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Pyridoxine sensitivity in Primary Hyperoxaluria

Pyridoxine sensitivity in Primary Hyperoxaluria . Christiaan v Woerden, Hans Waterham, Frits Wijburg, Ronald Wanders, Jaap Groothoff Emma Children’s hospital AMC, Amsterdam. What has brought them to the top?. What made them the greatest?. genes?. environment?.

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Pyridoxine sensitivity in Primary Hyperoxaluria

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  1. Pyridoxine sensitivity in Primary Hyperoxaluria Christiaan v Woerden, Hans Waterham, Frits Wijburg, Ronald Wanders, Jaap GroothoffEmma Children’s hospital AMC, Amsterdam

  2. What has brought them to the top? What made them the greatest? genes? environment?

  3. Primary Hyperoxaluria I (PHI): peroxisomal enzyme (AGT) deficiency in the liver

  4. Role of pyridoxine (B6) • Essential co-factor of AGT • mutation Gly82Glu: inhibits B6 binding no AGT activity • Reduction of oxalate excretion by B6 in B6 deficiency • Reduction oxalate excretion pharmacological dosages B6 in 30% of PH1 patients W Europe

  5. PH1: extreme heterogenous phenotypical expression No symptoms, sole kidney stones, nephrocalcinosis, UTI or Interstitial nephritis & fibrosis, ESRD systemic oxalosis: retinopathy , blunted vision, bone pain, fractures, growth, arthopathy peripheral neuropathy, heartblock, myocarditis, skin calcification, peripheral, gangreen, pancytopenia, splenomegaly, vascular calcification, arterial wall stiffening

  6. Genotype-phenotype association? Impact B6 sensitivity? AGT mutation AGT metabolic activity level of endogenous oxalate Clinical severity oxalate diet, hydration medication Infection Renal handling oxalate

  7. Mrs. A • Age 22: kidney stone  Hyperoxaluria (5x normal) & hyperglycoluria • Liver biopsy: AGT residual activity of 48% • Reduction of hyperoxaluria to “high normal” (0.057 mmol/mmol kreat) under pyridoxine 50 mg • Age 38: good health, 1 new stone removed, US small calcifications

  8. Mrs. B, sister of Mrs. A • Age 6: kidney stones, surgical removal • Age 30: diagnosis PH1, lost to follow-up • Age 50: kreat 200 μmol/l, nephrocalcinosis • Liver biopsy: 15% AGT-activity • Age 51: ESRD

  9. Mrs. C, sister of A & B • Age 48: ESRD (1 year after diagnosis B) • AGT-activity 9% • Age 49: renal tx • Nephrocalcinosis renal graft

  10. Mrs. C, sister of A & B • Age 48: ESRD (1 year after diagnosis B) • AGT-activity 9% • Age 49: renal tx • Nephrocalcinosis renal graft • All 3 sisters homozygous G170R mutation

  11. AGT in liver biopsy specimens O Immunoreactive AGT -; • immunoreactive AGT + (Danpure ea J Inher Metab Dis 17: 487-499, 1994)

  12. AGT deficiency: over 50 mutations liver biopsy: immunoreactivity enzyme activity • Protein not synthesized (nonsense m) - - • Protein synthesized OK but inactive + - • Protein synthesized OK but unstable: • Protein rapidly degraded + - • Protein aggregates + +/- • Protein mistargeting: mitochondrion + +

  13. Gly82Glu (Pyr-) mutation abolishes pyridoxine (PLP) binding (imm+/enz-) Gly41Arg (Pyr-) abolishes contact 2 monomers: destablilisation aggregation AGT From Zhang et al, JMB, 2003

  14. Minor allele: 4% population Europe/USA Normal AGT: peroxisomal localisation by way of Peroxisomal Targeting Sequence 1 as folded dimer Minor allele: P11L aa replacement:  catalytic act AGT to 30%  dimerisation AGT in vitro at 37° 5% mitochondrial location AGT by a weak Mitochondrial Targeting Sequence at N-terminus Mitochondrial AGT import only as an unfolded monomer 2 polymorphic variants: a “major” & “minor” allele

  15. G170R & F152I  activity of P11L-induced mitochondrial mistargetingto 90% by unfolding the AGT from Danpure et al

  16. G170R & F152I  activity of P11L-induced mitochondrial mistargetingto 90% by unfolding the AGT pyridoxine may increase the activity of 10% peroxisomal AGT association pyridoxine sensitivity? from Danpure et al

  17. Association B6 sensitivity - outcome 1. the Dutch experience • follow-up PH 1972-2002 • search for patients: • Dutch Registration Renal Replacement Therapy (RENINE) • Dutch Society of Pediatric Nephrology • Dutch Society of Nephrology • if no answer: contact by phone • review of all available medical charts • Total number of patients: 62 • PH1: 57 PH2: 1 • PH-unidentified: 4 • Prevalence PH1 = 2.9 per 106 • Incidence PH1 = 0.15 per 106 per year v Woerden et al, NDT 18, 2003 & Kidney Int 66, 2004

  18. Age at diagnosis

  19. End-stage renal disease at diagnosis

  20. Outcome: renal function 57 at diagnosis 30 preserved renal function 27 renal insufficiency 19 ESRD

  21. Outcome: renal function 57 at diagnosis 30 preserved renal function 27 renal insufficiency 19 ESRD 2 improved/ 2 stabilized 4 ESRD at follow-up 24 preserved renal function 5 ESRD/ low GFR 28 ESRD/ low GFR 11 death

  22. Clinical & biochemical parameters in relation to renal insufficiency RR = relative risk, 95%CI = 95% confidence interval

  23. Mutation analysis: patients • 33/57 patients of 26 families • Median age onset of symptoms/diagnosis 5.7/6.6 (0.1-50/57) • Mean follow up after diagnosis 12.5 years (0.1- 49) • 20/33 patients onset < 18th years of age • 6/33 patients onset < 1st year of age

  24. Mutations • 11 patients homozygous for G170R - pyr+ • 4 patients homozygous for P152I - pyr+ • 3 patients homozygous for 33InsC - pyr- • 3 patients homozygous for G82R - pyr- • 1 patient homozygous for G170R & V336D mutation - pyr- • 11 patients compound heterozygous - pyr-

  25. G170R homozygosity (Pyr+) 11 at diagnosis 6 preserved renal function 5 ESRD 1 ESRD (not treated) 5 kidney Tx: all B6 responsive at follow-up 5 preserved function kidney Tx: preserved function 3 preserved function

  26. F152I homozygosity (Pyr+) 4 at diagnosis 2 preserved renal function 2 ESRD 1 dialysis 1 kidney Tx: B6 responsive at follow-up 2 preserved function 1 preserved function

  27. 33InsC homozygosity (pyr-) 3 at diagnosis 3 neonatal ESRD 1 deceased 2 liver kidney Tx at follow-up 1 preserved function 1 deceased (liver failure)

  28. G82R (pyr-) 3 at diagnosis 3 normal GFR 1 preserved 1decreased GFR 1 ESRD at follow-up 1 liver kidney-tx GFR decreasing

  29. Mrs. B, sister of Mrs. A • Age 6: kidney stones, surgical removal • Age 30: diagnosis PH1, lost to follow-up • Age 50: kreat 200, nephroclacinosis • Liverbiopsy: 15% AGT-activity • Age 51: ESRD Follow-up (8 years): • Same year renal Tx, calcification Tx kidney, GFR 46 at 5 years follow up • Normalisation oxalate excretion under pyridoxine

  30. Mrs. C, sister of A & B • Age 48: ESRD (1 year after diagnosis B) • AGT-activity 9% • Age 49: renal tx • Nephrocalcinosis graft Follow-up (7 years): • Normalisation oxalate excretion under B6 • GFR graft 56 after 5 years of follow-up • All 3 sisters homozygous G170R mutation

  31. The American experienceMonico et al Am J Nephrol 2005 • 23 PH1 patients • 6 homozygotes G170R • 1 homozygous F152I • Homozygotes G170R & F152I B6 responsive and high AGT residual act (19 vs.10 heterozygotes G170R & 8 non-G170R) • No follow up • Conclusion: association B6 and G170R & F152I

  32. The German experienceHoppe et al, Am J Nephrol 2005 • Patients: 65 PH; 42 PH1; 12 unclassified • 7 B6 full response - no mutation found - AGT 7.2 (1 patient) • 9 B6 partial response (25-50%)- 4 heterozygous G170R - AGT 4.7 • Time interval symptoms - diagnosis: 1-31 year • 17 no B6 response - AGT 5.2 • 25 (38%) ESRD - 2 homozygous G170R • 6 isolated kidney tx - 1 successful, 3 recurrences, 2 failed

  33. The Israel experienceFrishberg et al Am J Nephrol 2005 • 56 PH1 patients • 21 families • 15 mutations, 1 nonsense, 13 missense mutations • No B6 responsiveness, AGT-activity near to 0 • Prevalent phenotype; early onset CRF • 20 ESRD childhood (18†), 15 at infancy • Clinical presentation 43 < age 5 • 12 asymptomatic at diagnosis

  34. Conclusions pyridoxine sensitive PH1 • Homozygosity G170R and F152I & minor allele, others? • 20-30% PH1 patients Western Europe/USA • Relatively late onset: adult patients!! • Diagnosis often delayed • Good outcome if early diagnosed • no indication for liver Tx

  35. PH1 group Emma children’s Hospital AMC Christiaan van Woerden Resident Paediatrics Simone Denis Technician Hans Waterham Molecular Geneticist Ronald Wanders Biochemist Carla Annink Technician | Marinus Duran Clinical Chemist Frits Wijburg Pediatrician Metabolic Diseases Jaap Groothoff Pediatric Nephrologist

  36. AN Bosschaart (Enschede) WT v Dorp (Haarlem) MAGL ten Dam (Nijmegen) CFM Franssen (Groningen) IH Go (Nijmegen) JJ Homan vd Heide (Groningen) JP v Hooff (Maastricht) F Th Huysmans (Leiden) JE Kist-van Holthe tot Echten (Leiden) W Koning-Mulder (Enschede) G Kolsters (Zwolle) MR Liliën (Utrecht) S Lobatto (Hilversum) LAH Monnens (Nijmegen) J Le Noble (Schiedam) C Ramaker (Amsterdam) EMA vd Veer (Amsterdam) ED Wolff (Rotterdam) R Zietse (Rotterdam) Participating centres

  37. a kidney stone

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