Appendix
Survival and outcome in neonatal onset urea cycle disorders – Review and meta-analysis
of observational studies published over 35 years
Peter Burgard, Stefan Kölker, Gisela Haege, Martin Lindner , Georg F Hoffmann
List of publications included in the analysis
1.
Ah Mew N, Krivitzky L, McCarter R, Batshaw M, Tuchman M, Urea Cycle Disorders
Consortium of the Rare Diseases Clinical Research N. Clinical outcomes of neonatal onset proximal
versus distal urea cycle disorders do not differ. The Journal of pediatrics 2013; 162(2): 324-9 e1.
(excluded, same data as Krivitzky et al., 2009; only early onset patients)
2.
Arranz JA, Riudor E, Marco-Marin C, Rubio V. Estimation of the total number of diseasecausing mutations in ornithine transcarbamylase (OTC) deficiency. Value of the OTC structure in
predicting a mutation pathogenic potential. Journal of inherited metabolic disease 2007; 30(2): 21726.
3.
Bachmann C. Ornithine carbamoyl transferase deficiency: findings, models and problems.
Journal of inherited metabolic disease 1992; 15(4): 578-91.
4.
Bachmann C. Outcome and survival of 88 patients with urea cycle disorders: a retrospective
evaluation. European journal of pediatrics 2003; 162(6): 410-6.
5.
Batshaw ML, Brusilow S, Waber L, et al. Treatment of inborn errors of urea synthesis:
activation of alternative pathways of waste nitrogen synthesis and excretion. The New England
journal of medicine 1982; 306(23): 1387-92. (only early onset patients, excluded for calculation of
proportions for early onset)
6.
Bireley WR, Van Hove JL, Gallagher RC, Fenton LZ. Urea cycle disorders: brain MRI and
neurological outcome. Pediatric radiology 2012; 42(4): 455-62. (only early onset patients, excluded
for calculation of proportions for early onset)
7.
Burlina AB, Ogier H, Korall H, Trefz FK. Long-term treatment with sodium phenylbutyrate in
ornithine transcarbamylase-deficient patients. Molecular genetics and metabolism 2001; 72(4): 3515.
8.
Deodato F, Boenzi S, Rizzo C, et al. Inborn errors of metabolism: an update on epidemiology
and on neonatal-onset hyperammonemia. Acta Paediatr Suppl 2004; 93(445): 18-21. (only early
onset patients, excluded for calculation of proportions for early onset)
9.
Dionisi-Vici C, Rizzo C, Burlina AB, et al (2002) Inborn errors of metabolism in the Italian
pediatric population: a national retrospective survey. The Journal of pediatrics 140: 321-327.
10.
Enns GM, Berry SA, Berry GT, Rhead WJ, Brusilow SW, Hamosh A. Survival after treatment
with phenylacetate and benzoate for urea-cycle disorders. The New England journal of medicine
2007; 356(22): 2282-92.
11.
Funghini S, Thusberg J, Spada M, et al. Carbamoyl phosphate synthetase 1 deficiency in Italy:
clinical and genetic findings in a heterogeneous cohort. Gene 2012; 493(2): 228-34.
12.
Ibarra-Gonzalez I, Fernandez-Lainez C, Vela-Amieva M. Clinical and biochemical
characteristics of patients with urea cycle disorders in a developing country. Clinical biochemistry
2010; 43(4-5): 461-6.
13.
Kasahara M, Sakamoto S, Shigeta T, et al. Living-donor liver transplantation for carbamoyl
phosphate synthetase 1 deficiency. Pediatric transplantation 2010; 14(8): 1036-40. (only early onset
patients, excluded for calculation of proportions for early onset)
14.
Keskinen P, Siitonen A, Salo M. Hereditary urea cycle diseases in Finland. Acta paediatrica
2008; 97(10): 1412-9.
15.
Kido J, Nakamura K, Mitsubuchi H, et al. Long-term outcome and intervention of urea cycle
disorders in Japan. Journal of inherited metabolic disease 2012; 35(5): 777-85.
16.
Krivitzky L, Babikian T, Lee HS, Thomas NH, Burk-Paull KL, Batshaw ML. Intellectual, adaptive,
and behavioral functioning in children with urea cycle disorders. Pediatric research 2009; 66(1): 96101.
17.
Maestri NE, Clissold D, Brusilow SW. Neonatal onset ornithine transcarbamylase deficiency: A
retrospective analysis. The Journal of pediatrics 1999; 134(3): 268-72. (only early onset patients,
excluded for calculation of proportions for early onset)
18.
Martin-Hernandez E, Aldamiz-Echevarria L, Castejon-Ponce E, et al. Urea cycle disorders in
Spain: an observational, cross-sectional and multicentric study of 104 cases. Orphanet journal of rare
diseases 2014; 9(1): 187.
19.
Matsuda I, Nagata N, Matsuura T, et al. Retrospective survey of urea cycle disorders: Part 1.
Clinical and laboratory observations of thirty-two Japanese male patients with ornithine
transcarbamylase deficiency. American journal of medical genetics 1991; 38(1): 85-9. (excluded, data
contained in Uchino et al. 1998)
20.
Morioka D, Kasahara M, Takada Y, et al. Current role of liver transplantation for the
treatment of urea cycle disorders: a review of the worldwide English literature and 13 cases at Kyoto
University. Liver transplantation : official publication of the American Association for the Study of
Liver Diseases and the International Liver Transplantation Society 2005; 11(11): 1332-42.
21.
Msall M, Batshaw ML, Suss R, Brusilow SW, Mellits ED. Neurologic outcome in children with
inborn errors of urea synthesis. Outcome of urea-cycle enzymopathies. The New England journal of
medicine 1984; 310(23): 1500-5. (excluded, same data as Batshaw 1982)
22.
Nassogne MC, Heron B, Touati G, Rabier D, Saudubray JM. Urea cycle defects: management
and outcome. Journal of inherited metabolic disease 2005; 28(3): 407-14.
23.
Picca S, Dionisi-Vici C, Abeni D, et al. Extracorporeal dialysis in neonatal hyperammonemia:
modalities and prognostic indicators. Pediatric nephrology 2001; 16(11): 862-7. (excluded, data
contained in Deodato et al. 2004)
24.
Rowe PC, Newman SL, Brusilow SW. Natural history of symptomatic partial ornithine
transcarbamylase deficiency. The New England journal of medicine 1986; 314(9): 541-7.
25.
Schaefer F, Straube E, Oh J, Mehls O, Mayatepek E. Dialysis in neonates with inborn errors of
metabolism. Nephrology, dialysis, transplantation : official publication of the European Dialysis and
Transplant Association - European Renal Association 1999; 14(4): 910-8. (only early onset patients,
excluded for calculation of proportions for early onset)
26.
Shih V. Urea cycle disorders and other congenital hyperammonemic syndromes. In: JB
Stanbury, JB Wyngaarden, D Frederickson, eds. The metaboloic basis of inherited disease. New York:
McGraw-Hill; 1978: 363-86.
27.
Summar ML, Dobbelaere D, Brusilow S, Lee B. Diagnosis, symptoms, frequency and mortality
of 260 patients with urea cycle disorders from a 21-year, multicentre study of acute
hyperammonaemic episodes. Acta paediatrica 2008; 97(10): 1420-5. (excluded, same data as Enns et
al. 2007)
28.
Tokatli A, Coskun T, Ozalp I. Citrullinemia. Clinical experience with 23 cases. The Turkish
journal of pediatrics 1998; 40(2): 185-93.
29.
Tuchman M, Lee B, Lichter-Konecki U, et al. Cross-sectional multicenter study of patients
with urea cycle disorders in the United States. Molecular genetics and metabolism 2008; 94(4): 397402.
30.
Uchino T, Endo F, Matsuda I. Neurodevelopmental outcome of long-term therapy of urea
cycle disorders in Japan. Journal of inherited metabolic disease 1998; 21 Suppl 1: 151-9.
A. CPS1D: Proportion early onset (EO) patients
B. EO CPS1D: Proportion of EO patients surviving the
neonatal period
τ= 0.19; 95% CI [0.09;0.31]
I2= 72.30%; 95% CI [38.25;88.01]
τ= 0.22; 95% CI [0.10;0.32]
I2= 67.51%; 95% CI [31.20;80.37]
C. EO CPS1D: Outcome of EO patients surviving the neonatal period at age one year
τ= 0.00; 95% CI [0.00;0.96]
I2= 0.00%; 95% CI [0.00;73.40]
τ= 0.00; 95% CI [0.00;0.98]
I2= 0.00%; 95% CI [0.00;74.17]
τ= 0.00; 95% CI [0.00;0.88]
I2= 0.00%; 95% CI [0.00;69.56]
A. OTCm: Proportion (PR) early onset (EO)
τ= 0.20; 95% CI [0.12;0.34]
I2= 85.89%; 95% CI [70.63;94.85]
B. EO OTCm: Proportion EO Surviving (SURV) neonatal
period
τ= 0.36; 95% CI [0.24;0.62]
I2= 97.39%; 95% CI [94.47;99.10]
C. EO OTCm: Outcome EO Surviving neonatal period at 1 yr.
τ= <0.01; 95% CI [0.00;1.28]
I2= <0.01%; 95% CI [0.00;91.64]
τ= 0.31; 95% CI [0.00;1.99]
I2= 38.87%; 95% CI [0.00;96.40]
A. EO OTCf: Proportion (PR) early onset (EO)
τ= 0.04; 95% CI [0.01;0.14]
I2= 44.63%; 95% CI [3.64;91.74]
C. No published outcome data at age 1 year for OTCDf
τ= 0.45; 95% CI [0.00;1.66]
I2= 57.34%; 95% CI [0.00;94.89
B. EO OTCf: Proportion EO Surviving (SURV) neonatal
period
τ= 0.27; 95 % CI [0.08;0.60]
I2= 61.52%; 95% CI [10.94;88.72]
A. ASSD: Proportion (PR) early onset (EO)
τ= 0.11; 95% CI [0.03;0.16]
I2= 52.21%; 95% CI [7.78;70.70]
B. ASSD: Proportion EO Surviving (SURV) neonatal period
τ= 0.30; 95% CI [0.18;0.49]
I2= 91.81%; 95% CI [80.81;96.80]
C. ASSD: Outcome EO Surviving neonatal period at 1 yr.
τ= 0.56; 95% CI [0.22;1.55]
τ= 0.50; 95% CI [0.13;1.31]
I2= 66.21%; 95% CI [23.00;93.67]
I2= 61.17%; 95% CI [8.96;91.43]
τ= 0.59; 95% CI [0.24;1.35]
I2= 67.97%; 95% CI [25.86;91.83]
A. ASLD: Proportion (PR) early onset (EO)
τ= 0.19; 95% CI [0.09;0.40]
I2= 71.14%; 95% CI [37.87;91.64]
B. ASLD: Proportion EO Surviving (SURV) neonatal period
τ= 0.13; 95% CI [0.00;0.30]
I2= 54.15%; 95% CI [0.00;85.67]
C. ASLD: Outcome EO Surviving neonatal period at 1 yr.
τ= 0.08; 95% CI [0.00;0.70]
I2= 4.19%; 95% CI [0.00;75.09]
τ= <0.01; 95% CI [0.00;1.02]
I2= <0.01%; 95% CI [0.00;86.48]
τ= 0.44; 95% CI [0.00;1.26]
I2= 54.35%; 95% CI [0.00;90.73]
Supplementary Fig. 2. Forest plots of raw proportions of (A) early onset, (B) survival of the neonatal
period after early onset, and (C) outcome at the end of the first year of life of patients surviving the
neonatal period after early onset. Studies are ranked according to effect size.
N, total sample size; N_EO, sample size of early onset patients surviving (SURV) the neonatal period;
N_O, sample size of early onset patients surviving neonatal period in whom outcome was assessed at
age one year; PR, effect sizes of raw proportions; Dev. Delay, developmental delay; RE Model,
random effects model; τ =square root of τ2 estimate of between study heterogeneity, measured on
the same scale as PR.
= estimate of the single study effect, size of the symbol is proportional to the precision of the
estimate;
= estimate of the overall effect, the edges of the diamond represent the confidence interval limits
Supplementary Table 2a. Correlation of effect sizes with year of publication
PR EO
PR EO Surviving
neonatal period
Outcome EO Surviving neonatal period at 1 yr.
died
retarded
normal
Disorder
Total N
patients
(N studies)
Pearson r
(p value)
N EO patients
(N EO studies)
Pearson r
(p value)
N outcome patients
(N outcome studies)
Pearson r
(p value)
Pearson r
(p value)
Pearson r
(p value)
CPS1D
148 (12)
-0.271 (0.395)
107 (14)
0.263 (0.364)
23 (9)
0.089 (0.819)
0.540 (0.133)
-0.699 (0.036)
OTCDm
517 (14)
-0.363 (0.202)
303 (12)
0.194 (0.546)
44 (5)
0.199 (0.749)
0.269 (0.662)
-0.541 (0.347)
OTCDf
434 (15)
-0.019 (0.946)
27 (8)
0.176 (0.677)
3 (1)
n.a.
n.a.
n.a.
ASSD
298 (13)
0.197 (0.519)
153 (13)
0.140 (0.649)
55 (9)
-0.236 (0.540)
-0.187 (0.630)
0.453 (0.221)
ASLD
145 (10)
-0.253 (0.480)
75 (10)
-0.332 (0.349)
47 (8)
0.167 (0.694)
-0.210 (0.618)
0.123 (0.772)
Supplementary Table 2b. Meta-regression of effect sizes on year of publication, method: Linear mixed-effects model, Restricted Maximum Likelihood, method
by Knapp & Hartung (2003) for adjustment of test statistics and confidence intervals, calculation of approximately unbiased estimates of the sampling variances
according to Hedges (1989)
PR EO
PR EO Surviving neonatal period
Disorder
Total N patients
(N studies)
Regression
coefficient (rc)
(SE)
95% CI of rc
p value for rc
N EO patients (N
EO studies)
Regression
coefficient (rc)
(SE)
95% CI of rc
p value for rc
CPS1D
148 (12)
-0.004 (0.007)
[-0.020;0.012]
0.554
107 (14)
0.011 (0.007)
[-0.006;0.027]
0.179
OTCDm
517 (14)
-0.010 (0.006)
[-0.024;0.004]
0.138
303 (12)
0.006 (0.011)
[-0.017;0.030]
0.565
OTCDf
434 (15)
0.001 (0.002)
[-0.003;0.005]
0.570
27 (8)
0.006 (0.014)
[-0.029;0.041]
0.691
ASSD
298 (13)
0.002 (0.004)
[-0.008;0.012]
0.682
153 (13)
0.005 (0.009)
[-0.014;0.025]
0.560
ASLD
145 (10)
-0.014 (0.017)
[-0.053;0.026]
0.454
75 (10)
-0.006 (0.006)
[-0.020;0.008]
0.371
SE=Standard error
Supplementary Table 2c. Meta-regression of effect sizes on epoch, method: Linear mixed-effects model, Restricted Maximum Likelihood, method by Knapp &
Hartung (2003) for adjustment of test statistics and confidence intervals, calculation of approximately unbiased estimates of the sampling variances according to
Hedges (1989)
PR EO
PR EO Surviving neonatal period
Disorder
Total N patients
(N studies)
Regression
coefficient (rc)
(SE)
95% CI of rc
p value for rc
N EO patients (N
EO studies)
Regression
coefficient (rc)
(SE)
95% CI of rc
p value for rc
CPS1D
148 (12)
-0.002 (0.006)
[-0.014;0.011]
0.771
107 (14)
0.014 (0.005)
[0.002;0.025]
0.022
OTCDm
517 (14)
-0.014 (0.005)
[-0.024;-0.003]
0.015
303 (12)
0.019 (0.011)
[-0.006;0.044]
0.127
OTCDf
434 (15)
0.002 (0.002)
[-0.002;0.005]
0.390
27 (8)
0.019 (0.012)
[-0.011;0.048]
0.173
ASSD
298 (13)
0.001 (0.004)
[-0.007;0.009]
0.846
153 (13)
0.015 (0.009)
[-0.004;0.035]
0.110
ASLD
145 (10)
-0.008 (0.008)
[-0.025;0.010]
0.354
75 (10)
0.003 (0.007)
[-0.013;0.018]
0.716
SE=standard error
Supplementary Table 2d. Meta-regression of effect sizes on diagnosis and region. Method: Linear mixed-effects model, Restricted Maximum Likelihood, method
by Knapp & Hartung (2003) for adjustment of test statistics and confidence intervals, calculation of approximately unbiased estimates of the sampling variances
according to Hedges (1989), reference category for diagnosis: OTCDm, reference category for region: EU
PR EO
PR EO Surviving neonatal period
Predictor
Total N patients
(N studies)
Regression
coefficient (rc) (SE)
95% CI of rc
OTCDm
517 (14)
Reference
CPS1D
148 (12)
0.247 (0.078)
[0.090;0.404]
OTCDf
434 (15)
-0.387 (0.065)
ASSD
298 (13)
ASLD
N EO patients (N
EO studies)
Regression
coefficient (rc) (SE)
303 (12)
Reference
0.003
107 (14)
[-0.518;-0.256]
<0.001
0.175 (0.073)
[0.029;0.321]
145 (10)
0.101 (0.078)
[-0.056;0.258]
EU
543 (9)
Reference
Japan
385 (2)
0.021 (0.061)
[-0.102;0.145]
USA
569 (5)
-0.063 (0.054)
[-0.171;0.044]
Reference= Reference category; SE= standard error
p for rc
95% CI of rc
p for rc
0.282 (0.100)
[0.080;0.483]
0.007
27 (8)
0.259 (0.127)
[0.004;0.514]
0.047
0.020
153 (13)
0.331 (0.094)
[0.142;0.519]
<0.001
0.204
75 (10)
0.466 (0.100)
[0.265;0.667]
<0.001
235 (8)
Reference
0.732
172 (3)
0.326 (0.086)
[0.152;0.500]
<0.001
0.242
244 (7)
0.368 (0.078)
[0.212;0.525]
<0.001