damage in a large cohort of well-characterized untreated and treated female Fabry patients to identify parameters which would allow and facilitate recommendation about adequate diagnostic and therapy start.

COORDINATION / STATISTICAL ANALYSIS

Univ.-Prof. Dr. Dr. med. E. Brand, Dr. rer. nat. M. Lenders; Muenster

FINANCIAL SUPPORT

Shire International GmbH, 07/2014 – 06/2015

REFERENCES:

  1. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999;281:249-254. 
  2. Desnick RJ, Ioannou YA, Eng CM. Alpha-galactosidase A deficiency: Fabry disease. In: The metabolic bases of inherited disease, 8th edition. New York: McGraw-Hill, 2001:3733-3774. 
  3. Spada M, Pagliardini S, Yasuda M, Tukel T, Thiagarajan G, Sakuraba H, Ponzone A, Desnick RJ. High incidence of later-onset fabry disease revealed by newborn screening. Am J Hum Genet. 2006;79:31-40. 
  4. Zarate YA, Hopkin RJ. Fabry’s disease. Lancet. 2008;372:1427-1435.