Inborn Errors of Metabolism
Transcript of Inborn Errors of Metabolism
INBORN ERRORS OF METABOLISM
Stefano Picca, MDDept. of Nephrology and Urology,
Dialysis Unit
“Bambino Gesù” Pediatric Research Hospital
ROMA, Italy
5th International Conference on Pediatric Continuous Renal Replacement Therapy Orlando, FLA. 2008, June 19 – 21
INCIDENCE•Overall: 1:9160•Organic Acidurias: 1:21422•Urea Cycle Defects: 1:41506•Fatty Acids Oxidation Defects: 1:91599
AGE OF ONSETNeonate: 40%Infant: 30%Child: 20%Adult: 5-10% (?) Dionisi-Vici et al, J Pediatrics, 2002.
“SMALL MOLECULES” DISEASES INDUCING CONGENITAL HYPERAMMONEMIA
• 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,
thus:• emergency treatment has to be started even before
having a precise diagnosis since prognosis may depend on:
coma duration (total and/or before treatment) (Msall, 1984; Picca, 2001; McBryde, 2006)
peak ammonium level (Enns, 2007)
detoxification rapidity (Schaefer, 1999)
KEY POINTS FACING TO A HYPERAMMONEMIC NEWBORN
THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-1
PATIENT DIAGNOSIS TREATMENT
home Mother: “sleeps too long”
(May) Start Pharmacological Treatment
peripheral hospital
Hyperammonemia
3rd level hospital
Metabolic defect Starts (continues) Pharmacological Treatment
DIALYSIS
NO RESPONSERESPONSE
RE-FEEDING
Metabolism expert
Biochemistry Lab
Neonatologist
Nephrologist
OUTCOME ANALYSIS
• Pharmacological “cocktail”
NO RESPONSERESPONSE
Starts (continues) Pharmacological Treatment
DIALYSISRE-FEEDING
OUTCOME ANALYSIS
THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-2
Pharmacological treatmentbefore having a diagnosis
AIMSprecursors catabolism anabolism
• stop protein • caloric intake 100 kcal/kg• insulin …and
endogenous depuration• arginine 250 mg/Kg/2 hrs + 250 - 500 mg/Kg/day • carnitine 1g i.v. bolus 250 - 500 mg/Kg/day • vitamins (B12 1 mg,biotin 5-15 mg)• benzoate/phenylbutyrate 250 mg/Kg/2 hrs + 250
mg/Kg/day (UCD only?)• peroral carbamylglutamate 100 – 300 mg/kg
Picca et al. Ped Nephrol 2001
• Pharmacological “cocktail”
NO RESPONSERESPONSE
Starts (continues) Pharmacological Treatment
DIALYSISRE-FEEDING
OUTCOME ANALYSIS
THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-3
• Waiting for…
0 4 8 12 16 20 24
0
250
500
750
1000
200040006000
pN
H4 (
m
ol/l
)
HOURS
non-responders(dialysis)
responders(med. treatment
alone)
0-4 HOURS MEDICAL TREATMENT IN NEONATAL
HYPERAMMONEMIA
Picca, 2002, unpublished
• Pharmacological “cocktail”
NO RESPONSERESPONSE
Starts (continues) Pharmacological Treatment
DIALYSISRE-FEEDING
OUTCOME ANALYSIS
THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-4
• Waiting for…
• Dialysis
VCG KC
KD
Ke
PLASMA NH4 (DIS)EQUILIBRIUM
Modified from Sargent JA, Gotch FA, 1996.
Glutamate dehydrogenase
NADH NAD+
-Ketoglutarate + NH4+ Glutamate
Glutamine synthetase
Glutamine
NH4+ + ATP
ADP + Pi
Figure 3. In non-hepatic tissues the linked reactions of glutamate dehydrogenaseand glutamine synthetase remove two ammonia molecules from the tissues as a way of ridding the tissues of nitrogen waste.
PLASMA NH4 AND GLUTAMINE DURING NEONATAL HYPERAMMONEMIA
from Scriver CR et al, 1995.
0 10 20 30 40 50 60
0
20
40
60
80
100 CAVHD patients
0 10 20 30 40 50 600
20
40
60
80
100 HD patients
TIME (hours)
0 10 20 30 40 50 60
0
20
40
60
80
100 CVVHD patients
NH
4p (
per
cen
t o
f in
itia
l val
ue)
Picca et al. Ped Nephrol 2001
AMMONIUM CLEARANCE AND FILTRATION FRACTION USING DIFFERENT DIALYSIS MODALITIES.
Patient
(n)
Type of
Dialysis
Qb
(ml/min)
Qd
(ml/min)
Ammonium Clearance (ml/min/kg
BW)
Ammonium Filtration Fraction
(%)
3
CAVHD
10-20
8.3 (0.5 l/h)
0.87-0.97
12.5-14.3
3
CVVHD
20-40
33.3-83.3 (2-5 l/h)
2.65-6.80
53.0-58.0
2
HD
10-15
500
3.95-5.37
95.0-96.0
Picca et al., 2001
Dialysis in hyperammonemia: the “beyond ammonium removal” effects
DIALYSIS
NH4
removalGOOD
BAD
Protein loss in the dialysate:
10-12 g/1.73m2/day(Maxvold, 2000)
Dialysis-inducedcatabolism
(Schulman, 2004)
NH4 scavengers (NaBz+NaPh)
removal(Bunchman, 2007)
Correction of AKI
Citrulline removal(McBryde, 2004)
Glutamine removal(McBryde, 2004)
Starts (continues) Pharmacological Treatment
DIALYSIS
NO RESPONSERESPONSE
RE-FEEDING
• Pharmacological “cocktail”
OUTCOME ANALYSIS
• Waiting for…
• Dialysis
THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-5
• Have we been successful?
PROGNOSTIC INDICATORS: SURVIVALMcBryde,
2006•pNH4 at admission<180 mol/L
•Time to RRT<24 hrs•Medical treatment<24 hrs•BP> 5%ile at RRT initiation •HD initial RRT (trend)
Bachman, 2003
•pNH4 at admission<300 mol/L
•Peak pNH4 <480 mol/L
Uchino,
1998
•pNH4 at admission<180 mol/L
Schaefer,
1999
•50% pNH4 decay time < 7 hrs
•(catheter > 5F)
Picca,
2001
•pre-treatment coma duration < 33 hrs (no influence of post-treatment duration)•responsiveness to pharmacological therapy
Pela,
2008
• pre-treatment coma duration < 10 hrs
SINP
ITALIAN SOCIETY OF PEDIATRIC NEPHROLOGY
Italian Study Group
“Dialysis Treatment of Neonatal hyperammonemia”
(Coord.: S. Picca, MD)
1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 20060
1
2
3
4
5
6p
atie
nts
years
n= 48
DESCRIPTIVE (1)Continuous Variable n Mean SEM
Year of treatment (yrs after 1985) 47 14.0 0.6
GA 39 39.0 0.28
Birth BW (g) 43 3240 67.6
Apgar (1 min) 31 8.45 0.18
Apgar (5 min) 31 9.6 0.11
Creatinine (mg/dl) 36 1.13 0.09
Age at admission (hrs) 46 120.8 18.5
BW at admission (g) 46 2985 69.6
BE at admission 29 -9.10 1.7
pNH4 pre-medical treatment (mol/L) 46 685 103
pNH4 pre-dialysis (mol/L) 47 839 84
pNH4 peak (mol/L) 39 1124 141
pNH4 dialysis 50% decay time (hrs) 37 11.4 1.8
Dialysis duration (hrs) 45 50.9 7.2
Coma total duration (hrs) 39 75.5 7.8
Predialysis coma duration (hrs) 44 18.3 2.4
DESCRIPTIVE (2)
Non continuous variable n
CAVHD 6
CVVHD 16
HD 3
PD 25
Gender M 32/46
Intubation 31/ 42
Survival at discharge 35/46 (76%)
Survival at 2 years *
(*follow up N/A in 6 pts)
23/39
(59%)
Normal development at 2 years 12/ 27
(44%)
DEP. VARIABLE 1: SURVIVAL AT DISCHARGE
Year of treatment Birth BW (g)Age at admission (hrs)BW at admission (g)BE at admissionCreatinine (mg/dl)
pNH4 pre-medical treatment (mol/L)
pNH4 pre-dialysis (mol/L)
pNH4 peak (mol/L)
pNH4 dialysis 50% decay time (hrs) Dialysis duration (hrs) Coma total duration (hrs) Predialysis coma duration (hrs) CAVHDCVVHDHDDPGenderIntubation
NS
0.0560.620.25
0.930.075
NS
NS
0.08
NS
0 8 16 24 32 40 48
0
20
40
60
80
100A
mm
onia
Dec
ay (
%)
Time (h)
PD
CVVH, HD, CAVH
PD
n=25
No PD
n=21
p
pNH4 pre-medical treatment (mol/L) 546±82 850±202 0.146
pNH4 pre-dialysis (mol/L) 848±112 829±128 0.914
pNH4 increase (mol/L) 302±80 -8±154 0.061
Dialysis duration (hrs) 75 ± 11 22 ± 3.9 <0.001
Predialysis coma duration (hrs) 13.2± 2.3 24.3± 18.2 0.017
PD vs. EXTRACORPOREAL
DEP. VARIABLE 2: DEVELOPMENT AT 2 YEARS
Year of treatment Birth BW (g)Age at admission (hrs)BW at admission (g)BE at admissionCreatinine (mg/dl)
pNH4 pre-medical treatment (mol/L)
pNH4 pre-dialysis (mol/L)
pNH4 peak (mol/L)
pNH4 dialysis 50% decay time (hrs) Dialysis duration (hrs) Coma total duration (hrs) Predialysis coma duration (hrs) CAVHDCVVHDHDDPGenderIntubation
0.017 (M-W); 0.056 (Regr. analysis)
0.150.073
NS
NS
NS
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
DEP. VARIABLE 3: UCD vs OA
Year of treatment Birth BW (g)Age at admission (hrs)BW at admission (g)BW loss from birth BW at admission (%)BE at admission
pNH4 pre-medical treatment (mol/L)
pNH4 pre-dialysis (mol/L)
pNH4 peak (mol/L)
pNH4 dialysis 50% decay time (hrs) Creatinine (mg/dl)Dialysis duration (hrs) Coma total duration (hrs) Predialysis coma duration (hrs) CAVHDCVVHDHDDPGenderIntubation
CONCLUSIONS-DIALYSIS
• PD provides NH4 clearance lower than HD and CRRT
• 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
• This may have been the consequence of a shorter coma duration and of a lower intoxication level before dialysis initiation
• Extracorporeal should be the first-line dialysis modality in neonatal hyperammonemia
• 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.
• In our and in other series, dialysis modality did not affect the outcome in the presence of a long mean pre-treatment duration
• In fact, plasma ammonium level before every treatment and
predialysis coma duration resulted to be the main determinants of survival both at short and long term
• 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)
• 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.
CONCLUSIONS-OUTCOME
Short-term <2nd year of life
Mortality 27.5%
Cognitive development
Normal 71%
Mild MR 4.7%
Severe MR 23%
Outcome Neonatal Onset pts
Long-term >2nd year of life (2-18 yrs)
48%
28.5%
9.5%
57%
No significant difference between UCDs and OAs
Deodato F et al, 2004
ACKNOWLEDGEMENTS
Bambino Gesù Children Hospital:• Metabolic Unit: Carlo Dionisi-Vici, MD; Andrea Bartuli, MD;
Gaetano Sabetta, MD• Clinical Biochemistry Lab: Cristiano Rizzo BSc, PhD; Anna
Pastore BSc, PhD• NICU: all doctors and nurses• Dialysis Unit: Francesco Emma, MD, all doctors and nurses
(thanks!)In Italy:• SINP (Italian Society of Pediatric Nephrology)• All doctors from Pediatric Nephrology and NICUs of
Genova, Milan, Turin, Padua, Florence, Naples, Bari.