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Fabry disease

Author : Sanofi
Editorial team

Fabry disease is an X-linked lysosomal storage disease due to a defect in the gene encoding the lysosomal enzyme alpha-galactosidase A (α-Gal A), causing progressive cellular accumulation of the substrate globotriaosylceramide (GL-3) and globo-triaosylsphingosine (lyso-GL-3).

Fabry disease is an X-linked lysosomal storage disease due to a defect in the gene encoding the lysosomal enzyme alpha-galactosidase A (α-Gal A), causing progressive cellular accumulation of the substrate globotriaosylceramide (GL-3) and globo-triaosylsphingosine (lyso-GL-3).

This accumulation occurs in a variety of cell types and can lead to debilitating symptoms such as neurological pain, angiokeratoma, hypohidrosis in childhood, in girls usually a few years later than in boys. With age, progressive damage to the vital organs develops in both sexes that leads to organ failure. End-stage kidney disease and life-threatening cardiovascular or cerebrovascular complications limit life expectancy.

Although the disease is X-linked, most women develop symptoms. Fabry disease is pan-ethnic. Newborn screenings report frequencies of 1 in 22,570 men for the classic phenotype and of 1 in 1,390 men for the late-onset phenotype.1-3

Fabry disease is classified into two main phenotypes:1,3,4

  • Classic – absent of very low α-GAL A activity, multiple-organ systems involved, presentation generally begins in childhood
  • Nonclassic – also referred to as late-onset, varying levels of residual α-GAL A activity and symptoms are more variable, most frequently beginning in adulthood
GL-3_Accumulation_Graph

classic-male-image

α-GAL A, α-galactosidase A; GLA, galactosidase alpha; GL-3, globotriaosylceramide.

Irreversible damage to multiple vital organs can cause renal, cardiovascular, and cerebrovascular complications if Fabry disease is left untreated.1,3,6

Multisystemic signs and symptoms

  • Neuropathic pain
  • Pain crises
  • Heat and/or cold intolerance
  • Hypohidrosis/anhidrosis
  • Hearing loss/tinnitus
  • Dizziness
  • Burning of hands and feet

  • Angiokeratomas

  • Nausea/vomiting
  • Diarrhea and constipation
  • Abdominal pain and/or bloating
  • Difficulty gaining weight in childhood 

  • Cornea verticillate
  • Tortuous vessels (conjunctival)
  • Fabry cataract
  • Corneal whorling

  • Aortic stiffness
Classic_Male_Walking

  • Depression/anxiety
  • Fatigue

  • Dyspnea
  • Wheezing
  • Chronic cough
  • Shortness of breath

  • Progressive LVH
  • Chest pain
  • Bradycardia
  • Cardiomyopathy
  • Arrhythmias, some of which can be lethal
  • Ventricular fibrosis
  • Heart failure

  • Pathological albuminuria/proteinuria
  • Decreased glomerular filtration rate
  • Kidney failure

  • Transient ischemic attack
  • Early stroke

Patients with Fabry disease experience an approximated 16-year reduction in lifespan for males and a 5- to 14-year reduction for females compared with the general population14-16

Safety

  1. Germain DP. Fabry disease. Orphanet J Rare Dis 2010;5:30.

  2. Germain D., Fabry Disease. Orphanet encyclopedia, March 2022, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=EN&Expert=324

  3. Ortiz A, Germain DP, Desnick RJ et al. Fabry disease revisited: management and treatment recommendations for adult patients. Molecular genetics and metabolism 123.4 (2018): 416-427.

  4. Arends M et al. Mol Genet Metab. 2017;121:157-161.

  5. Eng CM et al. J Inherit Metab Dis. 2007;30(2):184-192.

  6. Wanner C et al. Mol Genet Metab. 2019;126(3):210-211. 

  7. Lidove O et al. Intl J Clin Pract. 2006;60(9):1053-1059.

  8. Burlina A et al. BMC Neurol. 2011;11(61).

  9. Sodi A et al. Br J Ophthalmol. 2007;91(2):210-214.

  10. Zarate Y, Hopkin R. Lancet. 2008;372:1427-1435

  11. Yousef Z et al. Eur Heart J. 2013;34(11):802-808

  12. Linhart A et al. J Inherit Metab Dis. 2001;24(2):75-83.

  13. Shi Q et al. J Stroke Cerebrovasc Dis. 2014;25(5):985-992.

  14. Waldek S et al. Genet Med. 2009;11(11):790-796. 

  15. Mehta A et al. J Med Genet. 2009;46(8):548-552. 

  16. Arias E et al. NVSS Vital Statistics Rapid Release Report No. 015. 2021;1-12. Available at: https://www.researchgate.net/publication/362689060_Provisional_Life_ Expecta ncy_Estimates_for_2020. Accessed: May 2024.

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