Fabry Disease Manifests Variably

Fabry disease is a progressive, multisystemic disease.Neurological symptoms such as pain, acroparesthesia (abnormal tingling and numbness sensation), and episodic “Fabry crises” of acute pain lasting hours to days and dermatological conditions such as angiokeratomas (reddish-purple, nonblanching maculopapular lesions) are early signals of Fabry disease.2

Gastrointestinal symptoms such as diarrhea, constipation, and abdominal pain, and other signs and symptoms such as hypohidrosis, heat, cold, and exercise intolerance, and corneal verticillata are often reported early.3

As Fabry disease progresses, major organ system dysfunction may worsen. This may include renal failure, cardiovascular complications (such as left ventricular hypertrophy [LVH] and conduction abnormalities), and cerebrovascular complications (such as transient ischemic attack [TIA] and stroke). These conditions may lead to serious morbidity as well as death.3,4

Although the disease presents differently in each individual who has it, it can prove to be a significant burden regardless of presentation.2 Even when symptoms may not be visible or are mild, globotriaosylceramide (GL-3), plasma globotriaosylsphingosine (lyso-Gb3), and other disease substrates may accumulate, which can lead to organ and tissue damage over time.5,6

Common Symptoms and Patterns of Presentation

  • Acroparesthesia2–tingling/burning/abnormal sensation in extremities
  • Acute pain (“Fabry crises”)2–episodic severe pain, often in hands and feet, accompanied by fever that may last from hours to days
  • Hypohidrosis2–too little sweat, affecting regulation of body temperature
  • Corneal verticillata5–streaks or whorls in cornea
  • Angiokeratomas2–benign red and blue skin lesions
  • Gastrointestinal problems, such as abdominal pain and bloating, diarrhea, and early satiety2,7
  • Renal disease, typically requiring dialysis or transplantation after prolonged disease2
  • Cardiac disease, such as left ventricular hypertrophy, valvular disease, and rhythm disturbances2
  • Cerebrovascular symptoms, including dizziness, vertigo, transient ischemic attacks, and stroke2

How Fabry Symptoms Can Affect the Organ Systems

Fabry disease is a progressive, multisystemic, multi-organ disorder.

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Cardiology

Cardiac abnormalities
  • Involvement of all cardiac structures3
  • Angina pectoris, coronary artery disease, myocardial infarction occur3
  • Arrhythmia—frequency increasing with age (permanent artificial pacing needed in 10%-20% of patients)3,8
  • Left ventricular hypertrophy (LVH) in ~50% of patients3
  • Other possible symptoms include trouble regulating blood pressure, poor cerebrovascular activity8
  • Cardiovascular disease is a major cause of mortality
Cerebrovascular manifestations
  • TIA and stroke are common – often before Fabry diagnosis3
  • Recurrence is common and associated with poor prognosis3
  • White matter lesions have been associated with Fabry disease3
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Dermatology

Dermatological symptoms
  • Angiokeratomas are a hallmark of Fabry disease and an early clinical sign. Commonly occur around the lower trunk, also in the oral mucosa and conjunctiva.3,8
  • Diffuse angiokeratomas tend to increase in number and size over time8
  • Hypohidrosis, telangiectasia, and lymphedema are also common3
  • Increasing recognition of facial dysmorphism3
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Gastroenterology

GI symptoms
  • ~50% of patients with Fabry disease3
  • Postprandial abdominal pain and diarrhea are common GI symptoms3
  • Constipation, nausea, and vomiting are also common3
  • Many affected individuals experience symptoms in childhood and have difficulty gaining weight and height8
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Nephrology

Accumulation of GL-3 within lysosomes of glomerular podocytes

Renal dysfunction3,8
  • ~50% of patients with Fabry disease3
  • Proteinuria is the most common symptom3
  • Initial manifestations also include impaired glomerular filtration rate and tubular derangements8
  • Eventual glomerular sclerosis, tubular atrophy, interstitial fibrosis may lead to kidney failure8
  • Chronic kidney disease is the main cause of premature death in classic phenotype. Availability of dialysis and transplant has helped to extend life.8
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Neurology

Neurological symptoms
  • Most frequently reported symptoms in Fabry disease (~80% of patients). Neuropathic pain commonly affects the hands and feet3
  • Early symptoms related to dysfunction of peripheral and autonomic nervous systems; late symptoms due to vascular complications of central nervous system8
  • CNS symptoms increase with age8
  • Burning/tingling pain—widespread but most frequent in hands/feet8
  • Pain may be triggered by physical activity, cold/heat, fever, stress8
  • Autonomic dysfunction—hypohidrosis, exercise intolerance, altered temperature sensitivity8
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Opthalmology

Tortuosity of retinal vessels indicate cornea verticillata

Ocular symptoms
  • Cornea verticillata (pale, spiral streaks or haze in the corneal epithelium) is a diagnostic criterion (>70% of patients)3,8,9
  • Vessel tortuosity may represent a severe phenotype3
  • Ophthalmic features in ~60% of children with Fabry disease3
  • Vascular involvement is common in conjunctival blood vessels and retina, and reduced lacrimal secretions may occur8
  • Ophthalmic manifestations do not usually lead to major visual impairment or symptoms9
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Otolaryngology

Hearing loss

Auditory and vestibular abnormalities
  • Hearing loss (especially in the high tone range), tinnitus, and vertigo are common2,3
  • Sudden deafness may also occur8
  • ~16% of patients with clinically relevant hearing loss3
  • Hearing loss correlates with neuropathic and vascular damage5
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Psychiatry/Psychology

Quality of Life (QoL), depression, and psychosocial effects
  • Multiple disease symptoms can significantly influence patient quality of life3
  • Results from a UK-based survey showed that ~ 46% of patients with Fabry disease experienced depression, 28% of whom could be considered clinically severe3,12
  • Most common association with depression was neuropathic pain13
  • Depression may be caused by coping with symptoms and/or cerebrovascular disease which can interfere with affective functioning and increase frequency/severity of depression13
  • May be severe neuropsychological impairment due to decline in intellectual and global cognitive functioning13
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Pulmonology

Pulmonary effects
  • Dyspnea with exercise, chronic couth/wheezing are frequent5
  • Airway obstruction is common finding5, clinically presenting more like chronic obstructive pulmonary disease than asthma10
  • Sleep-disordered breathing and obstructive sleep apnea is highly prevalent11

Click on the specialty or organ to learn how Fabry disease affects the body.

More information on the organ effects of Fabry disease can be found here or via the National Organization of Rare Diseases.

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  1. Hoffmann B, Mayatepek E. Fabry disease-often seen, rarely diagnosed. Dtsch Arztebl Int. 2009;106(26):440-447.
  2. Desnick RJ, Brady R, Barranger J, et al. Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med. 2003;138(4):338-346.
  3. Mehta A, Beck M, Eyskens F, et al. Fabry disease: a review of current management strategies. Q J Med. 2010;103(9):641-659.
  4. Mehta A, Clarke JT, Giugliani R, et al. Natural course of Fabry disease: changing pattern of causes of death in FOS – Fabry Outcome Survey. J Med Genet. 2009;46(8):548-552.
  5. Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30. doi:10.1186/1750-1172-5-30.
  6. Namdar M, Gebhard C, Studiger R, et al. Globotriaosylsphingosine accumulation and not alpha-galactosidase-A deficiency causes endothelial dysfunction in Fabry disease. PLoS One. 2012;7(4):e36373. doi:10.1371/journal.pone.0036373.
  7. Keshav S. Gastrointestinal manifestations of Fabry disease. In: Mehta A, Beck
    M, Sunder-Plassmann G, eds. Fabry Disease: Perspectives From 5 Years of FOS. Oxford, England: Oxford PharmaGenesis; 2006: Chapter 28. NCBI website. http://www.ncbi.nlm.nih.gov/books/NBK11570/. Accessed December 4, 2015.
  8. Eng CM, Germain DP, Banikazemi M, et al. Fabry disease: guidelines for the evaluation and management of multi-organ system involvement. Genet Med. 2006;8(9):539-548.
  9. Sodi A, Ioannidis A, Pitz S. Ophthalmological manifestations of Fabry disease. In: Mehta A, Beck M, Sunder-Plassmann G, eds. Fabry Disease: Perspectives from 5 Years of FOS. Oxford, England: Oxford PharmaGenesis; 2006: Chapter 26. Available from: https://www.ncbi.nlm.nih.gov/books/NBK11599/. Accessed April 10, 2017.
  10. Aubert JD, Barbey F. Pulmonary involvement in Fabry disease. In: Mehta A, Beck M, Sunder-Plassmann G, eds. Fabry Disease: Perspectives from 5 Years of FOS. Oxford, England: Oxford PharmaGenesis; 2006: Chapter 27. Available from: https://www.ncbi.nlm.nih.gov/books/NBK11589/. Accessed April 10, 2017.
  11. Franzen D, Gerard N, Bratton DJ, et al. Prevalence and risk factors of sleep disordered breathing in Fabry disease. Medicine. 2015;94(52):1-6. Accessed April 10, 2107.
  12. Cole AL, Lee PJ, Hughes DA, Deegan PB, Waldek S, Lachmann RH. Depression in adults with Fabry disease: a common and under-diagnosed problem. J Inherit Metab Dis. 2007;30(6):943-951.
  13. Bolsover FE, Murphy E, Cipolotti L, Werring DJ, Lachmann RH. Cognitive dysfunction and depression in Fabry disease: a systematic review. J Inherit Metab Dis. 2014;37:177-187. doi 10.1007/s10545-013-9643-x.
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