Kamal Akl MD Associate Professor of Pediatrics/Nephrology Jordan University Hospital

To review the various genetic etiologies of the hereditary nephropathies Emphasis on genetic nephrotic syndrome The new taxonomy of the podocytopathies

Clinical Presentation  GBM diseases  Hematuria  Podocyte diseases  Proteinuria

Type IV collagen ( hematuric diseases) a) Alport syndrome b) TBMN c) Familial hematuria with retinal arteriolar tortuosity & contractures Laminin β2 Pierson syndrome Gubler MC Nat Genet Clin Practice Nephrology 2008

 X – linked dominant : 85%  Autosomal recessive : 10-15%  Autosomal dominant

Type III collagen a) Nail patella syndrome b) Idiopathic collagen type III glomerulopathy Fibronectin Fibronectin glomerulopathy

 Dominant mutation of LMX1B gene  Hypoplastic nails  Absent patellae  Renal dysplasia  Chen et al Nat Genet 1998

 Disorders of early glomerular development -> manifesting antenatally, perinatally, or in early infancy  Disorders with late onset NS -> manifesting as FSGS in adulthood

 EM

Proteinuria Proteinuria

 (1) No change in podocyte number-> MCN  (2) Podocyte detachment/death -> FSGS  (3) Podocyte proliferation : (a) Low -> DMS (b) High -> CG Barisoni L, et al Clin J Am Soc Nephrol 2007

 LM -> segmental solidification of the tuft with accumulation of extracellular matrix synechiae from between the tuft and bowmans capsule. Podocytes are lost in the area of sclerosis

 LM-> The characteristic features of CG include wrinkling and folding of the glomerular basement membranes (collapse) and proliferation of overlying podocytes forming pseudocrescents.

. Albaqumi M, Barisoni L JASN 2008;19: ©2008 by American Society of Nephrology

Nonsyndromic : (1) NPHS2 -> SRMCN (AR) (2) AD FSGS or MCN ( chromosome 19q) Syndromic DYSF ( limb- girdle muscular dystrophy 2B ) Vats A et al Kidney Int 2000 Winn MP et al Science 2005 Izzedine H et al Am J Kidney Dis 2006

 Nonsyndromic NPHS1+NPHS2 NPHS2 ACTN4 CD 2 AP TRPC6 WT1 mt DNA t RNA leu Tryggvason K et al N Engl J Med 2006

 Syndromic WT1 ( Frasier) mDNA t RNA leu (MELAS) Guery B et al J Am Soc Nephrolk 2003 PAX2 ( renal – coloboma syndrome with oligomeganephronia LMX1B ( Nail-patella ) BongersEM et al Europ J Hum Genet 2005 ITGB4 COL4A3,A4,A5 (Alport) ( Churg J et al Arch Pathol 1973) GLA(Fabry) ( Branton MH et al Medicine (Baltimore) 2002 )

 NPHS2 AR Homozygous or compound heterozygous mutations Caridi G et al J Am Soc Nephrol 2003 Onset : childhood---4 th decade Tsukaguchi H et al J Clin Invest 2002

 Morphologic presentations :  (1) MCN  (2) Diffuse mesangial hypercellularity  (3) FSGS  Importance of genetic testing  Ruf RG et al J Am Soc Nephrol 2004

 AD : Present in adulthood : (1)ACTN4 ( Kaplan JM et al Nat Genet 2000 ) (2)Unidentified gene near same location (Winn MP et al Kidney Int 1999 ) (3)TRPC6 ( Izzedine H et al Am J Kidney Dis 2006 )

 Chromosome 19q13 mutations  present with morphologic heterogeneity (=NPHS2 mutations) : (a) SR MCN (b) Mesangial hypercellularity (3) FSGS Vats A et al Kidney Int 2000 Winn MP et al Kidney Int 1999

 Nonsyndromic (1) NPHS1 (2) WT1 (3) NPHS2 (4) PLCE1

 Syndromic : (1) LAMB2 (Pierson) (2) WT1 ( Deny- Drash)

 Columbia classification D, Agati VD Am J Kidney Dis 2004

 May-Hegglin anomaly  Sebastian syndrome  Fechtner syndrome  Epstein syndrome  Isolated sensorineural deafness

 R 702 mutations in MHY9 chain encoding non muscle myosin IIA heavy chain  Sekine T et al. Kidney Int 2010.

 Giant platelets

 FSGS at an early stage of CKD  ? Primary podocyte injury rather than postadaptive FSGS consequent to decreased number of functioning nephrons

MYH9 kidney risk variants:  HIV associated CG  FSGS  Hypertension-attributed ESKD among african descent population Kopp JB et al. Nat Genet 2008

 Different from Fechtner & Epstein syndromes  Autosomal recessive rather than dominant  ? New mutation of a known disease  ? A new syndrome

 Hereditary glomerular diseases were reviewed  Clinical classification alone is not suffient  Histopathologic classication alone is not adequate  Best is : genetic +clinical + histopathologic

Limitations in classifying the podocytopathies  Different morphologic presentations for a particular genetic mutation  Various histopathologic of a particular disease vs progression from one disease to another  Multiple glomerular morphologies on one renal biopsy (Meyrier A Semin Nephrol 2003

Thank you