Fabry disease

Fabry disease
Other names: Fabry's disease, Anderson–Fabry disease, angiokeratoma corporis diffusum, alpha-galactosidase A deficiency
Alpha galactosidase - the deficient protein in Fabry disease
Pronunciation
  • /ˈfɑːbri/
SpecialtyEndocrinology, cardiology, nephrology, dermatology
ComplicationsHeart failure, abnormal heart rhythms
Usual onsetChildhood
CausesGenetic
Diagnostic methodEnzyme activity assay, genetic testing
Differential diagnosisHypertrophic cardiomyopathy
TreatmentEnzyme replacement

Fabry disease, also known as Anderson–Fabry disease, is a rare genetic disease that can affect many parts of the body, including the kidneys, heart, and skin.[1] Fabry disease is one of a group of conditions known as lysosomal storage diseases.[2]

The genetic mutation that causes Fabry disease interferes with the function of an enzyme that processes biomolecules known as sphingolipids, leading to these substances building up in the walls of blood vessels and other organs. It is inherited in an X-linked manner. Fabry disease is sometimes diagnosed using a blood test that measures the activity of the affected enzyme called alpha-galactosidase, but genetic testing is also sometimes used, particularly in females.

The treatment for Fabry disease varies depending on the organs affected by the condition, and the underlying cause can be addressed by replacing the enzyme that is lacking.

The first descriptions of the condition were made simultaneously by dermatologist Johannes Fabry[3] and the surgeon William Anderson[4] in 1898.[5]

Signs and symptoms

A bilateral, whorl-like corneal pattern of cream-colored lines in a person with Fabry disease
Angiokeratoma, a common skin manifestation in Fabry disease

Symptoms are typically first experienced in early childhood and can be very difficult to understand; the rarity of Fabry disease to many clinicians sometimes leads to misdiagnoses. Manifestations of the disease usually increase in number and severity as an individual ages.[6]

Pain

Full-body or localized pain to the extremities (known as acroparesthesia) or gastrointestinal (GI) tract is common in patients with Fabry disease. This pain can increase over time. This acroparesthesia is believed to be related to the damage of peripheral nerve fibers that transmit pain. GI-tract pain is likely caused by accumulation of lipids in the small vasculature of the GI tract, which obstructs blood flow and causes pain.[7]

Kidney

Kidney complications are common and serious effects of the disease; chronic kidney disease and kidney failure may worsen throughout life. The presence of protein in the urine (which causes foamy urine) is often the first sign of kidney involvement. End-stage kidney failure in those with Fabry disease typically occurs in the third decade of life, and is a common cause of death due to the disease.

Heart

Fabry disease can affect the heart in several ways. The accumulation of sphingolipids within heart muscle cells causes abnormal thickening of the heart muscle or hypertrophy. This hypertrophy can cause the heart muscle to become abnormally stiff and unable to relax, leading to a restrictive cardiomyopathy causing shortness of breath.[8][9]

Fabry disease can also affect the way in which the heart conducts electrical impulses, leading to both abnormally slow heart rhythms such as complete heart block, and abnormally rapid heart rhythms such as ventricular tachycardia. These abnormal heart rhythms can cause blackouts, palpitations, or even sudden cardiac death.[8][9]

Sphingolipids can also build up within the heart valves, thickening the valves and affecting the way they open and close. If severe, this can cause the valves to leak (regurgitation) or to restrict the forward flow of blood (stenosis). The aortic and mitral valves are more commonly affected than the valves on the right side of the heart.[8][9]

Skin

Angiokeratomas (tiny, painless papules that can appear on any region of the body, but are predominant on the thighs, around the navel, buttocks, lower abdomen, and groin) are common.[10]

Anhidrosis (lack of sweating) is a common symptom, and less commonly hyperhidrosis (excessive sweating).

Additionally, patients can exhibit Raynaud's disease-like symptoms with neuropathy (in particular, burning extremity pain).

Ocular involvement may be present showing cornea verticillata (also known as vortex keratopathy), i.e. clouding of the corneas. Keratopathy may be the presenting feature in asymptomatic patients, and must be differentiated from other causes of vortex keratopathy (e.g. drug deposition in the cornea).[11] This clouding does not affect vision.[11]

Other ocular findings can include conjunctival and retinal vascular abnormalities and anterior/posterior spoke-like cataract. Visual reduction from these manifestations is uncommon.

Other manifestations

Fatigue, neuropathy (in particular, burning extremity pain, red hands and feet on and off), cerebrovascular effects leading to an increased risk of stroke - early strokes, mostly vertebrobasilar system tinnitus (ringing in the ears), vertigo, nausea, inability to gain weight, chemical imbalances, and diarrhea are other common symptoms.

Causes

Fabry disease is caused by a DNA sequence (gene) that is not functioning as it should. A person who inherits this gene does not have enough of a functioning enzyme known as alpha-galactosidase A. The lack of alpha-galactosidase leads to Fabry disease. A deficiency of alpha galactosidase A (a-GAL A, encoded by GLA) due to mutation causes a glycolipid known as globotriaosylceramide (abbreviated as Gb3, GL-3, or ceramide trihexoside) to accumulate within the blood vessels, other tissues, and organs.[12] This accumulation leads to an impairment of their proper functions.

At least 443 disease-causing mutations in the GLA gene have been discovered.[13] The DNA mutations that cause the disease are X-linked recessive with incomplete penetrance in heterozygous females. The condition affects hemizygous males (i.e. all non-intersex males), as well as homozygous, and in many cases heterozygous females. While males typically experience severe symptoms, women can range from being asymptomatic to having severe symptoms. New research suggests many women suffer from severe symptoms ranging from early cataracts or strokes to hypertrophic left ventricular heart problems and kidney failure. This variability is thought to be due to X-inactivation patterns during embryonic development of the female.[14]

Mechanism

Fabry disease is an inherited lysosomal storage disorder that is caused by a deficiency of alpha-galactosidase A. This enzyme deficiency is a result of an accumulation of glycosphingolipids found in the lysosomes and most cell types and tissues, which leads it to be considered a multisystem disease. Indications include painful crisis, angiokeratomas, corneal dystrophy, and hypohydrosis.[15] In severe cases there is renal, cerebrovascular, and cardiac involvement and it is predominately responsible for premature mortality in Fabry patients.[15] Fabry disease is X-linked and manifests mostly in homozygous males but also in heterozygous females. Cardiac involvement is recurrent in Fabry patients. Patients have developed hypertrophic cardiomyopathy, arrhythmias, conduction abnormalities, and valvular abnormalities.[15] Deficient activity of lysosomal alpha-galactosidase results in progressive accumulation of globotriaosylceramide (GL-3) within lysosomes, that is believed to trigger a cascade of cellular events.[16] The demonstration of marked alpha-galactosidase deficiency is the conclusive method for the diagnosis in homozygous males. It may be detected in heterozygotous females, but it is often inconclusive due to random X-chromosomal inactivation, so molecular testing (genotyping) of females is mandatory.[16]

Diagnosis

a)DEXA of the femoral neck b) and the lumbar spine

Fabry disease is suspected based on the individual's clinical presentation, and can be diagnosed by an enzyme assay (usually done on leukocytes) to measure the level of alpha-galactosidase activity. An enzyme assay is not reliable for the diagnosis of disease in females due to the random nature of X-inactivation. Molecular genetic analysis of the GLA gene is the most accurate method of diagnosis in females, particularly if the mutations have already been identified in male family members. Many disease-causing mutations have been noted. Kidney biopsy may also be suggestive of Fabry disease if excessive lipid buildup is noted. Pediatricians, as well as internists, commonly misdiagnose Fabry disease.[17] All immediate and extended family members in the same family have the same family mutation, so if one member of a family has a DNA sequence analysis performed, other members of the family can be diagnosed by performing a targeted sequence analysis instead of testing the entire gene.[18] Targeted sequencing is quicker and less expensive to perform. One study reported that for every first diagnosis in a family, on average five more family members (immediate and extended) are also diagnosed.[18]

MRI is accurate in accessing left ventricular mass and thickness and hypertrophy. Late gadolinium enhancement shows increased signal of the midwall at the inferolateral wall of the base of the left ventricle, usually in the non-hypertrophic ventricle. T1-weighted imaging can show low T1 signal due to sphingolipid storage in the heart even without ventricular hypertrophy in 40% of the those affected by the disease. Thus, MRI is a useful way of diagnosing the disease early.[19] T2 signal is increased in inflammation and oedema.[20]

Treatment

The treatments available for Fabry disease can be divided into therapies that aim to correct the underlying problem of decreased activity of the alpha galactosidase A enzyme and thereby reduce the risk of organ damage, and therapies to improve symptoms and life expectancy once organ damage has already occurred.

Enzyme replacement therapy

Enzyme replacement therapy is designed to provide the enzyme the patient is missing as a result of a genetic malfunction. This treatment is not a cure, but can partially prevent disease progression, and potentially reverse some symptoms.[21]

The pharmaceutical company Shire manufactures agalsidase alpha (which differs in the structure of its oligosaccharide side chains[22]) under the brand name Replagal as a treatment for Fabry's disease,[23] and was granted marketing approval in the EU in 2001.[24] FDA approval was applied for the United States.[25] However, Shire withdrew their application for approval in the United States in 2012, citing that the agency will require additional clinical trials before approval.[26]

The first treatment for Fabry's disease to be approved by the US FDA was Fabrazyme (agalsidase beta, or alpha-galactosidase) in 2003, licensed to the Genzyme Corporation.[27] The drug is expensive — in 2012, Fabrazyme's annual cost was about US$200,000 per patient,[28] which is unaffordable to many patients around the world without enough resources or insurance. Infusion of the enzyme preparation seems to be well tolerated and effective in catabolizing the lipid deposits.[15]

Clinically, the two products are generally perceived to be similar in effectiveness. Both are available in Europe and in many other parts of the world, but treatment costs remain very high.[29] While increasing evidence shows that long-term enzyme therapy can halt the disease progression, the importance of adjunctive therapies should be emphasized and the possibility of developing an oral therapy pushes research forward into active site specific chaperones.[16]

Besides these drugs, a gene therapy treatment is in clinical trials,[30][31] with the technology licensed to AvroBio.[32] Other treatments under research include: plant-based ERT from Protalix, substrate reduction therapy from Sanofi-Genzyme, bio-better ERT from Codexis, and a gene editing solution from Sangamo.[33]

Organ-specific treatment

Pain associated with Fabry disease may be partially alleviated by enzyme replacement therapy in some patients, but pain management regimens may also include analgesics, anticonvulsants, and nonsteroidal anti-inflammatory drugs, though the latter are usually best avoided in kidney disease. The kidney failure seen in some of those with Fabry disease sometimes requires haemodialysis. The cardiac complications of Fabry disease include abnormal heart rhythms, which may require a pacemaker or implantable cardioverter-defibrillator, while the restrictive cardiomyopathy often seen may require diuretics.[21]

Prognosis

Life expectancy with Fabry disease for males was 58.2 years, compared with 74.7 years in the general population, and for females 75.4 years compared with 80.0 years in the general population, according to registry data from 2001 to 2008. The most common cause of death was cardiovascular disease, and most of those had received kidney replacements.[34]

Epidemiology

Fabry disease is panethnic, but due to its rarity, determining an accurate disease frequency is difficult.[16] Reported incidences, ranging from one in 476,000 to one in 117,000 in the general population, may largely underestimate the true prevalence.[16] Newborn screening initiatives have found an unexpectedly high prevalence of the disease, as high as one in about 3,100 newborns in Italy and have identified a surprisingly high frequency of newborn males around one in 1,500 in Taiwan.[16]

Research

  • Enzyme replacement therapy: Replacement of the missing enzyme to clear the lipids (GL-3) from the cells[18]
  • Substrate synthesis inhibition, also called substrate reduction therapy: Inhibits the production of the lipid (GL-3) that accumulates in the cells[18]
  • Chaperone therapy: Uses small-molecule drugs that bind to the defective enzyme and stabilize it to increase enzyme activity and increase cellular function[18]
  • Gene editing: Technology that can potentially cut and fix a broken gene in a cell[18]
  • Gene therapy: Genetically modifies the affected cells to produce the missing enzyme.[18]

History

Fabry disease was first described by dermatologist Johannes Fabry[3] and surgeon William Anderson[4] independently in 1898.[5] It was recognised to be due to abnormal storage of lipids in 1952. In the 1960s, the inheritance pattern was established as being X-linked, as well as the molecular defect responsible for causing the accumulation of glycolipids.[5]

Ken Hashimoto published his classic paper on his electron microscopic findings in Fabry disease in 1965.[35][36]

The first specific treatment for Fabry disease was approved in 2001.[21][24]

Society and culture

  • House ("Epic Fail", season six, episode three) centers on a patient with Fabry disease.
  • Scrubs ("My Catalyst", season three, episode 12) features a Fabry disease diagnosis.
  • Crossing Jordan ("There's No Place Like Home", season two, episode one) features a patient who died suffering from Fabry disease.
  • The Village (Korean drama): "Achiara's Secret"[37] features daughters of a serial rapist who find each other because they share Fabry disease.
  • Doctor John (Korean drama): In episode two, a prisoner is diagnosed with Fabry disease.
  • In Lincoln Rhyme: Hunt for the Bone Collector, a copycat of the titular Bone Collector has Fabry disease and takes Galafold, which allows the detectives to learn his identity.
  • Partners for Justice 2 (Korean drama), features Doctor K, who suffered from Fabry disease.

See also

References

  1. ↑ James, Berger & Elston 2006, p. 538
  2. ↑ Yacoob, M. Magdi; Ashman, Neil (2020). "36. Kidney and urinary tract disease". In Feather, Adam; Randall, David; Waterhouse, Mona (eds.). Kumar and Clark's Clinical Medicine (10th ed.). Elsevier. p. 1367. ISBN 978-0-7020-7870-5. Archived from the original on 2022-12-28. Retrieved 2022-12-28.
  3. 1 2 Fabry, Joh (December 1898). "Ein Beitrag zur Kenntniss der Purpura haemorrhagica nodularis (Purpura papulosa haemorrhagica Hebrae)" [A contribution to the knowledge of the purpura haemorrhagica nodularis (purpura papulosa haemorrhagica Hebrae)]. Archiv für Dermatologie und Syphilis (in Deutsch). 43 (1): 187–200. doi:10.1007/bf01986897. S2CID 33956139. Archived from the original on 2022-01-25. Retrieved 2022-01-03.
  4. 1 2 Anderson, William (April 1898). "A Case of 'Angeio-Keratoma'". British Journal of Dermatology. 10 (4): 113–117. doi:10.1111/j.1365-2133.1898.tb16317.x. S2CID 70966125. Archived from the original on 2022-01-25. Retrieved 2022-01-03.
  5. 1 2 3 Schiffmann, Raphael (2015). "Fabry disease". Neurocutaneous Syndromes. Handbook of Clinical Neurology. Vol. 132. pp. 231–248. doi:10.1016/B978-0-444-62702-5.00017-2. ISBN 9780444627025. PMID 26564084.
  6. ↑ "Fabry disease | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Archived from the original on 2018-04-18. Retrieved 2018-04-17.
  7. ↑ Hoffmann, Bjoern; Beck, Michael; Sunder-Plassmann, Gere; Borsini, Walter; Ricci, Roberta; Mehta, Atul; FOS European, Investigators. (July 2007). "Nature and Prevalence of Pain in Fabry Disease and Its Response to Enzyme Replacement Therapy—A Retrospective Analysis From the Fabry Outcome Survey". The Clinical Journal of Pain. 23 (6): 535–542. doi:10.1097/AJP.0b013e318074c986. PMID 17575495. S2CID 36215895.
  8. 1 2 3 Putko, Brendan N.; Wen, Kevin; Thompson, Richard B.; Mullen, John; Shanks, Miriam; Yogasundaram, Haran; Sergi, Consolato; Oudit, Gavin Y. (March 2015). "Anderson-Fabry cardiomyopathy: prevalence, pathophysiology, diagnosis and treatment". Heart Failure Reviews. 20 (2): 179–191. doi:10.1007/s10741-014-9452-9. ISSN 1573-7322. PMID 25030479. S2CID 11521278.
  9. 1 2 3 Akhtar, M. M.; Elliott, P. M. (2018-06-16). "Anderson-Fabry disease in heart failure". Biophysical Reviews. 10 (4): 1107–1119. doi:10.1007/s12551-018-0432-5. ISSN 1867-2450. PMC 6082315. PMID 29909504.
  10. ↑ "Proceedings of the 24th Paediatric Rheumatology European Society Congress: Part two". Pediatric Rheumatology Online Journal. 15 (Suppl 2): 65. 1 September 2017. doi:10.1186/s12969-017-0186-9. PMC 5592437.
  11. 1 2 Chew, E.; Ghosh, M.; McCulloch, C. (June 1982). "Amiodarone-induced cornea verticillata". Canadian Journal of Ophthalmology. 17 (3): 96–99. PMID 7116220.
  12. ↑ Karen, Julie K.; Hale, Elizabeth K.; Ma, Linglei (2005). "Angiokeratoma corporis diffusum (Fabry disease)". Dermatology Online Journal. 11 (4): 8. doi:10.5070/D30TT696NJ. PMID 16403380. Archived from the original on 2021-12-05. Retrieved 2022-01-03.
  13. ↑ Šimčíková D, Heneberg P (December 2019). "Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases". Scientific Reports. 9 (1): 18577. Bibcode:2019NatSR...918577S. doi:10.1038/s41598-019-54976-4. PMC 6901466. PMID 31819097.
  14. ↑ James, Berger & Elston 2006, pp. 
  15. 1 2 3 4 Perrot, Andreas; Osterziel, Karl Josef; Beck, Michael; Dietz, Rainer; Kampmann, Christoph (1 November 2002). "Fabry Disease: Focus on Cardiac Manifestations and Molecular Mechanisms". Herz. 27 (7): 699–702. doi:10.1007/s00059-002-2429-9. PMID 12439642. S2CID 25962218.
  16. 1 2 3 4 5 6 Germain, Dominique P (2010). "Fabry disease". Orphanet Journal of Rare Diseases. 5 (1): 30. doi:10.1186/1750-1172-5-30. PMC 3009617. PMID 21092187.
  17. ↑ Marchesoni, Cintia L.; Roa, Norma; Pardal, Ana María; Neumann, Pablo; Cáceres, Guillermo; Martínez, Pablo; Kisinovsky, Isaac; Bianchi, Silvia; Tarabuso, Ana Lía; Reisin, Ricardo C. (May 2010). "Misdiagnosis in Fabry disease". The Journal of Pediatrics. 156 (5): 828–31. doi:10.1016/j.jpeds.2010.02.012. PMID 20385321.
  18. 1 2 3 4 5 6 7 "You are being redirected..." www.fabrydisease.org. Archived from the original on 2019-12-13. Retrieved 2019-12-13.
  19. ↑ Hagège, Albert; Réant, Patricia; Habib, Gilbert; Damy, Thibaud; Barone-Rochette, Gilles; Soulat, Gilles; Donal, Erwan; Germain, Dominique P. (April 2019). "Fabry disease in cardiology practice: Literature review and expert point of view". Archives of Cardiovascular Diseases. 112 (4): 278–287. doi:10.1016/j.acvd.2019.01.002. PMID 30826269.
  20. ↑ Baig, S; Vijapurapu, R; Alharbi, F; Nordin, S; Kozor, R; Moon, J; Bembi, B; Geberhiwot, T; Steeds, R P (2019-01-01). "Diagnosis and treatment of the cardiovascular consequences of Fabry disease". QJM: An International Journal of Medicine. 112 (1): 3–9. doi:10.1093/qjmed/hcy120. ISSN 1460-2725. PMID 29878206. Archived from the original on 2020-06-29. Retrieved 2022-01-03.
  21. 1 2 3 Wanner, Christoph; Arad, Michael; Baron, Ralf; Burlina, Alessandro; Elliott, Perry M.; Feldt-Rasmussen, Ulla; Fomin, Victor V.; Germain, Dominique P.; Hughes, Derralynn A. (June 2018). "European expert consensus statement on therapeutic goals in Fabry disease" (PDF). Molecular Genetics and Metabolism. 124 (3): 189–203. doi:10.1016/j.ymgme.2018.06.004. ISSN 1096-7206. PMID 30017653. S2CID 51676692. Archived (PDF) from the original on 2021-01-20. Retrieved 2022-01-03.
  22. ↑ Fervenza, Fernando C.; Torra, Roser; Warnock, David G. (December 2008) [13 November 2008]. "Safety and efficacy of enzyme replacement therapy in the nephropathy of Fabry disease". Biologics. 2 (4): 823–843. doi:10.2147/btt.s3770. PMC 2727881. PMID 19707461.
  23. ↑ Keating, Gillian M. (October 2012). "Agalsidase alfa: a review of its use in the management of Fabry disease". BioDrugs. 26 (5): 335–354. doi:10.2165/11209690-000000000-00000. PMID 22946754.
  24. 1 2 "Shire Submits Biologics License Application (BLA) for Replagal with the U.S. Food and Drug Administration (FDA)". FierceBiotech. Archived from the original on 2016-03-03. Retrieved 2022-01-03.
  25. ↑ "With A Life-Saving Medicine In Short Supply, Patients Want Patent Broken". NPR.org. 2010-08-04. Archived from the original on 14 September 2010. Retrieved 2010-09-02.
  26. ↑ Grogan, K. (2012-03-15). "Shire withdraws Replagal in USA as FDA wants more trials". PharmaTimes. Archived from the original on 2014-08-19.
  27. ↑ "Fabrazyme Prescribing Information (USA)" (PDF). www.fda.gov. Archived (PDF) from the original on 2017-02-22. Retrieved 2022-01-03.
  28. ↑ Pollack, Andrew (April 15, 2010). "Genzyme Drug Shortage Leaves Users Feeling Betrayed". The New York Times. Archived from the original on August 7, 2018. Retrieved January 3, 2022.
  29. ↑ Turner, Neil N; Turner, Neil N; Lameire, Norbert; Goldsmith, David J; Winearls, Christopher G; Himmelfarb, Jonathan; Remuzzi, Giuseppe, eds. (2015). Fabry disease: Management and outcome. Vol. 1. Oxford University Press. doi:10.1093/med/9780199592548.003.0338. ISBN 9780199592548. Archived from the original on 2020-04-15. Retrieved 2022-01-03.
  30. ↑ "Canada launches first gene therapy trial for Fabry disease". EurekAlert!. Archived from the original on January 17, 2021. Retrieved May 31, 2020.
  31. ↑ "Open-Label, Study Of Efficacy and Safety Of AVR-RD-01 for Treatment -Naive Subjects With Classic Fabry Disease - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Archived from the original on July 6, 2020. Retrieved May 31, 2020.
  32. ↑ "UHN Start-up AVROBIO, Inc. Announces $60 Million Series B Financing to Advance Gene Therapy Pipeline for Lysosomal Storage Disorders and Apply Lentiviral Platform to Other Genetic Diseases | TDC". Archived from the original on 2020-11-29. Retrieved 2022-01-03.
  33. ↑ "You are being redirected..." www.fabrydisease.org. Archived from the original on May 14, 2020. Retrieved May 31, 2020.
  34. ↑ Waldek, Stephen; Patel, Manesh R.; Banikazemi, Maryam; Lemay, Roberta; Lee, Philip (November 2009). "Life expectancy and cause of death in males and females with Fabry disease: findings from the Fabry Registry". Genetics in Medicine. 11 (11): 790–796. doi:10.1097/GIM.0b013e3181bb05bb. PMID 19745746.
  35. ↑ John Thorne Crissey; Lawrence C. Parish; Karl Holubar (2013). Historical Atlas of Dermatology and Dermatologists. CRC Press. p. 179. ISBN 978-1-84214-100-7. Archived from the original on 2022-01-11. Retrieved 2022-01-03.
  36. ↑ Mehta, Atul; Beck, Michael; Linhart, Aleš; Sunder-Plassmann, Gere; Widmer, Urs (2006), Mehta, Atul; Beck, Michael; Sunder-Plassmann, Gere (eds.), "History of lysosomal storage diseases: an overview", Fabry Disease: Perspectives from 5 Years of FOS, Oxford PharmaGenesis, ISBN 978-1903539033, PMID 21290707, archived from the original on 25 May 2016, retrieved 10 August 2018
  37. ↑ "The Village: Achiara's Secret". Archived from the original on 2020-02-22. Retrieved 2022-01-03.

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