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Fabry Disease

  • Fabry disease is a rare, progressive, X-linked inherited disorder caused by deficiency of the enzyme α-galactosidase A (α-GAL A)1

  • It is a multisystemic disorder that may ultimately result in irreversible, potentially life-altering disease of the kidney, heart and brain1,2

What are the symptoms of Fabry disease?

Fabry disease affects many parts of the body and is commonly misdiagnosed. Be on the lookout for presenting symptoms and manifestations of Fabry disease.

Fabry Disease Symptom Overview:1,3,4

TIA=transient ischemic attack.

Diagnostic delays are common due to the heterogeneous nature of the disease and the fact that many symptoms are nonspecific1

In a US study of 2848 patients in the Fabry Registry:

  • The life expectancy in males was 58.2 years (vs. 74.7 years in the general population), while in females it was 75.4 years (vs. 80.0 years in the general population).*

If you suspect Fabry disease in one of your patients, take action.
Learn about testing options for Fabry disease

* Data from 2848 patients in the Fabry Registry were summarized using descriptive statistics. Life expectancy at birth was compared with that of the United States general population.

How is Fabry disease inherited?

Explaining Fabry Disease Inheritance to Patients and Families: X-Linked, Not Recessive1te

Random X-chromosome inactivation in Fabry disease means heterozygous females may be symptomatic, which may be a consequence of a skewed X-chromosome inactivation1

 

What are the clinical red flags?

Are you looking for Fabry disease?

You play an important role in identifying patients with this progressive, often life-altering genetic disease.

 

Clinical manifestations of Fabry disease include stroke, cardiomyopathy, and renal insufficiency6

From an online database study of 67 publications that spanned 1995–2017 and screened for people living with Fabry disease (n=51,363), the prevalence of Fabry disease in patients who present with these manifestations was:7

~0.13%
in patients with stroke

~0.18%
in patients with end-stage renal disease

 

What is the hallmark of Fabry disease?8

GL-3 accumulation and Alpha-Galactosidase (α-GAL A) Deficiency

  • Fabry disease is caused by mutations in the galactosidase alpha (GLA) gene that cause deficiency of the enzyme α-galactosidase A (α-GAL A)8
  • This results in continuous, progressive cellular accumulation of lysosomal globotriaosylceramide (GL-3) and its deacetylated form (Lyso-GL3) throughout the body8,9
  • GL-3 buildup starts in utero and accumulation of GL-3 eventually leads to life-threatening complications typically in the third to fifth decade of life10

 

Adapted from Smid BE, et al.
α-GAL A=lysosomal α-galactosidase A enzyme; GLA mutation=defined as any abnormality found in GLA gene; LVH=left ventricular hypertrophy defined as MWT N 12 mm Gb3=globotriaosylsphingosine; GVUS=genetic variant of unknown significance, is defined as a GLA mutation that has unknown clinical significance because it does not fulfill the criteria of a definite diagnosis of Fabry disease.

In patients with an uncertain diagnosis of Fabry disease, presenting with signs such as LVH, renal failure, or proteinuria, the gold standard for a diagnosis of Fabry disease is demonstration of the characteristic in the affected organ.

Please see guidelines for complete recommendations.

 

 

Explore clinical red flags in your specialty

Recommendations for cardiac disease implications of Fabry disease12

  • 2D and Doppler echocardiography is recommended in all patients at first clinical visit, with the development of new symptoms and every 12 to 24 months
  • In symptomatic patients with LVH, Doppler echocardiography during exercise in the standing, sitting or semi-supine position is recommended to detect provocable LV outflow obstruction and exercise-induced mitral regurgitation

Consider cardiac MRI over echocardiography when available

Please see guidelines for complete recommendations.

LV=left ventricle; LVH=left ventricular hypertrophy.

dark blue divider line

Case study cardiomyopathies visualized by imaging techniques

Cardiomyopathies of Fabry disease include left ventricular hypertrophy (LVH) and/or hypertrophic cardiomyopathy (HCM)

A “cardiac variant” of Fabry disease may include patients who present with LVH and conduction disease but without the classic extracardiac symptoms of Fabry disease.13

Cardiac imaging may include:14

Concentric ventricular hypertrophy on echocardiography
Echocardiogram showing ventricular hypertrophy via the left chamber (A) and 4-chamber apical (B)

Hypertrophic cardiomyopathy on cardiac magnetic resonance
Cardiac magnetic resonance (T1) showing hypertrophic cardiomyopathy with hyperenhancement relief at the left ventricular wall.

Actual Fabry patient. May not be representative of all patients.

Adapted from Serra W and Marziliano N.

Angiokeratomas are the most visible early signs of Fabry disease and a common dermatological manifestation1
Dermatology example image 1
Example Dermatology image 2

Images reproduced with permission of Robert Desnick, MD.

Angiokeratomas appear as clusters of small reddish purple, raised, non-blanchable skin lesions. They are usually found between the umbilicus and thigh in Fabry disease, with onset typically in childhood.1,2

Other cutaneous manifestations1

  • Telangiectasias
  • Hypohidrosis/anhidrosis
  • Lymphedema

In a 2,446 patient registry, 138 patients had a stroke. It was shown that stroke was often the first major clinical event in patients with Fabry disease15*

 

Median age of Fabry patients at first stroke15

39 Years

46 years

Risk of stroke in Fabry patients vs. general population15 (patients 35-45 years)

 

4.89 strokes per 1,000 person years of follow-up in males

1.83 strokes per 1,000 person years of follow-up in females

 

 

Other neurological manifestations1

  • Pain
  • Auditory abnormalities
  • White matter lesions

Adapted from Sims K.
* Data analysis of 2,446 patients in the Fabry Registry to identify clinical characteristics of patients experiencing stroke during the natural history period (i.e., before enzyme replacement therapy).

Persistent albuminuria, persistent proteinuria, and eGFR <90 mL/min/1.73 m2 are screening markers for Fabry disease16

 

Renal histopathology may include:

Podocyte injury
Vacuolization of mesangial cells and podocytes. The black arrows point to mesangial cells and the blue arrow points to the podocyte cell.

Adapted from Rozenfeld PA, et al.17

Glomerular sclerosis
Glomerulus with early signs of focal segmental glomerulosclerosis. The arrows point to the glomerulus.

Adapted from Tøndel C, et al.18

Tubulo-interstitial fibrosis
Mallory trichromic reaction showing mild interstitial fibrosis. Erythrocytes and tissue are stained red, whereas the fibrosis is stained blue.

Adapted from Rozenfeld PA, et al.17

Actual Fabry patient. May not be representative of all patients.

Corneal opacities are common and early ocular signs to manifest in Fabry disease:1,19
  • Cornea verticillata
  • Posterior capsular cataracts with whitish spoke-like deposits of granular material (Fabry cataract)
  • Aneurysmal dilation of thin-walled venules on the bulbar conjunctiva
  • Mild-to-marked tortuosity and angulation of the retinal vessels

Typical cornea verticillata and corneal haze

Typical cornea verticillata and corneal haze

Tortuosity of the retinal vessels

Tortuosity of the retinal vessels

Actual Fabry patient. May not be representative of all patients.

Images used with permission of Langis Michaud, OD, MSc, FAAO (Dipl).

 

 

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How is Fabry disease diagnosed?

Consensus recommendations define a definite diagnosis of Fabry disease as follows:12

  1. GLA mutation with ≤5% GLA activity (leucocytes, mean of reference value, males only)
  2. ≥1 characteristic Fabry disease symptom or sign (neuropathic pain, cornea verticillata, angiokeratoma) or increased plasma (lyso) GL-3 (classical male range) or family members with definite Fabry disease
  3. Gold standard is defined as characteristic storage in an endomyocardial biopsy on electron microscopy

Subjects with LVH failing these criteria have GVUS and an uncertain diagnosis.

Diagnostic delays are common due to the heterogenous nature of the disease and the fact that many symptoms are nonspecific1,20

From an analysis of the US Fabry Registry patients (n=2,236) and data collection period that finalized in 2007, the median age of onset was 13 years for females and 9 years for males.

  • From symptoms onset to a diagnosis of Fabry disease, there was a delay of at least 15 years in both males and females

 

Fabry Disease Genetic Testing Options and Workflow

 

Dried Blood Spot (DBS) Testing for Fabry Disease

In case of Fabry disease suspicion, you can test your patient using a dried blood spot (DBS) sample. In males, the level of α-galactosidase A (α-GAL A) enzyme activity is determined and, if low, should revert to single-gene sequencing. In females, single-gene sequencing should be performed first.

HCM panel

In the event of uncharacterized left ventricular hypertrophy (LVH), you can have your patient undergo genetic testing for hypertrophic cardiomyopathy (HCM) at your cardiovascular genetics reference centre or through external laboratory testing.1,21

GLA Gene Panel and Sequencing for Fabry Disease

DNA analysis for GLA gene mutations is necessary to confirm a diagnosis of Fabry disease in females.1,21

Family and Cascade Testing for Fabry Disease

X-linked genetic condition with a high transmission rate – testing may identify affected relatives early.1,21,22

 

Test the patient, test the family

For every index patient diagnosed, an average of 5 additional affected family members may be identified22

 

 

Canadian Regional Expert Centres for Fabry Disease

You can also refer your patient to the regional expert centre for the diagnosis, treatment and follow-up of Fabry disease.

Click on your region for the contact information in your province.

ATLANTIC REGIONAL EXPERT CENTRE FOR FABRY DISEASE

Halifax

Queen Elizabeth II Health Sciences Centre
Dr. Michael West – Nephrologist

Contact:
Phone: 1-877-998-9797
Fax: 902-473-8099
Email: michael.west@nshealth.ca

Centre for Clinical Research
5790 University Avenue, Rm. B06
Halifax, NS B3H 1V7

 

BRITISH COLUMBIA REGIONAL EXPERT CENTRES FOR FABRY DISEASE

Vancouver

Adult Metabolic Diseases Clinic
Dr. Anna Lehman

Contact:
Phone: 604-875-5965
Fax: 604-875-5967
Email: anna.lehman@vch.ca

2775 Laurel Street, 4th Floor Vancouver, BC V5Z 1 M9 
Gordon and Leslie Diamond Health Care Centre

ALBERTA REGIONAL EXPERT CENTRES FOR FABRY DISEASE 

Calgary 

Metabolics and Genetics in Calgary (M.A.G.I.C.) Clinic
Dr. Aneal Khan

Contact:
Phone: 587-885-3158
Fax: 587-441-8380
Email: clinic@magiccalgary.ca

#102, 6715 8 Street NE, T2E 7H7
Calgary, AB

Calgary 

Metabolic Genetics Clinic Alberta Children's Hospital 
Dr. Kim McBride

Contact:
Phone: 403-955-2711
Fax: 403-592-4218
Email: Kim.McBride@albertahealthservices.ca

28 Oki Drive NW, T3B 6A8
Calgary, AB

Edmonton 

Clinical and Metabolic Genetics Clinic Department of Medical Genetics University of Alberta
Dr. Shailly Jain

Contact:
Phone: 780-407-7333
Fax: 780-407-6845
Email: shailly.jain@albertahealthservices.ca

8-53 Medical Sciences Building 
8613 114 Street, T6G 2H7
Edmonton, AB

ONTARIO REGIONAL EXPERT CENTRES FOR FABRY DISEASE

Ottawa

CHEO (Children’s Hospital of Eastern Ontario)
Dr. Danielle Bourque – Biochemical Geneticist

Contact:
Stacey Smallshaw – Nurse Case Manager
Phone: 613-737-7600 #6522
Email: ssmallshaw@cheo.on.ca

 

Hamilton

McMaster Children’s Hospital, Genetics Clinic
Dr. Shaymaa Shurrab – Pediatric Geneticist

Contact:
Phone: 905-521-2100 #75085
905-521-5085 (Newborn Screening Centre)
Fax: 905-521-2602

 

Toronto

University Health Network (UHN), Fred A. Litwin Family Centre for Genetic Medicine
Dr. Chantal Morel – Medical Geneticist

Contact:
Phone: 416-586-4800 #4220
Referral Fax: 416-619-5523

Crystal Quist, RN BScN MPH Clinical Nurse Specialist – Inherited Metabolic Diseases Program
Phone: 416-586-4800 #3083
Email: crystal.quist@uhn.ca

 

QUEBEC REGIONAL EXPERT CENTRES FOR FABRY DISEASE

Montreal

Hôpital Sacré-Cœur
Dr. Daniel Bichet – Nephrologist

Contact:
Nurse team
Carole Fortier – Clinical Nurse, Nephrology
Phone: 514-338-2222#3110
Email: carole.fortier.cnmtl@ssss.gouv.qc.ca

Claudia Ménard
Phone: 514-338-2222#3720
Email: claudia.menard.cnmtl@ssss.gouv.qc.ca

Kim Beauchesne
Phone: 514-338-2222#2748
Email: kim.beauchesne.cnmtl@ssss.gouv.qc.ca

 

Quebec City

Hôpital Hôtel-Dieu
Dr. Paul Isenring – Nephrologist

Contact:
Phone: 418-525-4444 #15464 or #15886
Email: paul.isenring@crchudequebec.ulaval.ca

 

Sherbrooke

Hôpital Fleurimont
Dr. Bruno Maranda – Geneticist

Contact:
Caroline Barr – Clinical Nurse, Genetics
Phone: 819-346-1110 #13933
Email: caroline.barr.ciussse-chus@ssss.gouv.qc.ca

 

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  2. Desnick RJ, et al. Ann Intern Med 2003;138:338–46
  3. Mehta A, Beck M, Sunder-Plassmann G, editors. Fabry Disease: Perspectives from 5 Years of FOS. Oxford: Oxford PharmaGenesis; 2006. Available from: https://www.ncbi.nlm.nih.gov/books/NBK11586/.
  4. Laney DA, et al. Genet Med 2015;17(5):323–33.
  5. Waldek S, et al. Genet Med 2009;11(11):790–6.
  6. Kolodny EH and Pastores GM. J Am Soc Nephrol 2002;13(suppl 2):S150–3.
  7. Doheny D, et al. J Med Genet 2018;55:261–8.
  8. Bokhari SRA, et al. Fabry Disease. In: StatPearls. Treasure Island, FL: StatPearls Publishing; 2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK435996/.
  9. Svarstad E & Marti HP. The Changing landscape of Fabry Disease. Clin J Am Soc Nephrol 2020;15(4):569–76.
  10. Ellaway C. Transl Pediatr 2016;5(1):37–42.
  11. Smid BE, et al. Int J Cardiol 2014;177:400-8.
  12. Linhart A, et al. Eur J Heart Fail 2020;22:1076–96.
  13. Linhart A and Elliott PM. Heart 2007;93:528–35.
  14. Serra W and Marziliano N. J Cardiovasc Ultrasound 2019;17:1.
  15. Sims K, et al. Stroke 2009;40:788–94.
  16. Terryn W, et al. Nephrol Dial Transplant 2013;28(3):505–17.
  17. Rozenfeld PA, et al. Mol Genet Metab 2020;129(2):132–41.
  18. Tøndel C, et al. Am J Kidney Dis 2008;51(5):767–76.
  19. Desnick RJ, Ioannou YA and Eng CM. α-Galactosidase A Deficiency: Fabry Disease. In: Valle D, et al. eds. New York, NY: McGraw-Hill; 2014. Available from: http://ommbid.mhmedical.com/content.aspx?bookid=971&Sectionid=62644837.
  20. Wilcox WR, et al. Mol Genet Metab 2008;93(2):112–28.
  21. Mehta A, et al. Q J Med 2010;103(9):641–59.
  22. Laney D and Fernhoff PM. J Genet Counsel 2008;17:79–83.

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