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. 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. Normal Components of GBM
• Type IV collagen
• Laminins
• Nidogen
• Sulfated proteoglycans

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. Triple Helical Organization of the Type IV
Collagen Family
HUDSON et al, N Engl J Med, 2003

6. Assembly and Network Organization
Type IV Collagen Protomers in the GBM
HUDSON et al, N Engl J Med, 2003

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. 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. 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. Clinical pedigree of the family BM
(X-linked AS?)
?
Hematuria
Renal failure
Hypoacusis
proband

11. BM, F, 55 yr (X-linked AS ?)

12. BM, F, 55 yr (X-linked AS?)

13. OR, M, 21 yr (X-linked AS?)

14. Clinical pedigree of the family RM
(AR –AS?)
?
Hematuria
Renal insufficiency / failure
Hypoacusis

15. RM, F, 32 yr (AR –AS?)

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. PM, F, 30 yr (AD – AS?)

18. FG, M, 37yr (AD – AS?)

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.