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Fabry Disease

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Fabry Disease

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  1. <?xml version="1.0"?><AllQuestions><Question><slideID>360</slideID><slideType>Q&amp;A_QSlide</slideType><questionText>Enter your question.....</questionText><teamScoringFlag></teamScoringFlag><correctValue></correctValue><incorrectValue></incorrectValue></Question><Question><slideID>361</slideID><slideType>Q&amp;A_QSlide</slideType><questionText>Enter your question.....</questionText><teamScoringFlag></teamScoringFlag><correctValue></correctValue><incorrectValue></incorrectValue></Question></AllQuestions> <?xml version="1.0"?><Settings><answerBulletFormat>Alpha</answerBulletFormat><answerNowAutoInsert>No</answerNowAutoInsert><answerNowStyle>Explosion</answerNowStyle><answerNowText>Answer Now</answerNowText><chartColors>Use PowerPoint Color 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<?xml version="1.0"?><TeamNames><Team1></Team1><NewTeam1></NewTeam1><Team2></Team2><NewTeam2></NewTeam2><Team3></Team3><NewTeam3></NewTeam3><Team4></Team4><NewTeam4></NewTeam4><Team5></Team5><NewTeam5></NewTeam5><Team6></Team6><NewTeam6></NewTeam6><Team7></Team7><NewTeam7></NewTeam7><Team8></Team8><NewTeam8></NewTeam8><Team9></Team9><NewTeam9></NewTeam9><Team10></Team10><NewTeam10></NewTeam10></TeamNames> <?xml version="1.0"?><SlideMaster><tagSlideID>361</tagSlideID><slideID></slideID></SlideMaster> <?xml version="1.0"?><AllAnswers><Answers><slideID>360</slideID><answerID>0</answerID><answerText>I do not have any female patients</answerText><isCorrect>None</isCorrect><pointValue>0</pointValue></Answers><Answers><slideID>360</slideID><answerID>1</answerID><answerText>Normal activity</answerText><isCorrect>None</isCorrect><pointValue>0</pointValue></Answers><Answers><slideID>360</slideID><answerID>2</answerID><answerText>Low activity</answerText><isCorrect>None</isCorrect><pointValue>0</pointValue></Answers><Answers><slideID>360</slideID><answerID>3</answerID><answerText>No activity</answerText><isCorrect>None</isCorrect><pointValue>0</pointValue></Answers><Answers><slideID>361</slideID><answerID>0</answerID><answerText>Rheumatological disease</answerText><isCorrect>None</isCorrect><pointValue>0</pointValue></Answers><Answers><slideID>361</slideID><answerID>1</answerID><answerText>Arthritis</answerText><isCorrect>None</isCorrect><pointValue>0</pointValue></Answers><Answers><slideID>361</slideID><answerID>2</answerID><answerText>Neuropsychological disorder</answerText><isCorrect>None</isCorrect><pointValue>0</pointValue></Answers><Answers><slideID>361</slideID><answerID>3</answerID><answerText>Fibromyalgia</answerText><isCorrect>None</isCorrect><pointValue>0</pointValue></Answers></AllAnswers> Fabry Disease

  2. What is Fabry Disease? Fabry disease is due to a mutation on the X chromosome (Xq22)4 • One of the most common lysosomal storage disorders1,2 • Caused by α-galactosidase A deficiency3 • Due to a mutation on the X chromosome (Xq22)4 • Leads to pathological accumulation of sphingolipid Gb3*2,5 • Results in organ failure and premature death in males and females2,5 Chromosome X Xp Xq Gene *Gb3 = Globotriaosylceramide (sometimes abbreviated as GL-3, and also known as ceramide trihexoside [CTH]). From Beck M, Ries M, 2001.6 1. Fuller M, et al.In: Mehta A, et al(eds). Fabry disease: perspectives from five years of FOS. 2006. 2. Barbey F, et al. Curr Med Chem Cardiovasc Hematol Agents.2004;2:277–286. 3. Kint JA. Science. 1970;167:1268–1269. 4. Bishop DF, et al. Proc Natl Acad Sci USA 1988;85:3903–3907. 5. Mehta A, et al. Eur J Clin Invest.2004;34:236–242. 6. Beck M, Ries M. Fabry disease: clinical manifestations, diagnosis and therapy. 2001.

  3. Diagnosis of Fabry Disease • Pedigree analysis should be carried out whenever possible • Enzyme activity in females • Can be low, absent, or normal in affected females • Fabry disease should not be ruled out in females based on normal enzyme analysis • Prenatal diagnosis • α-galactosidase A activity present in fetal tissue • May be requested if mother is heterozygous for Fabry disease

  4. Clinical findings and Gb3 levels in 57 women with Fabry disease3 Elevated plasma Gb3 Elevated skin* Gb3 Cardiac, renal, or cerebrovascular abnormalities *Superficial endothelial dermal cells. Assessing Disease Severity • α-galactosidase A deficiency leads to deposition of lipid – mainly Gb3 (globotriaosylceramide) – in cells throughout the body1,2 • Nevertheless, Gb3 has not been established as an ideal marker in females3 • Urinary Gb3 is a better marker of Fabry disease than plasma Gb33 • Disease severity assessment • Mainz Severity Score Index (MSSI)4 • Fabry disease severity scoring system (DS3)5 • Fabry age-adjusted score6 1. Barbey F, et al. Curr Med Chem Cardiovasc Hematol Agents. 2004;2:277–286. 2. Mehta A, et al. Eur J Clin Invest. 2004;34:236–242. 3. Gupta S, et al. Medicine. 2005;84:261–268. 4. Whybra C, et al. Clin Genet. 2004;65:299–307. 5. Giannini EH, et al. Mol Genet Metab. 2010;99(3):283–290.6. Hughes DA, et al. Mol Genet Metab. 2010 Jun 22. [Epub ahead of print]

  5. Patients may receive a wide range of initial diagnoses1-3 Nephrologists 14% Geneticists 10% Other 51% Pediatricians 8% Dermatologists 7% Family doctors 5% Cardiologists 5% Different specialties involved in diagnosis.3 Fabry Disease May Be Initially Misdiagnosed • Fabry patients may be seen by many different specialists before a diagnosis is made1,2 Reproduced with permission from Mehta et al,2004. 1. Mehta A. Hosp Med. 2002;63:347–350. 2. Mehta A, et al. Eur J Clin Invest. 2004;34:236–242. 3. Beck M. In: Mehta A, et al(eds). Fabry disease: perspectives from five years of FOS. 2006.

  6. Kidneys Brain Heart Ears Eyes GI tract Skin Peripheralnerves Age (years: mean and SD) Symptom Onset: Males • Fabry disease affects almost all organs1-4 • Onset of symptoms in 375 adult males from the Fabry Outcome Survey5 • Females experience some of the same disease symptoms, and see a similar pattern of onset, but delayed by 10 years5 1. MacDermot KD, et al. J Med Genet. 2001;38:769–775. 2. MacDermot KD, et al. J Med Genet. 2001;38:750–760. 3. Mehta A, et al. Eur J Clin Invest. 2004;34:236–242. 4. Brady RO, et al. N Engl J Med. 1967;276:1163–1167. 5. Beck M. In: Mehta A, et al(eds). Fabry disease: perspectives from five years of FOS. 2006.

  7. Clinical Signs and Symptoms: Peripheral Neuropathy • Pain is an early, often debilitating symptom, seen in up to 77% of patients1 • Patients experience acroparesthesia and crisis of burning or lancinating pain1,2 • Exercise, temperature change, or stress may trigger a pain crisis1,3 • Reduced ability to sweat is common1 and contributes to poor exercise and heat tolerance4 Hands Feet 1. MacDermot KD, et al. J Med Genet. 2001;38:750–760. 2. Mehta A, et al. Eur J Clin Invest. 2004;34:236–242. 3. Barbey F, et al.Curr Med Chem Cardiovasc Hematol Agents. 2004;2:277–286. 4. Schiffmann R, et al. Muscle Nerve. 2003;28:703–710.

  8. Angiokeratomas Lips Umbilicus Trunk Signs and Symptoms: Dermatological Manifestations • Dermatological symptoms (telangiectases and angiokeratomas) are frequent (up to 78%) early signs of Fabry disease • Angiokeratomas are typically, but not exclusively, distributed within the bathing trunk area • May appear mild (few in number), moderate (dispersed, few in clusters) or severe (multiple, many, extensive) Reproduced with permission from Orteu CH, et al. 2007 Orteu CH, et al. Br J Dermatol. 2007;157(2):331–337.

  9. Signs and Symptoms: Gastrointestinal • Occur in up to 55% of patients1 • May be an early manifestationof Fabry disease2 • Symptoms include1-3 • Abdominal pain, bloating, constipation, and diarrhea • Delayed gastric emptying • Lack of appetite, early satiety • Nausea and vomiting Males Females Patients (%) Decade of life Adapted from Mehta, et al. 2004.1 1. Mehta A, et al. Eur J Clin Invest. 2004;34:236–242. 2. Dehout F, et al. J Inherit Metab Dis. 2004;27:499–505. 3. Hoffmann B, et al. Eur J Gastroenterol Hepatol. 2004;16:106–109.

  10. Signs and Symptoms: Ocular • Found in up to 62% of patients1 • Most specific manifestations are2,3 • Corneal opacities (cornea verticillata) • Retinal vascular abnormalities (vessel tortuosity) • Lens opacities (anterior orposterior subcapsular cataract) Reproduced with permission from Sodi, et al.2006.2 Reproduced with permission from Sodi, et al.2006.2 Reproduced with permission from Sodi, et al.2006.2 1. Mehta A, et al. Eur J Clin Invest 2004; 34: 236–242. 2. Sodi A, Ioannidis AS, Mehta A, et al. Ocular manifestations of Fabry’s disease: data from the Fabry Outcome Survey. Br J Ophthalmol. 2007;91:210–214. 3. Brady RO, Schiffmann R. JAMA. 2000;284:2771–2775.

  11. Signs and Symptoms: Cardiac • Up to 69% of male patients havecardiac symptoms (chest pain, palpitations, dyspnea, and syncope)1 • Cardiac abnormalities include2-4 • Left ventricular dysfunction (systolic and diastolic) • Conduction abnormalities • Left ventricular hypertrophy (mainly concentric) • Valve dysfunction (mainly mitral) Voltage criteria for LVH T-wave inversion Short PR interval Reproduced with permission from Linhart et al, 2006.5 Reproduced with permission from Linhart, et al.2006.5 1. Mehta A, et al. Eur J Clin Invest. 2004;34:236–242. 2. Elliott P. Curr Med Lit. 2006;6:1–6. 3. Kampmann C, et al. J Am Coll Cardiol. 2002;40:1668–1674.4. Shah JS, Elliott PM. Acta Paediatrica. 2005;94(Suppl. 447):11–14. 5. Linhart A, et al, In: Mehta A, et al(eds). Fabry disease: perspectives from five years of FOS. 2006.

  12. Signs and Symptoms: Cerebrovascular • Early onset (mean age 33.5 in males and 41.4 in females)1 • 13% of Fabry patients suffer stroke or TIA2 • Cerebrovascular abnormalities include • Increased regional cerebral blood flow3 • Vertebrobasilar vascular changes4 • Non-specific white matter lesions4 Middle cerebral artery Reproduced with permission from Ginsberg, et al.2005.4 Reproduced courtesy of Dr R Manara. 1. Beck M. In: Mehta A, et al(eds). Fabry disease: perspectives from five years of FOS. 2006. 2. Mehta A, et al. Acta Paediatrica. 2003;94(Suppl. 447):24–27. 3. Moore DF, et al. Stroke. 2002;33:525–531. 4. Ginsberg L, et al. Pract Neurol. 2005;5:110–113.

  13. Proteinuria CRI Death Patients (cumulative %) Age (years) Adapted from Branton, et al. 2002.2 Clinical Signs and Symptoms: Renal • Accumulation of Gb3 occurs in renal glomeruli and tubules1 • Glomerular injury leads to mesangial widening, ultimately leading to glomerulosclerosis2 • By age 40, most patients have proteinuria*2 • By age 50, most patients have CRI2 • CKD** stage 3 is present in approximately 20% of patients and 15% progress to ESRD***3 *Excess of serum proteins in the urine, as in renal disease. **Chronic Kidney Disease (eGFR < 60 ml/min/1.73 m2). ***End Stage Renal Disease (renal replacement therapy or serum creatinine > 6 mg/dL). 1. Brady RO, Schiffmann R. JAMA. 2000;284:2771–2775. 2. Branton MH, et al. Medicine. 2002;81:122–138. 3. Schiffmann R, et al. Nephrol Dial Transplant. 2009;24:2102-2111.

  14. Late-onset Variants of Fabry Disease • At screening, 1–6% of patients have cardiac disease (typically LVH) but few or no other classic symptoms1 Mehta A, Hughes DA. GeneReviews. 2002. 1. Sachdev B, et al. Circulation. 2002;105:1407–1411.

  15. Neurological Gastrointestinal Cardiac General Ear Eye Renal/urinary < 10 years old Dermatological > 10 years old Cerebrovascular % with signs/symptoms Clinical Manifestations in Fabry Children • Symptoms are reported from under 2 years of age1 • Most frequent early manifestations are neurological and gastrointestinal1 • Symptoms occur with similar frequency in boys and girls1 • Quality of life scores are lower for Fabry children compared with published values for healthy controls2 1. Ramaswami U, et al. Acta Paediatr. 2006;95:86–92. 2. Ries M, et al. Pediatrics. 2005;115:e344–55.

  16. Living With Fabry Disease • Progression of Fabry disease varies from person to person • It also means that symptoms appear at different ages and with differing severity • Infants • Pain and heat-related discomfort often appear first in young children with Fabry disease1 • Parents should be careful not to expose young children to extremes of temperature1 • Children and adolescents often experience • Episodes of pain and burning sensations in the hands and feet • Spotted, dark red skin rash seen most densely between the belly button and the knees • Changes in the appearance of the cornea • Parents and teachers should consider • Effects of physical exertion, exercise, and extremes of temperature • Social-related issues to do with school or employment • Adults • Fabry disease is slowly progressive and symptoms resulting from damage to the kidneys, heart, and central nervous system usually appear between the ages of 30 and 452 • Lifestyle considerations such as type of employment, choice of leisure activities, and diet are all important factors 1. Ramaswami U, et al. Acta Paediatrica. 2006;95:86–92. 2. Beck M. In: Mehta A, et al (eds). Fabry disease: perspectives from five years of FOS. 2006.

  17. Fabry Disease Overview

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