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Fabry disease

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Fabry disease

  1. 1. FABRY DISEASE Roshan Gunathilake MD John Hunter Hospital Newcastle, Australia
  2. 2. Case report  44 year-old-man  R/weakness, gait ataxia and nausea x 4 hours  Recurrent posterior circulation ischemic stroke /TIAs  Renal Transplant 2 yrs ago  Treated HTN
  3. 3. Background  CKD 2ry to FSGS 6 yrs ago  HD x 4 yrs  Cadaveric renal transplant 2 yrs ago  On MMF, Tacrolimus & prednisolone  Stable renal function, No Hx graft rejection  No Hx opportunistic infections / malignancy  HTN (irbesartan) x 8yrs, no other vascular risk factors
  4. 4. History  Recurrent transient vertigo 4 months ago, but no signs of brain stem dysfunction  Transient gait ataxia, and  R/occipital infarction 3 months ago  Normal work up incl. metabolic panel, Holter, TTE, Carotid duplex, MRA and thrombophilia screen  Started on clopidogrel + statin
  5. 5.  Sudden onset L/ hemiparesis, ataxia, dysarthria and nausea  No diplopia, facial weakness, vertigo, dysphagia or sensory loss  Symptoms started improving after 6-8 hrs, resolving after 24-48 hrs
  6. 6.  No cardiac Hx  No Hx of acroparesthesia  No family Hx of stroke, premature vascular disease or kidney disease  No Hx of alcohol, tobacco or drug abuse
  7. 7. Physical Exam  Residual L/visual field defect, otherwise normal CR N exam  L/ pronator drift, Grade 4 weakness  No sensory deficits  No cerebellar signs  Gait?
  8. 8. Physical Exam  Normal skin + cornea  HR 84/min SR  Periph pulses+  BP 138/84  S1S2, no murmur/ carotid bruit  Lungs clear  Abdo transplant kidney
  9. 9. Imaging  CT Brain: old R/occipital stroke  MRI brain : new lesion of high intensity in the right pons on T2- weighted images
  10. 10. Differential diagnosis of recurrent stroke/ TIAs  Cardioembolism  Premature atherosclerotic disease ± atheroembolism  Dissection  Cerebral vasculitis  Infection  Atrial Septal abnormalities  Substance abuse  Thrombophilia  Rare: Fabry disease, MELAS, CADASIL
  11. 11. Investigations  ESR 13  Hb 145  WBC 5.4  PLT 235  Cr 112  LFTs normal  Lipid profile normal  FBSL 4.9  CXR - NAD  Vasculitic screen – ve  Syphilis serology – ve  S.homocysteine normal  CSF exam – normal protein, glucose, cells & microscopy; no oligoclonal bands
  12. 12. Cardiac Investigations  ECG - SR, LVH  24 h telemetry - NAD  TTE – LVH, “binary apperance”  TOE – No septal defect/ PFO, No intracardiac source of thrombi
  13. 13. Investigations  Plasma α-galactosidase A activity very low (on 2 occasions)  Pedigree analysis : no other affected family members
  14. 14.  Referred to Statewide Fabry disease service for consideration for counseling, genetic testing and ?ERT
  15. 15. Fabry Disease  X-linked inborn error of metabolism  Deficient -Galactosidase A enzyme activity  Progressive globotriaosylceramide (GL-3) accumulation
  16. 16. Severe endothelial GL-3 accumulation
  17. 17. The classical phenotype  Early (adolescence) ◦ Acroparesthesia, ◦ Angiokeratomas, anhydrosis ◦ Corneal opacities  Late (4th- 5th decade) ◦ Renal failure ◦ Recurrent stroke ◦ Cardiomyopathy
  18. 18. Fabry Disease Progression 0 Acroparesthesia Renal Disease CNS Disease Cardiac Disease [Age] 40+ Diagnosis (average)
  19. 19. The later-onset phenotype  Residual α-galactosidase A activity due to missense and splicing mutations  Lack the early manifestations  Typically present with cardiac, renal or cerebrovascular manifestations
  20. 20. Diagnosis of Fabry Disease  Presumptive diagnosis – observation of symptoms and laboratory findings – family history/medical pedigree  Definitive diagnosis – enzyme assay in plasma, leukocytes, or biopsied tissue – gene mutation analysis or linkage analysis
  21. 21. Fabrazyme®  Shown in randomized, double-blind, placebo-controlled trials to be safe and effective at 1 mg/kg every 2 weeks  Clear the vascular endothelial glycolipid deposits and reverse, stabilize or markedly improve symptoms  Early intervention is essential to avoid the irreversible renal, cardiac and cerebro- vascular complications  Cost USD 200,000/ patient per annum

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