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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
Pyridoxine sensitivity in Primary Hyperoxaluria

Christiaan v Woerden, Hans Waterham, Frits Wijburg, Ronald Wanders, Jaap GroothoffEmma Children’s hospital AMC, Amsterdam

what has brought them to the top
What has brought them to the top?

What made them the greatest?

genes?

environment?

role of pyridoxine b6
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
ph1 extreme heterogenous phenotypical expression
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

slide6

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

mrs a
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
mrs b sister of mrs a
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
mrs c sister of a b
Mrs. C, sister of A & B
  • Age 48: ESRD (1 year after diagnosis B)
  • AGT-activity 9%
  • Age 49: renal tx
  • Nephrocalcinosis renal graft
mrs c sister of a b1
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
agt in liver biopsy specimens
AGT in liver biopsy specimens

O Immunoreactive AGT -; • immunoreactive AGT +

(Danpure ea J Inher Metab Dis 17: 487-499, 1994)

slide12

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 + +
slide13

Gly82Glu (Pyr-) mutation abolishes pyridoxine (PLP) binding

(imm+/enz-)

Gly41Arg (Pyr-) abolishes contact 2 monomers: destablilisation aggregation AGT

From Zhang et al, JMB, 2003

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

2 polymorphic variants: a “major” & “minor” allele
g170r f152i activity of p11l induced mitochondrial mistargeting to 90 by unfolding the agt
G170R & F152I  activity of P11L-induced mitochondrial mistargetingto 90% by unfolding the AGT

from Danpure et al

g170r f152i activity of p11l induced mitochondrial mistargeting to 90 by unfolding the agt1
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

association b6 sensitivity outcome 1 the dutch experience
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

outcome renal function
Outcome: renal function

57

at diagnosis

30

preserved renal function

27

renal insufficiency

19

ESRD

slide21

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

slide22

Clinical & biochemical parameters in relation to renal insufficiency

RR = relative risk, 95%CI = 95% confidence interval

mutation analysis patients
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
mutations
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-
slide25

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

slide26

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

slide27

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)

slide28

G82R (pyr-)

3

at diagnosis

3 normal GFR

1 preserved

1decreased GFR

1 ESRD

at follow-up

1 liver kidney-tx

GFR decreasing

mrs b sister of mrs a1
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
mrs c sister of a b2
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
the american experience monico et al am j nephrol 2005
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
the german experience hoppe et al am j nephrol 2005
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
the israel experience frishberg et al am j nephrol 2005
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
conclusions pyridoxine sensitive ph1
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
ph1 group emma children s hospital amc
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

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)

Participating centres