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INBORN ERROR S  OF METABOLISM   Stefano Picca, MD D ept.  of Nephrology  and Urology, Dialysis  Unit “ Bambino Gesù” Pedia...
<ul><li>INCIDENCE </li></ul><ul><li>Overall:  1:9160 </li></ul><ul><li>Organic Acidurias:  1:21422 </li></ul><ul><li>Urea ...
<ul><li>hyperammonemia is extremely  toxic  ( per se  or through intracellular excess glutamine formation) to the brain ca...
THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-1 PATIENT DIAGNOSIS TREATMENT home Mother: “sleeps too long” (May) Start Pharm...
THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-2 <ul><li>Pharmacological  </li></ul><ul><li>“ cocktail”  </li></ul>NO RESPONS...
<ul><li>AIMS </li></ul><ul><li> precursors    catabolism    anabolism </li></ul><ul><li>stop protein  </li></ul><ul><li...
THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-3 <ul><li>Pharmacological  </li></ul><ul><li>“ cocktail”  </li></ul>NO RESPONS...
0 4 8 12 16 20 24 0 250 500 750 1000 2000 4000 6000 pNH 4 HOURS 0-4 HOURS MEDICAL TREATMENT IN NEONATAL  HYPERAMMONEMIA Pi...
THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-4 <ul><li>Pharmacological  </li></ul><ul><li>“ cocktail”  </li></ul>NO RESPONS...
VC G KC PLASMA NH 4  (DIS)EQUILIBRIUM Modified from Sargent JA, Gotch FA, 1996. K D Ke
0 10 20 30 40 50 60 0 20 40 60 80 100 CAVHD patients 0 10 20 30 40 50 60 0 20 40 60 80 100 HD patients TIME (hours) 0 10 2...
AMMONIUM CLEARANCE AND FILTRATION FRACTION USING DIFFERENT DIALYSIS MODALITIES. Picca et al., 2001
Dialysis in hyperammonemia:  the “beyond ammonium removal” effects NH 4 removal GOOD  BAD DIALYSIS Protein loss in the dia...
Starts (continues) Pharmacological  Treatment DIALYSIS NO RESPONSE RESPONSE RE-FEEDING THE USUAL COURSE OF NEONATAL HYPERA...
PROGNOSTIC INDICATORS: SURVIVAL <ul><li>pre-treatment coma duration < 10 hrs </li></ul>Pela, 2008 <ul><li>pre-treatment co...
SINP ITALIAN SOCIETY OF PEDIATRIC NEPHROLOGY   Italian Study Group  “ Dialysis Treatment of Neonatal hyperammonemia” (Coor...
1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 0 1 2 3 4 5 6 patients years n= 48
DESCRIPTIVE (1) 0.28 39.0 39 GA 0.11 9.6 31 Apgar (5 min) 0.09 1.13 36 Creatinine (mg/dl) 0.18 8.45 31 Apgar (1 min) 0.6 1...
DESCRIPTIVE (2) 6 CAVHD n Non continuous variable 12/ 27 (44%) Normal development at 2 years  23/39 (59%) Survival at 2 ye...
DEP. VARIABLE 1: SURVIVAL AT DISCHARGE  <ul><li>Year of treatment  </li></ul><ul><li>Birth BW (g) </li></ul><ul><li>Age at...
0 8 16 24 32 40 48 0 20 40 60 80 100 Ammonia Decay (%) Time (h) PD CVVH, HD, CAVH
PD vs. EXTRACORPOREAL 0.061 -8 ±154 302 ±80 pNH 4  increase (  mol/L) 0.914 829 ±128 848 ±112 pNH 4  pre-dialysis (  mol...
DEP. VARIABLE 2: DEVELOPMENT AT 2 YEARS  <ul><li>Year of treatment  </li></ul><ul><li>Birth BW (g) </li></ul><ul><li>Age a...
DEP. VARIABLE 3: UCD vs OA  <ul><li>Year of treatment  </li></ul><ul><li>Birth BW (g) </li></ul><ul><li>Age at admission (...
CONCLUSIONS-DIALYSIS <ul><li>PD provides NH 4  clearance lower than HD and CRRT </li></ul><ul><li>However, in this series ...
<ul><li>In our and in other series, dialysis modality did not affect the outcome  in the presence of a long mean pre-treat...
Short-term  <2 nd  year of life Mortality   27.5% Cognitive development   Normal  71%  Mild MR  4.7%  Severe MR  23% Outco...
ACKNOWLEDGEMENTS <ul><li>Bambino Gesù Children Hospital: </li></ul><ul><li>Metabolic Unit : Carlo Dionisi-Vici, MD; Andrea...
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Inborn Errors of Metabolism

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  • so a t a short evaluation mortality rate was 27% and 71% of survivors with a normal development. But at a long follow-up mortality increaased up to 48% and more impressive most patients became mentally retarded. No difference was observed between UCD and OA.
  • Transcript of "Inborn Errors of Metabolism"

    1. 1. INBORN ERROR S OF METABOLISM Stefano Picca, MD D ept. of Nephrology and Urology, Dialysis Unit “ Bambino Gesù” Pediatric Research Hospital ROMA, Italy 5th International Conference on Pediatric C ontinuous Renal Replacement Therapy Orlando, FLA. 2008, June 19 – 21
    2. 2. <ul><li>INCIDENCE </li></ul><ul><li>Overall: 1:9160 </li></ul><ul><li>Organic Acidurias: 1:21422 </li></ul><ul><li>Urea Cycle Defects: 1:41506 </li></ul><ul><li>Fatty Acids Oxidation Defects: 1:91599 </li></ul><ul><li>AGE OF ONSET </li></ul><ul><li>Neonate: 40% </li></ul><ul><li>Infant: 30% </li></ul><ul><li>Child: 20% </li></ul><ul><li>Adult: 5-10% (?) Dionisi-Vici et al, J Pediatrics, 2002. </li></ul>“ SMALL MOLECULES” DISEASES INDUCING CONGENITAL HYPERAMMONEMIA
    3. 3. <ul><li>hyperammonemia is extremely toxic ( per se or through intracellular excess glutamine formation) to the brain causing astrocyte swelling, brain edema, coma, death or severe disability, </li></ul><ul><li>thus: </li></ul><ul><li>emergency treatment has to be started even before having a precise diagnosis since prognosis may depend on: </li></ul><ul><li>coma duration (total and/or before treatment) </li></ul><ul><li>(Msall, 1984; Picca, 2001; McBryde, 2006) </li></ul><ul><li>peak ammonium level </li></ul><ul><li>(Enns, 2007) </li></ul><ul><li>detoxification rapidity </li></ul><ul><li>(Schaefer, 1999) </li></ul>KEY POINTS FACING TO A HYPERAMMONEMIC NEWBORN
    4. 4. THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-1 PATIENT DIAGNOSIS TREATMENT home Mother: “sleeps too long” (May) Start Pharmacological Treatment peripheral hospital Hyperammonemia 3 rd level hospital Metabolic defect Starts (continues) Pharmacological Treatment DIALYSIS NO RESPONSE RESPONSE RE-FEEDING Metabolism expert Biochemistry Lab Neonatologist Nephrologist OUTCOME ANALYSIS
    5. 5. THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-2 <ul><li>Pharmacological </li></ul><ul><li>“ cocktail” </li></ul>NO RESPONSE RESPONSE Starts (continues) Pharmacological Treatment DIALYSIS RE-FEEDING OUTCOME ANALYSIS
    6. 6. <ul><li>AIMS </li></ul><ul><li> precursors  catabolism  anabolism </li></ul><ul><li>stop protein </li></ul><ul><li>caloric intake  100 kcal/kg </li></ul><ul><li>insulin …and </li></ul>Pharmacological treatment before having a diagnosis <ul><li>endogenous depuration </li></ul><ul><li>arginine 250 mg/Kg/2 hrs + 250 - 500 mg/Kg/day </li></ul><ul><li>carnitine 1g i.v. bolus 250 - 500 mg/Kg/day </li></ul><ul><li>vitamins (B12 1 mg,biotin 5-15 mg) </li></ul><ul><li>benzoate/phenylbutyrate 250 mg/Kg/2 hrs + 250 mg/Kg/day (UCD only?) </li></ul><ul><li>peroral carbamylglutamate 100 – 300 mg/kg </li></ul>Picca et al. Ped Nephrol 2001
    7. 7. THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-3 <ul><li>Pharmacological </li></ul><ul><li>“ cocktail” </li></ul>NO RESPONSE RESPONSE Starts (continues) Pharmacological Treatment DIALYSIS RE-FEEDING OUTCOME ANALYSIS <ul><li>Waiting for… </li></ul>
    8. 8. 0 4 8 12 16 20 24 0 250 500 750 1000 2000 4000 6000 pNH 4 HOURS 0-4 HOURS MEDICAL TREATMENT IN NEONATAL HYPERAMMONEMIA Picca, 2002, unpublished (  mol/l) non-responders (dialysis) responders (med. treatment alone)
    9. 9. THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-4 <ul><li>Pharmacological </li></ul><ul><li>“ cocktail” </li></ul>NO RESPONSE RESPONSE Starts (continues) Pharmacological Treatment DIALYSIS RE-FEEDING OUTCOME ANALYSIS <ul><li>Waiting for… </li></ul><ul><li>Dialysis </li></ul>
    10. 10. VC G KC PLASMA NH 4 (DIS)EQUILIBRIUM Modified from Sargent JA, Gotch FA, 1996. K D Ke
    11. 11. 0 10 20 30 40 50 60 0 20 40 60 80 100 CAVHD patients 0 10 20 30 40 50 60 0 20 40 60 80 100 HD patients TIME (hours) 0 10 20 30 40 50 60 0 20 40 60 80 100 CVVHD patients NH4p (percent of initial value) Picca et al. Ped Nephrol 2001
    12. 12. AMMONIUM CLEARANCE AND FILTRATION FRACTION USING DIFFERENT DIALYSIS MODALITIES. Picca et al., 2001
    13. 13. Dialysis in hyperammonemia: the “beyond ammonium removal” effects NH 4 removal GOOD BAD DIALYSIS Protein loss in the dialysate: 10-12 g/1.73m 2 /day (Maxvold, 2000) Dialysis-induced catabolism (Schulman, 2004) NH 4 scavengers (NaBz+NaPh) removal (Bunchman, 2007) Correction of AKI Citrulline removal (McBryde, 2004) Glutamine removal (McBryde, 2004)
    14. 14. Starts (continues) Pharmacological Treatment DIALYSIS NO RESPONSE RESPONSE RE-FEEDING THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-5 <ul><li>Pharmacological </li></ul><ul><li>“ cocktail” </li></ul>OUTCOME ANALYSIS <ul><li>Waiting for… </li></ul><ul><li>Dialysis </li></ul><ul><li>Have we been </li></ul><ul><li>successful? </li></ul>
    15. 15. PROGNOSTIC INDICATORS: SURVIVAL <ul><li>pre-treatment coma duration < 10 hrs </li></ul>Pela, 2008 <ul><li>pre-treatment coma duration < 33 hrs (no influence of post-treatment duration) </li></ul><ul><li>responsiveness to pharmacological therapy </li></ul>Picca, 2001 <ul><li>50% pNH 4 decay time < 7 hrs </li></ul><ul><li>(catheter > 5F) </li></ul>Schaefer, 1999 <ul><li>pNH 4 at admission<180  mol/L </li></ul>Uchino, 1998 <ul><li>pNH 4 at admission<300  mol/L </li></ul><ul><li>Peak pNH 4 <480  mol/L </li></ul>Bachman, 2003 <ul><li>pNH 4 at admission<180  mol/L </li></ul><ul><li>Time to RRT<24 hrs </li></ul><ul><li>Medical treatment<24 hrs </li></ul><ul><li>BP> 5%ile at RRT initiation </li></ul><ul><li>HD initial RRT (trend) </li></ul>McBryde, 2006
    16. 16. SINP ITALIAN SOCIETY OF PEDIATRIC NEPHROLOGY   Italian Study Group “ Dialysis Treatment of Neonatal hyperammonemia” (Coord.: S. Picca, MD)
    17. 17. 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 0 1 2 3 4 5 6 patients years n= 48
    18. 18. DESCRIPTIVE (1) 0.28 39.0 39 GA 0.11 9.6 31 Apgar (5 min) 0.09 1.13 36 Creatinine (mg/dl) 0.18 8.45 31 Apgar (1 min) 0.6 14.0 47 Year of treatment (yrs after 1985) SEM Mean n Continuous Variable 2.4 18.3 44 Predialysis coma duration (hrs) 7.8 75.5 39 Coma total duration (hrs) 7.2 50.9 45 Dialysis duration (hrs) 1.8 11.4 37 pNH 4 dialysis 50% decay time (hrs) 141 1124 39 pNH 4 peak (  mol/L) 84 839 47 pNH 4 pre-dialysis (  mol/L) 103 685 46 pNH 4 pre-medical treatment (  mol/L) 1.7 -9.10 29 BE at admission 69.6 2985 46 BW at admission (g) 18.5 120.8 46 Age at admission (hrs) 67.6 3240 43 Birth BW (g)
    19. 19. DESCRIPTIVE (2) 6 CAVHD n Non continuous variable 12/ 27 (44%) Normal development at 2 years 23/39 (59%) Survival at 2 years * (*follow up N/A in 6 pts) 35/46 (76%) Survival at discharge 31/ 42 Intubation M 32/46 Gender 25 PD 3 HD 16 CVVHD
    20. 20. DEP. VARIABLE 1: SURVIVAL AT DISCHARGE <ul><li>Year of treatment </li></ul><ul><li>Birth BW (g) </li></ul><ul><li>Age at admission (hrs) </li></ul><ul><li>BW at admission (g) </li></ul><ul><li>BE at admission </li></ul><ul><li>Creatinine (mg/dl) </li></ul><ul><li>pNH 4 pre-medical treatment (  mol/L) </li></ul><ul><li>pNH 4 pre-dialysis (  mol/L) </li></ul><ul><li>pNH 4 peak (  mol/L) </li></ul><ul><li>pNH 4 dialysis 50% decay time (hrs) </li></ul><ul><li>Dialysis duration (hrs) </li></ul><ul><li>Coma total duration (hrs) </li></ul><ul><li>Predialysis coma duration (hrs) </li></ul><ul><li>CAVHD </li></ul><ul><li>CVVHD </li></ul><ul><li>HD </li></ul><ul><li>DP </li></ul><ul><li>Gender </li></ul><ul><li>Intubation </li></ul>NS 0.056 0.62 0.25 0.93 0.075 NS NS 0.08 NS
    21. 21. 0 8 16 24 32 40 48 0 20 40 60 80 100 Ammonia Decay (%) Time (h) PD CVVH, HD, CAVH
    22. 22. PD vs. EXTRACORPOREAL 0.061 -8 ±154 302 ±80 pNH 4 increase (  mol/L) 0.914 829 ±128 848 ±112 pNH 4 pre-dialysis (  mol/L) <0.001 22 ± 3.9 75 ± 11 Dialysis duration (hrs) 0.017 24.3± 18.2 13.2 ± 2.3 Predialysis coma duration (hrs) 0.146 850 ±202 546 ±82 pNH 4 pre-medical treatment (  mol/L) p No PD n=21 PD n=25
    23. 23. DEP. VARIABLE 2: DEVELOPMENT AT 2 YEARS <ul><li>Year of treatment </li></ul><ul><li>Birth BW (g) </li></ul><ul><li>Age at admission (hrs) </li></ul><ul><li>BW at admission (g) </li></ul><ul><li>BE at admission </li></ul><ul><li>Creatinine (mg/dl) </li></ul><ul><li>pNH 4 pre-medical treatment (  mol/L) </li></ul><ul><li>pNH 4 pre-dialysis (  mol/L) </li></ul><ul><li>pNH 4 peak (  mol/L) </li></ul><ul><li>pNH 4 dialysis 50% decay time (hrs) </li></ul><ul><li>Dialysis duration (hrs) </li></ul><ul><li>Coma total duration (hrs) </li></ul><ul><li>Predialysis coma duration (hrs) </li></ul><ul><li>CAVHD </li></ul><ul><li>CVVHD </li></ul><ul><li>HD </li></ul><ul><li>DP </li></ul><ul><li>Gender </li></ul><ul><li>Intubation </li></ul>0.017 (M-W); 0.056 (Regr. analysis) 0.15 0.073 NS NS NS
    24. 24. DEP. VARIABLE 3: UCD vs OA <ul><li>Year of treatment </li></ul><ul><li>Birth BW (g) </li></ul><ul><li>Age at admission (hrs) </li></ul><ul><li>BW at admission (g) </li></ul><ul><li>BW loss from birth BW at admission (%) </li></ul><ul><li>BE at admission </li></ul><ul><li>pNH 4 pre-medical treatment (  mol/L) </li></ul><ul><li>pNH 4 pre-dialysis (  mol/L) </li></ul><ul><li>pNH 4 peak (  mol/L) </li></ul><ul><li>pNH 4 dialysis 50% decay time (hrs) </li></ul><ul><li>Creatinine (mg/dl) </li></ul><ul><li>Dialysis duration (hrs) </li></ul><ul><li>Coma total duration (hrs) </li></ul><ul><li>Predialysis coma duration (hrs) </li></ul><ul><li>CAVHD </li></ul><ul><li>CVVHD </li></ul><ul><li>HD </li></ul><ul><li>DP </li></ul><ul><li>Gender </li></ul><ul><li>Intubation </li></ul>NS 3126 ±91 vs 2765 ±88 p 0.018 -6.3 ±0.8 vs -12.2 ±1.0 p 0.018 -5.7 ±2 vs -14.6 ±1.9 p 0.023 997 ±124 vs 606 ±69 p 0.034 NS 779 ±121 vs 550±183 p 0.041
    25. 25. CONCLUSIONS-DIALYSIS <ul><li>PD provides NH 4 clearance lower than HD and CRRT </li></ul><ul><li>However, in this series and in that of Schaefer (1999) detoxification rapidity was not significantly different from that of extracorporeal dialysis and patients treated with PD showed a trend toward a better survival </li></ul><ul><li>This may have been the consequence of a shorter coma duration and of a lower intoxication level before dialysis initiation </li></ul><ul><li>Extracorporeal should be the first-line dialysis modality in neonatal hyperammonemia </li></ul><ul><li>When HD and/or CRRT facilities are not available, PD should be considered. However, results are likely similar to those obtained with extracorporeal dialysis only in less intoxicated patients. </li></ul>
    26. 26. <ul><li>In our and in other series, dialysis modality did not affect the outcome in the presence of a long mean pre-treatment duration </li></ul><ul><li>In fact, p lasma ammonium level before every treatment and predialysis coma duration resulted to be the main determinants of survival both at short and long term </li></ul><ul><li>It is thus likely that the influence of detoxification rapidity on the outcome becomes evident when pre-treatment duration is shorter than that reported in our series, as reported by others (Schaefer 1999, Pela 2008) </li></ul><ul><li>However, as high intoxication level and long pre-treatment duration are the consequence of a delayed intervention, the need for an early diagnosis and treatment remains the crucial issue of neonatal hyperammonemia. </li></ul>CONCLUSIONS-OUTCOME
    27. 27. Short-term <2 nd year of life Mortality 27.5% Cognitive development Normal 71% Mild MR 4.7% Severe MR 23% Outcome Neonatal Onset pts Long-term >2 nd year of life (2-18 yrs) 48% 28.5% 9.5% 57% Deodato F et al, 2004 No significa nt difference between UCDs and OAs
    28. 28. ACKNOWLEDGEMENTS <ul><li>Bambino Gesù Children Hospital: </li></ul><ul><li>Metabolic Unit : Carlo Dionisi-Vici, MD; Andrea Bartuli, MD; Gaetano Sabetta, MD </li></ul><ul><li>Clinical Biochemistry Lab : Cristiano Rizzo BSc, PhD; Anna Pastore BSc, PhD </li></ul><ul><li>NICU: all doctors and nurses </li></ul><ul><li>Dialysis Unit : Francesco Emma, MD, all doctors and nurses (thanks!) </li></ul><ul><li>In Italy: </li></ul><ul><li>SINP (Italian Society of Pediatric Nephrology) </li></ul><ul><li>All doctors from Pediatric Nephrology and NICUs of Genova, Milan, Turin, Padua, Florence, Naples, Bari. </li></ul>
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