Familial Membranous Nephropathy D. Bockenhauer R. Kleta Gene - - PowerPoint PPT Presentation

Familial Membranous Nephropathy

• D. Bockenhauer
• R. Kleta

Gene identification

• Positional cloning: Independent of conventional

clinical concepts

• Reveal pathophysiology
• Identify treatment targets

Index patient: (903017)

• Presented at 1 y of age with nephrotic

syndrome, microscopic haematuria and hypertension

• No improvement with prednisolone

treatment

• Renal biopsy

Family History

90317 90309 90311 90302

All affected male and connected through maternal line =>X-linked recessive inheritance

Family History

• Uncles 90309 and 90311 presented at ages 3 and

10 year, respectively, with nephrotic syndrome

• Both experienced progressive kidney failure; one

in CKD IV, the other transplanted (no recurrence)

• Great-uncle 90302 presented age 67 with

cholecystitis, noted to have nephrotic range proteinuria (16.6g/24h) and CKD III

• Biopsies consistent with membranous nephropathy

Conclusions-1

• Family with 4 male members affected with primary MN
• Incidence of nephrotic syndrome in childhood due to

MN is ~1:106

• Incidence of MN in adulthood ~ 1:105
• Therefore, likelihood of all 4 members affected just by

chance is 1:1023

• An underlying genetic basis must be assumed
• Inheritance pattern consistent with X-linked recessive

Assessment of further family members

Genetic Analysis

Conclusions-2

• There is a small segment on the X-chromosome

potentially shared by all affected members

• Regions potentially shared also by unaffected

members, consistent with decreased penetrance => “susceptibility” factor for MN

• May also explain variable age of onset
• 70% of patients with primary MN are male
• X-linked factor may explain sporadic cases
• Potential therapeutic target

Acknowledgements

• Family for collaboration
• Halpin foundation
• Drs Debiec and Ronco