2006 - clinical approach to treatable inborn metabolic diseases

J Inherit Metab Dis (2006) 29:261274DOI 10.1007/s10545-006-0358-0

S S I E M S Y M P O S I U M 2 0 0 5

Clinical approach to treatable inborn metabolic diseases:An introductionJ.-M. Saudubray F. Sedel J. H. Walter

Received: 6 March 2006 / Accepted: 9 March 2006C SSIEM and Springer 2006

Summary In view of the major improvements in treatment,it has become increasingly important that in order for first-line physicians not to miss a treatable disorder they shouldbe able initiate a simple method of clinical screening, par-ticularly in the emergency room. We present a simplifiedclassification of treatable inborn errors of metabolism inthree groups. Group 1 includes inborn errors of intermediarymetabolism that give rise to an acute or chronic intoxication.It encompasses aminoacidopathies, organic acidurias, ureacycle disorders, sugar intolerances, metal disorders and por-phyrias. Clinical expression can be acute or systemic or caninvolve a specific organ, and can strike in the neonatal periodor later and intermittently from infancy to late adulthood.Most of these disorders are treatable and require the emer-gency removal of the toxin by special diets, extracorporealprocedures, cleansing drugs or vitamins. Group 2 includesinborn errors of intermediary metabolism that affect the cyto-plasmic and mitochondrial energetic processes. Cytoplasmic

Communicating editor: Jean-Marie Saudubray

Competing interests: None declared

Presented at the 42nd Annual Meeting of the SSIEM, Paris, 69September, 2005

J.-M. Saudubray ()Centre de Reference des Maladies Hereditaires du Metabolisme,Hopital Necker Enfants-Malades, Universite Rene Descartes, 149rue de Se`vres, 75743 Paris Cedex 15, Francee-mail: [email protected]

F. SedelFederation des Maladies du Syste`me Nerveux, HopitalPitie-Salpetrie`re, AP-HP, Paris, France

J. H. WalterWillink Biochemical Genetics Unit, Royal Manchester ChildrensHospital, Manchester, UK

defects encompass those affecting glycolysis, glycogenosis,gluconeogenesis, hyperinsulinisms, and creatine and pentosephosphate pathways; the latter are untreatable. Mitochondrialdefects include respiratory chain disorders, and Krebs cycleand pyruvate oxidation defects, mostly untreatable, and dis-orders of fatty acid oxidation and ketone bodies that are treat-able. Group 3 involves cellular organelles and includes lyso-somal, peroxisomal, glycosylation, and cholesterol synthesisdefects. Among these, some lysosomal disorders can be effi-ciently treated by enzyme replacement or substrate reductiontherapies. Physicians can be faced with the possibility of atreatable inborn error in an emergency, either in the neona-tal period or late in infancy to adulthood, or as chronic andprogressive symptoms general (failure to thrive), neurolog-ical, or specific for various organs or systems. These symp-toms are summarized in four tables. In addition, an extensivelist of medications used in the treatment of inborn errors ispresented.

Abbreviations3PGD 3-phosphoglycerate dehydrogenaseBCAA branched-chain amino acidBRBGD biotin-responsive basal ganglia diseaseCbl cobalaminCDG congenital disorder of glycosylationCPT I carnitine palmitoyltransferase type ICPT II carnitine palmitoyltransferase type IICTX cerebrotendinous xanthomatosisFAO fatty acid oxidationGTP guanosine triphosphateHELLP haemolysis, elevated liver function, low

plateletsHFI hereditary fructose intoleranceIE inborn errorIEM inborn error of metabolism

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262 J Inherit Metab Dis (2006) 29:261274

LPI lysinuric protein intoleranceHMG CoA 3-hydroxy-3-methylglutaryl coenzyme AIVA isovaleric acidaemiaLCHADD long-chain 3-hydroxy-acyl-CoA

dehydrogenase deficiencyMCD multiple carboxylase deficiencyMMA methylmalonic acidaemiaMSUD maple syrup urine diseaseMTHFR methylene tetrahydrofolate reductaseOA organic aciduriaOTC ornithine transcarbamylasePA propionic acidaemiaPC pyruvate carboxylasePDH pyruvate dehydrogenasePKU phenylketonuriaPNPO pyridox(am)ine-5-phosphate oxidasePTP 6-pyruvoyltetrahydropterin synthaseTFP trifunctional proteinTH tyrosine hydroxylaseTL carnitine acyltranslocaseUCD urea cycle disordersVLCADD very long-chain acyl-CoA dehydrogenase

deficiency

Introduction

Some 50 years after the first nutritional treatment ofphenylketonuria (PKU) and 30 years after the publicationof the first book entirely devoted to the treatment of in-born errors of metabolism (IEMs) (Raine 1975), we felt thatthis was an appropriate time to choose Treatment of In-born Errors of Metabolism as the main theme for the 42ndAnnual Symposium of the Society for the Study of InbornErrors of Metabolism, held in Paris in September 2005. Dur-ing the last half century, many new disorders have been dis-covered and many therapeutic procedures have been tried.Some of these are well established and life-saving; othersare still experimental. The long-term outcome of our oldestpatients, who have already reached adulthood, must questionour methods for diagnosis, management and treatment. Thenew field of adult metabolic medicine also raises many newtherapeutic problems, including the management of preg-nancy in affected mothers. Finally, our technical ability toundertake systematic neonatal screening for many metabolicdisorders raises a number of ethical issues.

This special issue of the Journal gathers original papersand reviews on the diverse aspects of treatment that werepresented at the Paris Symposium. We largely focused ondiseases in which treatment is both well tried and successful.This issue contains a great deal of specialist information, butit also shows how the paediatrician and various adult physi-cians with little experience of these individually uncommon

diseases can cooperate with special centres. Given these veryimportant instances of therapeutic progress, it becomes evermore important to initiate a simple method of clinical screen-ing by the first-line physicians with the goal Do not miss atreatable disorder, in particular in the emergency room.

Classification of inborn errors

Pathophysiology

From a therapeutic perspective, metabolic disorders can bedivided into the following three useful groups.

Group 1: Disorders that give rise to intoxication

This group includes inborn errors of intermediarymetabolism that lead to an acute or progressive intoxica-tion from the accumulation of toxic compounds proximal tothe metabolic block. In this group are the inborn errors ofamino acid catabolism (phenylketonuria, maple syrup urinedisease, homocystinuria, tyrosinaemia, etc.), most organicacidurias (methylmalonic, propionic, isovaleric, etc.), con-genital urea cycle defects, sugar intolerances (galactosaemia,hereditary fructose intolerance), metal intoxication (Wilsondisease, Menkes disease, haemochromatosis), and porphyr-ias. All the conditions in this group share clinical similari-ties: they do not interfere with the embryofetal developmentand they present with a symptom-free interval and clinicalsigns of intoxication, which may be acute (vomiting, coma,liver failure, thromboembolic complications) or chronic (fail-ure to thrive, developmental delay, ectopia lentis, cardiomy-opathy). Circumstances that can provoke acute metabolic at-tacks include catabolism, fever, intercurrent illness and foodintake. Clinical expression is often both late in onset and in-termittent. Most of these disorders are treatable and requirethe emergency removal of the toxin by special diets, extra-corporeal procedures or cleansing drugs (carnitine, sodiumbenzoate, penicillamine, vitamins, etc.). Nutritional therapyis the backbone of the treatment in this group. It includesapproaches to deplete the toxic substrate that accumulatesor to replace the crucial metabolic product that is deficient.Breast milk can still play an important role in these specialdiets. The long-term consequences of artificial diets on theoffspring will have to be evaluated particularly as regardspossible mechanisms of metabolic imprinting (Junien 2006,this issue). Strategies to decrease the concentration of toxicsubstrates or their precursors also involve the administra-tion of a variety of cleansing drugs that bind the accumu-lated metabolites and allow their excretion. Pharmacologicaldoses of vitamins have also shown remarkable efficiency invitamin-responsive disorders.

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J Inherit Metab Dis (2006) 29:261274 263

Table 1 Treatable IEMs presenting in neonates and infants


Table 2 Late-onset (late infancy to adulthood) recurrent comas, ataxia, psychiatric signsMain clinical presentation Other important signs Treatable metabolic disease

Metabolic coma without focalneurological signs

Acidosis Multiple carboxylase deficiencyOrganic acidurias, MSUD

Acute ataxia with lethargy Ketolysis, ketogenesis defectsFAO disordersFructose bisphosphatase deficiencyPDH deficiency

Hyperammonaemia Urea cycle disorders, Triple HLysinuric protein intoleranceFAO defectsHMGCoA lyase deficiency

Hypoglycaemia Gluconeogenesis defectsGlycogen synthetase deficiencyHMGCoA lyase/synthetase deficiencyFAO defects

Hyperlactacidaemia Multiple carboxylase deficiencyPDH deficiencyGluconeogenesis defectsFAO defects

Neurological coma with focalsigns, seizures, or intracranialhypertension

Cerebral oedema MSUDOTC deficiencyOrganic acidurias

Extrapyramidal signs (dystonia, Parkinson) Glutaric aciduria type IMMAWilson diseaseHomocystinuriaBRBGD

Stroke-like UCDOrganic aciduriasHomocystinuriasB1-responsive macrocytic megaloblastic anemiasFabry disease

Thromboembolic accidents Homocystinurias (all types)Hepatic coma Hyperammonaemia, lactic acidosis FAO defectsCytolysis UCDReye syndrome Haemolytic jaundice Wilson disease

Enteropathy, hypoglycaemia CDG IbPsychiatric symptoms,

hallucinations, deliriumHyperammonaemia UCD

Lysinuric protein intoleranceKetoacidosis Organic acid disordersHyperhomocysteinaemia MTHFR deficiency, CblC deficiencyPortwine urine Acute intermittent porphyria

Hereditary coproporphyria

ing such as 1-antitrypsin, carbohydrate deficient glyco-protein (CDG) syndrome, and inborn errors of cholesterolsynthesis belong to this group. For many years, none wastreatable. In the last decade however, efficient enzyme re-placement therapy has become available for several lysoso-mal disorders such as Gaucher and Fabry diseases.

Various cell and organ transplantation strategies havebeen also developed for certain disorders, some of themsuccessful, but many others are still experimental or underevaluation. Finally, besides gene therapy, new therapeutic

approaches such as chaperon therapy appear promising butcurrently remain mostly inaccessible in clinical practice. Allthese aspects of treatment are presented in the second partof this issue.

Clinical presentation

Besides newborn screening in the general population (as forphenylketonuria) or in at-risk families, there are four groups

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J Inherit Metab Dis (2006) 29:261274 265

Table 3 Neurological symptoms

Presenting or predominant symptom Other accompanying signs Treatable metabolic disease

Dystonia Parkinsonism Isolated Homocystinuria, PKUGTP cyclohydrolase deficiencyPTP synthase deficiencySepiapterin reductase deficiencyTH deficiency

Basal ganglia involvement BRBGD, PDH deficiency, Wilson disease, CTX,glutaric aciduria type I

Bitemporal atrophy Glutaric aciduria type ISpastic (or pseudo-spastic) paraparesia GTP cyclohydrolase deficiency

TH deficiency, homocystinuriaCTX, cerebral folate deficiency

Polyneuropathy PDH deficiency, CTX, homocystinuriasPsychiatric signs Homocystinurias, Wilson disease, CTX, PKU,

PDH deficiencyAcute attacks Nonketotic hyperglycinaemia, PTP deficiency,

PDH deficiency, BRBGDPolyneuropathy Isolated PDH deficiency, Refsum disease, CTX, TFP

deficiency, MTHFR deficiency, serinedeficiency

Ataxia PDH deficiency, cerebral folate deficiency,Refsum, disease, CTX, vitamin E deficiency,abetalipoproteinaemia

Exercise intolerance LCHADD, TFP deficiencyRecurrent attacks Porphyria, tyrosinaemia type I, Refsum disease,

PDH deficiencySpastic paraplegia (and pseudo-spastic) Isolated PKU, cerebral folate deficiency, TH deficiency,

arginase deficiency, GTP cyclohydrolasedeficiency

Extrapyramidal signs Cerebral folate deficiency, GTP cyclohydrolasedeficiency, TH deficiency, CTX,homocystinurias

Polyneuropathy CTX, MTHFR deficiency, Cbl synthesis defects,cerebral folate deficiency

Recurrent attacks Arginase deficiency, Triple HAtaxia Isolated PDH deficiency, coenzyme Q10 deficiency

Spastic paraparesis CTX, nonketotic hyperglycinaemia, vitamin Edeficiency

Dystonia/parkinsonism CTX, PDH deficiency, Cbl synthesis defectsRecurrent attacks CTX, UCD

Psychiatric signs Isolated Cbl synthesis defects, MTHFR deficiency, PKU,Homocystinuria, Wilson disease, CTX

Leukodystrophy Cbl synthesis defects, MTHFR deficiency, PKU,CTX

Recurrent attacks UCD, PDH deficiency, Cbl synthesis defects,porphyrias

Progressive Wilson disease, CTX

of clinical circumstances in which physicians are faced withthe possibility of a metabolic disorder:

Early symptoms in the antenatal and neonatal period Later-onset acute and recurrent attacks of symptoms such

as coma, ataxia, vomiting and acidosis

Chronic and progressive symptoms which can be gen-eral (failure to thrive), muscular or neurological (de-velopmental delay, neurological deterioration, psychiatricsigns)

Specific and permanent adverse effects on various organor systems

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bala

min

met

abol

ismCe

rebr

alfo

late

tran

spor

ter

515

mg

perd

ayO

ral,

i.v

Gal

sulfa

seR

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bina

ntan

alog

ueo

fhu

man

N-ac

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gala

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amin

e4-

sulp

hata

sem

anu

fact

ured

inCh

ines

eha

mste

rovar

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HO)c

elll

ine

Muc

opol

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char

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isty

peV

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0mg/

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2005

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tinue

do

nn

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age)

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icat

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dose

Rou

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fibro

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Fibr

ates

decr

ease

TGle

vel

s;o

ther

fibra

tesi

nclu

debe

zafib

rate

and

feno

fibra

te

Mix

edo

rco

mbi

ned

hype

rlipi

daem

iaA

dult

dose

:1.2

gda

ily,u

sual

lyin

2di

vid

eddo

ses;

ran

ge0.

91.

5gda

ily

Ora

lCa

nca

use

am

yosit

is-lik

e

synd

rom

e,es

peci

ally

with

impa

ired

ren

alfu

nctio

n;co

mbi

natio

nw

itha

stat

inin

crea

ses

risk

ofr

habd

omyo

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SFSt

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ates

gran

uloc

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prod

uctio

nN

eutro

peni

ain

GSD

Ib,I

c5

g/kg

on

ceda

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c.

Gly

cine

Form

siso

val

eryl

glyc

ine

with

high

ren

alcl

eara

nce

Isov

aler

icac

idae

mia

150m

g/kg

perd

ayin

3di

vid

eddo

ses

Ora

lU

pto

600m

g/kg

perd

aydu

ring

deco

mpe

nsat

ion

Hae

mar

gina

teIn

hibi

ts5-

amin

olev

ulin

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seA

cute

porp

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s3

4mg/

kgo

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daily

for4

days

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lam

in(vi

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fco

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min

met

abol

ism1m

gi.m

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10m

go

nce

or

twic

eda

ilyi.m

.or

ora

lD

ose

may

bere

duce

dto

on

ceo

rtw

ice

wee

kly

acco

rdin

gto

resp

onse

5-H

ydro

xytry

ptop

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Neu

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nsm

itter

repl

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Diso

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sofn

euro

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ersy

nthe

sis1

2mg/

kgin

crea

sing

grad

ually

to8

10m

g/kg

in4

div

ided

dose

sO

ral

Mon

itorC

SF5H

IAA

level

s

Imig

luce

rase

Rec

ombi

nant

anal

ogue

of

hum

an

-gl

ucoc

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rosid

ase

man

ufa

ctur

edin

Chin

ese

ham

stero

var

y(C

HO)l

ine

Gau

cher

dise

ase

Vario

usre

gim

ens:

2.5U

/kg

3pe

rw

eek

to60

U/k

gpe

r2w

eeks

for

type

IIIG

auch

erdi

seas

eso

me

I.v.

clin

icia

nsre

com

men

dhi

gher

dosa

ges:

120U

/kg

per2

wee

ksK

etam

ine

ND

MA

chan

nela

nta

goni

stN

KH

130

mg/

kgpe

rday

in4

div

ided

dose

sO

ralo

ri.v

.

L-A

rgin

ine

Rep

leni

shes

argi

nine

;su

bstra

teo

fnitr

ouso

xid

eU

rea

cycl

edi

sord

ers;

MEL

AS

(Ko

gaet

al20

05)

501

70m

g/kg

(OCT

and

CPS

defic

ienc

y)u

pto

700

mg/

kgin

AL

and

AS

defic

ienc

y)

Ora

lor

i.v.

I.v.

load

ing

dose

:(20

0mg/

kg)o

ver

90m

in

Laro

nida

seR

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bina

ntan

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man

-L-

idur

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ase

man

ufa

ctur

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CHO

cell

line

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100

U/k

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age)

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Med

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dose

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dyst

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moves

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term

edia

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with

inth

em

itoch

ondr

ia

Prim

ary

and

seco

nda

ryca

rniti

nede

ficie

ncie

s10

020

0mg/

kgpe

rday

Ora

lor

i.v.

Do

no

tuse

race

mic

mix

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L-Ci

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dar

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asan

alte

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ive

toar

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CPS

defic

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dOT

Cde

ficie

ncy;

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CPS

and

OTC

defic

ienc

y:17

0mg/

kgpe

rday

or

3.8g

m/m

2 /day

indi

vid

eddo

ses,

LPI:

100m

g/kg

perd

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35

dose

s

Ora

l

L-D

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Rep

lace

men

tof

neu

rotr

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itter

sD

isord

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hesis

12m

g/kg

incr

easin

gslo

wly

to10

12m

g/kg

in4

div

ided

dose

sO

ral

Giv

eas

L-do

pa/c

arbi

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(1:10

or

1:5)

mo

nito

rCSF

HVA

level

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e-H

ClA

llow

sly

sine

abso

rptio

nLy

sinur

icPr

otei

nIn

tole

ranc

e20

30m

g/kg

perd

ayin

3di

vid

eddo

ses

Ora

l

L-Se

rine

Rep

leni

shes

serin

e3-

Phos

phog

lyce

rate

dehy

drog

enas

ede

ficie

ncy

Up

to60

0mg

perd

ayin

6di

vid

eddo

ses

Ora

l

L-Tr

ypto

phan

Incr

ease

skyn

uren

icac

idw

hich

isan

endo

geno

usan

tago

nist

oft

heN

MD

Are

cept

or

NK

H10

0mg/

kgpe

rday

in3

div

ided

dose

sO

ral

Mag

nesiu

m(M

g)R

eple

nish

esM

gPr

imar

yhy

pom

agne

saem

iaw

ithse

con

dary

hypo

calc

emia

0.5

1.5m

l/kg

perd

ayM

gSO

410

%so

lutio

ni.v

.;o

ralm

aint

enan

ce0.

73.

5mm

ol/k

gpe

rday

elem

enta

lMg

in3

5di

vid

eddo

ses

I.v./o

ral

Man

nose

Impr

oves

glyc

osyl

atio

nCD

GIb

(PM

Idefi

cien

cy)

1g/k

gpe

rday

in5

div

ided

dose

sO

ral

Not

ofp

roven

bene

fitin

CDG

Ia(K

jaerga

ard

etal

1998

;May

atep

eket

al19

97)

Mer

capt

opro

pion

ylgl

ycin

eCh

elat

ing

agen

tCy

stinu

ria15

20m

g/kg

perd

ay,u

pto

max

.o

f10

00m

gpe

rday

in3

div

ided

dose

s

Ora

l

Met

roni

dazo

leR

educ

espr

opio

nate

prod

uctio

nby

gutb

acte

riaPr

opio

nic

and

met

hylm

alon

icac

idae

mia

7.5m

gth

ree

times

ada

yO

ral

Mig

lusta

tIn

hibi

toro

fglu

cosy

lcer

amid

esy

ntha

se,t

hefir

sten

zym

ere

spon

sible

for

glyc

osph

ingo

lipid

(GSL

)sy

nthe

sis

Gau

cher

dise

ase

100m

gst.d

.s.O

ral

Onl

yre

com

men

ded

for

patie

ntsw

ithm

ildto

mo

dera

teG

auch

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e

un

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Med

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Mod

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Diso

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rbam

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imul

ates

N-ac

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glut

amat

esy

ntha

seN-

Ace

tylg

luta

mat

esy

ntha

sede

ficie

ncy

100

300m

g/kg

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4di

vid

eddo

ses

Ora

l

Carb

amoy

lpho

spha

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sede

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Nic

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amid

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300

mg/

day

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icot

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acid

Inhi

bits

the

rele

ase

off

ree

fatty

acid

sfro

mad

ipos

etis

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incr

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sHD

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oles

tero

l

Hyp

erlip

idae

mia

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se:1

002

00m

g3

times

daily

,gr

adua

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crea

sed

over

24

wee

ksto

12g

3tim

esda

ily

Ora

l

NTB

CIn

hibi

ts4-

hydr

oxyp

heny

lpyr

uvat

edi

oxyg

enas

e

Tyro

sinae

mia

type

I1m

g/kg

in1

2di

vid

eddo

ses

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lCo

mbi

new

ithlo

w-t

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low

-phe

nyla

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npl

asm

aTy

r

1000

mg

daily

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phos

phat

eA

ctiv

eco

-fact

orPy

ridox

(am)in

e5 -p

hosp

hate

ox

idas

ede

ficie

ncy

40m

g/kg

perd

ayin

4di

vid

eddo

ses

Ora

l

Rib

oflav

inCo

-enz

yme

Glu

taric

acid

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iant

sof

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DH

and

SCA

D;

con

geni

tall

actic

acid

osis

(comp

lexId

efici

ency

)

100m

gpe

rday

in2

3di

vid

eddo

ses

Ora

l

Sele

gilin

eM

onoa

min

e-ox

idas

eB

inhi

bito

rA

sadju

nctto

ther

apy

with

5HT

and

L-do

pain

BH

4de

fect

s0.

10.

25m

gpe

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in3

4di

vid

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ses

Ora

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Mod

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Diso

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ins

HM

G-C

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duct

ase

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bito

rsH

yper

lipid

aem

ias

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lSi

mva

stat

inha

sbee

nu

sed

expe

rimen

tally

inSL

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dium

benz

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Com

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swith

glyc

ine

tofo

rmhi

ppur

icac

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hich

hash

igh

ren

alcl

eara

nce

Hyp

eram

mon

aem

ia25

0mg

perd

ayin

div

ided

dose

sor

byco

ntin

uous

i.v.

infu

sion

Ora

lor

i.v.

I.v.

load

ing

dose

:25

0mg/

kgover

90m

in

Rem

oves

N2

toam

mo

nia

and

redu

cesb

lood

amm

on

iaD

ose

may

bedo

uble

dif

sever

e

hype

ram

mon

aem

iaSo

dium

phen

ylbu

tyra

teCo

nver

ted

toph

enyl

acet

ate,

whi

chco

mbi

nesw

ithgl

utam

ine

tofo

rmph

enyl

glut

amin

ew

hich

has

high

ren

alcl

eara

nce

Hyp

eram

mon

aem

ia25

065

0mg/

kgpe

rday

;max

i.o

ral

dose

20g/

day

Ora

lor

i.v.

Tetr

ahyd

robi

opte

rin(B

H 4)

Rep

lace

men

tofB

H4

Diso

rder

sofB

H4

synt

hesis

or

recy

clin

g;B

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resp

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e

form

sofP

AH

defic

ienc

y

13m

g/kg

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ayin

BH

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fect

s;7

20m

g/kg

perd

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PAH

defic

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y

Ora

lM

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con

trai

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ated

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defic

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Thia

min

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min

resp

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evar

iant

sof

MSU

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DH

defic

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yan

dco

mpl

exId

efici

ency

101

5mg

perd

ayO

ral

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eso

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to30

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have

been

use

din

CLA

;50

020

00m

gpe

rday

inth

iam

in-re

spon

sive

PDH

?Tr

ieth

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ram

ine

Chel

atin

gag

ent

Wils

ondi

seas

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perd

ayin

div

ided

dose

sin

crea

sing

toa

max

imum

of

2.4g

/day

ifn

eces

sary

Ora

lM

ayre

duce

seru

miro

nIr

onsu

pple

men

tsm

aybe

nec

essa

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tano

inA

napl

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quin

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(co-en

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Q 10)

Inbo

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rors

ofC

oQ10

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100

300m

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Ora

lH

asbe

enu

sed

ino

ther

mito

chon

dria

lcy

topa

thie

sbu

tof

un

prov

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nefit

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ine

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PU

MP

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defic

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redita

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rotic

acid

uria

)10

015

0mg/

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indi

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l

Viga

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rever

sible

inhi

bito

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ABA

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sam

inas

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ccin

icse

mia

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yde

dehy

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enas

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501

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g/kg

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2di

vid

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ses

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lM

onito

rcar

eful

ly:i

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ases

CSF

GA

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vel

san

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sible

visu

alfie

ldde

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poss

ible

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min

AFr

eera

dica

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ven

ger

Glu

tath

ione

synt

heta

sede

ficie

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100m

g/kg

perd

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min

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-fact

or;a

ntio

xida

ntH

awki

nsin

uria

200

1000

mg

perd

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ral

Tyro

sinae

mia

III(

4hy

drox

yphe

nylp

yruv

ate

diox

ygen

ase

defic

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iao

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new

born

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beta

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mia

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min

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-to

coph

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free

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10m

g/kg

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kgpe

rda

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Zinc

sulp

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sZn,

impa

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abso

rptio

nA

crod

erm

atiti

sen

tero

path

ica

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ondi

seas

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E:30

100

mg

Zn/d

ay;W

ilson

dise

ase:

600m

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lad

ultd

ose),

300m

gpe

rday

(main

tenan

cead

ultd

ose).

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e

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vid

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ses

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l

aA

dapt

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ETF-

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stro

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The first two categories often present as treatable emer-gencies, either in the neonatal period (Table 1) or late ininfancy to adulthood (Table 2). The main chronic or progres-sive symptoms and signs that raise suspicion of a treatableIEM are listed in Table 3 (neurological symptoms) and Table4 (other organ/system symptoms). Of course these tables arenot exhaustive and are mostly based on the personal experi-ence of the authors (Saudubray et al 2006). They should besupplemented by readers.

Medications used in the treatment of IEMS (Table 5)

Readers should consult relevant pharmacopoeias foradditional details, particularly as regards side-effectsand contraindications (for example, BNF for childrenwww.bnfc.org).

References

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Koga Y, Akita Y, Nishioka J, et al (2005) L-Arginine improves thesymptoms of strokelike episodes in MELAS. Neurology 64: 710712.

Mayatepek E, Schroder M, Kohlmuller D, et al (1997) Continuous man-nose infusion in carbohydrate-deficient glycoprotein syndrometype I. Acta Paediatr 86: 11381140.

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Saudubray JM, Desguerre I, Sedel F, Charpentier C (2006) A clin-ical approach to inherited metabolic disorders. In: Fernandes J,Saudubray JM, van den Berghe G, Walter J, eds. Inborn MetabolicDiseases: Diagnosis and Treatment, 4th edn. Berlin: Springer-Verlag, 2006 in press.

Valayannopoulos V, Verhoeven NV, Mention K, et al (2006) Transal-dolase deficiency: a new cause of hydrops foetalis and neonatalmultiorgan disease. J Pediatr, in press.

Van Spronsen FJ, Smit GPA, Erwich JJHM (2005) Inherited metabolicdiseases and pregnancy. BJOG Int J Obstet Gynaecol 112: 211.

Walter JH, Wraith J (2006) Treatment: present status and new trends.In: Fernandes J, Saudubray JM, van den Berghe G, Walter J,eds. Inborn Metabolic Diseases: Diagnosis and Treatment. Berlin:Springer-Verlag, 4th edition, in press.

Zeng WQ, Al Yamani E, Acierno JS Jr, et al (2005) Biotin-responsivebasal ganglia disease maps to 2q36.3 and is due to mutations inSLC19A3. Am J Hum Genet 77: 1626.

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2006 - clinical approach to treatable inborn metabolic diseases

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