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Pyridoxine sensitivity in Primary Hyperoxaluria Christiaan v Woerden, Hans Waterham, Frits Wijburg, Ronald Wanders, Jaap Groothoff Emma Childrens hospital.

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Presentation on theme: "Pyridoxine sensitivity in Primary Hyperoxaluria Christiaan v Woerden, Hans Waterham, Frits Wijburg, Ronald Wanders, Jaap Groothoff Emma Childrens hospital."— Presentation transcript:

1 Pyridoxine sensitivity in Primary Hyperoxaluria Christiaan v Woerden, Hans Waterham, Frits Wijburg, Ronald Wanders, Jaap Groothoff Emma Childrens hospital AMC, Amsterdam

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

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

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

12 AGT deficiency: over 50 mutations liver biopsy: immunoreactivity enzyme activity 1.Protein not synthesized (nonsense m)-- 2.Protein synthesized OK but inactive+- 3.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 2 polymorphic variants: a major & minor allele 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

15 G170R & F152I activity of P11L-induced mitochondrial mistargeting to 90% by unfolding the AGT from Danpure et al

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

17 Association B6 sensitivity - outcome 1. the Dutch experience follow-up PH 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 10 6 Incidence PH1 = 0.15 per 10 6 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 preserved renal function 27 renal insufficiency at diagnosis 19 ESRD

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

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 ( ) 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 6 preserved renal function 5 ESRD at diagnosis 5 kidney Tx: all B6 responsive at follow-up 5 preserved function 3 preserved function 1 ESRD (not treated) kidney Tx: preserved function

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

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

28 G82R (pyr-) 3 3 normal GFR at diagnosis at follow-up 1 preserved 1 liver kidney-tx 1 decreased GFR 1 ESRD 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 experience Monico et al Am J Nephrol 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 experience Hoppe 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 (38%) ESRD - 2 homozygous G170R 6 isolated kidney tx - 1 successful, 3 recurrences, 2 failed

33 The Israel experience Frishberg et al Am J Nephrol 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

36 PH1 group Emma childrens Hospital AMC Christiaan van WoerdenResident Paediatrics Simone DenisTechnician Hans WaterhamMolecular Geneticist Ronald WandersBiochemist Carla AnninkTechnician| Marinus DuranClinical Chemist Frits WijburgPediatrician Metabolic Diseases Jaap Groothoff Pediatric Nephrologist

37 Participating centres 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)

38 a kidney stone


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