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| {{Infobox medical condition (new)
| | ==Fabry Disease== |
| | name = Fabry disease
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| | pronounce = {{IPAc-en|'|f|ɑː|b|r|i}}
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| | synonyms = Fabry's disease, Anderson–Fabry disease, angiokeratoma corporis diffusum, alpha-galactosidase A deficiency
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| | image = PBB Protein GLA image.jpg
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| |alt=| caption = [[Alpha galactosidase]] - the deficient protein in Fabry disease
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| |specialty=Endocrinology, cardiology, nephrology, dermatology| symptoms =
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| | complications = [[Heart failure]], [[Cardiac arrhythmia|abnormal heart rhythms]]
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| | onset = Childhood
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| | duration =
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| | types =
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| | causes = Genetic
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| | risks =
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| | diagnosis = Enzyme activity assay, genetic testing
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| | differential = [[Hypertrophic cardiomyopathy]]
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| | prevention =
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| | treatment = Enzyme replacement
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| | medication =
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| | prognosis =
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| | frequency =
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| | deaths =
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| }}
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| '''Fabry disease''', also known as '''Anderson–Fabry disease''', is a rare [[genetic disease]] that can affect many parts of the body including the [[kidney]]s, [[heart]], and [[integumentary system|skin]]. Fabry disease is one of a group of conditions known as [[lysosomal storage disease]]s. The [[genetic mutation]] that causes Fabry disease interferes with the function of an [[enzyme]] which processes [[biomolecule]]s known as [[sphingolipids]], leading to these substances building up in the walls of [[blood vessel]]s and other organs. It is inherited in an [[X-linked]] manner.
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| 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. | | '''Fabry disease''' is a rare genetic disorder that results from the buildup of a particular type of fat, called globotriaosylceramide, in the body's cells. It is an [[X-linked recessive]] disorder caused by mutations in the ''GLA'' gene, which leads to a deficiency of the enzyme [[alpha-galactosidase A]]. |
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| 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.
| | ==Pathophysiology== |
| | Fabry disease is characterized by the accumulation of [[glycosphingolipids]] in the [[lysosomes]] of various cell types. The deficiency of alpha-galactosidase A enzyme activity results in the progressive deposition of globotriaosylceramide in the [[vascular endothelium]], [[smooth muscle cells]], and other tissues, leading to multi-systemic manifestations. |
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| The first descriptions of the condition were made simultaneously by the [[Dermatology|dermatologist]] [[Johannes Fabry]] | | ==Clinical Manifestations== |
| | The symptoms of Fabry disease can vary widely among affected individuals, but common manifestations include: |
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| | * [[Angiokeratomas]]: Small, dark red spots on the skin, often found in the "bathing trunk" area. |
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| | * [[Acroparesthesia]]: Episodes of pain and burning sensations in the hands and feet. |
| movie_url=http://www.youtube.com/v/AUkqYvZ9tn0
| | * [[Corneal verticillata]]: Whorled patterns on the cornea, detectable by an eye examination. |
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| | * [[Renal impairment]]: Progressive kidney damage leading to [[chronic kidney disease]]. |
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| | * [[Cardiac involvement]]: Hypertrophic cardiomyopathy, arrhythmias, and heart failure. |
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| | * [[Cerebrovascular disease]]: Increased risk of [[stroke]] and transient ischemic attacks. |
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| </youtube>
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| ==Signs and symptoms== | | ==Diagnosis== |
| [[File:Morbus Fabry Cornea verticillata 01.jpg|thumb|right|A bilateral, whorl-like corneal pattern of cream-colored lines in a person with Fabry disease]]
| | Diagnosis of Fabry disease is typically confirmed through: |
| [[File:Angiokreatoma.jpg|thumb|right|Angiokeratoma, a common skin manifestation in Fabry's]]
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| 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.
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| ===Pain===
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| 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.
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| ===Kidney===
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| Kidney complications are a common and serious effect of the disease; [[chronic kidney disease]] and [[kidney failure]] may worsen throughout life. The presence of [[Proteinuria|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.
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| ===Heart===
| | * [[Enzyme assay]]: Measurement of alpha-galactosidase A activity in blood or skin fibroblasts. |
| Fabry disease can affect the [[heart]] in several ways. The accumulation of [[sphingolipid]]s within [[Cardiac muscle cell|heart muscle cells]] causes abnormal thickening of the [[Cardiac muscle|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|breathlessness]].
| | * [[Genetic testing]]: Identification of mutations in the ''GLA'' gene. |
| Fabry disease can also affect the way in which the heart [[Electrical conduction system of the heart|conducts electrical impulses]], leading to both [[Heart arrhythmia|abnormally slow heart rhythms]] such as [[Third-degree atrioventricular block|complete heart block]], but also abnormally rapid heart rhythms such as [[ventricular tachycardia]]. These abnormal heart rhythms can cause blackouts, [[palpitations]], or even [[Cardiac arrest|sudden cardiac death]].
| | * [[Biopsy]]: Histological examination of affected tissues may show characteristic lipid deposits. |
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| [[Sphingolipid]]s can also build up within the [[heart valve]]s, thickening the valves and affecting the way they open and close. If severe, this can cause the valves to leak ([[Mitral insufficiency|regurgitation]]) or to restrict the forward flow of blood ([[Aortic stenosis|stenosis]]). The [[Aortic valve|aortic]] and [[mitral valve]]s are more commonly affected than the [[Tricuspid valve|valves on the right side of the heart]]. | |
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| ===Skin===
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| [[Angiokeratoma]]s (tiny, painless [[papules]] that can appear on any region of the body, but are predominant on the thighs, around the belly button, buttocks, lower abdomen, and groin) are common.
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| [[Anhidrosis]] (lack of sweating) is a common symptom, and less commonly [[hyperhidrosis]] (excessive sweating).
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| Additionally, patients can exhibit [[Raynaud's disease]]-like symptoms with [[neuropathy]] (in particular, burning extremity pain).
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| 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).
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| Other ocular findings can include conjunctival and retinal vascular abnormalities and anterior/posterior spoke-like cataract. Visual reduction from these manifestations is uncommon.
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| ===Other manifestations===
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| [[Fatigue (medical)|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 vertebro-basilar system [[tinnitus]] (ringing in the ears), [[Vertigo (medical)|vertigo]], nausea, inability to gain weight, chemical imbalances, and diarrhea are other common symptoms.
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| ==Causes==
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| 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|alpha-galactosidase A]]. The lack of alpha-galactosidase is what leads to Fabry disease. A deficiency of the [[enzyme]] [[alpha galactosidase|alpha galactosidase A]] (a-GAL A, encoded by [https://web.archive.org/web/20080515200440/http://www.genenames.org/data/hgnc_data.php?match=GLA ''GLA'']) due to mutation causes a [[glycolipid]] known as [[globotriaosylceramide]] (abbreviated as Gb3, GL-3, or ceramide trihexoside) to accumulate within the [[blood vessel]]s, other tissues, and organs.This accumulation leads to an impairment of their proper functions.
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| [[File:X-linked recessive (2).svg|thumb|right|upright=1.75|X-linked recessive inheritance]] | |
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| The [[DNA]] mutations which cause the disease are X-linked recessive with incomplete penetrance in heterozygous females. The condition affects [[Zygosity|hemizygous]] males (i.e. all males), as well as [[Zygosity|homozygous]], and in many cases [[Zygosity|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 [[cataract]]s or strokes to [[Hypertrophy|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.
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| == Mechanism/pathophysiology ==
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| Fabry disease is an inherited lysosomal storage disorder that is caused by a deficiency of [[alpha-galactosidase]]. This enzyme deficiency is a result of an accumulation of [[glycosphingolipid]]s found in the [[lysosome]]s and most cell types and tissues, which leads it to be considered a multi system disease. Indications include painful crisis, [[angiokeratoma]]s, [[corneal dystrophy]], and [[Hypohidrosis|hypohydrosis]].In severe cases there is renal, cerebrovascular, and cardiac involvement and it is predominately responsible for premature mortality in Fabry patients.
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| Fabry disease is [[X-linked]] and manifests mostly in [[homozygous]] males but also in [[Heterozygous|heteozygous]] females. Cardiac involvement is recurrent in Fabry patients. Patients have developed [[hypertrophic cardiomyopathy]], [[arrhythmia]]s, conduction abnormalities, and valvular abnormalities. 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. 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.
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| ==Diagnosis==
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| 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. 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.
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| ==Treatment== | | ==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. | | The management of Fabry disease includes: |
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| === Enzyme replacement therapy ===
| | * [[Enzyme replacement therapy]] (ERT): Intravenous administration of recombinant alpha-galactosidase A to reduce globotriaosylceramide accumulation. |
| [[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, as well as potentially reverse some symptoms. | | * [[Chaperone therapy]]: Use of pharmacological chaperones to stabilize the mutant enzyme and enhance its activity. |
| | | * [[Symptomatic treatment]]: Pain management, renal protection, and cardiovascular care. |
| The pharmaceutical company [[Shire plc|Shire]] manufactures agalsidase alpha (which differs in the structure of its [[oligosaccharide]] side chains
| | * [[Gene therapy]]: An emerging approach aimed at correcting the underlying genetic defect. |
| 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. which is unaffordable to many patients around the world without enough insurance. Infusion of the enzyme preparation seems to be well tolerated and effective in catabolizing the lipid deposits.
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| 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. 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.
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| Besides these drugs, a gene therapy treatment is in clinical trials,<ref>[https://www.eurekalert.org/pub_releases/2013-01/ahs-clf012413.php Gene therapy treatment for Fabry disease patients]</ref><ref>[https://www.clinicaltrials.gov/ct2/show/NCT03454893]</ref> with the technology licensed to AvroBio.
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| 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.
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| === Organ-specific treatment ===
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| Pain associated with Fabry disease may be partially alleviated by enzyme replacement therapy in some patients, but pain management regimens may also include [[analgesic]]s, [[anticonvulsant]]s, and [[nonsteroidal anti-inflammatory drug]]s, 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 [[Arrhythmia|abnormal heart rhythms]] which may require a [[Artificial pacemaker|pacemaker]] or [[implantable cardioverter-defibrillator]], while the restrictive cardiomyopathy often seen may require [[diuretics]]. | |
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| == Clinical trials ==
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| * Enzyme Replacement Therapy: Replacement of the missing enzyme to clear the lipids (GL-3) from the cells
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| * Substrate Synthesis Inhibition also called Substrate Reduction Therapy (SRT): Inhibits the production of the lipid (GL-3) that accumulates in the cells.
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| * Chaperone Therapy: Uses small molecule drugs that bind to the defective enzyme and stabilize it to increase enzyme activity and increase cellular function.
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| * Gene Editing: Technology that can potentially cut and fix a broken gene in a cell.
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| * Gene Therapy: Genetically modifies the affected cells to produce the missing enzyme.
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| ==Prognosis== | | ==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.
| | The prognosis of Fabry disease varies depending on the severity of organ involvement and the effectiveness of treatment. Early diagnosis and initiation of therapy can improve outcomes and quality of life. |
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| ==Epidemiology== | | ==Epidemiology== |
| Fabry disease is pan-ethnic, but due to its rarity, determining an accurate disease frequency is difficult.Newborn screening initiative have found an unexpectedly high prevalence of the disease, as high as 1 in about 3,100 newborns in Italy and have identified a surprisingly high frequency of newborn males of approximately 1 in 1,500 in Taiwan. | | Fabry disease is estimated to affect approximately 1 in 40,000 to 1 in 117,000 live births. It is more common in males due to its X-linked inheritance pattern, but females can also be affected, often with milder symptoms. |
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| == History == | | ==See Also== |
| Fabry disease was first described by the [[Dermatology|dermatologist]] [[Johannes Fabry]] and the surgeon [[William Anderson (collector)|William Anderson]] independently in 1898.<ref name=":4" /> It was recognised that this was 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.
| | * [[Lysosomal storage disease]] |
| | * [[X-linked genetic disorders]] |
| | * [[Hypertrophic cardiomyopathy]] |
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| [[Ken Hashimoto]] published his classic paper on his electron microscopic findings in Fabry disease in 1965.
| | {{Lysosomal storage disorders}} |
| | {{Genetic disorders}} |
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| The first specific treatment for Fabry disease was approved in 2001.
| | [[Category:Genetic disorders]] |
| | | [[Category:Lysosomal storage diseases]] |
| ==Society and culture==
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| * ''[[House (TV series)|House]]'' ("[[Epic Fail (House)|Epic Fail]]", season 6 episode 2) centers on a patient with Fabry disease.
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| * ''[[Scrubs (TV series)|Scrubs]]'' ("My Catalyst", season 3 episode 12) features a Fabry disease diagnosis.
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| * ''[[Crossing Jordan]]'' ("There's No Place Like Home", season 2 episode 1) features a patient who died suffering Fabry disease.
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| * ''The Village'' (Korean drama): "Achiara's Secret"features daughters of a serial rapist who find each other because they share Fabry disease.
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| * ''Doctor John'' (Korean drama): In episode 2 a prisoner is diagnosed with fabry disease
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| * 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.
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| ==See also==
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| * [[Lysosomal storage disorder]]
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| * [[Sphingolipidoses]]
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| * [[Migalastat]]
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| == External links ==
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| {{Medical resources
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| | ICD10 = {{ICD10|E|75|2|e|70}} ([[ILDS]] E75.25)
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| | ICD9 = {{ICD9|272.7}}
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| | ICDO =
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| | OMIM = 301500
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| | OMIM_mult =
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| | MedlinePlus =
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| | eMedicineSubj = neuro
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| | eMedicineTopic = 579
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| | eMedicine_mult = {{eMedicine2|derm|707}} {{eMedicine2|ped|2888}}
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| | DiseasesDB = 4638
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| | MeshID = D000795
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| | GeneReviewsNBK = NBK1292
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| | GeneReviewsName = Fabry disease
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| }}
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| * [http://www.ninds.nih.gov/disorders/fabrys/fabrys.htm Fabry Disease Information Page] at [[NINDS]]
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| * [http://ghr.nlm.nih.gov/condition=fabrydisease Fabry disease] at [[United States National Library of Medicine|NLM]] Genetics Home Reference
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| {{Authority control}}
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| {{DEFAULTSORT:Fabry Disease}}
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| [[Category:X-linked recessive disorders]] | |
| [[Category:Rare diseases]] | | [[Category:Rare diseases]] |
| [[Category:Lipid storage disorders]]
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| [[Category:Skin conditions resulting from errors in metabolism]]
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| [[Category:Lysosomal storage diseases]]
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| [[Category:Cardiogenetic disorders]]
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| {{rarediseases}}
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