Presentation is loading. Please wait.

Presentation is loading. Please wait.

A mild form of Alport syndrome: Hereditary nephropathy in the absence of extra-renal features Yoon H-S, Wilson JC & Eccles MR Pathology, University of.

Similar presentations


Presentation on theme: "A mild form of Alport syndrome: Hereditary nephropathy in the absence of extra-renal features Yoon H-S, Wilson JC & Eccles MR Pathology, University of."— Presentation transcript:

1 A mild form of Alport syndrome: Hereditary nephropathy in the absence of extra-renal features Yoon H-S, Wilson JC & Eccles MR Pathology, University of Otago, Dunedin, New Zealand

2 Alport syndrome (AS) A hereditary disorder resulting from abnormal type IV collagen Nephropathy with considerable genetic and clinical heterogeneity characterized by haematuria, proteinuria and progressive renal failure, first reported by Alport in 1927 Frequently associated with: – Eye abnormalities – High tone sensorineural deafness Rarely associated with: – Mental retardation – Leiomyomatois

3 Alport syndrome: genetics 85% of AS patients: X-linked inheritance of mutations in the COL4A5 gene on Xq22 encoding the  5(IV) collagen chain – COL4A5 is a large gene comprising 51 exons – As many as 609 mutations have been described to date and are spread throughout the gene without any hot spots (Arup Laboratory 2011) 15%: Autosomal inheritance of mutations of the COL4A3 or COL4A4 gene encoding the  3(IV) or  4(IV) on 2q36-37: – 14%: autosomal recessive – 1%: autosomal dominant

4 Type IV collagen formation Protomer  (VI) chain Meshwork formation 11 44 22 33 55 66 112112 345345 556556 Hudson et al, NEJM 348:2543, 2003 NC1Collagenous7S

5 Type IV collagen distribution  1.  1.  2(IV): Ubiquitously present in basement membrane (BM) in many tissue  3.  4.  5(IV) and  5.  5.  6(IV): Restricted tissue distribution – In the kidney  1.  1.  2(IV) network predominates during early nephrogenesis in GBM. – During the 2 nd trimester of foetal development,  3.  4.  5(IV) network gradually becomes dominant  3.  4.  5(IV) is also expressed in the eye, cochlea, lung and testis while  5.  5.  6(IV) network is present in skin, oesophagus and smooth muscle.

6 Initial presentation of the NZ family Two sisters (IV6:58 yo and IV8:54 yo) presented to the clinic to be considered as potential live kidney donors for their sons (V29:27 yo and V35:33 yo, respectively) who had ESRF. Both women were found to have significant proteinuria (1.8, 1.4g/d, respectively) and hypertension and they proceeded to a renal biopsy (mild mesangial proliferation and hypertensive arteriosclerosis). Routine questioning revealed a strong familial history of hypertension and the possibility of a familial form of renal disease. Subsequent clinical review of the family identified a number of additional family members with renal disease. Negative for hearing loss or eye abnormalities in all individuals tested.

7 Identif- ication number Age (yrs old) Gender PresentationRenal Function and Blood Pressure BiopsyInheritance III2F Died on dialysisNot doneAffected/ Carrier IV357 M ESRF. Dialysis Renal Transplant at 41 Not doneAffected IV546 M Proteinuria Hypertension Chronic kidney disease Not doneAffected V2439 M Proteinuria Haematuria Normal renal function Mild mesangial matrix expansion Affected V2927 M Acute nephritic syndrome Hypertension ESRF. Dialysis 2 nd renal transplant at 26 Chronic glomerulo- nephritis Affected V3136 M Proteinuria Hypertension Chronic kidney disease BP 136/86 Mesangial cell proliferation Affected V3533 M Proteinuria Haematuria ESRF and renal transplant at 28 Chronic glomerulo- nephritis Affected IV3972 M Proteinuria 1.6g/24 hr No haematuria Hypertension Mild chronic kidney disease BP 144/76 Not doneAffected V4239 M Proteinuria 1.1g/24 hr Normal renal function BP 126/80 Mesangial cell proliferation Affected Identif- ication number Age(yrs old) Gender PresentationRenal Function and Blood Pressure BiopsyInheritance IV2658 F Proteinuria 1.8g/24 hr Hypertension BP 152/76Mesangial cell proliferation Hypertensive arteriosclerosis Carrier IV2854 F Proteinuria 1.4g/24 hr Hypertension Normal renal function Mesangial cell proliferation Hypertensive arteriosclerosis Carrier 1. Subjects with renal disease identified before DNA tests Dead:1, ESRF:3, Chronic disease:3

8 Histology of V42

9

10 IHC for  3,  4 and  5(IV) 33 44 55 Abs gift from Dr Sado

11 Diagnostic dilemma Is this Alport syndrome? – No hearing or eye abnormalities – Mild form of kidney disease and late onset 11 Glomerulonephritis 4 ESRF (3 males and 1 female) Low penetrance!! A new entity of hereditary kidney disease?

12 Extended family pedigree A total of 155 family members for 6 generations examined (81M and 74F). Black symbols: Biopsy confirmed GN (6M). Gray symbols: Clinically GN, biopsy not done (4M & 1F). Black dots: Obligate carriers (21F). White symbols: No clinical disease (71M & 73F). Cross: Confirmed by DNA testing. Predominance of GN in males and lack of male to male transmission consistent with X-linked inheritance

13 Family pedigree (simplified) X-chromosome microsatellite marker

14 Two point LOD scores between the GN locus and markers mapping to chromosome Xq Theta DXS6809-infinity DXS DXS DXS DXS6749-infinity The linked region encompassing COL4A5

15 Nucleotide sequence alteration in COL4A5 in affected family members Mae III digest of exon 50 PCR products M NC Affected males Affected & carrier females A allele Present in all affected family members and not in 192 healthy control

16 Identif- ication number Age (yrs old) Gender PresentationRenal Function and Blood Pressure BiopsyInheritance III2F Died on dialysisNot doneAffected/ Carrier IV357 M ESRF. Dialysis Renal Transplant at 41 Not doneAffected IV546 M Proteinuria Hypertension Chronic kidney disease Not doneAffected V2439 M Proteinuria Haematuria Normal renal function Mild mesangial matrix expansion Affected V2927 M Acute nephritic syndrome Hypertension ESRF. Dialysis 2 nd renal transplant at 26 Chronic glomerulo- nephritis Affected V3136 M Proteinuria Hypertension Chronic kidney disease BP 136/86 Mesangial cell proliferation Affected V3533 M Proteinuria Haematuria ESRF and renal transplant at 28 Chronic glomerulo- nephritis Affected IV3972 M Proteinuria 1.6g/24 hr No haematuria Hypertension Mild chronic kidney disease BP 144/76 Not doneAffected V4239 M Proteinuria 1.1g/24 hr Normal renal function BP 126/80 Mesangial cell proliferation Affected Identif- ication number Age(yrs old) Gender PresentationRenal Function and Blood Pressure BiopsyInheritance IV2469 F Trace microscopic haematuria Normal renal function BP 168/86 Not doneCarrier IV2658 F Proteinuria 1.8g/24 hr Hypertension BP 152/76Mesangial cell proliferation Hypertensive arteriosclerosis Carrier IV2854 F Proteinuria 1.4g/24 hr Hypertension Normal renal function Mesangial cell proliferation Hypertensive arteriosclerosis Carrier IV3169 F Hypertension Negative urine Normal renal function Not doneCarrier IV3465 F Hypertension Negative urine Normal renal function Not doneCarrier IV3661 F Microscopic haematuria Normal renal function Not doneCarrier V4038 F HaematuriaNormal renal function BP 118/60 Mild mesangial cell proliferation Carrier IV4754 F Negative urineBP 148/70Not doneCarrier V4436 F Intermittent microscopic haematuria Normal renal function BP 120/76 Not doneCarrier V4943 F Negative urineNormal renal function BP 120/70 Not doneCarrier V3739 F Negative urineNormal renal function Not doneCarrier 1.Renal disease identified before DNA tests2.Renal disease/carriers identified after DNA tests

17 Depiction of NC1 domain showing locations of cysteine sequence alterations and clinical details of patients

18 Summary We report a unique cysteine to tyrosine substitution in the NC1 domain of COL4A5 in a New Zealand family who presented with a phenotypically mild form of Alport syndrome, suggesting that in this family substitution of Cys1638Tyr led to late onset renal failure without hearing loss or eye abnormalities.

19 Histology of female carriers (IV26) 6A 6B

20 EM (carrier IV26) 150nm

21 EM (carriers IV26)

22 Summary Thin basement membrane nephropathy could be seen in some carrier women containing COL4A5 mutations.


Download ppt "A mild form of Alport syndrome: Hereditary nephropathy in the absence of extra-renal features Yoon H-S, Wilson JC & Eccles MR Pathology, University of."

Similar presentations


Ads by Google