J. Fernandes- J.-M.Saudubray
`G.van den Berghe
`Editors
`
`Inborn
`Metabolic
`ss
`
`Page 1 of 8
`
`Diagnosis
`and
`Treatment
`
`Third Edition
`
`Par Pharmaceutical, Inc. Ex. 1015
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`
`

`

`Tokyo
`
`Springer
`Berlin
`Heidelberg
`NewYork
`Barcelona
`Hongkong
`London
`Milan
`Paris
`Singapore
`
`
`
`
`
`ancierereeeeennresienteruserEscrtar.—emannieaveerns.“AISTINIST
`
`
`
`
`
`J. Fernandes J.-M. Saudubray G. Van den Berghe (Eds.)
`
`Inborn Metabolic Diseases
`
`Diagnosis and Treatment
`
`3™, Revised Edition
`
`With 66 Figures and 57 Tables
`
` Springer
`
`Par Pharmaceutical, Inc. Ex. 1015
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`Page 2 of 8
`
`

`

`Professor Emeritus of Pediatrics
`Veldweg 87
`8051 NP Hattem, The Netherlands
`
`Professor JEAN-MARIE SAUDUBRAY
`Hospital Necker-Enfants Malades
`149 Rue de Sevres
`75743 Paris Cedex 15, France
`
`Professor GEORGES VAN DEN BERGHE
`Christian de Duve
`Institute of Cellular Pathology
`Université Catholique de Louvain
`Avenue Hippocrate 75
`1200 Brussels, Belgium
`
`Cover Illustration: Putti by della Robbia at Spedale degli Innocenti, Firenze, Italy
`
`
`
`
`ISBN 3-540-65626-X Springer-Verlag Berlin Heidelberg New York
`pring
`s
`8
`ISBN 3-540-58546-X, 2°4 edition, Springer-Verlag Berlin Heidelberg New York
`
` Dr. JOHN FERNANDES
`
`Library of Congress Cataloging in Publication Data appliedfor.
`Die Deutsche Bibliothek-CIP-Einheitsaufnahme
`Inborn metabolic diseases: diagnosis and treatment/). Fernandes... - 3., rey. ed. - Berlin; Heidelberg; New York; Barcelona; Hong Kong;
`London; Milano; Paris; Singapore; Springer, 2000.
`ISBN 3-540-65626-X
`
`This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of
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`prosecution under the German Copyright Law.
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`Par Pharmaceutical, Inc. Ex. 1015
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`Page 3 of 8
`
`

`

`a4
`
`
`
`|
`
`
`
`’
`o
`N-acetyt
`glutemate
`
`NH,
`
`+
`
`he
`
`©
`
`:
`Carbamoy!
`phosphate
`J+
`7 a
`e
`
`aioehandivan
`\
`~
`Ornithine
`
`foo
`
`
`
`Ginical Presentation
`S
`at
`pre
`Patients with
`area-cycle disorders may
`'
`'5
`"
`there are certain
`almost any age. However,
`
`
`.
`
`us
`tc
`lop symptom:
`which they
`are more
`likely
`
`such
`nfection precig
`secause of metabolic stress,
`
`‘ae
`are
`Mating protein catabolis
`hese
`‘
`1
`neonatal
`e@
`The
`7
`during
`st
`«© ©During late infancy. Children are wulnore
`
`
`us
`ee
`af pera
`.
`.
`'
`this period because of
`the
`slowing of growth,
`the
`;
`change 10
`cow's milk
`and weaning foods
`and the
`
`native Pathways for Nitrogen Excretion
`aw
`declining maternal antibody and consequent devel
`ersPy
`ed
`opment of intercurrent
`infections
`Puberty.
`The changing growth
`and psychoso.
`cial
`factors mayprecipitate decompensation
`
`ent
`4
`T
`However,
`many patien
`it must be emphasised that
`may
`pres
`patterns of
`outside these periods.
`The
`r
`i
`p
`he
`
`clinical
`presentation of hyperammonaemia are
`he
`
`rather characteristic
`and are broadly similar
`all
`
`
`orders cxcept arginase deficiency, which
`he
`is
`Wi
`7
`are
`ofte:
`discussed separately.
`y
`sympto:
`The
`
`therefore,
`the
`non-spe
`and
`initially,
`dia
`is
`s
`inherited disorders of
`the urea cycle are
`Five
`iy y
`now
`i ;
`ae
`Cen
`st
`important po
`easily
`overlooked
`f
`
`
`well described, These are characterised by hyper
`”
`:
`Scoked.
`Th Pears
`~
`id metabo:
`vias eee
`pants: 4
`ammonaemia and
`portant:
`disorilere
`pokes
`
`
`
`hcg,
`|
`diagnosing byperammonsernis
`) thinkof it during
`Kaen.
`“Thy greskannton
`ta Wd
`
`|
`diagnosis and
`plasma ammonia con
`:
`to measure
`the
`:
`catratior
`‘
`
`the nenborn period usually have an
`ating im
`
`overwhelmingillness that
`rapidly progresses from|
`Y
`prog
`poor feeding, vomiting,
`irritability and
`letharg
`
`
`.
`tachypnoes to
`fits,
`coma
`and
`respiratory arrest.
`In
`Neonatal Presentation
`.
`;
`infancy,
`the
`less severe
`symptoms
`are
`and more
`:
`variable. Poor developmental progress, behavioural! ,,
`i
`wine
`oie
`Mast babies with urea
`cycle disorders
`are of normal
`sothena Saiectanee
`vttatatestinal symp.
`
`
`cytosol
`paren
`alesdarl beara Lani
`Sec aabannaauSee
`toms
`are
`asually obser
`EOEEATscities
`es
`c
`characterised
`by
`
`chronic
`neur
` rritat
`;
`Common early symptomsare poor
`feeding, vomiting,
`
`‘confer:
`y
`and
`
`
`| interval that canbeless than 24 h,a gcc A+) they become unwell |
`
`
`
`
`
`,
`ov
`sfiaseal prot
`Argmnino. 6
`cyclic vomiting,
`
`Ye Urea
`mn,
`trritabili
`|
`lethargy and/or irritability and tachypnoea.
`The initial
`hich deteriorates to acute encepha
`
`aa
`diagnosis
`is almost
`invariably
`’
`working
`sis.
`Rathe
`
`
`
`
`lopathy duringr
`olic stress.
`A
`se deficiency
`ork
`6
`is
`almost
`tavariabl
`Rather
`vrr
`speci
`shows
`more
`mptoms,
`such as
`spastic
`F
`
`{at
`oon
`cares
`tic|
`Characteristically,
`these babies may have
`a
`transient
`enunads
`be
`mild respiratory alkalosis, which can
`:
`Urine
`re
`:
`!
`a useful
`oretitine
`dystonia,
`ataxia and fi
`All
`.
`diple
`urea-cycle
`:
`
`4
`4
`diagnostic clue at
`this stage. Usually,
`they deteriorate
`
`
`
`.
`‘
`cco
`ders have antosomal-recessive iniveritance ex
`tt
`I
`‘4
`mcrete
`eyren &
`1
`\
`.
`dis.
`|
`with
`more obvious neurological
`and
`autonomic
`rapidly,
`agininonecinate
`byase:
`5.
`avcarbarn:
`mie:
`‘
`
`
`
`;
`8
`cept ornithine carbamoyl!
`transferase deficien
`.
`barn
`| which is X-linked.
`ms,
`including changes of
`tone with loss of
`1
`pr
`1
`wlefects
`normal reflexes, vasomotor
`and hypother-
`instal
`
`
`The Urea Cycle
`
`
`is the main pathway for the
`is only present in the liver,
`The urea cycle which, im its complete form,
`disposal of excess of ammonium nitrogen. This cyde sequence of reactions, localised im part in the
`mitochondria and in part
`in the cytosol, converts the toxic ammonia molecule into the non-toxic
`product, urea, which is excreted in the urine, There are genetic defects of each of the enzymes of the
`:
`ms
`:
`°
`
`
`urea cycle which lead to hyperammonacmia, Some genetic defects of other important metabolic
`
`pathways may lead to secondary inhibition of the urea cycle. Alternative pathways for nitrogen
`excretion, namcly conjugation of glycine with benzoate and of glutamine with phenylacetate can be
`exploited in the treatment of paticnts with defective arcagenesis,
`
`|
`
`Pronylacety!
`Guam
`sd Seniiaien’
`
`—
`—-—® Giutemine
`Breroste © Bereoyst CoA
`\
`> Glycine
`———® Hippurate
`
`Poverryltratyrate
`~
`‘.
`HEPATIC NITROGEN pane
`POOL
`Phenytocorate
`os
`Clutamine
`Alanine
`‘apenas
`Gtycine
`
`Giutamate
`Acetyl Cod
`
`CHAPTER 1
`
`
`
`Disorders of the Urea Cycle
`
`\
`
`215
`
`|
`
`:
`
`|
`
`
`
`|
`
`—
`
`
`
`
`
`
`
`Reference
`
`Diagn
`
`
`
`
`
`
`
`©
`
`1
`sx,
`
`
`
`|
`
`|
`
`|
`
`}
`
`|
`|
`
`}
`
`
`
`alterna
`j.
`BF
`depicted
`
`are
`
`Pp
`3
`
`sa
`
`by
`
`|
`
`bet
`
`
`
`synthetase
`osphaie
`6
`N-scecyigh
`te
`
`an
`
`Par Pharmaceutical, Inc. Ex. 1015
`Parv. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 4 of 8
`
`

`

`
`
`
`
`
`
`
`
`
`
`rpi
`
`'
`
`1
`ally
`
`er
`
`arning
`retardation
`are
`larly the
`th
`arly
`
`ental
`part
`F
`
`difficult
`common,
`pin
`
`‘
`
`a
`in
`
`
` he cin intake
`atadoliser
`nfection,
`fev
`
`
`
`
`
`
`
`
`
`
`Diagnostic Tests
`Biochemical Tests
` Routine
`tests
`of
`
`an
`aa
`ms
`saly.
`
`itot
`
`‘
`
`‘
`
`this
`
`ati
`
`i.
`
`4
`
`.
`
`
`
`7
`
`r
`
`i
`
`.
`
`a
`
`e
`:
`
`A:
`Htake,
`pe.
`
`
` fia
`
`er
`
`
`ic
`a more
`cansciot
`
`ge
`
`phage
`all g
`lagn
`Jevelops
`in
`
`Ic
`4
`
`Children and Adults
`
`0
`
`mally,
`
`petients
`
`ma
`
`r
`
`d
`j
`or
`
`a
`
`a
`
`r
`
`a:
`
`‘
`
`at
`ti
`ot
`any
`particu
`
`‘
`ne
`?
`as
`ntermediar
`ycle
`
`
`
`teps
`
`:
`Toxicity
`
`.
`‘
`«
`I
`G
`disord
`.
`than
`creater
`However
`nigher.
`ormal when patients
`
`in
`
`‘
`
`ar
`
`ll,
`
`are
`
`ea
`
`Par Pharmaceutical, Inc. Ex. 1015
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`Page 5 of 8
`
`

`

`Chapter 17
`ammonia concentrations may increase to 180 pmol/
`Patients with inborn errors presenting in the newborn
`usually
`have
` ix
`pe
`oncentrations
`greater
`than
`
`200 pmol/l, often ver
`much
`greater,
`In
`that case,
`further
`of
`investigations
`(particularly
`the plasma
`aminoacid and urine organic acid levels) are urgent
`The following investigations should be performed
`© Blood pH and gases
`and electrolytes,
`© Plasma chemistry: sodium, urea
`glucose andcreatinine
`Liver-function tests and clotting studies
`Plasma amino acids
`
`
`Urine organic
`acids, orotic acid and
`amino acids
`Plasmafree and acy! carnitines
`
`ion of
`ccumulat
`n
`
`rea-cycle disorders,
`there is
`
`
`
`
`glutamine ar
`in citrullinacmia, ar
`alanine
`and,
`gininosuccinic aciduria and arginase deficiency,
`the
`changes
`in the amino acids are usually diagnostic
`Table
`17.1). Orotic aciduria with raised plasma gluta
`mine and alanine concentrations suggests OTC defi
`ciency.
`The diagnosis of this and the other disorders
`can be confirmed by measuring enzymeactivity in
`appropriate tissue (Table 17.9), The e z diagnosis
`ecety! glutamate synthetase defic
`is
`not
`
`
`straightforward,
`and the
`response
`to
`a
`load
`of
`
`
`N-carbamy! glatemate, an orally active analogue of
`
`
`roth diagnostically
`N-acetyl glutamaic, may behelpf
`andfor treatment
`
` 2i8
`
`imaging
` tients who present with an acute encephalopathy
`
`commonly receive brain imaging at an early stage. This
`tered
`may show no abnormality, a localised area of
`ead
`signal
`or,
`if the patient
`is very seriouslyill, widesp
`cerebral oedema
`[12]
`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.
`Imagingin patients who have recovered from a severe
`episode of hyperammonacmia usually show cerebral
`atrophy that may befocal, particularly in those areas in
`which there were
`altered signals during the acute
`illness,
`
`Differential Diagnosis
`
`of hyperammonaemia is
`The differential
`diagnosis
`
`wide, and the most common conditions arc summa
`
`rised in Table
`2.
`In the neonatal period,
`the most
`
`commondifferential diagnoses are organic acidaemias
`
`ionic and methylmalonic acidacmia.
`particularly
`
`have had marked
`Patients with these disorders may
`hyperammonaemia with minimal metabolic acidosis
`
`Table 17.2. Dificrential diagnosis of hyperammonaemia
`Inherited disordersyee
`
`defects
`Urea
`cys
`arbarnoy! phosphae ayntherase deficiency
`ine tranvcarbarneyluse deficieacy
`fictency (clawlls
`
`(arginceuccinic acicturia)
` weccinae lyase deficiency
`Arginase
`deficiency
`
` fice
`N-acetylglutamate synthetase ¢
`wt defects of urea cycle
`termediates
` wtic p
`
`Hyperammenenis hyperorathinesss-homocitrullinyria
`syndrome
`rgenkc
`acidur
`Propionic acidaemia
`jethylmabonic ocidaernia and other organic acidecsnia
`
`
`sorders
` ty acid ondation ¢
`
`Mediur
`chain acyl-Cad dehydrogenase deSciency
`ine deficiency
`y acid oxidation defects and other relaced
` Pyruvate
`carbonylase deficiency
`(acematal form
`Acquired
`Transient hyperaminanemes of the newborn
`Reye's syndrome
`wer (lure,
`any
`Case (both acute and chronic)
`Valproate
`therapy
`Infection with urease-positive bucteria (particularly with
`stasis inthe urinary tract
` paraginace
`Leukaemia therapy,
`sicludeng treatment with
`
`
`Severe cyt
`liners, particularly i neonates
`oA,
`cosmnpine
`A
`
`or ketosis. Although babies with transient hype
`ammonacmia of the newborn are often born prema
`.
`it may be
`
`turely, with carly onset of symptoms {1
`
`ween urea-cycle disorders
`difficult
`to distinguish |
`
`of the newborn. All
`and transient hyperarnmonaemi:
`
`patients
`in whom a
`tentative diagnosis of Reye's
`
`syndrome is made
`should be
`investigaied in detail
`
`for
`inherited metabolic disorders,
`including urea-cyel
`disorders.
`Treatment
`The aim of
`the biochemical
`10 correct
`is
`treatment
`disorder
`ary
`
`to ensure thatal) the nutritional needs are
`met. The major strategies used are to reduce protein
`
`intake,
`to utilise alternative
`pathways
`of nitrogen
`excretion andto replace nutrients that are deficient.
`Low-Protein Diet
`
`low-protein diet. The exact
`Most patients require a
`quantity will depend mainly onthe age of thepatient
`
`and the
`severity of
`the disorder.
`Many published
`
`
`regimens
`suggest
`severe
`protein restriction but,
`in
`early
`infancy,
`patients may need
`1,8-2 g/ke/day or
`
`more during phases of very rapid growth. The prote
`
`intake usually decreases to approximately
`2-15 why
`late
`
`
`day during pre-school years and 1 g/kg/day
`
`childhood, After puber' the quantity of natural
`’
`protein may
`be
`less than 0.5 g/kp/day. However,
`i
`must be ¢:
`siderable varia
`
` phasised that
`there is
`tion in the
`needs of
`
`
` ndividual patients
`
`Essential Amino Acids
` may not be possiblete
`it
`In the most severe variants,
` story nutri
`xt metabolic control and sati
`
`tion with restriction of natural protein alone. Other
`
`patients will not
`¢ their
`full protein allowance.
`In
`both these groups of patients, some of
`the natural
`protcin may be replaced with an essential amino acid
`mixture, giving up t 0.7 g/kg/day. Using this,
`the
`requirements for essential amino acids can be met; in
`addition, waste nitrogen is
`re-utiliced to synthesise
`
`
`non-essential amino acids, heace redw
`& the load of
`waste nitrogen
`
`Alternative Pathways for Nitrogen Excretion
`n many patients, additional
`therapy is necessary. A
`major
`advance in this field has been the development
`
`of compoundsthat are conjugated 10 amino acids and
`rapidly excreted [14,
`35). The effect of the adminisira
`
`ion of these substances is that nitrogen is excreted in
`urea; hence, the load on the
`compounds other
`th.
`
`
`urea cycle
`ound
`
`s reduced (Fig. 17.4).
`The first comp
` ate is < pj
`ntiroduced was sodium bemaoate. Be
`
`gated with glycine to form hipp
`
`purate, whichis rapid
`For each mole of be:
`
`excreted.
`1 mol of
`te given,
`nitrogen is removed. Sodiam benzoate is usually given
`”
`
`in acute emer
`in doses up
`to 250 mg/kg/day but,
`The
`cies,
`this can be
`increased to s00 mg/kp/day
`major side effects are nausea, vorniting andirritability
`
`In neonates, conjugation may
`be
`incom plete, with
`Increased
`risk
`of
`toxicity [C.
`Bachmann, persona’
`communication]
`Theneat drug used was phenylacetate, but thie has
`nowbeen superseded by phenylbutyrate, because the
`former
`has a peculiarly unpleasant, clinging, mousy
`dour.
`In the
`liver phenylbutyrate
`is oxidised to
`phenylacetate, which is then conjugated with glutamine
`The resulting phenylacetylglutamineis rapidlyexcretec
`
`Nurine; hence, 2 mol of nitrogen are lost for each mole
`
`of phenylbutyrate given. Phenylbutyrate is usually
`given as the sodium salt
`in doses of
`aco mg/kp/day,
`but has been givenin doses of up to 650 mg/kg/day [16]
`fa recent study of the side effects {;
` }, there was a high
`incidence of menstrual dicturbar,
`
`in femules, Other
`
`problems
`incladed anorexia, but
`it was not
`easy to
`distinguish between the effects of
`the disorder
`and
`
`nt
`to
`those of the medicine. Patients are often relucta
`
` dicine, and great
`take the m
`ingenuity is sometimes
`
`needed to ensure that the patient
`takesit
`
`219
`of the Urea Cycle
`Disorders
`CrTAULUNE Asginine is normally a noncs-
`ANCHE AND
`
`amino acid, because it is synthesised within the
`sential
`
`urea cycle. For this reason,
`all patients with urea-cycle
`disorders (except
`those with arginase deficiency)
`are
`
`likely to need a sup:
`ment of arginine to replace that
` synthesised (18).
`which is o
`The air should be to
`
` rations
`maintain plasma
`arginine
`conce
`t
`so pum
`i and 200 yrmol/l. For OTC
`and CPS
`
`
`cs, a
` of
`erence:
`to be
`100-150 mg/ky/day appe
`sufficient
`for most pationts. However,
`im severe vari
`ants of OTC am
`
`CPS. citrulline may be substituted for
`
` ay.
`urgin
`as
`this wil
`in doses up to
`170 mg
`
`wiilise an additional nitrogen molecule. Patients with
`citrullingemia and argminosuceinic aciduria have a
`
`
`higher requirement, because ornithine is
`lost axa result
`of the metabolic block:
`this
`is replaced by administer
`
`ing afginine. Doses of up to 700
`ing/keAday may be
`needed.
`but
`this dees
`have
`the
`disidvintage of
`increasing the concentrations
`of citrulline
`and
`
`Pininosuccinate, respectively, The consequences
`of this
`are thought to
`be less important then those
`caused by
`the secumulation of ammonia aad glutamine
`
`HEE MED Avion. Citrate has long been used to provide
`4 supply of Krebs-cycle intermediates[19]. It is known
`io and may
`
`to reduce postprandial elevation of ammo’
`gininosuccinic
`in the management of
`be helpful
`aciduria [20]
`j-acetyl
`Necarbainyl glutamate can
`be used in
`
`giutamate synthetase deficiencyto replace the missing
`The dose is 100-
`compound,
`as it
`is active orally.
`
`300 mg/kg/day [23]. Pati
`s who respond may require
`this cot pound only, Anticonvulsants
`treatment with
`
`may be needed for patients with urea-cycle disorders,
`but sodium valproate should not be
`used, as this drug
`
`may precipitate fatal decompensation, particularly in
`OTC patients {22}
`
`General Aspects of Therepy
`All treatment must be monitored with regular quanti
`tative estimation of plasma ammonia and amino acids,
`paying particular attention to
`the concentrations of
`glutamine andessential amino acids. The aim is to keep
`plasma ammonia levels below $0 pmol/l and plesma
`
`
`glutamine levels below S00 mol/l
`[23].
`In
`practice, a
`
`ghitamine concentration of
`1000 janoU/l together with
`
`concentrations
`of ease
`amino acids within the
`normal range (see the algorithm, Fig.
`17.2)
`is probably
`
`morerealistic. All diets must, of course,
`be nutritionally
`
`complete and must meet requirements
`for growth and
`normal development
`
`
`
`edici
`he concept of balance of diet and m
`ce
`i
`consi
`portant. The protein intake
`the patients varies
`of
` erably,
`and the figures
`that have been given
`
`should be
`regarded only
`as
`a guide. The variation
`
`
`
`Par Pharmaceutical, Inc. Ex. 1015
`Parv. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page6 of 8
`
`

`

`Chapter 17
`
`Patient previously).
`stabilised
`
`Y
`no_|Patient’s condition) yes| Emergency regimen
`? acutely unwoll
`’
`|
`
`Y
`int
`Maintain a
`plasma arginine
`50 - 200 uymoll
`= —"
`
`!
`—.
`| Plasma ammonia
`pmol
`—“
`
`< 60
`
` 2x
`
`the management of
`17.2. Guidelines for
`fig.
`patients with urea-cycle disorders (except
`arginave deficiency
`previously aadst
`puide, a8 some pater
`For more detail a
`requirements,
`FAAS. 3
`
`
`use in patients who
`
`>120
`; _
`t]
`
`> 80
`
`'
`Plasma glutamine
`pmol
`> 1000
`
`< 1000
`
`'
`Plasma glutamine
`uma
`> 1000
`
`< 1000
`y
`| plasma
`EAA
`N
`low
`
`YW
`| plasma
`EAAs
`N
`
`!
`plasma
`
`N
`
`'
`
`[no
`| change
`
`|
`
`|
`
`j
`
`ton
`
`rm
`
`eat
`la
`.
`jow| | #medicines *
`i SCAG ,
`| tmedicines |
`and
`<
`>| tproteinor |
`EMs
`_|
`
`|
`
`>} fPorctein of
`AAS
`
`=a
`plasma
`EAAS
`
`N
`
`low
`
`|
`
`
`
`
`reflects not only the residual enzyme activity but also
`many other factors, including appetite and growthrate.
`Somepatients have an aversionto protein, #0 it can be
`difficult
`to get them to take even their recommended
`intake. Consequently,
`they are likely to need smaller
`doses of sodium benzoate and phenylbutyrate. Others
`prefer
`to take more protein, and this has
`to be
`balanced by an increase in the dosages of benzoate
`and phenylbutyrate.
`Some will not
`take adequate
`quantities of sodiumbenzoate or sodium phenylbuty
`
`intakes necessarily
`rate and, therefore,
`their prot
`haveto be stricter than would be neededif they took
`the medicines. Hence, for each patient, a balance must
`be found betweentheir protein intake andthe dose of
`their medicines to achieve good metabolic control
`Assessment for Treatment
`
`risk of
`All patients with urea cycle disorders are at
`acute decompensation with acute hyperammonaemia
`This can be precipitated bydifferent kinds of meta-
`bolic stress,
`such as
`fasting,
`a
`large protein load,
`
`this reason, all
`infection, anaesthesia or surgery. For
`patients should have detailed instructions of what
`to
`do when they are at risk. We routinely use a three:
`stage procedure |24}.
`If
`the patient
`is off-colour,
`the
`protein is reduced, and more carbohydrate is given.
`If symptoms continue, protein should be stopped and
`
`a high
`intake given with their medication by
`day and night. However,
`if
`they cannot
`tolerate oral
`drinks and medicines, are vomiting or ate becoming
`they should go to a
`progressively encephalopathic,
`for assessment and intravenous therapy with-
`hospital
`out delay. For further practical details, sce Dixon and
`Leonard [24].
`Patients
`should also
`have
`a high
`carbohydrate intake before any anaesthesia or surgery.
`For patients who are seriously ill with hype-
`rammonaemis,
`treatment
`is urgent. The
`steps are
`listed below, andearly treatment is essential (Chap.
`3).
`
`Emergency Treatment
`
`
`are related to age and the
`The volumes whichare given
`condition of
`the patient. Fluid volumes
`should be
`
`restricted if
`oedema.
`
`there is
`
`any concern about cerebral
`
`Genetics and Prenatal Diagnosis
`
`
`
`Disorders of the Urea Cycle
`
`
`
`
`in
`
`citrullinaemia
`
`e Stop proteinintake.
`e Give a high energy intake.
`1. Orally: (a) 10-20%soluble glucose polymer or (b)
`protein-free formula or
`2.
`Intravenously:
`4) 10% glucose by peripheral
`infusion or (b) 10-25%glucose by central venous
`line
`e Give sodium benzoate up to $00 mg/kg/dayorally
`or intravenow
`
`Give sodium phenylbutyrate up to 600 mg/kg/day.
`Give t-arginine
`Up
`to
`700 mg/kg/day
`arginosuccinic aciduria
`- Upto iso mg/kg/dayin OTC and CPS deficiencies
`- For
`the
`emergency
`treatment
`of
`hype
`rammonaemia before diagnosis is known,
`this
`may be replaced by .-arginine 300 mg/kg/24 h
`and t-carnitine 200 mg/kg/24h. Both can be
`given orally or intravenously.
`
`e Dialysis.
`If hyperammonaemia is not controlled or
`the medicines are not
`immediately available, ha
` tation)
`emofiltration (or haemodialysis/hacmodiafi
`should be
`started without delay. Alternatively,
`peritoncal dialysis can be used, but
`this is a less
`effective method for reducing hyperammonacmia
`© Treat other conditions (sepsis, fits, etc.)
`© Monitor intracranial pressure with the usual mea
`sures
`to reduce
`raised pressure
`and maintain
`perfusion pressure
`
`and
`
`Prognosis
`
`The prognosis in these disorders is closely related to
`the age of the patient andtheir conditionat the time of
`diagnosis. For those patients who present with symp
`tomatic hyperammonaemiain the newborn period, the
`outlook is very poor. Even with the most aggressive
`treatment,
`the majority
`of
`the
`survivors will be
`
`indicapped. Those whoare treated prospectively do
`better, but there maystill be significant complications
`[25]. For these patients, there remains a serious risk of
`decompensation, and careful consideration should be
`
`given to early liver
`transplantation, which may offer
`the hope of a better long-term outlook [26]. Of those
`whopresent later, their neurological problems at
`the
`timeof diagaosis are critical, as most will have already
`suffered neurological damage.
`At
`best,
`this may
` h some
`apparently resolve, but almost
`all are left w
`degreeof learning and neurological problems. Patients
`whohave widespread cerebral oedema almost all dieor
`
`rive with severe handicaps. By contrast,
`those who
`are treated prospectively have a better outcome
`
`
`
`The genes for urea-cycle enzymes {except N-acety
`glutamate synthetase) have been mapped, isolated and
`fully characterised
`[27). Many mutations ha
`described.
`The most common ures cycle disorder
`ix
`OTC deficiency, which is an X-linked disorder in which
`molecular genetic studics are particularly helpful. When
`the diagnosis of OTC deficiency ir
`«stablished,
`it
`is
`necessary to take a careful family nistory and for
`the
`mother’s carrier status to be assessed. Currently,if the
`mutationis not known, the most convenient investiga
`
`tion is
`the allopurinol
`test, which is used
`to detect
`increased de novosynthesis of pyrimidines (see “Met
`abolic Derangement”
`d sensi-
`
`
`
`It appears to have go
`tivity and specificity [28, 29]. This is easier than the
`
`protein- or alanine-loading tests and carries no risk of
`hyperammonsemia. Prenatal diagnosis using a gene
`probe for mutationdetectionor toidentify informative
`
`families. However, whilst
`polymorphisms can help most
`the phenotype of the males can bepredicted, that of the
`females cannot because of the randominactivation of
`the X chromosome. This presents a problem when
`counselling families, but the prognosis for females who
`are treated prospectively from birth is good
`
`All
`the other conditions }
`ave autosomal-recessive
` nosis is possible for all
`inheritance, and prenatal d
`disorders except N-acetyl glutamate synthetase defi
`ciency.
`For CPS deficiency, prenatal diagnosis using
`closely linked gene markers
`is now possible for
`a
`substantial proportion of
`families.
`If
`the molecular
`genetic studies are uninformative, prenatal liver biopsy
`is
`a
`possible
`alternative, Citrellinaemia and ar
`gininosuccinic aciduria can both be diagnosed on
`chorionic villus biopsy. Arginase deficiency can be
`diagnosed cither with molecular-genetic studies or,
`if
`theyare not informative, with a foetal blood sample
`
`References
`PH, Heuser ER,
`(sy90)
`tal
` f
`mmonemia
`in women with a
`at
`the orn
`tation
`
`
`
`carbamwyltransferace |
`A
`cause of pentpartam co
`
`
`Engl
`| Med
`e JT (ig
`
`
`
`
`ye ornt
` Powler GW (i979)
`nscarbamylase deficiency, Aan Neurol é:85~156
`
`1S, Van't Hoff W, LeonardJV (1994) Arginase deficiency
`
`convulsions.
`|
`Inherit Metab Dis 17-954
`Leech
`AR
`(1985) Biochemistry
`for
`the
`
`\
`494
`mptomatic hype
`ants.
`Pediatr Res
`
`plopha:
`Sci
`ay
`
`(s9Sy)
`1?
`in hyperammor
`
`
`
`
`‘
`.
`
`
`
`
`
`Par Pharmaceutical, Inc. Ex. 1015
`Parv. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 7 of 8
`
`

`

`CHAPTER 18
`
`
`
`Par Pharmaceutical, Inc. Ex. 1015
`Parv. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 8 of 8
`
`