fenotipo acidurias
TRANSCRIPT
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Journal of Inherited Metabolic DiseaseOcial Journal of the Society for the Study of Inborn Errors ofMetabolism
SSIEM 201510100!"s105#5$015$%&'%$'
Ori(inal )rticle
The phenotypic spectrum of organicacidurias and urea cycle disorders. Part 1:the initial presentationStefan *+l,er1 -)n(eles .arcia /aorla 2- assili alayannooulos'- )llan M 3und#- )lberto 44urlina5-Jolanta Sy,ut$/e(iels,a- 6rits ) 7i8bur(!- Elisa 3e9o :eles&- Jiri ;eman%- /arlo Dionisi$ici10- Iersehone )u(oustides$SaeGa$Huintana'1-Dani8ela >et,o
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L12/linic for >ediatrics I- Inherited Metabolic Disorders- Medical Nni
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SerFdiatriKue- /liniKues Nni
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ASL
)r(ininosuccinate lyaseASS
)r(ininosuccinate synthetaseCPS1
/arbamylhoshate synthetase 1E-HOD
Euroean netBor, and re(istry for homocystinurias and methylation defectsE-IMD
Euroean re(istry and netBor, for into?ication tye metabolic diseasesGA1
.lutaric aciduria tye 1HHH
yerornithinemia$hyerammonemia$homocitrullinuriaIVA
Isoroionic aciduriaQ
HuartileQoL
Huality of lifeUCD
Nrea cycle disorder
Introduction:he clinical resentation of atients Bith inherited or(anic acidurias LO)D and ureacycle disorders LN/D is
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Since O)D and N/D are rare diseases and most studies ha
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6or descritiSS LI4M S>SS Statistics 220 Bas used Standard de
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before the cut$o date for inclusion Lie 1 January 2011 >atients Bith late onset ofsymtoms shoBed more often and more ronounced dia(nostic delay than those Bithneonatal onset of symtoms L:able 1 7ithout aroriate metabolic treatment it isli,ely to assume that in both (rous an un,noBn number of atients died undia(nosed
Fig. 6reKuency of O)D and N/D in the E$IMD samle )bbreS1-carbamylhoshate synthetase 1Z D- de[ciencyZ .)1- (lutaric aciduria tye 1Z syndr- hyerornithinemia$hyerammonemia$homocitrullinuria syndromeZ I)- iso
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Patientsper onsett$pe
#ime to diagnosis after onset of%rst s$mptoms
&'da$s (&"da$s
"!&
")*da$s
+")* da$s
,n- ,n- ,n- ,n- ,n-
N/D
EO & 5! 2 '
3O 12% !' % 25 22
MM)
E
O '& 2& 2 2
3O #& 2& # 12 #
>)
EO 2! 1% 2 0
3O 25 1 5 2 2
I)
EO 11 # # 1 2
3O 12 # 0 2
.)$I
EO # 0 1 ' 0
3O ' '1 2 1 1#
).S$D
EO 1 1 0 0 0
3O 1 1 0 0 0
/>S1$D
EO ! ' 0 1 '
3O 5 0 0 2 '
O:/$DLm
EO
1 1 0 0 0
http://link.springer.com.sci-hub.org/search?dc.title=NAGS&facet-content-type=ReferenceWorkEntry&sortOrder=relevancehttp://link.springer.com.sci-hub.org/search?dc.title=NAGS&facet-content-type=ReferenceWorkEntry&sortOrder=relevance -
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Patientsper onsett$pe
#ime to diagnosis after onset of%rst s$mptoms
&'da$s (&"da$s
"!&
")*da$s
+")* da$s
,n- ,n- ,n- ,n- ,n-
3O '% 25 # 5 5
O:/$DLf
EO ' 2 0 1 0
3O 52 2& # 10 10
)SS$D
EO 2& 2# 1 ' 0
3O 12 & 1 ' 0
)S3$D
EO 1' 11 1 1 0
3O 12 0 ' '
)@.1$D
E
O 0 0 0 0 0
3O ' 2 0 0 1
syndr
EO 0 0 0 0 0
3O 5 ' 0 2 0
)symtomatic atients Bho Bere dia(nosed Bhile bein( asymtomatic Lby neBbornscreenin(- hi(h$ris, family screenin(- renatal testin( or symtomatic atients Bithincomlete clinical data LO)DY #0Z N/DY '# Bere e?cluded from this analysis)bbre
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atients- the mode of dia(nosis Bas not reorted ) detailed e
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iseasegroup
iseasename
Patients
,n-
S$mptomatic,n-
As$mptomatic
,n-All E/
0/
0/
12oA3
D
)S3$D ## '2 1& 5 % 12
)@.1$D 10 # 1 ' 0
syndr % ! 2 ' 2 2
:otalLN/D '#'
2#2 %1
110
#1 101
O)D N/D :otal !%5
5#&
220
2#'
&5 2#!
)bbre
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disease L)S3 de[ciency- renal disease L)SS de[ciency and O)D renal disease L.)1-sychiatric disease LI)- re$eclamsia L>)- I)- eclamsia L.)1- and eilesy L>)/ardiac roblems Bere not reortede?t- Be studied Bhether there is eostnatal roblems Bere common in O)D Ln ] 111 and N/D Ln ] !2atients- Bith feedin( roblems LO)DY 20 ^- N/DY 1# ^ and hyerbilirubinemia LO)DY% ^- N/DY ! ^ bein( most freKuently reorted Some of these roblems Le( feedin(roblems most li,ely re`ect the be(innin( of a neonatal metabolic crisis- Bhereasothers Le( hyerbilirubinemia are found in the same ran(e as in the (eneraloulation )nthroometrical arameters Bere mostly in the normal ran(e- hoBe
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is
easename
Patientsperdis
ease
4estational age
5od$1eight
Supinelength
6eadcircumference
n n
7eeks,8edian-
n
SS,8edian-
n
SS,8edian-
n
SS,8edian-
/>S1$D 1&
1' #0
1#
010
1' 0
1'
0'!
O:/$DLf
11#
!1 #0
!0
02%
55 0
#' 0
O:/$DLm &2
' '%
5
0'
5
0''
#% 0
)SS$D 1
52 #0
51
02#
##
01'
#2
0##
)S3$D ##
'& '%
'
0#!
'1
0#'
2% 0
)@.1$D 10 &
'%5 &
0'
0!%
011
syndr % ! #0
01& 5
0#' #
0!5
6or descriti
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Acute metabolic crisis ) clinical presentation and metabolicderangement
) metabolic crisis is an acute life$threatenin( e
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Patientsperons
ett$pe
ur
es
6$per&e?c
itabilit$
/dour
/ther
s
n n,
n,
n,
n,
n,
n,
n,
n,
a O)D atients
M
E 5 ' ' 2 ' 2 # 1 ' ! 2 # 2 # ' '
3 # 2 2 ' 2 2 1 1 1 % 1 1 2 2
>
E 5 ' ! 2 1 ' ! 1 # ! 1 2 2 2 1 ' #
3 2 2 1 1 1 1 1 ' 2 ! 1 0 n 0 n 1 1
I
E 1 % ! # 5 1 ! ' 2 1 # 1 # 1 5
3 1 ' & % 5 # ' 2 1 0 n 0 n 2 1 5 '
b N/D atients
E 2 1 1 1 2 0 n 0 n 0 n 0 n 1 2
3 1 1 ' 0 n 0 n 1 ' 0 n 0 n 0 n 0 n
/
E 1 ! ' ' 2 ' # ' 2 # # 2 0 n & '
3 ' ' 1 1 1 1 & 1 0 n 1 1 1 0 n
O
E # ' # 2 1 ' ' # 0 n 0 n 0 n 2 '
3 # ' ! 2 1 5 2 1 & 1 ' 1 0 n 2
O
E 1 1 ' ! & ' 1 2 1 2 2 2 0 n & '
3 ' ' ! 2 5 1 ' 2 2 % ' ! & 1 2 1 '
)
E ' 2 ' ! 2 2 ' 1 ' 1 ' # # 0 n 1 '
3 & ' 5 # 2 1 0 n 0 n 1 # 0 n 2 5
)
E 1 1 ' # 5 5 ' # ' % ' ' 2 0 n % 2
3 5 # ! ' ! ' 1 1 ! 2 2 0 n 0 n 2 2
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Patientsperons
ett$pe
ur
es
6$per&e?c
itabilit$
/dour
/ther
s
n n,
n,
n,
n,
n,
n,
n,
n,
)
E 1 1 0 0 n 0 n 0 n 0 n 0 n 0 n 0 n
3 ' 1 2 1 ' 1 2 2 1 1 2 1 2 0 n 1 2
E 2 2 # 0 n 1 2 1 2 1 2 1 2 0 n 1 3 ' 2 5 2 5 1 1 0 n 0 n 1 # 0 n 2 '
>atients Bith .)1 are e?cluded from this table- since they resent Bith anencehaloathic crisis but not Bith a classic metabolic crisis 6or descriti) atients shoBed astron(er decrease in standard bicarbonate and j less ronounced j in /O 2and L>) only than those Bith early$onset of symtoms L:able 5Z Sul :able 5 In the N/D(rou- early$onset male O:/ atients had a si(ni[cantly hi(her concentration ofammonia- (lutamine- ornithine- orotic acid and lactate- and a loBer concentration of
standard bicarbonate and citrulline than late$onset atients Similarly- symtomaticfemale O:/ carriers Bho had a neonatal metabolic crisis had a hi(her ammonia andtendency toBards hi(her lactate and loBer than those Bith late onset of symtoms)lthou(h early$onset atients Bith />S1- )SS and )S3 de[ciency also seemed to ha
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isease
nam
e
Patientsper
p6p3/
!
Standard
0actate,p-
4lucose,s-
Ammonia
,p-
4lutamine
,p-
ons
ett$pe
bica
rbonate
n
/nset
n
-
-
-
n
kPa
n
mmol20
n
mmol20
n
mmol20
n
@mol20
n
@mol20
,8edian-
,8edian-
,8edian-
,8edian-
,8edian-
,8edian-
8edian
MM)
5
EO
#0
!2!
'!
2!
!L
k
2&
1
'#k
''
2
2!
52
#2
'
2'kk
1%
#0!k
#
3O
'0
!1&
2' 2
21
&2
1 '
22
#5
2#
11! !
!05
>) 5' EO '# !'1k
2! '''L
k
2 1!#L
k
25 25
2' 5 #' ###k
1! #
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isease
nam
e
Patientsper
p6p3/
!
Standard
0actate,p-
4lucose,s-
Ammonia
,p-
4lutamine
,p-
ons
ett$pe
bica
rbonate
n
/nset
n
-
-
-
n
kPa
n
mmol20
n
mmol20
n
mmol20
n
@mol20
n
@mol20
,8edian-
,8edian-
,8edian-
,8edian-
,8edian-
,8edian-
8edian
2
!
3
O
1
%
!
2
1
1
2#
!
1
#
%
2
1
#
2
1
1
'
'
5
2
1
1#
2 &
#2
5
I)
1!
EO
12
!#L
k
11
'51
10
20
10
1 &
52
1'
2'% 5
'!1L
k
12
3O 5
!
'2 #
'
55 '
1 1
0! 5
5
22
!0 2
5&&
6or descriti
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arameters ha
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In late$onset O)D atients- mo
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Patients(
n
)
Feed
ingproblems,
n-
6epa
ticmanifestation,
n-
Epileps$,n
-
8ovem
entdisorders
,n-
8ent
alretardation,
n-
Ps$ch
iatricdisorder
,n
-
Ren
almanifestation,n
-
Ab
normal753,n
-
3ardi
acmanifestation,
n-
/thers,n
-
I)
)/
12 2 0 0 0 1 0 0 0 0 5
B"o 2 1 0 0 0 1 0 0 0 0 1
.)1
)/ #& % 0 ! 1! 0 1 0 0 1&
B"o
2 2 0 5
12 # 0 0 0 0
15
).S$
D
)/ 1 0 0 0 0 1 0 0 0 0 0
B"
o 0 0 0 0 0 0 0 0 0 0 0
/>S1$
)/ ' ' 0 0 1 1 0 0 0 0 '
B"o
2 0 0 0 1 0 1 0 0 0 2
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Patients(
n
)
Feed
ingproblems,
n-
6epa
ticmanifestation,
n-
Epileps$,n
-
8ovem
entdisorders
,n-
8ent
alretardation,
n-
Ps$ch
iatricdisorder
,n
-
Ren
almanifestation,n
-
Ab
normal753,n
-
3ardi
acmanifestation,
n-
/thers,n
-
O:/$D
Lm
)/
'& % 2 ' # 2 2 0 0 0 %
B"o # # 0 0 0 0 1 0 0 0 1
O:/$D
Lf
)/
#% %
12 ' 2 1 # 1 0 0
1!
B"o
1! & 5 2 0 1 1 0 0 0 !
)SS$
)/ & ' ' 0 0 0 0 0 0 0 2
B ! # 1 1 2 2 0 0 0 0 2
-
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Patients(
n
)
Feed
ingproblems,
n-
6epa
ticmanifestation,
n-
Epileps$,n
-
8ovem
entdisorders
,n-
8ent
alretardation,
n-
Ps$ch
iatricdisorder
,n
-
Ren
almanifestation,n
-
Ab
normal753,n
-
3ardi
acmanifestation,
n-
/thers,n
-
"o
)S3
$D
)/ 5 1 1 0 1 1 0 0 0 0 '
B
"o % 1 2 2 0 0 0 0 0 2
)@.1$D
)/ ' 1 0 0 1 1 0 0 0 0 1
B"o 0 0 0 0 0 0 0 0 0 0 0
syndr
)/ ' 2 2 0 0 1 0 0 0 0 1
B"o
2 0 0 0 0 1 0 0 0 0 1
-
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Patients(
n
)
Feed
ingproblems,
n-
6epa
ticmanifestation,
n-
Epileps$,n
-
8ovem
entdisorders
,n-
8ent
alretardation,
n-
Ps$ch
iatricdisorder
,n
-
Ren
almanifestation,n
-
Ab
normal753,n
-
3ardi
acmanifestation,
n-
/thers,n
-
)bbre
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+hen does the disease start,
)ccumulation of to?ic metabolites in fetuses Bith O)D and N/D is usually thou(ht to bematernally re
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Since N/D atients resentin( Bith a neonatal metabolic crisis ha
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countries are increasin(ly included in neBborn screenin( ro(rammes in Euroe- andsome countries also screen for MM) Lisolated forms- n ] 1Z combined forms- n ] !- >)Ln ] !- )S3 Ln ] and )SS de[ciency Ln ] 5 L4ur(ard et al 2012Z 3oeber et al 2012eBborn screenin( for some N/D L).Sand />S1 de[ciency is technicallychallen(in(- and screenin( of female O:/ carriers results in a dia(nostic and ethicaldilemma E?cet for sin(le diseases such as .)1- there is still uncertainty Bhetheratients Bith O)D and N/D Bill bene[t from neBborn screenin( L*+l,er et al 2007Zerin(er et al 2010 :herefore- more Bor, is reKuired to understand Bhether neBbornscreenin( for MM)- >) and N/D imro
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anni(an L/3IM4- /hildren 3i
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Members of the Nrea /ycle Disorders /onsortium- 4atshaB M3- :uchman M- Summar M-
Seminara J L201# ) lon(itudinal study of urea cycle disorders Mol .enet Metab
11'Y12!1'0/ross@ef
4aum(artner M@- +rster 6- Dionisi$ici / et al L201# >roosed (uidelines for the
dia(nosis and mana(ement of methylmalonic and roionic acidemia Orhanet J @are
Dis %Y1'0/ross@ef>ubMed/entral>ubMed
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utr ##Y#50>ubMed
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Bei(ht- hei(ht- body mass inde? and head circumference [tted by ma?imum enalied
li,elihood Stat Med 1!Y#0!#2%/ross@ef>ubMed
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syndr % ! 2 ' 2 2
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diabetes in O)D re(nancies L55 and that of arterial hyertension in N/Dre(nancies L' ^ Bas similar to that found in re(nancies in (eneral- ie 2$10 ^ for(estational diabetes L.abbe et al 2012 and #! ^ for arterial hyertension L3iu etal 2014 Other medical roblems Bere only reorted in sin(le cases for N/D heaticdisease L)S3 de[ciency- renal disease L)SS de[ciency and O)D renal disease L.)1-sychiatric disease LI)- re$eclamsia L>)- I)- eclamsia L.)1- and eilesy L>)/ardiac roblems Bere not reortede?t- Be studied Bhether there is eostnatal roblems Bere common in O)D Ln ] 111 and N/D Ln ] !2atients- Bith feedin( roblems LO)DY 20 ^- N/DY 1# ^ and hyerbilirubinemia LO)DY% ^- N/DY ! ^ bein( most freKuently reorted Some of these roblems Le( feedin(roblems most li,ely re`ect the be(innin( of a neonatal metabolic crisis- Bhereasothers Le( hyerbilirubinemia are found in the same ran(e as in the (eneraloulation )nthroometrical arameters Bere mostly in the normal ran(e- hoBe
-
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is
easename
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4old tyes indicate statistically si(ni[cant anthroometric arameters- ie loB birthBei(ht in MM) atients and increased head circumference in .)1 atients
Acute metabolic crisis ) clinical presentation and metabolicderangement
) metabolic crisis is an acute life$threatenin( e
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Patientsperons
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s
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>atients Bith .)1 are e?cluded from this table- since they resent Bith anencehaloathic crisis but not Bith a classic metabolic crisis 6or descriti) atients shoBed astron(er decrease in standard bicarbonate and j less ronounced j in /O 2and L>) only than those Bith early$onset of symtoms L:able 5Z Sul :able 5 In the N/D(rou- early$onset male O:/ atients had a si(ni[cantly hi(her concentration ofammonia- (lutamine- ornithine- orotic acid and lactate- and a loBer concentration of
standard bicarbonate and citrulline than late$onset atients Similarly- symtomaticfemale O:/ carriers Bho had a neonatal metabolic crisis had a hi(her ammonia andtendency toBards hi(her lactate and loBer than those Bith late onset of symtoms)lthou(h early$onset atients Bith />S1- )SS and )S3 de[ciency also seemed to ha
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isease
nam
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isease
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arameters ha
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Patients(
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+hen does the disease start,
)ccumulation of to?ic metabolites in fetuses Bith O)D and N/D is usually thou(ht to bematernally re
-
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Since N/D atients resentin( Bith a neonatal metabolic crisis ha
-
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countries are increasin(ly included in neBborn screenin( ro(rammes in Euroe- andsome countries also screen for MM) Lisolated forms- n ] 1Z combined forms- n ] !- >)Ln ] !- )S3 Ln ] and )SS de[ciency Ln ] 5 L4ur(ard et al 2012Z 3oeber et al 2012eBborn screenin( for some N/D L).Sand />S1 de[ciency is technicallychallen(in(- and screenin( of female O:/ carriers results in a dia(nostic and ethicaldilemma E?cet for sin(le diseases such as .)1- there is still uncertainty Bhetheratients Bith O)D and N/D Bill bene[t from neBborn screenin( L*+l,er et al 2007Zerin(er et al 2010 :herefore- more Bor, is reKuired to understand Bhether neBbornscreenin( for MM)- >) and N/D imro
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anni(an L/3IM4- /hildren 3i
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Members of the Nrea /ycle Disorders /onsortium- 4atshaB M3- :uchman M- Summar M-
Seminara J L201# ) lon(itudinal study of urea cycle disorders Mol .enet Metab
11'Y12!1'0/ross@ef
4aum(artner M@- +rster 6- Dionisi$ici / et al L201# >roosed (uidelines for the
dia(nosis and mana(ement of methylmalonic and roionic acidemia Orhanet J @are
Dis %Y1'0/ross@ef>ubMed/entral>ubMed
4oy - ae(e .- erin(er J et al L201' 3oB lysine diet in (lutaric aciduria tye I j
eect on anthroometrical and biochemical folloB$u arameters J Inherit Metab Dis
'Y5255''/ross@ef>ubMed
4ur(ard >- @u *- 3indner M et al L2012 eBborn screenin( ro(rammes in EuroeZ
ar(uments and eorts re(ardin( harmoniation >art 2 6rom screenin( laboratory
results to treatment- folloB$u and Kuality assurance J Inherit Metab Dis '5Y1'
25/ross@ef>ubMed
/handler @J- ;erfas >M- Shans,e S- Sloan J- omann - DiMauro S- enditti /> L200%
Mitochondrial dysfunction in mut methylmalonic acidemia 6)SE4 J 2'Y1252
121/ross@ef>ubMed/entral >ubMed
/haman *)- .roman )- Mac3eod E et al L2012 )cute mana(ement of roionic
acidemia Mol .enet Metab 105Y125/ross@ef>ubMed/entral>ubMed
/ole :J L1%%0 :he 3MS method for constructin( normalied (roBth standards Eur J /lin
utr ##Y#50>ubMed
/ole :J- 6reeman J- >reece M) L1%%& 4ritish 1%%0 (roBth reference centiles for
Bei(ht- hei(ht- body mass inde? and head circumference [tted by ma?imum enalied
li,elihood Stat Med 1!Y#0!#2%/ross@ef>ubMed
/ole :J- 7illiams )6- 7ri(ht /M L2011 @eubMed
de *eyer p- alayannooulos - 4enoist J6 et al L200% Multile O>OS de[ciency in
the liediatr @es Y%1%5/ross@ef>ubMed
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