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FABRY DISEASE: PROGRESSIVE. OFTEN LIFE-THREATENING.1-3

Time is of the essence for diagnosing and managing Fabry disease.

DISEASE OVERVIEW

Fabry disease is multisystemic, impacting essential organs such as the kidney, heart, and brain.4

Fabry disease is a genetic, X-linked disorder that affects men, women, and children. It is classified into 2 main phenotypes, classic and nonclassic, both of which can lead to organ failure and serious complications in adulthood and reduction in life expectancy.4,5

Progressive accumulation of GL-3 and Lyso-GL-3 is the hallmark of Fabry disease.6,7

Fabry disease is caused by pathogenic mutations in the galactosidase alpha (GLA) gene that lead to complete or partial deficiency of α-galactosidase (α-GAL A). This results in progressive accumulation of glycolipids—globotriaosylceramide (GL-3) and globotriaosylsphingosine (Lyso-GL-3)—in lysosomes throughout the body.6,7

Accumulation of GL-3 and Lyso-GL-3 starts in utero, causing cellular damage that can progress before overt clinical signs, often leading to organ damage and premature death.4,9

Learn more about Fabry disease »

DISEASE PROGRESSION

AS GL-3 ACCUMULATES, EARLY SYMPTOMS OF FABRY DISEASE CAN PROGRESS TO LIFE-THREATENING COMPLICATIONS.1

  • Progression of Fabry disease can be subclinical for years, even as GL-3 is continually accumulating at the cellular level.9
  • Over time, this buildup may lead to irreversible damage and life-threatening events such as kidney failure, heart failure, early stroke, or premature death.1
  • Fabry disease can also cause life-altering symptoms, including GI issues, pain, angiokeratomas, and heat and cold intolerance.5

MONITORING

Regular assessments are important for evaluating and managing Fabry disease.5

It is important to monitor pediatric and adult patients in order to identify early symptoms and manage previously identified symptoms—before they progress to life-threatening conditions.5


Along with GL-3, accumulation of Lyso-GL-3 is associated with disease progression and severity. The role of Lyso-GL-3 as a key factor in disease pathology makes it an important biomarker for monitoring disease progression and can help inform clinical decision-making in Fabry disease.4,8,10

NEW SYMPTOMS

It is important to identify symptoms that are just starting to emerge.

WORSENING SYMPTOMS

Previously identified symptoms should be monitored to see if they have gotten worse.

KNOW WHEN TO TREAT

Treatment guidelines

ENZYME REPLACEMENT THERAPY (ERT) SHOULD BE CONSIDERED IN SYMPTOMATIC PATIENTS AGED ≥8 YEARS.15*

Signs and symptoms warranting treatment15

Physicians should consider initiating treatment at approximately 8-10 years of age in asymptomatic boys with classical Fabry mutations.15

  • In asymptomatic male patients with classical mutations, timing of treatment should be based on individual cases, weighing the risks and benefits.
  • In asymptomatic female patients and asymptomatic male patients with late-onset mutations, a decision to defer treatment should be based on comprehensive longitudinal monitoring for the development of symptoms; family history should also be considered.

*Patients younger than 8 years of age were not included in clinical studies of Fabrazyme. The safety and efficacy of Fabrazyme in patients younger than 8 years of age have not been evaluated.

ERT SHOULD BE CONSIDERED UPON EARLY SIGNS OF FABRY DISEASE IN WOMEN.14,16

Female patients presenting with renal, cardiac, CNS, or GI symptoms, or pain should be considered for ERT16

ERT SHOULD BE CONSIDERED FOR MEN AT TIME OF DIAGNOSIS.14

Classic Fabry mutation (symptomatic or asymptomatic):

  • ERT should be considered and is appropriate.
  • Treatment decisions may be influenced by advanced age and severe comorbidity.

Nonclassic Fabry mutation or missense GLA VUS14*:

  • ERT should be considered and is appropriate if there is laboratory, histologic, or imaging evidence of injury to the kidney, heart, or central nervous system, even in the absence of typical Fabry symptoms.
  • The abnormalities should be attributable to Fabry disease with a histological assessment or biochemical evidence of GL-3 accumulation.
  • The advice of an expert in genetics and management of Fabry disease should be sought for interpretation of the pathogenicity of any VUS.

VUS=variant of unknown significance.
*Nonclassic or missense GLA VUS have the same recommendation for males and females.

Fabrazyme (agalsidase beta) reduces globotriaosylceramide (GL-3) deposition in capillary endothelium of the kidney and certain other cell types. The reduction of GL-3 inclusions suggests that Fabrazyme may ameliorate disease expression; however, the relationship of GL-3 inclusion reduction to specific clinical manifestations of Fabry disease has not been established.

References:
  1. Eng CM, Fletcher J, Wilcox WR, et al. J Inherit Metab Dis. 2007;30(2):184-192.
  2. MacDermot KD, Holmes A, Miners AH. J Med Gen. 2001;38(11):750-760.
  3. MacDermot KD, Holmes A, Miners AH. J Med Gen. 2001;38(11):769-807.
  4. Germain DP. Orphanet J Rare Dis. 2010;5:30.
  5. Eng CM, Germain DP, Banikazemi M, et al. Genet Med. 2006;8(9):539-548.
  6. Mehta A. Q J Med. 2002;95(10):647-653.
  7. Biomarker standards for Fabry disease diagnosis and monitoring. Newsletter for Glyco/Sphingolipid Research. Matreya LLC website. https://www.matreya.com/files/matreya-newsletter-jun-2017.pdf. Published June 2017. Accessed June 21, 2018.
  8. Spada M, Kasper D, Pagliardini V, Biamino E, Giachero S, Porta F. Ital J Pediatr. 2017;43(1):1.
  9. Ellaway C. Transl Pediatr. 2016;5(1):37-42.
  10. Aerts JM, Groener JE, Kuiper S, et al. Proc Natl Acad Sci U S A. 2008;(105):2812-2817.
  11. Martins AM, D’Almeida V, Kyosen SO, et al. J Pediatr. 2009;155(4 suppl):S19-S31.
  12. Hopkin RJ, Bissler J, Banikazemi M, et al. Pediatr Res. 2008;64(5):550-555.
  13. Fabry Registry. Schedule of Assessments. Ortiz A, Germain DP, Desnick RJ, et al. Mol Genet Metab. 2018;123(4): 416-427.
  14. Ortiz A, Germain DP, Desnick RJ, et al. Mol Genet Metab. 2018;123(4): 416-427. Mehta A, Beck M, Linhart A, Sunder-Plassmann G, eds.. Fabry Disease: Perspectives From 5 Years of FOS. Oxford, UK: Oxford PharmaGenesis; 2006. https://www.ncbi.nlm.nih.gov/books/NBK11569. Accessed June 21, 2018.
  15. Hopkins RJ, Jefferies JL, Laney DA, et al. Mol Genet Metab. 2016;117(2):104-113. Fabry Registry. Schedule of Assessments.
  16. Biegstraaten M, Arngrimsson R, Barbey F, et al. Orphanet J Rare Dis. 2015;10:36.