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C.Spanu Alport.Syndr.Cong.Balcanic.2009

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C.Spanu Alport.Syndr.Cong.Balcanic.2009

  1. 1. Alport Syndrome: a challenging diagnosis in clinical practice C.Spânu, C.Crăciun, I. Kacso, M. Crăciun, P.Florescu, E. Bodurian, S.Spânu, Mirela Gherman-Căprioară
  2. 2. Genetic Diseases of the GBM Clinicopathological Features Alport Syndrome (AS) Progressive hematuric renal disease + typical ultrastructural GBM lesion Sensorineural hearing loss Ocular abnormalities (lenticonus, white dot-and-fleck retinopathy) Leiomyomatosis Thin GBM Disease / “Benign Familial Hematuria” Micro/macro hematuria - familial in > 60% of cases- Normal renal function Thinning of the GBM Nail-Patella Syndrome Multiple osseous abnormalities (elbows, knees) Nail dysplasia Renal disease (in 50% of cases)→ Nephrotic syndrome
  3. 3. Normal Components of GBM • Type IV collagen • Laminins • Nidogen • Sulfated proteoglycans
  4. 4. Genetic Diseases of the GBM Involved Genes and Mode of Inheritance Involved genes Inheritance Alport Syndrome COL4A5* / Xq22, or X-linked dominant COL4A5 and COL4A6 / Xq22 Autosomal recessive COL4A4 / 2q35-37, or or dominant COL4A3 / 2q35-37 Thin GBM Disease COL4A4 or COL4A3 Autosomal dominant Others (?) Nail-Patella LMX1B / 9q Autosomal dominant Syndrome * > 300 mutations characterized at COL4A5
  5. 5. Triple Helical Organization of the Type IV Collagen Family HUDSON et al, N Engl J Med, 2003
  6. 6. Assembly and Network Organization Type IV Collagen Protomers in the GBM HUDSON et al, N Engl J Med, 2003
  7. 7. Assembly of Collagen IV Protomers at Different Sites α3.α4.α5. - α3.α4.α5. : GBM, distal tubular BM, cochlea, eye, lung α1.α1.α2. - α5.α5.α6. : Bowman‘s capsule, skin (epidermal BM), smooth muscle, esophagus α1.α1.α2. - α1.α1.α2. : mesangium, the other basement membranes
  8. 8. Patients and methods • 9 patients (6F, 3M) from 6 families • Clinical exam, including extensive family history • Routine laboratory and imaging techniques • Renal biopsy: - LM and IF all cases - EM 8 cases; GBM thickness measurement according to Das AK et al, Nephrol Dial Transplant, 1996; limits of normal: - 156-336 nm (women) - 209-377 nm (men) • Screening exam for additional 40 subjects from 5 families
  9. 9. Main clinical features in 9 pts with AS Patient Gender/ Hematuria Proteinuria Creatinine Audiometry Age (g/24hr) cl.(ml/min) BM F/55 + 1 91 hypoacusis RM F/32 + 3.3 27 hypoacusis PM* F/30 + 1.6 122 normal FG* M/37 + 3 108 hypoacusis BE* F/33 + 2.4 60 normal ME** F/53 + 1.7 50 normal MS** F/48 + 1 113 normal OR M/21 + 4.5 84 hypoacusis TS M/30 + 2 84 hypoacusis *, ** - Members of the same family
  10. 10. Clinical pedigree of the family BM (X-linked AS?) ? Hematuria Renal failure Hypoacusis proband
  11. 11. BM, F, 55 yr (X-linked AS ?)
  12. 12. BM, F, 55 yr (X-linked AS?)
  13. 13. OR, M, 21 yr (X-linked AS?)
  14. 14. Clinical pedigree of the family RM (AR –AS?) ? Hematuria Renal insufficiency / failure Hypoacusis
  15. 15. RM, F, 32 yr (AR –AS?)
  16. 16. Clinical pedigree of the family PM (AD-AS?) I II III IV V Hematuria VI Renal insufficiency / failure; RRT in pts: III6, III7, IV7, IV17, IV20 Hypoacusis Renal failure Hematuria
  17. 17. PM, F, 30 yr (AD – AS?)
  18. 18. FG, M, 37yr (AD – AS?)
  19. 19. Conclusions • Our study demonstrates the importance of clinical evaluation of the proband and their relatives, completed with the ultrastructural examination of renal biopsies; • Clinical pedigree alone was not relevant for the mode of inheritance in five of the six reported families with Alport syndrome; • In the future, better accessibility to linkage and DNA analysis would improve the diagnosis of our Alport syndrome patients.

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