1. Fabry disease 순환기 내과 R4 김정욱 / Prof. 김우식 2011.08.25 MGR

2. Introduction Anderson-Fabry disease - 2 nd most prevalent lysosomal storage disorder - X-linked recessive inborn error - glycosphingolipid metabolic pathway  deficiency of the lysosomal hydrolase alpha-galactosidase A (Xq22.1 region)  accumulation of globotriaosylceramide(Gb3) in a variety cells

3. Epidemiology prevalence ① 1:17,000~117,000 males in Coucassian ② 1:4,000 male neonates (in a screening study of 37,104) ③ 1:40,000~117,000 live male birth underestimation - The manifestation of the disease are nonspecific - Dx is often not considered by physicians given the rarity of the disease - The wrong Dx is often made initially

6. Pathophysiology

7. Deficiency of α-galactosidase ① storage of neutral glycosphingolipid (GL-3) ② as little as 5~10% residual enzyme activity : sufficient ③ cellular dysfunction → inflammation or fibrosis ④ mechanism of tissue damage : storage in vascular endothelium (kidney, heart, nerve system, skin) → poor perfusion

8. Clinical presentation

9. Three consecutive age period ① children & adolescent Burning pain in the hands/feet, hypohidrosis, nausea, abdominal pain, postprandial diarrhea, poor growth, school difficulty First Sx : Boys (5~6 year) / Girls (9 years) ② > 20 Sx tend to progress proteinuria ③ > 30~40 Renal failure Life-threatening cardiac and CV manifestation

10. Clinical presentation

11. Ⅰ. Pain the earliest manifestation 1 st two decades of life tend to decrease in advancing age Fabry crisis : severe episodes of limb pain (hand/feet → prox.) Triggered by environmental factor (heat, stress, common illness, fatigue, exercise) Ⅱ. Renal failure the earliest functional signs (??) signs of renal dysfunction (2 nd & 3 rd decade) : hyperfiltration, microalbuminuria, proteinuria or isosthenuria proteinuria (poor Px sign) / renal insufficiency (irreversible)

12. Clinical presentation Ⅲ.Cardiac manifestation : initially by myocardial hypertrophy interstitial abnormalities & replacement myocardial fibrosis ① Cardiomyopathy global LVH or an ASH (d/t myocardial infiltration) systolic function : preserved mild diastolic dysfunction (early) → systolic or severe diastolic dysfunction (later) ② Coronary artery disease / Angina Angina : 13~20% of pts Obstructive CAD ↓ myocardial O 2 demand ↑, endothelial dysfx, microvascular dysfx with impaired myocardial blood flow / CFR

13. Clinical presentation Ⅲ.Cardiac manifestation ③ Arrhythmia Atrial > venticular arrhythmias d/t glycosphingolipid deposition & fibrosis m/c ECG findings : short PR → voltage criteria of LVH or block Complete block, symptomatic bradycardia, VT menwomen Jaymin S et al. AJC 2005;96:842-6

14. Clinical presentation Ⅲ.Cardiac manifestation ④ valvular disease GL accumulation in valve with 2ndary fibrosis/calcification Mitral / aortic valve abnormalities (57% & 47%) No severe regurgitation (m/c mild MR) ⑤ vascular disease GL has a particular affinity to vascular endothelium initima & smooth m. of the media of arterial walls → thinning or thickening of the vessel wall & stenosis arterial >> venous system

15. Clinical presentation Ⅳ.Stroke & TIA frequency of stroke in men aged 25-44 : 12 times higher (women : 9 times) prominent thickening of CCA intima, abnormalities of CV autoregulation & vasoreactivity and dysfunction of Cb circulation Ⅴ.Occular distinctive corneal opacities (cornea verticillata) opacities of the posterior lens & retinal vascular tortuosity retinal infarction & permanent loss of vision (rare)

17. Clinical presentation Ⅵ.Gastrointestinal disturbance 2 nd m/c Sx in childhood, 19~52% N/V, abdominal pain, diarrhea (esp. a/w meal)

18. Clinical presentation Ⅶ.Angiokeratomas 40% of male adolescents increase in No and size with age cluster around the umbilicus and swimming trunk region valuable clue to the Dx

19. Clinical presentation Ⅶ.Others substantial hearing loss hypohidrosis with heat intolerance / exercise ability ↓ hyperhidrosis d/t involvement of sweat gland or autonomic neuropathy decreased BMD azoospermia a range of latent endocrine dysfunction depression or generalized anxiety characteristics facial feature

20. Clinical presentation

21. Diagnosis Sx (suspicion) frequently delayed (non-specific Sx) Acute/unexplained pain, exercise intolerance, unexplained GI disturbance, hypohidrosis, angiokeratomas Characteristics corneal lesions (cornea verticillata) Unexplained renal dysfunction Unexplained cardiomyopathy (LVH) Echocardiography subendocardial binary appearance Posterobasal fibrosis

23. Diagnosis α-galactosidase A activity Peripheral leukocyte or plasma Screening test Genetic analysis α-galactosidase A gene sequenicing & identification of disease-causing mutation for all Fabry family female carrier

25. Diagnosis Tissue diagnosis usually done only if no other means of Dx are available skin : characteristic glycolipid deposits kidney (nephrotics Synd, gross hematuria or exclusion of other Dx) - LM : vacuolization of podocyte & distal tubular epithelial cell - foam cell - EM : deposits of Gb3 within enlarged 2ndary lysosome as lamellated membrane structure (myeloid or zebra bodies) → hallmark of glycolipid storage disease

26. Diagnosis Tissue diagnosis Endocardial Bx - confirm echocardiographic LVH is the result of intramyocyte accumulation of glycospingolipid - borderline LVH : accumulation of GL-3 in the myocardium - HE stain : storage (perinuclea vacuoles) / hypertrophy of cardiomyocyte - EM : accumulation of osminophilic lamellar bodies within myocytes & endothelial cells

28. Management Enzyme replacement therapy approval in Europe in 2001 / USA in 2003 agalsidase α and β in a modified human cell line and chinese hamber recommended of all affected men (adolescent/older) male children should be treated early if symptomatic heterozygous female adults and children (?) signs of Sx of cerebrovascular disease, unresponsive acroparaesthesias, LVH, substaintial valvular regurgitation, compromised GFR or proteinuria

29. Management Long-term ERT ① Reducing heart size & LV mass ② LV fractional shortening ③ Pain crisis ↓ ④ Stabilizes kidney function ⑤ Delays the progression of renal failure ⑥ Delays the onset of clinical events

30. Management Symptom management Addresses affected organ systems separately Does not address the underlying cause of Fabry disease ① pain - avoid stimuli that precipitate pain - responds poorly to conventional analgesics - prophylactic neuroleptic treatment - narcotics - concerns about side effects ② Angiokeratomas : argon laser treatment ③ GI Sx : pancreatic enzyme supplements, diets, motility drug ④ CKD / proteinuria : ARB/ACEi, dialysis, KTP