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The Impact of Fabry Disease

Cardiovascular, cerebrovascular, and renal complications
can have serious consequences

The life expectancy of patients with Fabry disease is significantly shorter than that of the general population. Lifespans for patients with Fabry disease may be shortened to ~50 years for untreated men and ~70 years for untreated women—a 20- and 10-year reduction, respectively.1

Cardiovascular disease is the most common cause of death for both men and women with Fabry disease.2 According to data from the Fabry Registry, the leading causes of death were2:

  1. Cardiovascular disease (53.6% and 50.0% of male and female deaths, respectively)
  2. Cerebrovascular complications (12.5% of males)
  3. Renal disease (10.7% of males)

Below, we’ll break down each of the leading causes of death in more detail, exploring the impact the disease has over that specific organ system, as well as progression of the disease over time.

Cardiac symptoms appear ~10 years earlier in males than in females. However, both sexes are affected, with ~90% of patients being affected by cardiomyopathy.3 Cardiac involvement is often present early in life but may not be detected clinically until the third or fourth decade.4

Cardiac changes in Fabry disease include infiltrative hypertrophic cardiomyopathy (which is most often identified as left ventricular hypertrophy [LVH]), as well as conduction abnormalities.3 LVH is associated with an increased risk of cardiac events.4,5

Functional impairment, as evidenced by midwall fractional shortening (MWFS), is one of the first signs of systolic impairment and may occur early in the course of Fabry disease.6 Functional impairment worsens in Fabry disease as LVH progresses.7

As the disease progresses, cardiac symptoms and cardiomyopathy develop, as indicated by myocardial fibrosis, which, in end-stage patients, can result in congestive heart failure and death.1,8

Rhythm and conduction abnormalities are also common in patients with Fabry disease9,10 and lead to the requirement of anticoagulation for atrial fibrillation and implantable pacemakers or defibrillators for ventricular arrhythmia.10 A study of 1,448 untreated patients with Fabry disease reported ventricular arrhythmias in 14% and 20% of affected males and females, respectively.9 This is of particular note as arrhythmias are a common source of morbidity and mortality.9,10

Onset of cerebrovascular complications is often earlier in males than females.11 In males, accumulation of lyso-Gb3 was shown to be an independent risk factor for the development of cerebrovascular white matter lesions.1

Signs and symptoms range from mild to severe and include headaches, dizziness, transient ischemic attacks, stroke, and sometimes vascular dementia.1

The prevalence of hypertension, cardiac disease, and renal disease is higher for patients with Fabry disease who have had a stroke. In addition, the prevelance of stroke is much higher for patients with Fabry disease than in the general population.1 Stroke may even be the first manifestation of Fabry disease for these patients. Before being diagnosed with Fabry disease, 50% of males and 38.3% of females had their first stroke.11 Recurrence is common and, once detected, the prognosis is poor.11

Studies on kidney involvement in Fabry disease demonstrate that multiple cell types are affected by GL-3 deposition. These include glomerular endothelial cells, mesangial cells, interstitial cells, distal tubules, and podocytes.1,12

Renal impairment, as indicated by the presence of microalbuminuria and proteinuria, often begins in the second to third decades of life and leads to progression to Fabry nephropathy and ultimately, end-stage renal disease, a major cause of morbidity and mortality.1

Impact on quality of life

The presence of serious, chronic, and debilitating complications, including cardiovascular and renal complications, and comorbid conditions such as pain, can have a significant impact on the psychological well-being of patients with Fabry disease. This, along with the impact on social functioning, means that patients often experience a reduction in quality of life (QoL).13

A meta-analysis from 11 studies that included 599 affected patients compared with healthy individuals demonstrated that Fabry disease had a significant impact across multiple QoL domains, including13:

  • Physical functioning
  • Social functioning
  • Bodily pain
  • General health
  • Vitality
  • Mental health
  • Emotional well-being

This pooled analysis also demonstrated that disease severity, the presence of renal disease, and advanced age impacted the quality of life of patients with Fabry disease.13

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References:

  1. Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30.
  2. Waldek S, Patel MR, Banikazemi M, Lemay R, Lee P. Life expectancy and cause of death in males and females with Fabry disease: findings from the Fabry Registry. Genet Med. 2009;11(11):790-796.
  3. Kampmann C, Perrin A, Beck M. Effectiveness of agalsidase alfa enzyme replacement in Fabry disease: cardiac outcomes after 10 years’ treatment. Orphanet J Rare Dis. 2015;10:125.
  4. Linhart A, Kampmann C, Zamorano JL, et al. Cardiac manifestations of Anderson-Fabry disease: results from the international Fabry outcome survey. Eur Heart J. 2007;28(10):1228-1235.
  5. Patel MR, Cecchi F, Cizmarik M, et al. Cardiovascular events in patients with Fabry disease: natural history data from the Fabry registry. J Am Coll Cardiol. 2011;57(9):1093-1099.
  6. Jovanovic A, Schiffmann R, Nicholls K, et al. Improvements in cardiac mass with long-term migalastat treatment in patients with Fabry disease: results from two Phase 3 trials (FACETS and ATTRACT). Presented at the 13th International Congress of Inborn Errors of Metabolism. Rio de Janeiro, Brazil; September 5-8, 2017.
  7. Kampmann C, Linhart A, Devereux RB, Schiffmann R. Effect of agalsidase alfa replacement therapy on Fabry disease-related hypertrophic cardiomyopathy: a 12- to 36-month, retrospective, blinded echocardiographic pooled analysis. Clin Ther. 2009;31(9):1966-1976.
  8. Seydelmann N, Wanner C, Stork S, Ertl G, Weidemann F. Fabry disease and the heart. Best Pract Res Clin Endocrinol Metab. 2015;29(2):195-204.
  9. Acharya D, Robertson P, Kay N, et al. Arrhythmias in Fabry cardiomyopathy. Clin Cardiol. 2012;35(12):738-740.
  10. Vijapurapu R, Geberhiwot T, Jovanovic A, et al. Study of indications for cardiac device implantation and utilisation in Fabry cardiomyopathy. Heart. 2019. pii: heartjnl-2019-315229. doi: 10.1136/heartjnl-2019-315229. [Epub ahead of print]
  11. Mehta A, Beck M, Eyskens F, et al. Fabry disease: a review of current management strategies. QJM. 2010;103(9):641-659.
  12. Wijburg FA, Benichou B, Bichet DG, et al. Characterization of early disease status in treatment-naive male paediatric patients with Fabry disease enrolled in a randomized clinical trial. PLoS One. 2015;10(5):e0124987.
  13. Arends M, Hollak CE, Biegstraaten M. Quality of life in patients with Fabry disease: a systematic review of the literature. Orphanet J Rare Dis. 2015;10:77.