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Fabry Disease

Anderson Fabry Disease

Fabry disease, also known as Anderson-Fabry disease, angiokeratoma corporis diffusum and alpha-galactosidase A deficiency, is a rare genetic lysosomal storage disorder.

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Presentation

Some cases show no significant clinical manifestations. In other cases, the clinical manifestations of Fabrys disease appear early in life. With age, these manifestations may increase in severity.

One of the common clinical features of this disease is pain. This pain is usually episodic. It may appear in the whole body or may be localized to the arms and legs. In the latter case, the pain is referred to as acroparesthesia [1]. This pain is usually of a burning sensation and is often further localized to the most distal parts of the limbs, i.e. the hands and the feet. It is believed that this pain results from damage to the peripheral nerves. Pain also commonly occurs in gastrointestinal tract, is of a diffuse nature and results from a generalized obstruction in the lipid laden blood vessels of the gastrointestinal tract. Episodes of pain can be triggered by a number of factors such as physical activity, fatigue, fever, stress and environmental changes.

A number of skin abnormalities frequently occur in the sufferers of Fabry diseases. Raised papules called angiokeratomas are common. These are dark red rashes and can occur anywhere on the body; but usually occur only on the lower half; more particularly around the umbilicus & on the thighs, buttocks and legs. Sweat gland dysfunction is also present in most cases. Usually there is reduced sweating but cases of excessive sweating have also been seen.

Ocular changes are very frequent in Fabry disease. The corneas of both eyes are typically affected. They have visible clouding which upon closer inspection is found to consist of golden brown lines arranged in a whorled pattern. This is known as cornea verticillata or whorl keratopathy. It is one of the most characteristic features of Fabry disease. However it must be noted that despite the apparent clouding of the cornea, there is no disturbance in vision.

With time, lipids deposit in the heart, kidneys and nerves of the patient. Symptoms related to these organs begin to manifest after the age of 30. Glycolipid deposition in the heart predisposes the heart to the development of various kinds of diseases. Cardiovascular disorders such as hypertension and cardiomyopathies, most particularly, left ventricular hypertrophy, are very common in the sufferers of Fabry disease [2]. Patients of Fabry disease may suffer from angina and myocardial infarction. Syncope and dyspnea are also seen in a majority of the patients with cardiovascular manifestations. Conduction defects such as VT that occur in these patients may be secondary to cardiomyopathies.

Chronic lipid deposition in the nephrons results in the renal manifestations of Fabry disease. The earliest clinical feature is proteinuria. The urine has a higher viscosity and may even appear foamy. There is progressive deterioration in the function of the kidney, causing renal insufficiency. Later, the kidneys may shut down completely and cause renal failure [3].

Dyspnea
  • Other signs include angiokeratoma, corneal changes, tinnitus, chronic fatigue, cardiac and cerebrovascular abnormalities (left ventricular hypertrophy, arrhythmia, angina), dyspnea, and nephropathy.[orpha.net]
  • LV hypertrophy, arrhythmia, angina, and dyspnea are reported in 40% to 60% of patients with FD.[circgenetics.ahajournals.org]
  • Obstructive and constrictive lung diseases have both been documented in a subgroup of patients, often presenting as wheezing, dyspnea, or bronchitis. Priapism has been associated with Fabry disease.[emedicine.medscape.com]
  • Syncope and dyspnea are also seen in a majority of the patients with cardiovascular manifestations. Conduction defects such as VT that occur in these patients may be secondary to cardiomyopathies.[symptoma.com]
Cough
  • Other organs and systems: widespread involvement produces many other manifestations of the disease, including cough, breathlessness, wheeze, etc. Male homozygotes with atypical manifestation Some alpha-galactosidase activity in plasma (5-35%) .[patient.info]
  • Chronic cough is a common complaint in men as well as women. 60 While the cough may be worsened by reactive airway disease or tobacco use, it can occur in individuals without these risk factors. 61 , 62 Spirometry may show signs of obstructive ventilatory[nature.com]
  • Adverse events such as nasopharyngitis, rhinitis, nasal congestion, aggravation of allergic rhinitis with nasal discharge, dyspnea, cough, dizziness, flushing, pruritus, neuralgia, nausea, vomiting, diarrhea, abdominal pain, and arthralgia were also analyzed[journals.plos.org]
Pain
  • Pain is a common early symptom of FD (chronic pain characterized by burning and tingling paresthesia and occasional episodic crises characterized by agonizing burning pain). Pain may resolve in adulthood.[orpha.net]
  • Extreme pain attacks, referred to as Fabry pain crises, usually affect male patients and are described as severe episodes that last several hours to days. These episodes may be accompanied by low-grade fever, body pains, and fatigue.[emedicine.medscape.com]
  • Medications are given to relieve pain in the body and the limbs. Pain in Fabry disease is often difficult to treat and does not respond to most of the over-the-counter pain medications.[symptoma.com]
  • The study that reported pain and pain-related quality of life showed an improvement for participants receiving treatment over the six-month observation period. Death was not an outcome in either study .[cochrane.org]
  • This acroparesthesia is believed to be related to the damage of peripheral nerve fibers that transmit pain.[en.wikipedia.org]
Fever
  • Some patients may have recurrent fevers with no obvious source. Pain usually accompanies the fevers, and an elevated erythrocyte sedimentation rate may be present.[emedicine.medscape.com]
  • For patients who have had reactions to their infusions, it is recommended that they be given anti-fever and antihistamine medications right before their next infusions.[fabrazyme.com]
  • Treatment of Fabry disease is enzyme replacement with recombinant α -galactosidase A (agalsidase beta) combined with supportive measures for fever and pain. Kidney transplantation is effective for treating renal failure.[merckmanuals.com]
  • This pain can be triggered by stress , fatigue , fever , physical activity, and even changes in the weather. Clouding of the corneas : Also called keratopathy. This does not affect vision.[medicalnewstoday.com]
  • ., rigors, fever) were more significant with agalsidase beta as compared to placebo .[cochrane.org]
Fatigue
  • Patients may report lack of energy and fatigue.[emedicine.medscape.com]
  • […] pains in hands and feet) Hypohidrosis Corneal and lenticular opacities Heat and cold intolerance GI dysmotility with nausea, bloating and post-prandial diarrhea Adolescence Angiokeratomas GI dysmotility with nausea, bloating and post-prandial diarrhea Fatigue[massgeneral.org]
  • Often the first symptoms of the condition are intense burning pain in the hands and feet, skin rashes called angiokeratoma, heat intolerance, gastrointestinal issues and fatigue.[shire.com]
  • The progressive accumulation of GL-3 and its derivative, lyso-GL-3, results in symptoms that include characteristic skin lesions (angiokeratomas), decreased sweating (hypohidrosis), chronic fatigue, depression, neuropathic pain in the hands and feet ([sema4genomics.com]
  • Other signs include angiokeratoma, corneal changes, tinnitus, chronic fatigue, cardiac and cerebrovascular abnormalities (left ventricular hypertrophy, arrhythmia, angina), dyspnea, and nephropathy.[orpha.net]
Burning Pain
  • Fabry disease is a progressive genetic condition that causes health problems like extreme tiredness (fatigue), little to no sweating, a reddish-purplish skin rash (angiokeratomas), burning pain in the hands and feet, problems in the heat and cold, frequent[thinkgenetic.com]
  • Diagnosis in males is clinical, based on appearance of typical skin lesions (angiokeratomas) over the lower trunk and by characteristic features of peripheral neuropathy (causing recurrent burning pain in the extremities), corneal opacities, and recurrent[merckmanuals.com]
  • Often the first symptoms of the condition are intense burning pain in the hands and feet, skin rashes called angiokeratoma, heat intolerance, gastrointestinal issues and fatigue.[shire.com]
  • Symptoms in early childhood include severe "burning" pain in hands and feet, growth retardation, nausea and abdominal pain, post prandial diarrhoea and hypohidrosis.[renalandurologynews.com]
  • Pain is a common early symptom of FD (chronic pain characterized by burning and tingling paresthesia and occasional episodic crises characterized by agonizing burning pain). Pain may resolve in adulthood.[orpha.net]
Heat Intolerance
  • He had heat intolerance and decreased sweating. The diagnosis of Fabry's disease was confirmed by the detection of reduced α-galactosidase A activity in peripheral leukocytes. He received carbamazepine for the neuropathic pain.[nejm.org]
  • Often the first symptoms of the condition are intense burning pain in the hands and feet, skin rashes called angiokeratoma, heat intolerance, gastrointestinal issues and fatigue.[shire.com]
  • This results in heat intolerance and can be quite debilitating. The single most debilitating symptom associated with Fabry disease is pain. The patient develops significant burning pain in the extremities especially affecting the palms and soles.[aocd.org]
  • In addition to impaired kidney function, symptoms of Fabry disease include: pain, typically in the hands and feet clusters of small, dark red spots on the skin decreased ability to sweat chronic fatigue heat intolerance depression anxiety cloudiness of[aakp.org]
  • General tiredness, dizziness, headache, nausea, and heat intolerance. Males may have swelling in their feet and legs. As type 1 FD progresses, symptoms become more serious.[healthline.com]
Diarrhea
  • […] with nausea, bloating and post-prandial diarrhea Fatigue Episodic pain crises, acroparesthesia Hypohidrosis Corneal and lenticular opacities Heat and cold intolerance Adulthood Proteinuric renal insufficiency/failure Cerebrovascular disease with risk[massgeneral.org]
  • […] disease is a progressive genetic condition that causes health problems like extreme tiredness (fatigue), little to no sweating, a reddish-purplish skin rash (angiokeratomas), burning pain in the hands and feet, problems in the heat and cold, frequent diarrhea[thinkgenetic.com]
  • Common manifestations include episodes of postprandial abdominal pain and bloating, followed by multiple bowel movements, diarrhea, nausea, vomiting, and early satiety.[emedicine.medscape.com]
  • This includes cramps, gas, and diarrhea. Abnormal corneas. Blood vessels in the eyes may have a changed appearance, but this doesn’t affect vision. General tiredness, dizziness, headache, nausea, and heat intolerance.[healthline.com]
  • Symptoms (Males)  First symptoms in males average age 6 years  Most common first complaint Pain  Other common problems in childhood include fatigue, heat intolerance, anhydrosis, recurrent / chronic diarrhea  Adults: Kidney disease, Heart disease,[slideshare.net]
Nausea
  • […] with nausea, bloating and post-prandial diarrhea Fatigue Episodic pain crises, acroparesthesia Hypohidrosis Corneal and lenticular opacities Heat and cold intolerance Adulthood Proteinuric renal insufficiency/failure Cerebrovascular disease with risk[massgeneral.org]
  • Symptoms in early childhood include severe "burning" pain in hands and feet, growth retardation, nausea and abdominal pain, post prandial diarrhoea and hypohidrosis.[renalandurologynews.com]
  • Patients who have experienced a heart attack may have the following symptoms: Shortness of breath Chest pain that spreads into the arms, back or jaw Faintness Heavy pounding of the heart Abnormal heart rhythm Nausea Loss of consciousness Patients who[cedars-sinai.edu]
  • Pediatric Gastroenterology (see Services below for relevant providers) Referral may be helpful for treatment and management of constipation, diarrhea, abdominal pain, nausea, and vomiting that is not responding to usual treatments.[medicalhomeportal.org]
  • This may include pain after eating a meal, intense diarrhea, and nausea, all of which can be severe enough to disrupt daily life. Hearing Problems Tinnitus, or ringing in the ears, and hearing loss are common in Fabry disease.[fabrazyme.com]
Vomiting
  • […] rashes (angiokeratomas) Corneal whorling (pattern on the cornea of the eye – generally does not affect vision and can only be seen using special eye exam equipment called a slit lamp) Hearing problems Gastrointestinal problems, such as diarrhoea or vomiting[sanofi.co.za]
  • Pediatric Gastroenterology (see Services below for relevant providers) Referral may be helpful for treatment and management of constipation, diarrhea, abdominal pain, nausea, and vomiting that is not responding to usual treatments.[medicalhomeportal.org]
  • Common manifestations include episodes of postprandial abdominal pain and bloating, followed by multiple bowel movements, diarrhea, nausea, vomiting, and early satiety.[emedicine.medscape.com]
  • Symptoms include: Numbness or severe burning sensation and pain in the hands and feet Reduced sweating Cloudiness of the cornea, which covers the iris and pupil of the eye Red or purple skin lesions Gastrointestinal problems (stomach cramps, nausea, vomiting[davita.com]
  • Patients may experience : Gastrointestinal problems , including: nausea vomiting diarrhea Cardiovascular problems , including: heart failure arrhythmia heart attack faulty heart valves enlarged heart This happens because years of GL-3 buildup results[medicalnewstoday.com]
Abdominal Pain
  • Common manifestations include episodes of postprandial abdominal pain and bloating, followed by multiple bowel movements, diarrhea, nausea, vomiting, and early satiety.[emedicine.medscape.com]
  • Symptoms in early childhood include severe "burning" pain in hands and feet, growth retardation, nausea and abdominal pain, post prandial diarrhoea and hypohidrosis.[renalandurologynews.com]
  • Pediatric Gastroenterology (see Services below for relevant providers) Referral may be helpful for treatment and management of constipation, diarrhea, abdominal pain, nausea, and vomiting that is not responding to usual treatments.[medicalhomeportal.org]
  • Gastrointestinal Problems Many people with Fabry disease experience abdominal pain. This may include pain after eating a meal, intense diarrhea, and nausea, all of which can be severe enough to disrupt daily life.[fabrazyme.com]
  • Gastrointestinal disease: this can include symptoms of diarrhoea, weight loss abdominal pain, nausea and vomiting. Renal disease: this produces hypertension, proteinuria and progressive kidney disease.[patient.info]
Constipation
  • […] progressive genetic condition that causes health problems like extreme tiredness (fatigue), little to no sweating, a reddish-purplish skin rash (angiokeratomas), burning pain in the hands and feet, problems in the heat and cold, frequent diarrhea and constipation[thinkgenetic.com]
  • Severe pain in the feet, high fevers, headaches, constipation and fatigue. These were all symptoms our son Blake started experiencing at the age of 5 1/2.[globalgenes.org]
  • Pediatric Gastroenterology (see Services below for relevant providers) Referral may be helpful for treatment and management of constipation, diarrhea, abdominal pain, nausea, and vomiting that is not responding to usual treatments.[medicalhomeportal.org]
Heart Failure
  • Fabry disease is a sphingolipidosis , an inherited disorder of metabolism, caused by deficiency of α -galactosidase A, which causes angiokeratomas, acroparesthesias, corneal opacities, recurrent febrile episodes, and renal or heart failure.[merckmanuals.com]
  • Over time, these cardiac complications can progress to heart failure, life-threatening arrhythmias and, rarely, myocardial infarction (MI).[escardio.org]
  • Heart disease develops including hypertension, chest pain due to decrease blood flow (ischemia), heart attack (myocardial infarction), congestive heart failure and even cardiac arrhythmias may develop secondary to occlusion of coronary arteries.[aocd.org]
  • Clinical signs of congestive heart failure may accompany the progressive concentric LVH and diastolic dysfunction observed in advanced stages of the disease. Mitral valve prolapse and thickening may also be observed.[emedicine.medscape.com]
Hypertension
  • One of them showed no significant difference for any adverse events such as dyspnoea , hypertension and gastrointestinal symptoms - these are not adverse events as gastrointestinal problems are actually a symptom, as may be hypertension in the context[cochrane.org]
  • He has published research in many peer-reviewed journals, including the Journal of the American Society of Nephrology, Current Opinion in Nephrology & Hypertension, and the Clinical Journal of the American Society of Nephrology.[aakp.org]
  • Death results from renal failure or cardiac or cerebral complications of hypertension or other vascular disease. Heterozygous females are usually asymptomatic but may have an attenuated form of disease often characterized by corneal opacities.[merckmanuals.com]
  • Severe renal impairment leads to hypertension and uremia. Death usually occurs from renal failure or from cardiac or cerebrovascular disease.[ommbid.mhmedical.com]
  • Heart disease develops including hypertension, chest pain due to decrease blood flow (ischemia), heart attack (myocardial infarction), congestive heart failure and even cardiac arrhythmias may develop secondary to occlusion of coronary arteries.[aocd.org]
Tachycardia
  • (Insert Figure 3) Using cardiac MRI to quantify myocardial fibrosis and following a longitudinal protocol, Krämer et al [16] showed that myocardial fibrosis relates to malignant ventricular arrhythmias (non-sustained and sustained ventricular tachycardia[escardio.org]
Palpitations
  • Cardiology Adolescents and children with Fabry may manifest sinus bradycardia, systolic murmurs, chest pain, dyspnea, arrhythmias, decreased heart rate variability, left ventricular hypertrophy, palpitations, and syncope as early signs of cardiac involvement[medicalhomeportal.org]
Acroparesthesia
  • Some patients may experience spontaneous relief of these early symptoms during adulthood (eg, symptomatic improvement of acroparesthesias). The earliest reported symptom of Fabry disease is often intermittent or chronic acroparesthesias.[emedicine.medscape.com]
  • The cardinal presenting features of Fabry disease are intermittent acroparesthesia and episodic crises of pain and fever (especially in childhood), angiokeratomas, hypohidrosis, heat and cold intolerance and a characteristic "whorled" corneal opacity[massgeneral.org]
  • Symptoms such as milder left ventricular hypertrophy, acroparesthesias, and hypohidrosis have also been reported in cases with the renal variant.[invitae.com]
  • Fabry disease is a sphingolipidosis , an inherited disorder of metabolism, caused by deficiency of α -galactosidase A, which causes angiokeratomas, acroparesthesias, corneal opacities, recurrent febrile episodes, and renal or heart failure.[merckmanuals.com]
  • Signs and symptoms may include episodes of pain, particularly in the hands and feet (acroparesthesias); clusters of small, dark red spots on the skin called angiokeratomas; a decreased ability to sweat (hypohidrosis); cloudiness of the front part of the[checkorphan.org]
Tinnitus
  • Other symptoms include decreased sweating, gastrointestinal problems, joint pain, back pain, ringing in the ears (tinnitus) and fever. Symptoms may be triggered by exercise, fatigue, stress, and changes in the weather.[news-medical.net]
  • The following are some symptoms of Fabry disease: Pain, mainly in the hands and feet Clusters of small, dark red spots on the skin (angiokeratomas) Being less able to sweat (hypohidrosis) Hearing loss and ringing in the ears (tinnitus) Digestive system[my.clevelandclinic.org]
  • Other signs include angiokeratoma, corneal changes, tinnitus, chronic fatigue, cardiac and cerebrovascular abnormalities (left ventricular hypertrophy, arrhythmia, angina), dyspnea, and nephropathy.[orpha.net]
  • […] acroparesthesias); clusters of small, dark red spots on the skin called angiokeratomas; a decreased ability to sweat (hypohidrosis); cloudiness of the front part of the eye (corneal opacity); problems with the gastrointestinal system; ringing in the ears (tinnitus[fabry.com.au]
Hearing Problem
  • problems Gastrointestinal problems, such as diarrhoea or vomiting Heart problems (including enlarged heart and heart valve problems) Kidney problems Nervous system problems, such as stroke Psychological issues, such as depression Diagnosis: A test, called[sanofi.co.za]
  • Hearing problems - This may include a gradual loss of hearing or ringing in the ears (tinnitus). Emotional issues - Many patients may have feelings of fear and depression, related to their illness.[kidney.org]
  • Hearing problems may occur, such as gradual hearing loss or ringing in the ears, known as tinnitus . These are due to GL-3 accumulation.[medicalnewstoday.com]
  • problems Additionally, patients may benefit from working with physical therapists, nutritionists, and psychologists to help manage symptoms.[medicinenet.com]
  • Hearing Problems Tinnitus, or ringing in the ears, and hearing loss are common in Fabry disease.[fabrazyme.com]
Corneal Opacity
  • Heterozygous females are usually asymptomatic but may have an attenuated form of disease often characterized by corneal opacities.[merckmanuals.com]
  • Medical Dictionary : a disorder of lipid metabolism that is inherited as an X-linked recessive trait and is characterized by skin lesions especially on the lower trunk, severe pain in the extremities, corneal opacities, and vascular disease affecting[merriam-webster.com]
  • opacity); and hearing loss.[checkorphan.org]
  • The clinical course of Fabry disease is usually marked by chronic pain, angiokeratomas, hypohidrosis, heat and cold intolerance, corneal opacities, renal failure, stroke and cardiac complications.[massgeneral.org]
  • opacity) In some cases, Fabry disease is milder and appears later in life.[my.clevelandclinic.org]
Vortex Keratopathy
Angiokeratoma
  • Info Anderson-Fabry disease, Angiokeratoma corporis diffusum, Alpha-galactosidase A deficiency, Angiokeratoma, diffuse, GLA deficiency, Ceramide trihexosidase deficiency Overview Fabry disease is an inherited disorder that results from the buildup of[checkorphan.org]
  • They separately published papers in which they described patients with skin lesions, known as angiokeratomas, which are now recognised as a common sign of Fabry disease.[fabry.com.au]
  • Fabry disease is a sphingolipidosis , an inherited disorder of metabolism, caused by deficiency of α -galactosidase A, which causes angiokeratomas, acroparesthesias, corneal opacities, recurrent febrile episodes, and renal or heart failure.[merckmanuals.com]
  • The clinical course of Fabry disease is usually marked by chronic pain, angiokeratomas, hypohidrosis, heat and cold intolerance, corneal opacities, renal failure, stroke and cardiac complications.[massgeneral.org]
  • It is also known as angiokeratoma corporis diffusum as well as alpha-galactosidase-A deficiency . The condition is due to the lack of or ineffective enzyme known as alpha-glycosidase-A.[aocd.org]
Skin Lesion
  • The characteristic skin lesions of Fabry disease are the earliest signs that may lead to diagnosis in childhood. Death usually occurs in early adulthood from renal and cardiac complications of the vascular disease.[themedicalbiochemistrypage.org]
  • Medical Dictionary : a disorder of lipid metabolism that is inherited as an X-linked recessive trait and is characterized by skin lesions especially on the lower trunk, severe pain in the extremities, corneal opacities, and vascular disease affecting[merriam-webster.com]
  • If you have a specific question or concern about a skin lesion or disease, please consult a dermatologist.[aocd.org]
  • Diagnosis in males is clinical, based on appearance of typical skin lesions (angiokeratomas) over the lower trunk and by characteristic features of peripheral neuropathy (causing recurrent burning pain in the extremities), corneal opacities, and recurrent[merckmanuals.com]
  • The progressive accumulation of GL-3 and its derivative, lyso-GL-3, results in symptoms that include characteristic skin lesions (angiokeratomas), decreased sweating (hypohidrosis), chronic fatigue, depression, neuropathic pain in the hands and feet ([sema4genomics.com]
Anhidrosis
  • Dermal manifestations of Fabry disease include cutaneous vascular lesions (angiokeratomas) and abnormal sweating (anhidrosis or, more commonly, hypohidrosis).[emedicine.medscape.com]
  • Anhidrosis or hypohidrosis may occur causing heat and exercise intolerance.[orpha.net]
  • About one quarter of male patients develop anhidrosis, the complete inability to produce sweat. This results in heat intolerance and can be quite debilitating. The single most debilitating symptom associated with Fabry disease is pain.[aocd.org]
  • Symptoms include: periodic severe pain crises in the extremities (acroparesthesias) vascular cutaneous lesions (angiokeratomas), typically in the bathing-suit area sweating abnormalities (anhidrosis, hypohidrosis, and rarely hyperhidrosis) exercise, heat[invitae.com]
Decreased Sweating
  • He had heat intolerance and decreased sweating. The diagnosis of Fabry's disease was confirmed by the detection of reduced α-galactosidase A activity in peripheral leukocytes. He received carbamazepine for the neuropathic pain.[nejm.org]
  • The progressive accumulation of GL-3 and its derivative, lyso-GL-3, results in symptoms that include characteristic skin lesions (angiokeratomas), decreased sweating (hypohidrosis), chronic fatigue, depression, neuropathic pain in the hands and feet ([sema4genomics.com]
  • Other symptoms include decreased sweating, gastrointestinal problems, joint pain, back pain, ringing in the ears (tinnitus) and fever. Symptoms may be triggered by exercise, fatigue, stress, and changes in the weather.[news-medical.net]
  • Classic Fabry disease symptoms in males and females typically start in the first 3-10 years of life with onset of burning pain in the hands and feet, decreased sweating, problems in the heat, a reddish-purplish rash, and gastrointestinal issues such as[thinkgenetic.com]
  • sweating Personal or family history of: Burning pain in the hands and feet Renal failure Intolerance to heat, cold, or exercise Cardiac hypertrophy Consultation with a genetic metabolic specialist and a genetic counselor is recommended.[medicalhomeportal.org]
Flushing
  • These reactions have included: localized swelling of the face, mouth and throat, narrowing of breathing airways, low blood pressure, hives, difficulty swallowing, rash, trouble breathing, flushing, chest discomfort, itching and nasal congestion.[fabrazyme.com]
  • Adverse events such as nasopharyngitis, rhinitis, nasal congestion, aggravation of allergic rhinitis with nasal discharge, dyspnea, cough, dizziness, flushing, pruritus, neuralgia, nausea, vomiting, diarrhea, abdominal pain, and arthralgia were also analyzed[journals.plos.org]
Kidney Failure
  • Enzyme Replacement: Until recently the only treatments available helped to relieve symptoms but did not prevent long-term complications, such as heart attacks, strokes and kidney failure.[kidney.org]
  • GL-3 build-up in kidney cells may cause severe kidney problems, including kidney failure. People with Fabry disease may experience a wide range of signs and symptoms, including severe conditions such as kidney failure, heart problems, and stroke.[sanofi.co.za]
  • New research suggests many women suffer from severe symptoms ranging from early cataracts or strokes to hypertrophic left ventricular heart problems and kidney failure.[en.wikipedia.org]
  • Important clues are multi-system symptoms that vary in age of onset, severity and manner of progression; early onset of kidney failure; and stroke or heart disease in the absence of conventional vascular risk factors.[bjcardio.co.uk]
  • Prevention - Fabry disease Diagnosis - Fabry disease Prognosis - Fabry disease Patients with Fabry disease often survive into adulthood but are at increase risk of strokes, heart attack and heart disease, and kidney failure.[checkorphan.org]
Renal Impairment
  • Classic symptoms include pain and parathesis in the extremities, gastrointestinal disturbances, cardiomyopathy, progressive renal impairment, corneal and lenticular opacities and characteristic skin lesions called angiokeratomata.[themedicalbiochemistrypage.org]
  • Severe renal impairment leads to hypertension and uremia. Death usually occurs from renal failure or from cardiac or cerebrovascular disease.[ommbid.mhmedical.com]
  • Patient History in Fabry Disease Hypertension occurs with increased frequency in patients with Fabry disease because of progressive renal impairment.[emedicine.medscape.com]
  • impairment, cardiac event(s), central nervous system event(s) or gastrointestinal symptoms, and the following variables from the pre-randomisation visits: left ventricular hypertrophy (LVH) using echocardiography, eGFR, 24-hour urine protein and α-Gal[jmg.bmj.com]
  • Signs and symptoms include: angiokeratoma, progressive renal impairment, proteinuria, acropharestesia of hands and feet, cardiac hypertrophy and conduction abnormalities, ischemic events, corneal dystrophy, hypohidrosis and impaired temperature regulation[ojrd.biomedcentral.com]
Hematuria
  • […] females, who have more variable severity due to variable lyonization of X chromosome and may have normal leukocyte alpha-galactosidase A activity Clinical symptoms include angiokeratomas on skin of abdomen, buttocks, lips, genitalia and upper thighs Also hematuria[pathologyoutlines.com]
Stroke
  • Consultations in Stroke, Renal Failure, and Neuropathy Consultation with a neurologist is recommended if Fabry disease is suspected as a cause of stroke or if the usual causes of stroke are not present.[emedicine.medscape.com]
  • Patient care is generally broken down into three categories: stroke prevention, treatment immediately after a stroke, and post-stroke rehabilitation. Stroke Program or Call 1-800-CEDARS-1 (1-800-233-2771) Available 24 Hours a Day or[cedars-sinai.edu]
  • Twelve years later, Fabry’s disease was diagnosed by… Posterior versus Anterior Circulation Stroke in Young Adults: A Comparative Study of Stroke Aetiologies and Risk Factors in Stroke among Young Fabry Patients Although 20–30% of all strokes occur in[centogene.com]
  • Central nervous system problems - To help prevent strokes, doctors may prescribe medications to keep blood from clotting.[kidney.org]
  • Potentially severe complications can include progressive kidney damage, heart attack, and stroke. Milder forms of the disorder may appear later in life and affect only the heart or kidneys.[checkorphan.org]
Headache
  • Severe pain in the feet, high fevers, headaches, constipation and fatigue. These were all symptoms our son Blake started experiencing at the age of 5 1/2.[globalgenes.org]
  • […] numbness or weakness of the face, arm or leg, especially on one side of the body Sudden confusion Sudden trouble speaking Sudden trouble seeing in one or both eyes Sudden trouble walking Sudden dizziness, loss of balance or coordination Sudden, severe headache[cedars-sinai.edu]
  • Cerebrovascular/Central Nervous System Problems Dizziness or vertigo, headache, and early stroke are all cerebrovascular symptoms of Fabry disease. Anticoagulants (blood thinners) may be prescribed for those at risk of stroke.[fabrazyme.com]
  • Headache and muscle involvement responding to corticosteroid and methotrexate treatment We report the case of a 38-year-old female patient who had been diagnosed as lupus erythematosus because of generalized muscle and burning pain combined with slightly[centogene.com]
  • Patients have a higher risk of: stroke dizziness numbness headaches weakness Emotional and psychological problems , such as anxiety , fear and depression , can occur as a result of living with the symptoms associated with Fabry disease.[medicalnewstoday.com]
Vertigo
  • Paroxysmal attacks of severe rotational vertigo occur in many patients. Although these episodes are usually brief, some prolonged severe attacks require cessation of activities for several days.[emedicine.medscape.com]
  • […] syncope Fatigue Episodic pain crises, acroparesthesias Heat and cold intolerance Hypohidrosis Angiokeratomas Corneal and lenticular opacities Other Fabry-related cerebrovascular signs and symptoms associated with Fabry disease may include: Hemiparesis Vertigo[massgeneral.org]
  • Hemiparesis, vertigo, diplopia, dysarthria, hemianopia, sensory loss, and other typical stroke symptoms characterize CNS involvement.[emedicine.medscape.com]
  • […] manifestations [ edit ] 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[en.wikipedia.org]
  • Cerebrovascular/Central Nervous System Problems Dizziness or vertigo, headache, and early stroke are all cerebrovascular symptoms of Fabry disease. Anticoagulants (blood thinners) may be prescribed for those at risk of stroke.[fabrazyme.com]
Peripheral Neuropathy
  • Diagnosis in males is clinical, based on appearance of typical skin lesions (angiokeratomas) over the lower trunk and by characteristic features of peripheral neuropathy (causing recurrent burning pain in the extremities), corneal opacities, and recurrent[merckmanuals.com]
  • In the present review, the neurological manifestations of FD are summarized with emphasis on cerebral vasculopathy, cochlear nerve dysfunction, psychiatric and cognitive symptoms, autonomic dysfunction and peripheral neuropathy.[nnjournal.net]
  • Peripheral neuropathy in Fabry disease predominantly involves small nerve fibers. The progressive loss of temperature and pain sensation should be assessed during the physical examination.[emedicine.medscape.com]
  • Small vessel involvement resulting in cerebrovascular disease and painful peripheral neuropathy can be debilitating. The risk of ischemic strokes is increased.[disorders.eyes.arizona.edu]
  • neuropathy or nystagmus, internuclear ophthalmoplegia, dysarthria, aphasia, hemiparesis, and sensory loss caused by stroke lesions, especially in the posterior circulation.[emedicine.medscape.com]
Burning Sensation
  • Other treatments for Fabry disease are aimed at relieving individual symptoms. phenytoin ( Dilantin ), carbamazepine ( Tegretol ), or gabapentin ( Neurontin ) may help prevent episodes of pain and burning sensations (acroparesthesias).[medicinenet.com]
  • The disease can cause burning sensations, skin blemishes, and gastrointestinal symptoms as well. Individuals with the condition, mostly males, often die prematurely from complications of stroke, heart disease, or kidney failure.[raredr.com]
  • Episodes of pain and burning sensation, especially in hands and feet Small, dark red spots on the skin, usually between the belly button and knees Minimal sweating Ringing in the ears or even hearing loss Stomach pain or bowel movements immediately after[uclahealth.org]
  • Symptoms include: Numbness or severe burning sensation and pain in the hands and feet Reduced sweating Cloudiness of the cornea, which covers the iris and pupil of the eye Red or purple skin lesions Gastrointestinal problems (stomach cramps, nausea, vomiting[davita.com]
  • This pain is usually of a burning sensation and is often further localized to the most distal parts of the limbs, i.e. the hands and the feet. It is believed that this pain results from damage to the peripheral nerves.[symptoma.com]

Workup

The diagnosis of Fabry disease can be made by demonstrating below normal levels of the enzyme alpha galactosidase (or its activity) either in the blood plasma, white blood cells or other cultured cells. While this is an effective diagnostic method in males, it can be unreliable in females as it fails to identify the carrier state of this disease [4]. The carrier state results from X chromosome inactivation in some females, usually heterozygotes with one normal and one affected X chromosome. Recently, LysoGb3 has been introduced as a new biomarker, which is especially valued for therapeutic monitoring.

Another approach for diagnosing this disease is molecular genetic testing. Although expensive, it is a much more reliable method for the definite diagnosis of this disease in both males and females. Mutations in the GLA gene are identified through advanced biotechnological methods. If mutations exist, the diagnosis can be made with certainty. Mutations in several genes other than GLA are also attributed to be the cause of Fabry disease but their diagnostic importance is very limited.

Multiple Renal Cysts
  • On imaging, the kidneys have non-specific findings of medical renal disease including increased echogenicity, thinned renal cortex and multiple renal cysts .[radiopaedia.org]
Microalbuminuria
  • Microalbuminuria, proteinuria, and isosthenuria may be apparent in adolescence and early adulthood.[emedicine.medscape.com]
  • Hyperfiltration, microalbuminuria and proteinuria, sometimes nephrotic range, can be seen in the second or third decade of life, often progressing to renal failure by the fifth decade of life.[renalandurologynews.com]
  • Pediatric Nephrology (see Services below for relevant providers) Refer those with proteinuria or microalbuminuria for more extensive testing to determine renal involvement.[medicalhomeportal.org]
  • Initial manifestations include impaired filtration rate (GFR), proteinuria, and tubular derangements. 11 Microalbuminuria and blunted concentrating ability have been reported in adolescents.[nature.com]
Albuminuria
  • Laboratory Testing Labs may include: On initial exam (diagnosis): glomerular filtration rate, albuminuria & proteinuria Every 6–12 months: albuminuria & proteinuria Every 24–36 months: glomerular filtration test With therapy change or event: glomerular[medicalhomeportal.org]
  • Renal biopsy findings in children and adolescents with Fabry disease and minimal albuminuria. Am J Kidney Dis. 2008;51:767-776.[rarediseases.org]
Alpha-Galactosidase A Deficiency
  • Info Anderson-Fabry disease, Angiokeratoma corporis diffusum, Alpha-galactosidase A deficiency, Angiokeratoma, diffuse, GLA deficiency, Ceramide trihexosidase deficiency Overview Fabry disease is an inherited disorder that results from the buildup of[checkorphan.org]
  • The disease has a number of names, including angiokeratoma corporis diffusum, alpha-galactosidase A deficiency, and was for many years known as Anderson-Fabry disease, but is now usually referred to simply as Fabry disease.[fabry.com.au]
  • This condition is also called Anderson-Fabry disease, Fabry’s disease, angiokeratoma corporis diffusum and alpha-galactosidase A deficiency. The disease is named after a Johannes Fabry who discovered it.[news-medical.net]
  • Definition / general Also called alpha-galactosidase A deficiency, angiokeratoma corporis diffusum universale X linked (Xq22.1) recessive lysosomal storage disease which causes deficiency in lysosomal alpha-galactosidase A, which catabolizes neutral glycosphingolipids[pathologyoutlines.com]
  • It is also known as angiokeratoma corporis diffusum as well as alpha-galactosidase-A deficiency . The condition is due to the lack of or ineffective enzyme known as alpha-glycosidase-A.[aocd.org]
Myocardial Fibrosis
  • (Insert Figure 3) Using cardiac MRI to quantify myocardial fibrosis and following a longitudinal protocol, Krämer et al [16] showed that myocardial fibrosis relates to malignant ventricular arrhythmias (non-sustained and sustained ventricular tachycardia[escardio.org]
  • Cardiac Focal myocardial fibrosis leads to left ventricular hypertrophy. Thickening of the aortoventricular valve is seen in 25% of patients. Mitral valve disease with thickening and regurgitation is also demonstrated.[radiopaedia.org]
  • Seventeen IVS4 patients who had myocardial fibrosis without LVH underwent endomyocardial biopsy.[onlinejacc.org]
  • fibrosis with a predilection for the posterior-lateral LV wall, which, in advanced disease, contributes to LV aneurysm formation and systolic impairment. 7 The study by Adalsteinsdottir et al is at variance with the literature in 2 aspects.[circgenetics.ahajournals.org]
  • fibrosis found that post-treatment reductions in LV mass were associated with improvement in stress exercise. 48 The reductions in LVMi in migalastat-treated patients in this study correlate with changes in septal wall thickness but not posterior wall[jmg.bmj.com]

Treatment

Usually, Fabry disease is treated symptomatically. Medications are given to relieve pain in the body and the limbs. Pain in Fabry disease is often difficult to treat and does not respond to most of the over-the-counter pain medications. The drugs commonly used include diphenylhydantoin, carbamezipine, gabapentin and metoclopramide. Renal manifestation of proteinuria are treated either by ACE inhibitors (Angiotensin converting enzyme inhibitors) such as captopril; or angiotensin receptor blockers such as losartan. When renal failure starts to ensue, the patient has to resort to routine dialysis. Later when both the kidneys have failed, transplant is the only option.

In recent years, Enzyme Replacement Therapy (ERT) has emerged as one of the methods to manage and treat Fabry disease [5]. The patient is given recombinant forms of alpha galactosidase; such as agalsidase alpha and beta. The iminosugar 1-deoxygalactonojirimycin (migalastat), a pharmacological chaperone, is an analog of the terminal galactose of globotriaosylceramide and a reversible inhibitor of alpha-galactosidase A, which may increase the activity of mutant variants of alpha-galactosidase A. In addition, the effect of ERT is increased.

Prognosis

The prognosis of Fabry disease (when properly treated) is very good. Most of the males have more than 80% of the normal life expectancy. Females suffering from Fabry disease have an even better life expectancy than males; most live beyond 93% of their normal life expectancy. Most of the patients require renal transplantation. Death in these patients usually occur due to complications related to the vascular system [6].

Etiology

Fabry disease is essentially a genetic disease and is caused by mutations in the GLA gene on the X chromosome. Females have two copies of this chromosome and males have one. One defective gene in males can therefore cause the full-fledged disease. In contrast, females who have one normal gene and an inherited mutated gene suffer from a much milder form of the disease, with the symptoms being far less severe. In such instances, there may be little or no symptoms of the disease.

Epidemiology

Fabry disease is a rare disease. The incidence, according to a number of surveys, lies somewhere around 1 in 40,000 live births. However, recent newborn screening showed substantially higher rates of deficient α-Gal A activities and α-Gal A mutations.

Sex distribution
Age distribution

Pathophysiology

The GLA gene normally encodes a protein enzyme named alpha galactosidase A (a-GAL). Alpha galactosidase is normally responsible for the breakdown of a lipid named globotriaosylceramide. Mutations in the GLA gene result in a deficiency or abnormal function of this enzyme. As a result, globotriaosylceramide accumulates in the cells of all the tissues of the body; most importantly in the blood vessels, kidneys, heart and nervous system. In the cells, this lipid accumulates in lysosomes, due to which Fabry disease is referred to as one of the lysosomal (lipid) storage diseases. A multitude of signs and symptoms related to various systems of the body thus ensues in this disease.

Prevention

There is no prevention of Fabry disease.

Summary

Fabry disease is a lysosomal lipid storage disease which is caused by low levels of the enzyme alpha galactosidase A. This usually occurs due to defects in the GLA gene which lies on the X chromosome. There is an accumulation of glycosphingolipids in the skin, eyes, heart, kidneys, nervous system and vascular system. This results in a large number of clinical manifestations related to all these organs. Fabry disease has no definite cure but the symptoms can be treated through various groups of drugs. The prognosis of the patients who receive treatment is very good.

Patient Information

Fabry disease is caused by low levels of an enzyme that breaks down a certain lipid in the cells of various tissues of this body. This is due to the inheritance of a mutated gene on X chromosome – one of the two sex chromosomes. As the enzyme required to break the lipid is absent, it accumulates unchecked in the skin, eyes, heart, kidneys, nervous system and circulatory system of the patient. As a result, the patient suffers from a variety of symptoms related to these organs.

Fabry disease has no definite cure. However, it is possible to treat the symptoms of the disease through various medications. People who receive proper treatment live very long and also enjoy a good quality of life.

References

Article

  1. Hoffmann B, Beck M, Sunder-Plassmann G, Borsini W, Ricci R, Mehta A. Nature and prevalence of pain in Fabry disease and its response to enzyme replacement therapy--a retrospective analysis from the Fabry Outcome Survey. Clin J Pain. 2007;23(6):535-542.
  2. Linhart A, Kampmann C, Zamorano JL, et al. Cardiac manifestations of Anderson-Fabry disease: results from the international Fabry outcome survey. Eur Heart J. 2007 28(10):1228-1235.
  3. Ortiz A, Oliveira JP, Waldek S, Warnock DG, Cianciaruso B, Wanner C, Fabry Registry. Nephropathy in males and females with Fabry disease: cross-sectional description of patients before treatment with enzyme replacement therapy. Nephrol Dial Transplant. 2008;23(5):1600-1607.
  4. Linthorst GE, Poorthuis BJ, Hollak CE. Enzyme activity for determination of presence of Fabry disease in women results in 40% false-negative results. J Am Coll Cardiol. 2008;51(21):2082.
  5. Ioannou YA, Zeidner KM, Gordon RE, Desnick RJ. Fabry Disease: Preclinical Studies Demonstrate the Effectiveness of α-Galactosidase A Replacement in Enzyme-Deficient Mice. The American Journal of Human Genetics. 2001;68(1):14-25.
  6. MacDermot KD, Holmes A, Miners AH. Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males. J Med Genet. 2001;38(11):750-760.

Symptoms

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