I. Fernandes - I.-M. Saudubray
`G.Van den Berghe
`
`Editors
`
`lnborn
`
`Third Edition
`
` i
`
` LUPIN
`EX. 1011
`
`EX. 1011
`
`LUPIN
`
`

`
`
`
`
`
`
`
`_-nu.-nu-nu-nun.nn mumwA.."W|Iii|lwn
`
`I. Fernandes I.-M. Saudubray G. Van den Berghe (Eds.)
`
`lnborn Metabolic Diseases
`
`Diagnosis and Treatment
`
`3'“, Revised Edilion
`
`With 66 Figures and 5? Tables
`
`i.I
`
`I4 F
`
`La
`
`*e£5
`
`ii
`
`Springer
`
`
`
`Sprmger
`Berfirr
`Heirfefberg
`Ne w Yu H:
`Hurrralrma
`Hsmgim lug
`I.:1|Im’:m
`M Hr: :1
`Pkarfs
`Sr'r:gtI_D(Ira'
`Tukyr:
`
`

`
`Dr. ]oHN FERNANDES
`Professor Emeritus of Pediatrics
`
`Veldweg S7
`8051 NP Hattern, The Netherlands
`
`Professor IF.AN—MARIE SAUDUBRAY
`Hospital Necker-Enfants Malades
`149 Rue de Sevres
`75743 Paris Cedex 15, France
`
`Professor GEORGES van DEN BERG]-IE
`Christian de Duve
`
`Institute of Cellular Pathology
`Université Catholique de Louvain
`Avenue Hippocrate 75
`1200 Brussels, Belgium
`
`Cover Illustration: Putti by della Robbia at Speclale clegli Innocenti, Firenze, Italy
`
`ISBN 3-540-65626—X Springer-Verlag Berlin Heidelberg New York
`
`ISBN 3—54o—58546—X, 2"d edition, Springer—Verlag Berlin Heidelberg New York
`
`Library of Congress Cataloging in Publication Data applied for.
`Die Deutsche Bibliothek — ClI-’—Einheitsaufnah me
`inborn metabolic diseases: diagnosis and treatmentfl. Fernandes... — 3., rev. ed. — Berlin; Heidelberg; New York: Barcelona; I-long Kong;
`London; Milano; Paris; Singapore; Springer. moo.
`ISBN 3—54o—65626—X
`
`This work is subject to copyright. All rights are reserved, whether the whole or part ofthe material is concerned, specifically the rights of
`translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on Irticrofilrn or in any other way, and storage in
`data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of
`September 9, 1965, in its current version, and permission for use must always be obtained from Springer—\’erlag. Violations are liable for
`prosecution under the German Copyright Law.
`
`Springer-Verlag Berlin Heidelberg New York
`a member of Bertelsrnannspringer Science+ Business Media Gmbi-I
`© Springer-Verlag Berlin Heidelberg zooo
`Printed in Germany
`
`The use of general descriptive names. registered names, trademarks. etc. in this publication does not imply, even in the absence of a
`specific statement. that such names are exempt from the relevant protective laws and regulations and therefore free for general use.
`
`Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book.
`In every individual case the user must check such information by consulting other relevant literature.
`
`Cover Design: Springer—Verlag, E. Kirchner
`Production: Pro Edit GmbH, 69126 Heidelberg, Germany
`Typesetting: Scientific Publishing Services (P) Ltd, Madras
`
`Printed on acid-free paper
`
`SPIN: 1o843183
`
`22i'3i11 — 5 .4 3 21
`
` iii
`
`iii
`
`

`
`214
`
`215
`
`
`
`214
`
`The Urea Cycle
`
`CHAPTER 1)‘
`
`Disorders of the Urea Cycle
`l.\-'. Leonard
`
`The urea cycle which. in its complete form, is only present in the liver, is the main pathway for the
`disposal of excess of arnmoniutti nitrogen. This cycle sequence of rE=ICll01'IS. localised in Paff ill
`ll“!
`mitochondria and in part
`in the cytosol. converts the toxic ammonia I'JI0lcC|-lie lnlo the 1'I0l'I-loxit
`Product‘ urea, which is excreted in the urine. There are genetic defects of each ni the enzytnes of the
`urea .;3,v¢]¢_- which |¢.-u]
`to |typerammonaemist_ Some genetic defects of other irnpurtaul metabolic
`pathways may lead to secondary inhibition of the urea ct-‘tie. a-\llErI'1flli\'€
`pfItl'IW'=|}'S for I'Ii|rIJi;t—‘|1
`excretion, 1-..1m¢|y conjugation of glycine with benzoate and of glutarnine with phenylacetate can be
`exploited in the treatment of patients with ciefcclivt‘ I1rE«‘IgE1'IESi5-
`
`(.0‘l IENTS
`
`(ii cat Presentation
`
`
`t'.|init::t| i’re5ent1Iitin
`n
`.
`Ntroltittul Pres
`lnientile Presentation. ..
`
`(hiltlm ti .-\(luIts.. .
`
`rrantzentcnt
`.
`.
`'
`Tuxitity .
`.
`Diagnostic '
`.
`Lliuclwn. cal '|'eat.\
`Imaging .
`. ...
`L3it"I'e:t-nti:
`'
`....
`Trcatn|ent..
`.
`.
`.
`l.t>w-i“rtnt'itt Diet
`
`.
`.
`.
`.
`Essential Amino atetds .
`.
`.'\lIt'rtt'.tti\-t- E‘nt|tw:tys for Nitrogen F cretinn.
`ficncral Aspects oi '|'l:erap_r.
`Asst-seutett: tor Tlt.‘:lt:llt.‘n| ..
`Etncr5cncy'|'rt'atrtient. .
`.
`l’rugnasis......._..
`_
`.
`. . ..
`Genetics and Prenatal Uiagnu .
`lteferrttces..........__.......
`
`
`
`
`
`.
`
`HEPATIC NITROGEN
`pgo|_
`
`Prtunytnuaymte
`\
`°"'”’"’""”'3'3."
`ptiertytaceraae
`N;
`
`_
`
`Glutanilne ——|" Glutarninn
`Ala nine
`Bortzwni —D' Bnnzoyrcon
`Asparlale
`Gtyeine - —-—I-v Glycine
`
`I.
`Pt!
`my Wm‘
`glularnlne
`
`I-
`
`5-
`
`i- t-tnppurate —
`
`Glutamate fl(3
`Acotyl Con
`1
`NH,
`1'
`N.at:ely|
`gltrtarn ate
`
`€93
`
`I
`
`fl
`
`2:5
`its
`en‘:
`:m
`zto
`.‘.:_1
`11?
`1:;
`:tS
`zts
`2
`:t§t
`
`a
`
`Patients with urea-cycle (ll.‘iUT(l£‘r5 may present at
`almost any age. However. there are certain times at
`which they drc more iikely to develop syntplonts
`
`because of metabolic sires
`such as infection precip-
`itating protein catabolisrn. These are:
`n 'l'he neonatal period.
`I During late infamzy. Cltildren are vulnerable during
`this period because of the tilowiny. of _grot~'lh,
`the
`change to cow's milk and weaning foods and thc
`tleelittitig maternal antibody and consequent devel-
`opnicnt ol inturctirrcnt infections.
`l‘ttbet'ty. The changing growth rate and p5yt:]\:>sn-
`cial litctors may precipitate decompcnsation.
`However.
`it must be emphasised that rnttny patients
`may prcscnt outside these periods. The patterns of
`the clinical preseittatiort of hypcrantrnrsttaetnia are
`rather characteristic and are broadly similar lor all
`the tllS0l'(lCT$ except arginase deficiency. which is
`discussed separately. The early syrnptoni.-t are often
`nnn-specific and initially. therefore. the diagnosis is
`t:asi!‘_.' ot'er|nokt:d. The
`tnost
`itnportztrtt points
`in
`
`diagnosing hyperan'tn'.ton:tt'n'ti'
`trr: to think ofit during
`diagnosis and to measure the plasma amrnonitt cort-
`ctsntration.
`
`Neonatal Presentation
`
`Most.’ babies with urea cvclr: dittorrlers are of normal
`birtltweigltt and are initially hcttilliy but. after a short
`lIlIL!t‘\J.’ll that can be less than 2.1 h. they become unwcll.
`Common early sytrtptcnns are poor feeding. vomiting.
`letltargy andior irritability and tachypnuea. The initial
`working diagnosis is almost invariably sepsis. Rather
`characlcristically.
`these halaies nray have a
`transient
`tnild respirat.ot'_t' alkaiosis. which cart be a useful
`diagnostic clue at this stage. Usually. they d.ett:J'ittr.1tc
`rapidly. with more: obvious nettrological and autonomic
`problems.
`including changcs of Ittnt: Will!
`3038 of
`normal reflexes. vasomotor instability and hypother-
`
`
`
`Five inlteritctl disorders of the urea cycle are now
`well described. These are characterised by hyper-
`animonaemia and disordered antinonacid rnetabo:
`lisrn. The presentation is highly variable:
`those
`presenting in the newborn periotl usually have an
`overwhelming illness that rapidly progresses front
`poor feeding. vtnnilitag.
`lethargy or irritability and
`tacltypnoua to fits. coma and respiratory arrest.
`in
`infancy.
`the symptoms are less SE\'€]'E
`and more
`vari:IhIe. Poor developmental progress. hehaviottrall
`problcrns. hepatorrtcgaly and gastrointestinal syrup-
`toms are usually observed.
`In children and adults,
`chronit:
`tieurologieal
`illness
`is
`eliaracteriserl
`by
`behavioural problems. cuntttsioti.
`irritability and
`cyclic vomiting. which deteriorates to acttte e:tcepha- F
`lopztlhy during tnetabolic stress. Arginrtse deficiency
`shows
`rnurt‘ speciftr. syrnptums,
`such as spastic;
`diplegi-.1. dystonia. ataxia and fits. All urea-cycle;
`disorders have atttosomal-recessive inherit-antze ex-
`cept ornitltitn: carbantnyl
`tr.ms|'t-ruse
`tlcfich-n::y..
`\\'l1iEl1 is Xvlinked.
`
`
`
`Certtampyl
`phosphate
`
`O
`
`|_7=='5.t |
`
`°"'W"‘9
`
`Citrullirla
`
`-—~-~:
`Citrulllne
`
`asuartato f GArgininp-
`3t.tCCll'| ate 0
`
`'
`otottc Jtcltt
`orultrltne
`
`Arginine
`
`turnarata
`
`. carbamoyl phosphate syn1hct.:st:'.
`'
`of nitmgen excicltun l'it!x.tr'nt
`Fig. ‘|i|'.'I. The urea cycle and <'ll'.('llI'.lll\‘l' patht
`st: 5. ar§;itt'.tst'; 6.
`|\'1il(i<'[}‘]RillliI:l'lil[|.'
`tlL- sytttltetsse: -t. .\r§'.inino.<ttcc|n.1tel
`:.r_nni1|1inc I:
`tscar|mtnm"..1s
`3. argtttinusuc
`
`
`synthet-.tse. littzynte (infects:11:-tit-ptt'tt=tl by solid lmrs .tcros51|1c.'trrows
`
`

`
`
`
`These include enzyme induction. the concentrations of
`substrates, intermediates and N-acetyl glutamate, and
`hormonal nflt.-cts. Defects of each step lltrve now been
`described and are listed in Table t;.|.
`The plasma um:-rimrirr concentration is raised as a
`result of nietalrolic blocks in the urea-cycle. The degree
`to which it
`is elevated depends on several
`factors.
`itlelucling the enzyme involved and its residual activity,
`the protein Erttttlte and the rate of endogenous protein
`cataholism, particularly if this is lttcreased because of
`iiilection. fever or other metabolic stresses. The values
`may also he falsely elevatetl
`it the specimen is not
`collected and handled correctly.
`in the
`The concentrations of
`the amino acids
`metabolic pathway immediately proximal
`to the en-
`zyme defeci will increase. and those beyond the block
`will decrease (Table 12.1]. in addition. plasma alanine
`and particularly gtirt'rmri'iie accumulate in all
`the
`disorders. The concentration of cr'rrirl'l:'ue
`is often
`lielpliil, but
`it may not always be reliable during the
`netvhorn period [:1].
`Orotic ricirl arm‘ orori'dii-re are excreted in excess in
`the urine if there is a metabolic black distal
`to the
`formation of carharrioyl phosphate. as is the case in
`ornithine iranscarbamoylasc {OTC} deficiency. cir-
`rullinaernia, argininosticcinic aciduria and arginase
`drcliciency tFig.1;i'.1}.
`In these disorders. carbamoyl
`phosphate accumulates. leaves the mitoclrondrion and.
`once in the cytosol. enters the pathway for the de novo
`synthesis of pyrimidines. 'l'he urea cycle is also closely
`linked to many other pathways of
`intermediary
`metabolism, particularly the citric-acid cycle.
`
`Toxicity
`
`Ammonia increases the transport oftryptophan across
`the blnod—brain barrier, which then leads
`to an
`increased production and release of serotonin [2].
`
`Disorrli-rs of the Urea Cycle
`
`1 I ?
`
`Some of lJIt: symptoms of liyperammoriaentia can be
`cxplairted on this basis. and the dietary Iryptophari
`restriction has reversed anorexia in some patients with
`urea cycle disorders lfll. Ammonia induces manyuther
`elcctropliysiological, vascular arid biochemical changes
`in experimental systems. but it
`is not known to what
`extent all of these are relevant
`to the problems of
`clinical hyperarnmonaemia in man [9].
`Using proton nuclear magnetic 1'esonaiu;c spectros-
`copy. glutamine can also be shown to accumulate at
`high concentrations, both in experimental tttndels and
`in man in vivo [to]. The concentrations are such that
`the increase in osmolality could be responsible for
`cellular swelling and cerebral oedema.
`
`Diagnostic Tests
`
`Biochemical Tests
`
`for establishing the
`Routine tests are not helpful
`diagnosis
`of
`hyperaam-nonaeniia.
`Plasma
`traits-
`aminases may be elevated: combined with hep:ttome-
`galy,
`this may lead to the erroneous diagnosis of
`hepatitis.
`in urea cycle
`The most important diagnostic test
`disorders is measurement of the plasma ammonia
`coricentration. Normally. this is less than so iirnolrl but
`may be slightly raiserl as a result of a high protein
`intake, exercise. struggling nr
`a haemolysed blood
`sample. Generally. patients who are acutely unwell with
`urea cycle disorders have plasma ammonia concentra-
`lions greater than rso iii-iiolrl. and often significantly
`higher. However.
`the concentrations may be near
`normal when patients are well, are early in an episode
`of tleconipelisation or if they have been on a low-
`protein. higl1—carhohydrate intake for some time.
`Healthy neonates have slightly higher values [:1]. If
`they are ill (sepsis, perinatal asphyxia. etc.). plasma
`
`Elti
`
`Clrtrptur I?
`
`mia. apnoea and fits. Thi: baby may soon become totally
`unresponsive and may require full
`intensive care.
`Untreateii. most babies will die. often with complica-
`tions, such as cerebral or pulmonary liaernrrrrhage, the
`underlying nietaholic cninu:
`for which may not be
`recognised. Sonic survive neonatal hyperamnionaemia
`but are invariably handicapped to some degree.
`infantile Presentation
`
`the symptoms are gem.-rally rather less
`in infancy.
`acute and more variable than in the neonatal period
`and include ailore:-iia. lethargy. vomiting and failure to
`thrive. with poor developmental progress. Irritability
`and behavioural problems are also common. Tlie liver
`is often enlarged but. as the symptoms are rarely
`specific,
`the illness
`is
`initially attributed to many
`different causes that include gastrointcstiiial disorders
`{gastro-oesophageal rellus. cow's milk protein intoler-
`ance], food allergies. behaviour problems or hepatitis.
`The correct diagnosis is often only established when
`the patient develops a rnore obvious encephalopathy
`with changes in consciousness level and neurological
`signs (see helow).
`
`Children and itldttlls
`
`the p.'itit:nts commonly present with a
`At these ages.
`more obviously neurological illness.
`
`J\CL"!'l': E.NCEi‘tiAl.I."rl>J\'|'llt' Whilst older patients often pres-
`ent with episotles of acute metabolic encephalopathy,
`they may also have chronic syniptnnis. Usually,
`symptoms develop following metabolic stress precip-
`itated by infection. anaesthesia or protein cataholism,
`such as that produced by the rapid involution of the
`uterus in the puerperiirm 1:].
`llowt-.ver an obvious
`trigger
`is not always apparent. The patients first
`become anorexic.
`lethargic and unwell. Sometimes
`they are agitated and irritable, with behaviour prob-
`lems or confusion. Vomiting and headaches may be
`proniirient, suggesting migraine or cyclical vomiting.
`Otliers may be atattic as
`though intoxicated. On
`examination, hepalnmegaly may be present. particu-
`larly in tlinse with argininosuccinic acidirria. The
`patients may then recover cnniplelr.-ly but. if not. they
`may then develop neurological problems. including a
`lluctualing level of consciousness.
`fits and [some-
`times] focal neurological signs. such as lierniplegia I2]
`or cortical blindness. Untreatiztl,
`they continue to
`deteriorate, becnniing comatose. and they may die.
`Alternatively,
`they may recover with a
`significant
`neurological deficit. The cisiisc of death is usually
`ccrehral oedema.
`lietwexrn episodes. the patients are usually relatively
`well, although some, particularly younger ones. may
`
`continue to have problems, such as vomiting or poor
`developmental progress. Sonic patients may voluntarily
`restrict
`their protein intake.
`in addition to those
`disorders already mentioned. the illnr.-ss rn:-1y be attrib-
`uted to a wide variety of other di orders.
`including
`l'teye's syndrome, encephalitis. poisoning and psycho-
`social problems.
`
`IIINESS. Learning difficultie-s or
`:t|'.|.'Rt'r|.(
`tIl|lt(I:t|:'.
`more obvious mental retardation are common. and
`some patients. particularly those with argininosuccinic
`aciduria. may present with relatively few symptuiris
`apart train mental retardatioii and fits. About half the
`patients with argininosuccinic acid have brittle hair
`(trichorrhexis nodnsai]. Patients may present with
`chrnnic ataxia, which is worse during intercurrcnt
`infections [3].
`
`aittsiwisis t!EHtIl{rINt_'r'. Arginase deficiency commonly pre-
`selits with spastic diplegia and. initially. a diagnosis of
`cerebral palsy is almost always suspected. llowever. the
`neurological abnormalities appear to be slowly pro-
`gressive. although it may he difficiilt to distinguish this
`front an evolving cerebral palsy. During the course of
`the disease.
`fits, ataxia and Llystonia may develop.
`Occasionally, patients may present with an acute
`eirceplialopatlty or :1nticonvulsant-resistant fits [4].
`
`Metabolic Derangement
`
`The urea cycle is the Final common pathway for the
`ertcretion of waste nitrogen in niaarinials. The steps in
`the urea cycle are shown in Fig. 13.1. Ammonia is
`probably derived principally from glutamine and
`glutamate anal
`is converted to carhamoyl phosphate
`hy
`carlvrnrtayl
`pliosplrrite
`syrrrliettise
`{CPS}. This
`enzyme requires an allostcric activator, h'-acetylgluta-
`mate. for full activity. This compound is l0l'lt'll:(l by the
`coltdcnsalion of acetyl coemtytne :‘\ (acetyl Coal and
`glutamate in a reaction catalysed by N-acetytflritarrrure
`syrrrliernse. Carhamoyl phosphate condenses with or-
`nilhine to form citrulline in a reaction catalysed by
`irrrtitliirte trrrrrscnrbrimnylrtse. The product. citrulline,
`condenses with aspartate to produce argininosnccinate
`in a reaction catalysed by rirgiriirrrasirccikaute syrrrfretrrse.
`and the arginosuccinate is then hydrolysed to argi
`inc
`and fumarate lay rrrgirrinostirciriirte lyrise. The argininc
`is
`itself cleaved by nrgirrnse.
`releasing urea and
`re-forming ornithine. Within the urea cycle itself,
`ornithine acts as a carrier: it is neither formed not lost.
`Eaclt molecule of urea contains two atoms of waste
`nitrogen, one derived from ammonia and the other
`from aspartale. Regulation of the urea cycle is not fully
`understood. and it
`is
`likely that
`there are several
`ntechanisins controlling ltux through this pathway [5_l.
`
`Table ‘|l'.‘l. Urea-cycle disorders: biochemical and genetic. details
`Disorder
`.t\|tei'n.1iivt- names
`Plasma amino
`Urine
`acid concentrations
`orntic acid
`T Rllnille;
`1. :irgiIrIIte
`alanim-;
`T GIut:::rtini:.'
`iv citrulline: .l .trgininr:
`TT Citrutlinc: 1 argininc
`
`Tissiie for enzyme
`diagnosis
`
`Gem-tics tchroinosomc
`localisation)
`
`Lwcr
`l.i»'t-r
`l.i\-errfibrohlasl-.
`
`AR tchromnsonte 3p]
`it-liri kcd [X112 l.Il
`AR [clrroniosorw Bq}
`
`N
`ll
`T
`
`C75 ‘l°fi‘l°“‘l'
`OTC ilef:cicncy
`argininosirccinic
`syrithetmsv
`deficiency
`r\lglnll|D.EUCL‘ltIlt:
`
`}.Ise deficiency
`
`C95 *l¢'l"l'-"‘Cl‘
`OTC deficiency
`Citrullimeniia
`
`Arginiitusstlccinic
`acinluria
`
`arginiise deficiency
`NAGS deficieiicy
`
`Hyperargininaeuiiti
`NAG5 deficiency
`
`llBC.u'liver
`l
`Liver
`N
`
`N. normal:
`i'.1rb;rniyl plmrtpliate synllar.-r se-
`.5. decreased: AR. autn.mm:rl reL't:ssive: CPS.
`increased;
`7'.
`syntlietasct OTC. ornithine trmscttrhnmoylase: REC. red blood cell
`
`AR [cltromosonre bq)
`AR [not runiirmcd]
`\'AtI$.
`i\'-acetylglrit;zm:rte
`
`'
`
`Rl'iCFliv<'I.’
`fillroblssts
`
`All (|.‘ltI'|Jlll05tJl'l'lC Fql
`
`T Citrullltie.
`T argiiriimsticcinic acid:
`J. arginine
`T itrgiuine
`T Gliiiamine: 7 al:iriirii-
`
`

`
`ZIS
`Chapter 1?
`
`
`
`Table ‘l?.2. Differential diagnosis of hyperammonaetnia
` ammonia concentrations may increase to I80 ttmolll.
`Patients with int:-urn errors presenting in the newborn
`lnlierlted disorders:
`
`period
`usually have concentrations greater
`than
`Urrtr cycle t'nzyruc drfcrrs
`Carbsmnyl plmsphate syntltetase deficiency
`too pmolll. often very much greater.
`In that case,
`
`Urnilhine Iranscarbantoylase deficiency
`further
`investigations
`[particularly of
`the plasma
`
`.-trgininosuccinale ttyutltet-use deficiency lcitnillinaeminj
`amino acid and urine organic acid levels} are urgent.
`Argininusttccinatc lyase deficiency [argitmsuceinic aciduria]
`
`Arginnse deficiency
`The following investigations should be performed:
`
`N-acetylglttlamatr syntlaetase deficiency
`Trmtspon defects of urea cycle iiHt'rarrctl:rtt'rs
`
`a Blood pH and gases
`Lysitturic protein ilttctlcrance
`
`Iv Plasma chemistry: sodium, urea and electrolytes.
`Hyperantmoncmia—liyper(Imitltntemla-homocitrullinttria
`
`glucose and creatinirie
`syntlmnar
`
`Urgruric actihrrins
`n Liver-function tests and clotting studies
`I Plasma amino acids
`Proftltlitit ucitlaenrtiu
`
`Mclltylmalonic acidaemis anti uther organic acidaemias
`Fat
`arid (1.Ilid:ttion siisurtlm
`Urine organic acids, orutic acid and amino acids
`
`Mediutii-chain acyl-Co.-\ dehyrltogertase deficiency
`
`a Plasma free and acyl carnitines
`Systentie Cttrttitiitr deficiency
`
`Lo
`-chain fatty acid oxidation defects and other related
`[n all urea-cycle disorders.
`there is accumulation of
`
`disorders
`glutamine and alanine and,
`in citrullinaemia, ar-
`{Jrltcr irtlrortr crrurs
`
`gininosttccinic aciduria and atrginase deficiency,
`the
`Pytuvare carltoxylase deficiency (neonatal iorml
`Acquired
`changes in the amino acids are usually diagnostic
`
`Transient lxyperummonemia of the m:'t\'born
`{Table I7,t}, Orotic acicluria with raised plasma gluta-
`Etc)'e's syndrome
`minc and alanine concerttrzttiotts suggests OTC defi-
`Liver failure. any c:Iuat- (both acute and chronic]
`Valproate therapy
`ciency. The diagnosis of this and the other disorders
`lnfectian with u1e:tse-positive bacteria [particularly with
`can be couflrrrtetl by measuring enzyme activity in
`stasis in the urinary tract)
`appropriate tissue {Table t;r.1]. The enzyme diagnosis
`Leukaemia therapy, including treatment with :tsp:tr:tgin:|sr
`Severe systemic illness. particu|..trIy itt Itmuates
`of N-acetyl glutamate syttthctase deficiency is not
`straightforward,
`and the
`response to a
`load of
`Coal. cocnzyme A
`N-carbamyl glutamate. an orally active analogue of
`N-acetyl glutamate. may be helpful both diagnostically
`and for treatmeitt.
`
`
`
`tmaflfflg
`
`Patients who present with an acute encephalopathy
`commonly receive brain imaging at an early stage. This
`may show no abnortualily, a localised area of altered
`signal or. ifthe patient is very seriously ill. widespread
`cerebral oedema [:2].
`Focal areas of altered signal may be identified and
`need to be distinguished from herpes simplex enceph-
`alitis. A careful history revealing previous episodes of
`encephalopathy. albeit mild, may provide vital clues.
`imaging in patients who have recovered from a severe
`episode of Ityperarnmonaemia usually show cerebral
`atrophy that may be focal, particularly in those areas in
`which there were altered signals during the acute
`illness.
`
`Differential Diagnosis
`
`:‘\Ithot:gh babies with transient hype-
`or ketosis.
`rarnntunaemia of the newborn are often born prema-
`turely, with eariy onset of symptoms [13].
`it may be
`difficult
`to distinguislt between urea-cycle disorders
`and transient hyperamrnonaemia of the newborn. All
`patients in whom a tentative diagnosis of Reye‘s
`syndrome is Irtade should be investigated in detail
`for inherited metabolic disorders. including urea-cycle
`disorders.
`
`treatment
`
`the biochemical
`is to correct
`'l'he aim of treatment
`disorder and to ensure that all the nutritional needs are
`met. The major strategies used are to reduce protein
`intake,
`to utilise alternative pathways of nitrogen
`excretion and to replace nutrients that are deficient.
`l.au~Protein Diet
`
`the quantity of natural
`childhood. after puberty.
`protein may lie less than o.5 gfltgtday. However,
`it
`must
`lie emphasised that there is considerable varia-
`tion in the needs of individual patients.
`Essential Amino Acids
`
`In the most severe variants. it may ttot be possible to
`achieve good metabolic control and satisfactory nutri-
`tion with rcstriction of natural protein alone. Other
`patients will not
`take their full protein allowance.
`In
`hoth these groups of patients, some of the natural
`protein may be replaced with an essential amino acid
`mixture. giving up to o.7 glkglday. Using this.
`the
`requirements for essential amino acids can be met; in
`addition. waste nitrogen is re-utilised to synthesise
`non-essential amino acids, hence reducing the load of
`waste nitrogen.
`
`illtematlve Path ways for Nitrogen Excretion
`
`Disorders of the Urea Cycle
`
`2|‘)
`
`Al.«l|t~'tNlI Ann t_‘|Tl<|..‘t|.|tv-‘I-. nrginitte is normally a nones-
`sential amino acid. hccause It is synthesised within the
`urea cycle. For this reason, all patients with urea-cyclc
`disorders [except those with arginase deficiency] are
`likely to need a supplement ofarginine to replace that
`which is not synthesised [18]. The aim should he to
`maintain plasma arginine concentrations between
`
`5o t|Itl0l'l untt Zfltt umul.-'l. For 0'f('
`lltl CPS defi-
`
`
`Clt.'l1Cl
`El dose of H10-[SD I
`lt
`'r.|'.ty ttppeztts to he
`sttfltctutt for most patients‘. llowcx r. in set-‘en: vitri-
`unts ol'OTC and CPS. cttrullinc may he stlbslitttted for
`
`uI'git1inc in doses up to lift it
`day. as this will
`utilise an additional nitrogen molecule I’:
`ienls with
`citrttlliatucntitt and twgirtittosttecittic .-icitlltrtat
`ltttvc a
`ltii_tht:r :I't:t|ttirctnc11I. lJt:c:tusc ornillttlte is lost as -.| result
`oftltc ntetabnlit: block; this is t't.'DlEti.‘L‘{l by udtnittister-
`
`ing Il!'“tttlttU. Doses of up to "I00 mg g luv riuiv bc
` .ttlv'.tntage of
`neet
`tl. but
`this
`rloes
`ltEt\-'L‘
`the Li
`increasing the cttrtcentrtttiotts of citrulline untl
`.'tr-
`ginitmstlcciitzitc. rtzspectively. The oottscqueitec ‘ of this
`are Iltuugltt to be less important thtm Iltosc ottttscd by
`tltc '.teL'uuttIl:It|on u|'tttuntoni.': and glutamine.
`
`orttt-.'R .\u:Lucarto.~t. Citrrrie. has long been used to provide
`a supply of Krebs-cycle intermediates [I9]. It is known
`to reduce postprandial elevation of ammonia and may
`be helpful
`in the management of ztrgininosuccinic
`aciduria [zo].
`N-crtrltttmyl glutrtmr.-.re can be used in N-acetyl-
`glutamate synthetase deficiency to replace the missing
`compound. as it
`is active orally. The dose is
`too-
`jDO mgtkgltluy in]. Patients who respond may require
`treatment with this compound only. ztirticoiwrtlsrtttts
`may be needed for patients with urea-cycle disorders,
`but sodium valproate should mat be used. as this drug
`may precipitate fatal deeornpensatiou, particularly in
`OTC patients [22].
`
`Genera.‘ Aspects of Tlterapy
`
`All treatment must be monitored with regular quanti-
`tative estimation of plasma ammonia and amino acids,
`paying particular attention to the concentrations of
`glutamine and essential amino acids. The aim isto keep
`plasma ammonia levels belotv 80 |tTltDlfl and plasma
`glutamine levels below Soo prnolfl
`[2.3!. In practice. a
`glutarnine concentration of tooo |.tmolr"I together with
`concentrations of essential amino acids within the
`normal range (see the algorithm, Fig. 13.2} is probably
`more realistic. All diets must, ofcou1'se.he nutritionally
`complete and must meet requirements for growth and
`normal development.
`The concept of balance of diet and medicine is
`important. The protein intake of the patients varies
`considerably. and the figures that have been given
`should be regarded only as a guide. The variation
`
`
`
`In many patients. additional therapy is necessary. A
`major advance in this Iielcl has been the development
`of compounds that are conjugated to amino acids and
`rapidly excreted [L]. 15]. The effect of the administra-
`tion of these substattces is that nitrogen is excreted in
`compounds other than urea: hence.
`the load on the
`urea cycle is reduced (Fig. I;f.Il. The firs: compound
`iutrocluced was sodium henzoate. Benzortte is conju-
`gated with glycine to form ltippurate. which is rapidly
`excreted. For each mole of benaoate given.
`I moi of
`nitrogen is removed. Sodium benzoate is usually given
`in doses up to 250 mglkgtday hut. in acute emergen-
`cies.
`this can be increased to soo mg.-"l-tgfday. The
`ntajor side effects are nausea. vomiting and irritability.
`In neonates. conjugation may In:
`incomplete, with
`increased risk of taxi ity IC. Bachrnanrt, personal
`communication].
`The next drug used was phettylacctate. but this has
`now been superseded by phertyllmryrnte. because the
`former has a peculiarly unpleasant. clinging. rnousy
`odour,
`In
`the liver phenylbutyran;
`is oxidised to
`pltenylacetate. which is then conjugated with glutamine.
`The resulting phenylacetylghttamitte is rapidly excreted
`in urine; hence, 2 mo! of nitrogen are lost for each mole
`of phenylbutyrate given. Pheuylbutyrate is usually
`given as the sodium salt
`in doses of 25o tngllcglday,
`Most patients require a lnw-protein diet. The exact
`but has been given in doses ofup to 650 mgikglday [16].
`quantity will depend mainly on the age of the patient
`The differential diagnosis of hyperantrnottacmia is
`In a recent study of the side effects I17}. there was :1 high
`wide. and the most common conditions are summa-
`incidence of menstrual disturbance in females. Other
`and the severity of
`the disorder. Matty published
`rised in Table 1:.v.2.
`In the neonatal period,
`the most
`regimens suggest severe protein restriction hut.
`in
`Itml-'rl¢'I'ItS included attttrexia. but
`it was not easy to
`early infancy, patients may need 1.8-2 gtkglday or
`common differential diagnoses are organic aciduernias,
`distinguish between the effects of the disorder and
`prtrticulttrly propionic and rnethylmalonic acidaemia.
`those of the medicine. Patients are often reluctant to
`more during phases of very rapid growth. The protein
`Patients with these disorders may have had marked
`intake usually decreases to approximately 1.2—i.5 glkg-l
`take the medicine, and great ingenuity is sometimes
`hyperarnmonaemia with minimal Jnetalmlie acidosis
`day during pre-school years and 1 gjkglday in late
`needed to ensure that the patient takes it.
`
`
`
`

`
`Chapter I?
`
`Patient previously
`stabilised
`
`"°
`
`I
`Maintain
`plasma arginine!
`
`50 - 200 pmolll l :'
`
`P‘“[9"t'5 °°"dm°" 7” t-lErneI‘9ert::3' regimen
`‘P acutely unwell
`
`;
`Plasma ammonia i
`pmolll
`‘-
`
`Fig, ‘l'l'J.. Guirielittcs for the tnanagcmcnt of
`patients with urea-cycle disorders [except
`.1rgin:ts.e deficiency). This is intertdcd For
`n_z.r_- in Ftalicnls who have been stabilised
`previously and should only be regarded .15 :t
`guide, as some pu'|iet‘II$ may have t'nd:'v'tdun|
`requirements. For more dctm '.I1Ir.l infur-
`mmon about dost.-5. please refer to llti: text.
`F-.‘A.Hl.t, essential entitto tttiids
`
`PIa3_ma glutamlrte
`“morn
`
`Plasma glulamlfl
`|l|'|'|Dlll
`l 3 1DDO
`
`plasma
`I E“;
`'
`
`p1a_s'nta
`Ems
`N
`
`'
`
`Emeclioines
`4~medicines
`and
`«rprotein or
`EAA5
`
`otarxnn
`‘
`contntons
`etnrncnlo
`
`cotlecleu :mi
`
`'-1* protein or
` EAAs
`
`reflects not only the rcsiduai enzyme activity but 3'50
`many other factors. including appetite and gr‘-Iwlll ""9-
`Some patients have an aversion to proleln, 50 it C-‘TI be
`difficuit to get
`them to take even their recommended
`intake. Consequently.
`they are likely tD Mr-“Ll Smflllfit
`doses of sodium benzoate and phcnylbutymte. 01]“-"-‘l
`prefer
`to take more proleln. and |l1i5 I135 10 be
`balanced by an increasc in the dosages Ol lJEJ‘Z°3l9
`and phcnylliutyrate. Some will not
`take atlcfllme
`quantities of sodium l3e1t2O-‘Ite 0!’ 50di"m PhE"‘t'lb“i‘:"
`rate and, therefore,
`their protein ttllfiltlifi
`"ECE55"'Till"
`have to he stricter than would be needed if 111$!’ l°°k
`the medicines. Hence. for each paliet-L a balance must
`he Found between their protein intake and the ‘i059 0r
`[hair medicines to achieve good metrtbolic control.
`Assessment for Treatment
`
`int";-t:rion, anaesthesia or surgery. For this Nfi50“- all
`patients should have detailed instructions Df Wltfil 10
`do when they are at risk. We routinely use 1! three-
`srage procedure [24].
`if the patient is off-colour. the _
`pfutgin ‘rs reduced, and more carbohydrate is given-
`|f symptoms continue. protein should be Stopped and
`3 ]1igh.gnergy lmattc given with their medication by
`day and night, However, if they cannot
`tolerate Oral
`drinks and medicines. are vomiting or are bECOTI'|l|13
`progressively cnccpltalopathic.
`they sltould 550 lo :1
`hospital for assessment and intravenous therapy‘ ‘mil’
`out delay. For further practical details. See Dixon and
`Leonard |;,4], Patients
`should also have
`8
`l'Ilgl'|
`cm-brrhydrare intake before any anaesthesia or surgery.
`For patients who are 5ttrl(HI$l}"
`ill Wl'tl1
`l'I}'P¢‘-
`1-an-imnniiarniu,
`treatment
`is urgent. The Steps ‘-1112
`]'.sr.g.] below, and early treatment is essential {Chap 3}-
`
`rlfili _Dl
`All patients with urea cycle disorders are 11!
`acute decontpensatiorl with acute l'|y'Pt'f3mm°T“l9m1“-
`This can be precipitated by dlllererll kinds 03‘ WJEW‘
`bot}; 5|rc3sI such as
`fasting, a large protein load.
`
`Emeryerrcy Treatment
`
`The volumes which are given are related to age fiflll lhfi
`condition of
`the patient. Fluid volume.-= Sl'tOLI.lCl ht?
`
`Ltisordcrs nfthc Ljmi Cycli-
`
`restrictcd il
`oedema.
`
`llterc is any concern about cerebral
`
`Genetics and Prenatal Diagnosis
`
`0 Stop protein intake.
`9 Give it high energy intake.
`1. Orally: tn] 10-20% soluble glucose polymer or (b)
`prutciit-t'rttc formula or
`lntrrtvenously:
`{:1} 10% glttcusu: by peripheral
`infusion or {b} m—1-5% glucose by central venous
`line-
`
`2.
`
`and
`
`Give sodium benzoate up to soo mglkgrclay oratlly
`or iorravr.-nously.
`Give sodium plteoylbutyrate up to {too ntgrkgrday.
`Give L-arginlne:
`- Up
`to you mgrkgiday in citrullinaetrtia
`arglnosucclnic acidurits.
`Up to 150 ntglkgjday in OTC and CPS deficiencies.
`For
`the
`emergency
`treatment
`of
`hype-
`rammortaentia before diagnosis is known.
`this
`may be rcplacccl by L-argirtine 3oo1nykgJ:4 l1
`and L-carnitine zoo mgrkgjzmlt. Both can be
`given orally or intravenously.
`Dialysis. lf hyperamtnonctetnia is not controlled or
`the medicines are not
`intrnedintely avztitctnie.
`l'iE|-
`entnfiltrrtlion (or lracnt