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].

• Pain

  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]

  Early symptoms of burning pain and paraesthesia in the extremities (acroparaesthesia) are a major cause of morbidity. Painful crises may be triggered by temperature change, fever, sun, physical exertion, etc. General fatigue and weakness are common. [patient.info]

  She said Blake’s metabolic tests came back great and showed no sign of Complex Regional Pain Syndrome. [globalgenes.org]

  At 24 and 36 months after commencement of ERT, pain severity classification shifted towards lower severity (P<0.05). Moreover, after 36 months, "average pain" and "pain now" were significantly reduced (P<0.05). [ncbi.nlm.nih.gov]

  This pain can increase over time. This acroparesthesia is believed to be related to the damage of peripheral nerve fibers that transmit pain. [en.wikipedia.org]

• Fever

  KEYWORDS: Algorithm; Diagnosis; FUO; Fabry disease; Fever of unknown origin; RFUO; Rare diseases; Recommendations; Recurrent fever of unknown origin [ncbi.nlm.nih.gov]

  Treatment also consists of taking analgesics to help relieve pain and fever or antiseizure drugs. NOTE: This is the Consumer Version. [msdmanuals.com]

  Treatment also consists of taking analgesics to help relieve pain and fever or antiseizure drugs. Generic Name Select Brand Names agalsidase beta FABRAZYME NOTE: This is the Consumer Version. [merckmanuals.com]

  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]

• Fatigue

  The most frequent manifestations in female patients were fatigue and cornea verticillata (50%), and tinnitus, vertigo and angiokeratoma (25%). [ncbi.nlm.nih.gov]

  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]

  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.tr]

  Despite continuing to experience daily pain and fatigue, heart problems, concentration issues and gastrointestinal symptoms, he finds positivity and opportunity in each day. Martynas is not currently enrolled in any of AVROBIO’s clinical trials. [avrobio.com]

• Burning Pain

  CONCLUSION: Suspicion of Fabry disease in teenager males presenting with symptoms of burning pain in extremities may lead to early diagnosis and treatment of this condition before occurrences of complications. [ncbi.nlm.nih.gov]

  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]

  Pain is one of the earliest symptoms – and the most incapacitating – starting with acroparesthesia and a burning pain in the hands and feet, often in the first decade of life. [youtube.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.tr]

  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]

• 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]

  The most frequent manifestations in male patients were fatigue (100%), tinnitus, vertigo, acroparesthesia, hypohidrosis, cornea verticillata and angiokeratoma (all 85%), heat intolerance (71%), and abdominal pain (57%). [ncbi.nlm.nih.gov]

  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.tr]

  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]

• Dyspnea

  We present the case of a 60-year-old woman with symptoms of dyspnea, atypical chest pain and palpitations, in whom a transthoracic echocardiogram revealed an apical variant of hypertrophic cardiomyopathy. [ncbi.nlm.nih.gov]

  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]

  Other signs include angiokeratoma, corneal changes, tinnitus, chronic fatigue, cardiac and cerebrovascular abnormalities (left ventricular hypertrophy, arrhythmia, angina), dyspnea, and nephropathy. [orpha.net]

• 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]

  Symptoms Constitutional: fatigue, dyshidrosis/hypohydrosis Eyes: cloudiness, decreased vision HEENT: tinnitus, hearing loss Cardiovascular: exercise intolerance, palpitations Pulmonary: shortness of breath, cough GI: nausea and vomiting after meals, lower [eyewiki.aao.org]

  Common and Other Possible Side Effects: Common side effects reported in 20% or more of Fabrazyme treated patients in clinical studies compared to placebo were upper respiratory tract infection, headache, cough, burning and/or tingling sensation, fatigue [fabrazyme.com]

  […] streaks.2 Retinal vessels are commonly affected with arteriolar narrowing, venous dilatation, and irregularity and excessive tortuosity of retina vessels.2 The tear production may be reduced.2 Late pulmonary involvement can be manifested with chronic cough [journals.sagepub.com]

• Chronic Cough

  Pulmonary manifestations and exercise intolerance Pulmonary involvement may manifest as chronic cough, dyspnea with exercise, and wheezing. [nature.com]

  cough, shortness of breath with exercise, and sibilance2 due to obstructive lung disease.53 The otologic involvement is characterized by progressive hearing loss (especially for frequencies above 4000 Hz), sudden deafness (often asymmetrical), and vestibular [journals.sagepub.com]

  Respiratory involvement Respiratory involvement, manifesting as dyspnea with exercise, chronic cough and wheezing, is frequent in both genders with FD [ 147, 148 ]. [ncbi.nlm.nih.gov]

• Diarrhea

  […] 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]

  Gastrointestinal signs and symptoms-abdominal pain, nausea, diarrhea and diverticular disease--are some of the most frequently reported complaints in patients with Fabry disease but are often neglected. [ncbi.nlm.nih.gov]

  The second most common group of symptoms includes abdominal pain, nausea, vomiting, and diarrhea from early childhood. [youtube.com]

  A decline in kidney peritubular capillary globotriaosylceramide inclusions correlated with diarrhea improvement; patients with a reduction > 0.1 were 5.6 times more likely to have an improvement in diarrhea than those without (p = .031). [18] Results [emedicine.com]

• Abdominal Pain

  Ten patients sought medical consultation because of abdominal pain and were diagnosed with food intoxication or nonspecific pain. [ncbi.nlm.nih.gov]

  The second most common group of symptoms includes abdominal pain, nausea, vomiting, and diarrhea from early childhood. [youtube.com]

• Nausea

  Gastrointestinal signs and symptoms-abdominal pain, nausea, diarrhea and diverticular disease--are some of the most frequently reported complaints in patients with Fabry disease but are often neglected. [ncbi.nlm.nih.gov]

  […] 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]

  The second most common group of symptoms includes abdominal pain, nausea, vomiting, and diarrhea from early childhood. [youtube.com]

• Vomiting

  Non-specific gastrointestinal symptoms, including pain, diarrhoea, nausea, and vomiting, can be the first symptoms of Fabry disease. They may suggest more common disorders, e.g. irritable bowel syndrome or inflammatory bowel disease. [ncbi.nlm.nih.gov]

  The second most common group of symptoms includes abdominal pain, nausea, vomiting, and diarrhea from early childhood. [youtube.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]

  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 in [medicalnewstoday.com]

• 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]

  Stomach and bowel problems may also develop (including diarrhoea, constipation and stomach cramps). In adult life, ringing in the ears (tinnitus), heart problems and stroke may occur. Kidney disease often progresses further. [cuh.nhs.uk]

  Pediatric Gastroenterology (see Services below for local 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]

  […] hypohidrosis) Episodes of neuropathic pain in the hands and feet (acroparesthesia), precipitated by stress or extremes of temperature Cloudiness of the cornea Hearing loss [2] Abdominal symptoms such as pain, nausea, vomiting, and either diarrhoea or constipation [dermnetnz.org]

• Macroglossia

  We report the case of a 50-year-old male FD patient on hemodialysis who presented with macroglossia-related speaking difficulty and gastrointestinal symptoms. [ncbi.nlm.nih.gov]

• Heart Failure

  A 73-year-old woman with a first episode of heart failure was admitted to our hospital. Her left ventricular wall motion was mildly reduced without hypertrophy. Urine sediment revealed mulberry cells, leading to the diagnosis of Fabry disease. [ncbi.nlm.nih.gov]

  […] of an unknown cause.[4][5] These cause heart failure by changing either the structure or the function of the heart.[4] The two types of left ventricular heart failure – heart failure with reduced ejection fraction (HFrEF), and heart failure with preserved [en.wikipedia.org]

  Renal failure, heart failure and/or myocardial infarction, and stroke were among the most likely causes of death. [emedicine.medscape.com]

• Hypertension

  All true Fabry patients had arterial hypertension (AHT), and one had hypertrophic obstructive cardiomyopathy (HOCM). CONCLUSIONS: In a group of unselected patients with LVH, we found a prevalence of Fabry disease of 0.9%. [ncbi.nlm.nih.gov]

• Tachycardia

  Although ventricular tachycardia has been reported in male patients with Fabry disease, it is not thought to be a frequent finding in females. [ncbi.nlm.nih.gov]

  Tachycardias[edit] In adults and children over 15, resting heart rate faster than 100 beats per minute is labelled tachycardia. Tachycardia may result in palpitation; however, tachycardia is not necessarily an arrhythmia. [en.wikipedia.org]

  tachycardia (VT) or ventricular fibrillation (VF). [doi.org]

  Two years later, she has been troubled by runs of non-sustained ventricular tachycardia. A repeat MRI demonstrated left ventricular hypertrophy. [academic.oup.com]

• Palpitations

  A 58-year-old woman was referred to our cardiology service with chest pain, exertional dyspnoea and palpitations on a background of known Fabry disease diagnosed with genetic testing in 1994. [ncbi.nlm.nih.gov]

  The prevalence of angina was 23 vs. 22%; palpitations and arrhythmias 27 vs. 26%; exertional dyspnoea 23 vs. 23%; and syncope 2 vs. 4%, in women and men, respectively (all P = NS). [eurheartj.oxfordjournals.org]

  The most common symptom of an arrhythmia is an awareness of an abnormal heartbeat, called palpitations. These may be infrequent, frequent, or continuous. [en.wikipedia.org]

• Cardiomegaly

  Usually present with cardiac involvement including cardiomegaly, mitral insufficiency, and cardiomyopathy. Can present with proteinuria. Occasionally developing acroparaesthesia. [patient.info]

  However, males with residual alpha-Gal A activity as well as female carriers may have a mild form of the disease which is limited to cardiac involvement manifested by cardiomegaly with particular involvement of the left ventricle and interventricular [path.upmc.edu]

  Chest Radiographs and Echocardiography Cardiomegaly may be readily evident on a chest radiograph. Echocardiography may be indicated to investigate a possible source of emboli. [emedicine.com]

• Acroparesthesia

  What is Known: • Signs and symptoms of Fabry disease are seen in children KEYWORDS: Acroparesthesia; Alpha-galactosidase A; Children; Fabry disease; Limb pain; Screening [ncbi.nlm.nih.gov]

  The earliest manifestations include acroparesthesias, angiokeratomas, hypohidrosis, and lenticular and corneal changes. [emedicine.medscape.com]

• Osteoporosis

  Chondromalacia patellae Chronic synovitis Kronisk synovitis Chronic recurrent multifocal osteomyelitis Kronisk tilbagevendende multifokal osteomyelitis Churg-Strauss syndrome Churg-Strauss syndrom Cogan's syndrome Cogan syndrom Corticosteroid-induced osteoporosis [k10.dk]

  These can include: Higher chance of heart attack or stroke Serious kidney problems, including kidney failure High blood pressure Heart failure Enlarged heart Osteoporosis Getting a Diagnosis It can take a long time to get diagnosed with Fabry disease. [webmd.com]

• Osteopenia

  Osteopenia is common in Fabry disease patients. 20 Gastrointestinal symptoms were found to be common patients with Fabry disease, as reported by Hoffmann et al in 2008. [dermaamin.com]

  Osteopenia and osteoporosis: previously unrecognized manifestations of Fabry disease. Clin Genet 2005; 68 : 93–95. 81 Schiffmann R, Murray GJ, Treco D, Daniel P, et al. [nature.com]

  Progressive infiltration of Gaucher cells in the bone marrow may lead to thinning of the cortex, pathologic fractures, bone pain, bony infarcts, and osteopenia. These bony features may also be related to macrophage-produced cytokines. [emedicine.medscape.com]

  Depression, anxiety, panic attacks, and ADHD Integumentary: Angiokeratomas, anhydrosis or hypohydrosis, teleangiectasia, lymphoedema Ocular: Cornea verticillata (corneal whorling), tortuous retinal vessels, subcapsular cataracts Other: Joint and muscle pain, osteopenia [medicalhomeportal.org]

  Psychiatric: Depression, suicidal ideation and dementia. 5,15,55 Others: presence of AK in the respiratory and digestive tract mucosa 15, greater incidence of subclinical hypothyroidism, airway obstruction, osteopenia up to osteoporosis, anemia, and others [scielo.br]

• Leg Pain

  In this paper, we studied a 54 year-old female who had complaints of leg pain, palpebral edema and telangiectasis and in whom foam cells in renal biopsy as well as proteinuria in urinalysis were revealed. [jstage.jst.go.jp]

  MRI of 77-year-old man with leg pain believed to be secondary to degenerative disk disease. During evaluation, abdominal aortic aneurysm was discovered. Age is risk factor for development of aneurysm. [emedicine.medscape.com]

• Tinnitus

  The most frequent manifestations in female patients were fatigue and cornea verticillata (50%), and tinnitus, vertigo and angiokeratoma (25%). [ncbi.nlm.nih.gov]

  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]

• Hearing Problem

  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]

  Nervous system problems - Damage to blood vessels in the brain can cause weakness, head pain, numbness, dizziness and stroke. Hearing problems - This may include a gradual loss of hearing or ringing in the ears (tinnitus). [kidney.org]

  Gastroenterologist for digestive problems Otolaryngologist (ear, nose, and throat specialist, or ENT) for hearing 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]

• Hearing Impairment

  Configuration of hearing loss was classified according to the European Working Group on Genetics of Hearing Impairment. [ncbi.nlm.nih.gov]

  Typical manifestations had been described as angiokeratoma, sweating disturbances, neuropathic pain, and hearing impairment. In addition, affection of the heart, the kidney and the central nervous system had been seen [ 4, 5 ]. [ojrd.com]

  Rena Ellen Falk and Arti Pandya, Hereditary Hearing Impairment, Emery and Rimoin's Principles and Practice of Medical Genetics, 10.1016/B978-0-12-383834-6.00150-6, (1-38), (2013). [doi.org]

• Sudden Hearing Loss

  Sudden hearing loss can be managed with infusion of vasodilators and steroids. Hearing aids or cochlear implants should be considered in case of advanced deafness. [nature.com]

  Giovanni Felisati, Elisabetta Salvatici, Carlotta Pipolo, Sara Portaleone, Enrica Riva and Marcello Giovannini, Fabry disease presenting with sudden hearing loss and otosclerosis: a case report, Journal of Medical Case Reports, 6, 1, (2012). [doi.org]

• Angiokeratoma

  ANGIOKERATOMA CORPORIS DIFFUSUM (FABRY'S DISEASE). Arch Dermatol. 1965 Mar; 91 :206–218. [ PubMed ] [ Google Scholar ] HENRY EW, RALLY CR. The renal lesion in angiokeratoma corporis diffusum (Fabry's disease). [ncbi.nlm.nih.gov]

  Dystopic Lipidosis Fabry Disease, Cardiac Variant Ceramide Trihexosidase Deficiency Diffuse angiokeratoma FD Gla Deficiency FABRY DISEASE edit English Fabry disease human disease Fabry's disease Anderson-Fabry disease angiokeratoma corporis diffusum [wikidata.org]

  Ueber einen Fall von Angiokeratoma circumscriptum am linken Oberschenkel. Dermatologische Zeitschrift, 1915, 22: 1-4. Zur Klinik und Ätiologie der Angiokeratoma. Archiv für Dermatologie und Syphilis, Berlin, 1916, 123: 294-307. [whonamedit.com]

• 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]

  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]

• Anhidrosis

  Six patients sought consultation because of anhidrosis, considered of unclear cause, and angiokeratomas diagnosed as petechiae. Internists and pediatricians were the most frequently consulted specialists. [ncbi.nlm.nih.gov]

  Anhidrosis or hypohidrosis may occur causing heat and exercise intolerance. [orpha.net]

  Dermal manifestations of Fabry disease include cutaneous vascular lesions (angiokeratomas) and abnormal sweating (anhidrosis or, more commonly, hypohidrosis). [emedicine.medscape.com]

  Additional symptoms include joint pain, intolerance to heat and exercise due to hypohidrosis and anhidrosis, dry eyes and dry mouth, hearing loss and tinnitus, aphasia, dysarthria, diplopia, vertigo, seizures, and valve disease. [youtube.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]

  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]

  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]

  Other signs include decreased sweating, fever, and gastrointestinal difficulties. [brainfacts.org]

• Papule

  A 23-year-old man presented for cosmetic consultation for symmetrically distributed, red-to-purple, hyperkeratotic papules that had been present since early childhood. [ncbi.nlm.nih.gov]

  A retrospective physical examination showed subtle small telangietatic papules on the scrotum, possibly angiokeratomas. [path.upmc.edu]

  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. [symptoma.com]

  Classification[edit] Angiokeratoma may be classified as: Angiokeratoma of Mibelli (also known as "Mibelli's angiokeratoma,"[4] "Telangiectatic warts"[5]) consists of 1- to 5-mm red vascular papules, the surfaces of which become hyperkeratotic in the course [en.wikipedia.org]

  Angiokeratomas Angiokeratomas are dilated blood vessels in the upper dermis, presenting as red or black papules. The papules do not blanch with pressure, and older lesions can become warty. [dermnetnz.org]

• Corneal Opacity

  Heterozygous females are usually asymptomatic but may have an attenuated form of disease often characterized by corneal opacities. [merckmanuals.com]

  opacity, lysosomal disease with restrictive cardiomyopathy, lysosomal disease with hypertrophic cardiomyopathy, rare hereditary metabolic disease with peripheral neuropathy, syndrome associated with hypertrophic cardiomyopathy Benannt nach Johannes Fabry [commons.wikimedia.org]

  opacity), and hearing loss. [rarediseases.info.nih.gov]

• Cornea Verticillata

  There was no overall local association seen between cornea verticillata and Fabry cataract. [ncbi.nlm.nih.gov]

• Corneal Deposit

  deposits have been shown to regress in some cases. [eyewiki.aao.org]

• Coarse Face

  The patient is 10 years old and presents severe mental handicap, coarse face, hepatosplenomeagly, dysostosis multiplex, joint contractures, obstructive airway disease, mitral regurgitation, deafness, and hydrocephaly. [ncbi.nlm.nih.gov]

• Kidney Failure

  Children with Fabry disease eventually develop kidney failure and heart disease, although, most often, they live into adulthood. Kidney failure may lead to high blood pressure, which may result in stroke. [msdmanuals.com]

  kidney failure may worsen throughout life. [en.wikipedia.org]

  If kidney failure occurs, dialysis or a kidney transplant is needed. Central nervous system problems - To help prevent strokes, doctors may prescribe medications to keep blood from clotting. [kidney.org]

  Individuals with the condition, mostly males, often die prematurely from complications of stroke, heart disease, or kidney failure. Enzyme replacement therapy via infusion has been available for Fabry disease since 2001. [raredr.com]

• Uremia

  Severe renal impairment leads to hypertension and uremia. Death usually occurs from renal failure or from cardiac or cerebrovascular disease. [ommbid.mhmedical.com]

  Uremia usually ensues and heralds end-stage renal disease. When the GI system is affected, a patient with Fabry disease has a history of intermittent nonbloody diarrhea and proctocolitis. [dermaamin.com]

  Natural history and treatment of uremia secondary to Fabry?s disease: An European experience. Nephron 1987;46:353-9. Sheth KJ, Roth DA, Adams MB. Early renal failure in Fabry?s disease. Am J Kidney Dis 983;2:651-4. [amhsr.org]

  Uremia due to Fabry end-stage renal disease and overuse of alcohol may add to the large fiber pathology [ 40, 55, 66, 76 ]. [ncbi.nlm.nih.gov]

• Hematuria

  A 54-year-old male presented with proteinuria, hematuria, and hypertension, and a 33-year-old male presented with proteinuria without clinical signs or family history of Fabry disease. [ncbi.nlm.nih.gov]

  […] 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]

  The main symptom of TBMD is blood in the urine (hematuria). Another common symptom is protein in the urine (proteinuria). [kidney.org]

• Microscopic Hematuria

  Microscopic hematuria was observed in case 4. Extrarenal symptoms included: acroparesthesia in case 1, 2, and 6, hypohidrosis in case 6 and angiokeratomas with hearing loss in case 3. [ncbi.nlm.nih.gov]

  Clinically, the renal disease manifests as hypertension, moderate proteinuria, lipiduria, and microscopic hematuria. Many heterozygous females manifest some signs of the disease, but in an attenuated form. [jasn.asnjournals.org]

• Renal Function Impairment

  These beneficial effects were more evident in those patients with lower levels of proteinuria (< 1 g/24 h) and lesser renal function impairment (GF rate > 55 mL/min/1.73 m2), inferring that both proteinuria and renal function may be considered as markers [revistanefrologia.com]

• Stroke

  Summary of Demographics of Fabry Registry Patients by Stroke Category and by Gender Characteristics Males With Strokes (n=86) Males Without Strokes (n=1157) Females With Strokes (n=52) Females Without Strokes (n=1151) All Patients With Strokes (n=138) [stroke.ahajournals.org]

  BACKGROUND: Fabry disease (FD) is known as a rare cause of stroke. Recent studies suggested that FD is an underdiagnosed entity among young stroke patients. [ncbi.nlm.nih.gov]

  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.com]

• 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]

  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]

  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]

  […] 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]

  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]

• Peripheral Neuropathy

  neuropathy, syndrome associated with hypertrophic cardiomyopathy Benannt nach Johannes Fabry Normdatei Q615645 GND-Kennung: 4153455-4 Reasonator Scholia Statistik Unterkategorien Es werden 4 von insgesamt 4 Unterkategorien in dieser Kategorie angezeigt [commons.wikimedia.org]

  As a result, patients have a markedly increased risk of developing ischemic stroke, small-fiber peripheral neuropathy, cardiac dysfunction and chronic kidney disease. [ncbi.nlm.nih.gov]

• Vertigo

  The most frequent manifestations in female patients were fatigue and cornea verticillata (50%), and tinnitus, vertigo and angiokeratoma (25%). [ncbi.nlm.nih.gov]

  Additional symptoms include joint pain, intolerance to heat and exercise due to hypohidrosis and anhidrosis, dry eyes and dry mouth, hearing loss and tinnitus, aphasia, dysarthria, diplopia, vertigo, seizures, and valve disease. [youtube.com]

  The most frequent signs and symptoms are hemiparesis, vertigo/dizziness, diplopia, and dysarthria. (4) Other clinical manifestations which are variably present include hypohidrosis, corneal opacities, and obstructive pulmonary disease. (2,5) Morbidity [path.upmc.edu]

  Hemiparesis, vertigo, diplopia, dysarthria, hemianopia, sensory loss, and other typical stroke symptoms characterize CNS involvement. [emedicine.com]

• Tingling

  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]

  Most people with the disease experience two types of pain: Neuropathic pain - a burning, tingling pain that mainly affects the palms of the hands and soles of the feet. [fabrazyme.com]

  These pain episodes are described as burning, tingling, and numbness and are thought to be related to the involvement of the vascular supply and small fibers of the peripheral nervous system. [emedicine.medscape.com]

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]

  Renal ultrasound and haematuria Multiple renal cysts, mostly parapelvic, can be detected using ultrasonography in up to 50% of cases of patients [48]. Although uncommon, haematuria may also occur, but other causes must be excluded [46, 47]. [bmcnephrol.biomedcentral.com]

• Albuminuria

  RESULTS: No statistical differences were found in baseline or final GFR or albuminuria. [ncbi.nlm.nih.gov]

  He recorded that the patient had been afflicted since childhood and that varicose veins, rectal bleeding and albuminuria had developed. [whonamedit.com]

  We hypothesize that albuminuria may precede overt proteinuria, but additional longitudinal studies should define the prognostic value of albuminuria in patients with Fabry disease. [ndt.oxfordjournals.org]

  History of nonspecific bowel disturbances, especially crampy abdominal pain and diarrhea History of lethargy and fatigue Early adulthood (17-30 years) More extensive angiokeratomas High albuminuria (>1g/24 hours) Edema or lymphedema Fever Hypohidrosis [kidney.org]

• Microalbuminuria

  Patients with hearing loss presented a significantly higher value of microalbuminuria (p = .001) and a higher frequency of acroparesthesias (p = .032). Patients presented a comparable hearing level one year after starting ERT (p = .384). [ncbi.nlm.nih.gov]

  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]

• Alpha-Galactosidase A Deficiency

  alpha-galactosidase A deficiency Fabry's disease (disorder) alpha galactosidase deficiency deficiency of melibiase Hereditary Dystopic Lipidosis Fabry Disease, Cardiac Variant Ceramide Trihexosidase Deficiency Diffuse angiokeratoma FD Gla Deficiency FABRY [wikidata.org]

  Fabry Disease (FD) is a genetic disorder caused by alpha-galactosidase A deficiency. [ncbi.nlm.nih.gov]

  ファブリー病 (Fabry disease, Fabry's disease, Fabry病, alpha-galactosidase A deficiency, α-ガラクトシダーゼ欠損症, Anderson-Fabry disease, アンダーソン・ファブリー病, angiokeratoma corporis diffusum, びまん性体幹被角血管腫) [jcggdb.jp]

  […] of alpha-galactosidase A. [symptoma.com]

  A small percentage of females who carry a mutation in one copy of the GLA gene never develop signs and symptoms of Fabry disease. alpha-galactosidase A deficiency Anderson-Fabry disease angiokeratoma corporis diffusum angiokeratoma diffuse ceramide trihexosidase [ghr.nlm.nih.gov]

• Gb3 Increased

  Increased cellular and plasma levels of Gb3 and Lyso-Gb3 affect multiple organs, with specific clinical consequences for the kidneys, heart and brain. [ncbi.nlm.nih.gov]

• Short PR Interval

  In a subset of patients, FD is associated with short PR interval due to accelerated AV conduction [10]. In contrast, advanced cardiomyopathy may lead to conduction impairment (AV blocks) and/or bradycardia and chronotropic incompetence. [escardio.org]

  Sadick and Thomas 14 studied the heart pathology in 12 patients and reported that 5 had cardiovascular symptoms, 9 had left ventricular hypertrophy on ECG tracings, 1 had a short PR interval, 3 had epicardial coronary disease, 4 had a rat-tail appearance [dermaamin.com]

  General physicians and cardiologists should consider the diagnosis of FD in patients with LVH, cardiomyopathy, and conduction abnormalities, including short PR intervals and inverted ST segments without evidence of infarction. [ncbi.nlm.nih.gov]

  Pochis WT, Litzow JT, King BG, Kenny D (1994) Electrophysiologic findings in Fabry’s disease with a short PR interval. Am J Cardiol 74:203–204 PubMed Google Scholar 64. [doi.org]

• Premature Atrial Contractions

  atrial contractions, premature ventricular contractions and premature junctional contractions.[3] Supraventricular tachycardias include atrial fibrillation, atrial flutter and paroxysmal supraventricular tachycardia.[3] Ventricular arrhythmias include [en.wikipedia.org]

• T Wave Inversion

  ECG showed sinus rhythm, shortened PR interval, widespread t wave inversion, q waves in the lateral leads and left ventricular hypertrophy (LVH). Coronary angiogram showed only mild atheroma. [ncbi.nlm.nih.gov]

  Resting ECG showed T wave inversion in lateral chest leads, I and aVL. [academic.oup.com]

  Common initial electrocardiographic abnormalities include sinus bradycardia, nonspecific ST-segment changes, T-wave inversion, and shortened PR interval. [emedicine.medscape.com]

  There is also presence of large voltage QRS complexes (prominent R waves V4-6) and repolarisation abnormalities with T wave inversion inferolaterally (leads II, III, aVF and V4-6) meeting ECG criteria for LVH. e Chest X-ray demonstrating a dual chamber [doi.org]

• White Matter Lesions

  The presence of white matter lesions was assessed by cerebral MRI or computed tomography (CT). [ncbi.nlm.nih.gov]

  There are several anamnestic and clinical hints indicating when Fabry disease should be considered a relevant differential diagnosis of multiple sclerosis, e.g. female patients with asymmetric, confluent white matter lesions on MRI, normal spinal MR imaging [centogene.com]

• Myocardial Fibrosis

  A different cardiomyopathic disease progression between male and female patients was hypothesised in previous studies, as in female myocardial fibrosis was found without left ventricular (LV) hypertrophy, while myocardial fibrosis was always detected [ncbi.nlm.nih.gov]

  (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]

  At baseline, 9 patients demonstrated at least two fibrotic LV segments (severe myocardial fibrosis), 9 had one LV segment affected (mild fibrosis) and 12 patients were without fibrosis. [opus.bibliothek.uni-wuerzburg.de]

• Left Ventricular Hypertrophy

  […] such as apical variants of left ventricular hypertrophy. [ncbi.nlm.nih.gov]

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.

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].

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.

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.

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.

There is no prevention of Fabry disease.

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.

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.

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.