Pyridoxine sensitivity in Primary Hyperoxaluria Christiaan v Woerden, Hans Waterham, Frits Wijburg,...
Transcript of Pyridoxine sensitivity in Primary Hyperoxaluria Christiaan v Woerden, Hans Waterham, Frits Wijburg,...
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Pyridoxine sensitivity in Primary
Hyperoxaluria
Christiaan v Woerden, Hans Waterham, Frits Wijburg, Ronald Wanders, Jaap GroothoffEmma Children’s hospital AMC, Amsterdam
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What has brought them to the top?
environment?
genes?What made them the
greatest?
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Primary Hyperoxaluria I (PHI): peroxisomal enzyme (AGT) deficiency in the liver
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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
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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
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AGT mutation
AGT metabolic activity
level of endogenous oxalate
oxalate diet, hydration medicationInfectionRenal handling oxalate
Clinical severity
Genotype-phenotype association? Impact B6 sensitivity?
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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
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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
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Mrs. C, sister of A & B
• Age 48: ESRD (1 year after diagnosis B)
• AGT-activity 9%
• Age 49: renal tx
• Nephrocalcinosis renal graft
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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
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OO Immunoreactive AGT -; Immunoreactive AGT -; •• immunoreactive AGT + immunoreactive AGT + (Danpure ea J Inher Metab Dis 17: 487-499, 1994)(Danpure ea J Inher Metab Dis 17: 487-499, 1994)
AGT in liver biopsy specimens
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AGT deficiency: over 50 mutations
liver biopsy:immunoreactivity enzyme
activity1. 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 + +
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Gly82Glu (Pyr-) mutation abolishes pyridoxine (PLP) binding
(imm+/enz-)
Gly41Arg (Pyr-) abolishes contact 2 monomers: destablilisation aggregation AGT
From Zhang et al, JMB, 2003
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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
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G170R & F152I activity of P11L-induced
mitochondrial mistargeting to 90% by unfolding the AGT
from Danpure et al
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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?
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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
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Age at diagnosis
70
30%
pediatric age(n=40)
adult age(n=17)
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End-stage renal disease at diagnosis
pediatric age (n=10)
77%
23%ESRD
adult age (n=9)
41%
59%ESRD
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Outcome: renal function
57
30preserved renal function
27renal insufficiency
at diagnosis
19 ESRD
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Outcome: renal function
57
30preserved renal function
27renal insufficiency
at diagnosis
19 ESRD
at follow-up
24 preserved renal function
11death
28ESRD/ low GFR
5 ESRD/low GFR
4 ESRD2 improved/ 2 stabilized
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Clinical & biochemical parameters in relation to renal insufficiency
parameter n RR 95%CI
UOx > median 18/37 1.1 0.5-2.2
AGT<15% 19/29 0.45 0.3-1.8
nephro- calcinosis
33/57 1.8 1.0-3.4
Pyridoxine unresponsive
12/36 2.2 1.1-4.2
RR = relative risk, 95%CI = 95% confidence interval
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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
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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-
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G170R homozygosity (Pyr+)
11
6preserved renal function
5ESRD
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
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F152I homozygosity (Pyr+)
4
2preserved renal function
2ESRD
at diagnosis
1 kidney Tx: B6 responsive
at follow-up
2 preserved function 1 preserved function
1 dialysis
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33InsC homozygosity (pyr-)
3
3 neonatal ESRDat diagnosis
1 deceased(liver failure)
at follow-up 1 deceased
1 preserved function
2 liver kidney Tx
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G82R (pyr-)
3
3 normal GFRat diagnosis
at follow-up 1 preserved
1 liver kidney-tx
1 decreased GFR 1 ESRD
GFR decreasing
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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
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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
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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
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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
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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
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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
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PH1 group Emma children’s Hospital AMC
Christiaan van Woerden Resident PaediatricsSimone Denis TechnicianHans Waterham Molecular GeneticistRonald Wanders BiochemistCarla Annink Technician |Marinus Duran Clinical ChemistFrits Wijburg Pediatrician Metabolic DiseasesJaap Groothoff Pediatric Nephrologist
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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)
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a kidney stone