Think Fabry, think GL-3 accumulation
Pathogenic variants in the GLA gene lead to deficiency of α-GAL A activity resulting in GL-3 and lyso-GL-3 accumulation in various tissues.1,2 Accumulation of GL-3 in vascular endothelia causes tissue damage in a number of organ systems and is regarded as a distinguishing feature of Fabry disease.3
Accumulation of GL-3 and increased disease burden in classic Fabry disease over time4
α-GAL A=α-galactosidase A; GLA=galactosidase alpha; GL-3=globotriaosylceramide.
Think Fabry, think renal involvement that may present early in life and could go undetected
Renal manifestations over time
- Early and progressive GL-3 accumulation can lead to irreversible organ damage and potentially life-threatening clinical events5
- Renal damage may occur with podocyte injury, starting as early as the first decade of life, despite minimal or normal microalbuminuria6,7
- Renal biopsy can provide direct assessment of the level of pathological structural changes and may help guide the decision of when to initiate treatment8
Adapted from Schiffmann R et al, 2009; Ortiz A et al, 2008; Germain DP, 2010; Ramaswami U et al, 2010; Eng CM et al, 2006; Tøndel C et al, 2013; and Banikazemi M et al, 2007.1,5,7,9-12
aAccumulation of GL-3 starts in utero.6
ESRD=end-stage renal disease; GL-3=globotriaosylceramide.
See how Fabry could be linked to unexplained chronic kidney disease |
Think Fabry, think cardiac symptoms before serious complications occur13-15
Cardiac manifestations over time
EKG abnormalities in Fabry disease include:1,16,17
- Bradycardia, which is a common finding in adults and frequently present in children
- Voltage criteria and repolarization changes related to left ventricular hypertrophy and/or remodeling
- ST segment depression
- T-wave inversions
- Shortened P-wave duration, which is one of the earliest signs of cardiac involvement15
- Enlarged QRS complex and prolonged QTc intervals, which have been associated with advancing Fabry disease15
Adapted from Schiffmann R et al, 2009; Ortiz A et al, 2008; Germain DP, 2010; Ramaswami U et al, 2010; Eng CM et al, 2006; Tøndel C et al, 2013; and Banikazemi M et al, 2007.1,5,7,9-12
aAccumulation of GL-3 starts in utero.6
GL-3=globotriaosylceramide.
Think Fabry, think neurologic symptoms before serious consequences result
Neurologic manifestations over time1,18-20
Differentiating Fabry disease from multiple sclerosis
- As many as 7% of people with Fabry disease were previously misdiagnosed with multiple sclerosis due to overlapping
presentation21-23 - Absence of infratentorial and corpus collosum lesions on MRI can aid in the differential diagnosis between MS and Fabry disease24
GI=gastrointestinal; CNS=central nervous system; MS=multiple sclerosis.
Fabry disease results in the accumulation of glycosphingolipids, GL-3 and its deacylated form (without fatty acid), lyso-GL-325
The following are key recommendations for the practical application of GL-3 and lyso-GL-3 in clinical practice25
| Biomarker | Application | Recommendations |
| Plasma and/or DBS lyso-GL-3 | In the diagnosis and follow-up of patients with classic Fabry disease, regardless of age or sex of the patient. Assess in male patients with classic Fabry disease for monitoring pharmacodynamic response to the treatment. Aid in risk stratification for males and females with Fabry disease26 |
|
DBS=dried blood spot; ERT=enzyme replacement therapy.
aLimited evidence of benefit following change in ERT type in terms of predicting clinical events. Adapted from Burlina A et al, 2023.25
Think Fabry, think GL-3 accumulation
Pathogenic variants in the GLA gene lead to deficiency of α-GAL A activity resulting in GL-3 and lyso-GL-3 accumulation in various tissues.1,2 Accumulation of GL-3 in vascular endothelia causes tissue damage in a number of organ systems and is regarded as a distinguishing feature of Fabry disease.3
Accumulation of GL-3 and increased disease burden in classic Fabry disease over time4
α-GAL A=α-galactosidase A; GLA=galactosidase alpha; GL-3=globotriaosylceramide.
Think Fabry, think renal involvement that may present early in life and could go undetected
Renal manifestations over time
- Early and progressive GL-3 accumulation can lead to irreversible organ damage and potentially life-threatening clinical events5
- Renal damage may occur with podocyte injury, starting as early as the first decade of life, despite minimal or normal microalbuminuria6,7
- Renal biopsy can provide direct assessment of the level of pathological structural changes and may help guide the decision of when to initiate treatment8
Adapted from Schiffmann R et al, 2009; Ortiz A et al, 2008; Germain DP, 2010; Ramaswami U et al, 2010; Eng CM et al, 2006; Tøndel C et al, 2013; and Banikazemi M et al, 2007.1,5,7,9-12
aAccumulation of GL-3 starts in utero.6
ESRD=end-stage renal disease; GL-3=globotriaosylceramide.
See how Fabry could be linked to unexplained chronic kidney disease |
Think Fabry, think cardiac symptoms before serious complications occur13-15
Cardiac manifestations over time
EKG abnormalities in Fabry disease include:1,16,17
- Bradycardia, which is a common finding in adults and frequently present in children
- Voltage criteria and repolarization changes related to left ventricular hypertrophy and/or remodeling
- ST segment depression
- T-wave inversions
- Shortened P-wave duration, which is one of the earliest signs of cardiac involvement15
- Enlarged QRS complex and prolonged QTc intervals, which have been associated with advancing Fabry disease15
Adapted from Schiffmann R et al, 2009; Ortiz A et al, 2008; Germain DP, 2010; Ramaswami U et al, 2010; Eng CM et al, 2006; Tøndel C et al, 2013; and Banikazemi M et al, 2007.1,5,7,9-12
aAccumulation of GL-3 starts in utero.6
GL-3=globotriaosylceramide.
Think Fabry, think neurologic symptoms before serious consequences result
Neurologic manifestations over time1,18-20
Differentiating Fabry disease from multiple sclerosis
- As many as 7% of people with Fabry disease were previously misdiagnosed with multiple sclerosis due to overlapping
presentation21-23 - Absence of infratentorial and corpus collosum lesions on MRI can aid in the differential diagnosis between MS and Fabry disease24
GI=gastrointestinal; CNS=central nervous system; MS=multiple sclerosis.
Fabry disease results in the accumulation of glycosphingolipids, GL-3 and its deacylated form (without fatty acid), lyso-GL-325
The following are key recommendations for the practical application of GL-3 and lyso-GL-3 in clinical practice25
| Biomarker | Application | Recommendations |
| Plasma and/or DBS lyso-GL-3 | In the diagnosis and follow-up of patients with classic Fabry disease, regardless of age or sex of the patient. Assess in male patients with classic Fabry disease for monitoring pharmacodynamic response to the treatment. Aid in risk stratification for males and females with Fabry disease26 |
|
DBS=dried blood spot; ERT=enzyme replacement therapy.
aLimited evidence of benefit following change in ERT type in terms of predicting clinical events. Adapted from Burlina A et al, 2023.25
Think Fabry, think potentially life-threatening, multisystemic disease progression1,2,28
Irreversible damage to multiple vital organs can cause renal, cardiovascular, and cerebrovascular complications if Fabry disease is left untreated.1,2,28
Multisystemic signs and symptoms
Open the tabs below to learn more about the symptoms associated with each organ system
- Neuropathic pain
- Pain crises
- Heat and/or cold intolerance
- Hypohidrosis/hyperhidrosis
- 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
- Depression/anxiety
- Fatigue
- Dyspnea
- Wheezing
- Chronic cough
- Shortness of breath
- Progressive LVH
- Chest pain
- Bradycardia
- Cardiomyopathy
- Ventricular fibrosis
- Arrhythmias, some of which can be lethal
- Heart failure
- Pathological albuminuria/proteinuria
- Decreased glomerular filtration rate
- Kidney failure
- Transient ischemic attack
- Early stroke
Patients with classic 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 population36-38
Indication
References: 1. Germain DP. Orphanet J Rare Dis. 2010;5:30. 2. Ortiz A et al. Mol Genet Metab. 2018;123(4):416-427. 3. Wanner C et al. Mol Genet Metab. 2018;124(3):189-203. 4. Eng CM et al. J Inherit Metab Dis. 2007;30(2):184-192. 5. Eng CM et al. Genet Med. 2006;8(9):539-548. 6. Tøndel C et al. Nephron. 2015;129(1):16-21. 7. Tøndel C et al. J Am Soc Nephrol. 2013;24(1):37-148. 8. Hopkin JR et al. Mol Genet Metab. 2016;117(2):104-113. 9. Schiffmann R et al. Nephrol Dial Transplant. 2009;24(7):2102-2111. 10. Ortiz A et al. Nephrol Dial Transplant. 2008;23(5)1600-1607. 11. Ramaswami U et al. Clin J Am Soc Nephrol. 2010;5(2):365-370. 12. Banikazemi M et al. Ann Intern Med. 2007;146(2):77-86. 13. Seydelmann N et al. Best Pract Res Clin Endocrinol Metab. 2015;29(2):195-204. 14. Chimenti C et al. Hum Pathol. 2015;46(11):1760-1768. 15. Namdar M. Front Cardiovasc Med. 2016;3:1-7. 16. Pieroni M et al. J Am Coll Cardiol. 2021;77(7):923-936. 17. Wilson HC et al. Am J Cardiol. 2017;251-255. 18. Sims K. Stroke. 2009;40:788-794. 19. Fellgiebel A et al. Lancet Neurol. 2006;5(9):791-795. 20. Politei JM et al. CNS Neurosci Ther. 2016;22:568-576. 21. Lidove O et al. Clin Genet. 2012;81(6):571-577. 22. Colomba P et al. Oncotarget. 2018;9(8):7758-7762. 23. Bottcher T et al. PLoS One. 2013;8(8):e71894. 24. Ugga L et al. Brain Behav. 2018;8(11):e01121. 25. Burlina A et al. Mol Genet Metab. 2023;139(2):107585. 26. van der Veen S et al. Clin J Am Soc Nephrol. 2023;18(10):1272-1282. 27. Germain DP et al. Mol Gen Metab. 2022;137:49-61. 28. Wanner C et al. Mol Genet Metab. 2019;126(3):210-211. 29. Lidove O et al. Intl J Clin Pract. 2006;60(9):1053-1059. 30. Burlina A et al. BMC Neurol. 2011;11(61). 31. Sodi A et al. Br J Ophthalmol. 2007;91(2):210-214. 32. Zarate Y, Hopkin R. Lancet. 2008;372:1427-1435. 33. Yousef Z et al. Eur Heart J. 2013;34(11):802-808. 34. Linhart A et al. J Inherit Metab Dis. 2001;24(2):75-83. 35. Shi Q et al. J Stroke Cerebrovasc Dis. 2014;25(5):985-992. 36. Waldek S et al. Genet Med. 2009;11(11):790-796. 37. Mehta A et al. J Med Genet. 2009;46(8):548-552. 38. 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.
