MARINUS DURAN
`
`MILAN E. BLASKOVICS
`
`I}
`
`
`
`giggofiAEL Gmsouto e ‘
`Laboratory
`r,
`Diagnosm .
`of Metabohc u
`Dlseases SecondEdition
`
`
`-
`
`
`
`Par Pharmaceutical, Inc. Ex. 1006
`ar v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 1 of 20
`
`

`

`Physician’s Guide
`to the Laboratory Diagnosis
`of Metabolic Diseases
`
`with cn-nom _
`
`BLAU
`
`DURAN
`BLASKOVtcs
`GIBSON
`
`{EfiJ
`
`
`
`day and mistakes in the diagnosis'of inherited
`metabolic diseases mayr have devastating con-
`sequences. Reference laboratory data are scat—
`tered and clinical descriptions of rare conditions are hard
`to locate. This book describes 298 disorders, grouped into
`35 chapters according to the type of condition. Within
`each group of disorders, chapters provide tables of perti-
`nent clinical findings as well as reference and pathologi-
`cal values for crucial metabolites. Relevant metabolic path-
`ways and diagnostic flow charts are included. There are
`I three indices'to make the book as user—friendly as possi-
`ble: Disorders index, Signs and wmptoms index, and Tests
`index. The Physician’s Guide provides paediatricians and
`other physicians with a uniqne aid- to help them select the
`correct diagnosis from a bewildering array of complex
`-
`Clinical and laboratory data." 7
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`Par Pharmaceutical, Inc. Ex. 1006
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 2 of 20
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`

`

`
`
`N. Blau · M. Duran
`M. E. Blaskovics · K. M. Gibson
`N. Blau - M. Duran
`(Eds.)
`NLE. Blaskovics c K.M. Gibson
`
`,
`
`(Eds.)
`
`Physician's Guide
`Physician’s Guide
`to the Laboratory Diagnosis
`to the Laboratory Diagnosis
`of Metabolic Diseases
`of Metabolic Diseases
`
`Second Edition
`Second Edition
`
`Foreword by C. R. Scriver
`Foreword by CR. Scriver
`
`With 100 Figures and 270 Tables
`With 100 Figures and 270 Tables
`
`
`
`Springer
`
`'
`
`Springer
`
`
`
` iii
`
`Par Pharmaceutical, Inc. Ex. 1006
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 3 of 20
`
`

`

`>I o vY\ e.vL caJ
`~!) Nenad Blau
`Marinus Duran
`
`~ 1 Division of Clinical Chemistry
`Academic Medical Center
`Marinus Duran
`Dept. of Pediatrics
`Nenad Blau
`and Biochemistry
`)~l ~ University Children's Hospital
`Academic Medical Center
`and Clinical Chemistry
`Division of Clinical Chemistry
`Meibergdreef 9
`and Biochemistry
`Stein~iesstrasse 75
`Dept. of Pediatrics
`-DO'j 8032 Zurich
`and Clinical Chemistry
`1105 AZ Amsterdam
`.-; University Children’s Hospital
`Steinwiesstrasse 75
`Meibergdreef 9
`The Netherlands
`s~itzerland
`1105 AZ Amsterdam
`8032 Ziirich
`e-mail: m.duran@amc.uva.nl
`e-mail: blau@access.unizh.ch
`The Netherlands
`Switzerland
`e-mail: m.durar1@amc.uva.nl
`e—mail: blau@access.unizh.ch
`K. Michael Gibson
`Milan E. Blaskovics
`Biochemical Genetics Laboratory
`3639 Amesbury Road
`K. Michael Gibson
`Milan E. Blaskovics
`Dept. of Molecular and Med. Genetics
`Los Angeles, CA 90027
`Biochemical Genetics Laboratory
`3639 Amesbury Road
`Oregon Health & Science University
`USA
`Dept. of Molecular and Med. Genetics
`Los Angeles, CA 90027
`USA
`2525 SW 3rd Avenue, Suite 350
`e-mail: blaskk@earthlink.net
`Oregon Health 8r Science University
`2525 SW 3rd Avenue, Suite 350
`e-mail: blaskk@earthiink,net
`Portland, Oregon 97201, USA
`Portland, Oregon 97201, USA
`e-mail: gibsonm@ohsu.edu
`e-mail: gibsonm@ohsu.edu
`
`SPIN 10764999
`
`1
`
`ISBN 3-540-42542-X 2nd Edition Springer-Verlag Berlin Heidelberg Ne~ York
`ISBN 3A540-42542—X 2nd Edition Springer-Verlag Beriin Heidelberg New York
`Title of the lst Edition:
`Title of the 1st Edition:
`N. Blau, M. Duran, ME. Biaskovics
`N. Blau, M. Duran, M. E. Blaskovics
`Physician's Guide to the Laboratory Diagnosis of Metabolic Diseases
`Physician’s Guide to the Laboratory Diagnosis of Metabolic Diseases
`e 1996 Chapman & Hall
`in 1996 Chapman 8: Hall
`Library of Congress Cataloging,ineptiblication Data
`Library of Congress Cataloging-in-Publication Data
`Physician‘s guide to the laboratory diagnosis of metabolic diseases! [edited by! N. Blau
`Physician's guide to the laboratory diagnosis of metabolic diseases I [edited by) N. Blau
`..
`[et al.]. — 2nd ed.
`p.; cm.
`. . [et al.). - 2nd ed. p.; em.
`Includes bibliographical references and index.
`Includes bibliographical references and index.
`ISBN 3-540-42542-X {hd.: all-t.paperi
`ISBN 3-540-42542-X (hd.: alk.paper)
`i. Metabolism 7 Disorders — Diagnosis — Handbooks, manuals, etc, 2. Metabolism,
`l. Metabolism - Disorders - Diagnosis - Handbooks, manuals, etc. 2. Metabolism,
`inborn errors oi— Diagnosis — Handbooks. manuals, etc. 3. Diagnosis,
`Laboratory 7 Handbooks, manuais, etc. i. Blau. N. (Net-tad), 1946 —
`Inborn errors of- Diagnosis - Handbooks, manuals, etc. 3. Diagnosis,
`[DNLM 1. Metabolism. inborn Errors — diagnosis. 2. Diagnosis, Differentiai.
`Laboratory- Handbooks, manuals, etc. I. Blau, N. (Nenad), 1946-
`3. Laboratory Techniques and Procedures. WD 205 P578 2002]
`[DNLM: l. Metabolism, Inborn Errors - diagnosis. 2. Diagnosis, Differential.
`RBI47.P476 2002
`516.3’905‘5—dc2]
`2002021642
`3. Laboratory Techniques and Procedures. ~D 205 P578 2002)
`This work is subject to copyright. All rights are reserved, whether the whole or part of the material is
`RB147.P476 2002 616.3'9075-dc21 2002021642
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`reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication
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`or parts thereof is permitted only under the provisions of the German Copyright Law of September 9,
`tions are liable for prosecution under the German Copyright Law.
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`imply, even in the absence of a specific statement, that such names are exempt from the relevant protec(cid:173)
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`II
` iv
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`I
`I
`I
`
`Par Pharmaceutical, Inc. Ex. 1006
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 4 of 20
`
`_J
`
`

`

`
`II Inherited Hyperammonemias
`
`
`
`CLAUDE BACHMANN
`Inherited Hyperammonemias
`CLAUDE BACHMANN
`
`:
`
`I
`
`1
`l
`ii
`
`_
`'2';
`I
`
`11.1
`11.1
`
`Introduction
`Introduction
`
`Hyperammonemia (systemic venous or arterial plasma ammonia >80 in
`Hyperammonemia (systemic venous or arterial plasma ammonia >80 in
`newborns or >50 J.lmol!L after 28 days postnatally) is due either to an in(cid:173)
`newborns or >50 nmolfL after 28 days postnatally) is due either to an in-
`creased production exceeding the capacity to detoxify (as in colonization
`creased production exceeding the capacity to detoxify (as in colonization
`with urease containing microorganisms in an intestinal loop, a neurogenic
`with crease containing microorganisms in an intestinal loop, a neurogenic
`bladder or with a ureterosigmoidostomy), or to a decreased detoxification
`bladder or with a ureterosigmoidostomy), or to a decreased detoxification
`capacity. Among the latter causes are primary or secondary defects of an
`capacity. Among the latter causes are primary or secondary defects of en(cid:173)
`zymes involved in ammonia detoxification or a deficiency of intermediates
`zymes involved in ammonia detoxification or a deficiency of intermediates
`needed as substrates for a functional urea cycle, such as a nutritional, en-
`needed as substrates for a functional urea cycle, such as a nutritional, en(cid:173)
`zyme, or transport defect, or to interference with portal circulation so that
`zyme, or transport defect, or to interference with portal circulation so that
`portal blood does not reach the hepatocytes {a portacaval bypass or a pat—
`portal blood does not reach the hepatocytes (a portacaval bypass or a pat(cid:173)
`cut ductus), which can cause “transient hyperammonemia of the prema—
`ent ductus), which can cause "transient hyperammonemia of the prema(cid:173)
`tore". Ammonia detoxification is reduced in deficiencies of urea cycle en-
`ture". Ammonia detoxification is reduced in deficiencies of urea cycle en(cid:173)
`zymes, transport proteins [estimated incidence 1:30000 newborns, [1]) in
`zymes, transport proteins (estimated incidence 1:30000 newborns, [1]) in
`conditions where glutamate or acetyl CoA is decreased (valproate therapy
`conditions where glutamate or acetyl CoA is decreased (valproate therapy
`and organic acidurias), with carnitine and CoA (sequestered by pathologi—
`cal acyl moieties) and defects of mitochondrial beta-oxidation or carnitine
`and organic acidurias), with carnitine and CoA (sequestered by pathologi(cid:173)
`metabolism. These lead to a deficient
`formation of N—acetylglutamate
`cal acyl moieties) and defects of mitochondrial beta-oxidation or carnitine
`(NAG), an obligate activator of the first step of ammonia detoxification,
`metabolism. These lead to a deficient formation of N-acetylglutamate
`and thus to a functional NAGS deficiency. An acetyl CoA deficiency further
`(NAG), an obligate activator of the first step of ammonia detoxification,
`reduces pyruvate carboxylase, which blocks gluconeogenesis. These two ef-
`and thus to a functional NAGS deficiency. An acetyl CoA deficiency further
`fects of an acetyl CoA deficiency lead to a Reye syndrome. Today, because
`reduces pyruvate carboxylase, which blocks gluconeogenesis. These two ef(cid:173)
`more specific etiological diagnoses can be made, the Reye Syndrome is dis-
`fects of an acetyl CoA deficiency lead to a Reye syndrome. Today, because
`appearing.
`more specific etiological diagnoses can be made, the Reye Syndrome is dis-
`The actual enzyme activity in urea cycle disorders (UCD) in vivo is only
`partially assessed by in vitro assays (artificial conditions). It
`is a problem
`appearing.
`and must always be viewed in respect
`to the nitrogen load entering the
`The actual enzyme activity in urea cycle disorders (UCD) in vivo is only
`pathway (Fig. 11.3). This depends as well on the exogenous nutritional sup
`partially assessed by in vitro assays (artificial conditions). It is a problem
`ply or bacterial ammonia production in the got as on the endogenous bal—
`and must always be viewed in respect to the nitrogen load entering the
`ance or imbalance between protein synthesis and catabolism. The clinical
`pathway (Fig. 11.3). This depends as well on the exogenous nutritional sup(cid:173)
`heterogeneity of the disorders and any prognostic predictions will
`thus
`ply or bacterial ammonia production in the gut as on the endogenous bal(cid:173)
`only partly depend on the genetic background if residual protein is present.
`ance or imbalance between protein synthesis and catabolism. The clinical
`“Mild” leaky variants (unstable enzymes in vitro or residual enzyme activ-
`heterogeneity of the disorders and any prognostic predictions will thus
`only partly depend on the genetic background if residual protein is present.
`"Mild" leaky variants (unstable enzymes in vitro or residual enzyme activ-
`
`,
`
`‘3
`
`--
`
`26
`,-...._.—,.fim.m-;s..=.._..-_._“_._H.i._._-_;.H-_;'_".:.- :-
`
`-
`
`--- --=* ---.-v—*..a.
`
`Par Pharmaceutical, Inc. Ex. 1006
`I
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326 966
`Page 5 of 20
`
`

`

`ll.l
`
`262
`
`Inherited Hyperammonemias
`
`ity) may lead to severe hyperammonemic crises if protein catabolism pre(cid:173)
`inherited Hyper-ammonemias
`262
`dominates (e.g. major weight loss in newborns, viral infections etc.).
`Hyperammonemia is toxic to the brain. It exerts reversible (mostly sero(cid:173)
`ity) may lead to severe hyperammonemic crises if protein catabolism pref
`toninergic) and irreversible effects. Blood ammonia (NH3} concentrations
`dominates leg. major weight loss in newborns, viral infections etc).
`exceeding 180 ~unol/L, or a coma lasting more than 2-3 days appear to be
`Hyper-ammonemia is toxic to the brain. It exerts reversible (mostly sero—
`associated with irreversible defects which worsen with the duration of the
`toninergic) and irreversible effects. Blood ammonia (NI—I3) concentrations
`exceeding 180 umol/L, or a coma lasting more than 2&3 days appear to be
`coma. Thus, ammonia should be assayed in any sick newborn as a "stat"
`associated with irreversible defects which worsen with the duration of the
`analysis together with a sepsis work-up, or with the suspicion of an intra(cid:173)
`coma.
`'l'hus, ammonia should be assayed in any siclt newborn as a “stat”
`cerebral hemorrhage which is not confirmed. If hyperammonemia is found,
`analysis together with a sepsis t-vork—up, or with the suspicion of an intra-
`it should be confirmed by a second "stat" assay with samples obtained for
`cerebral hemorrhage which is not confirmed. if hyperammonemia is found,
`a complete laboratory evaluation (plasma and simultaneous spot urine). A
`it should be confirmed by a second "stat" assay with samples obtained for
`diagnosis should be made as rapidly as possible and not later than 12-24 h
`a complete laboratory evaluation (plasma and simultaneous spot urine). A
`in order to initiate specific treatment. Among the non-artefactual hyperam(cid:173)
`diagnosis should be made as rapidly as possible and not later than 12~2r1 h
`monemias, 2/3 are due to urea cycle defects, and 1/3 to organic acidemias
`in order to initiate specific treatment. Among the non-artefaclual hyperam-
`and other defects which can not be distinguished by the extent of the hy(cid:173)
`monemias, 2/3 are due to urea cycle defects, and U3 to organic acideinias
`and other defects which can not be distinguished by the extent of the hy—
`perammonemia. Blood gas analyses and anion gap determinations are of(cid:173)
`perammonemia. Blood gas analyses and anion gap determinations are of—
`ten not helpful since secondary lactic acidosis is often present in UCD pa(cid:173)
`ten not helpful since secondary lactic acidosis is often present in UCD pa,
`tients with circulatory failure. Since the specific treatment used for a UCD
`tients with circulatory failure. Since the specific treatment used for a UCD
`can be deleterious to patients with organic acidurias (e.g., amino acid mix(cid:173)
`can be deleterious to patients with organic acidurias (e.g., amino acid mix-
`tures containing high isoleucine or valine and to some extent benzoate and
`tures containing high isoleucine or valine and to some extent benzoate and
`phenylbutyrate, especially in an MCAD dehydrogenase deficiency and vice
`phenylbutyrate, especially in an MCAD dehydrogenase deficiency and vice
`versa), a rapid diagnosis is necessary. If a decision to treat is made, emer(cid:173)
`verse), 3 rapid diagnosis is necessary. [fa decision to treat
`is made, emer-
`gency therapy (see below) prolonged beyond 24 hours will lead to low es(cid:173)
`gency therapy (see below) prolonged beyoan 24 hours will lead to low es,
`sential amino acids and impaired protein synthesis with all the ensuing
`sential amino acids and impaired protein synthesis with all
`the ensuing
`risks and complications (coagulation problems, hemodialysis and or hemo-
`risks and complications (coagulation problems, hemodialysis and or heme(cid:173)
`filtration). This can be avoided or minimized by a rapid and complete labo
`filtration). This can be avoided or minimized by a rapid and complete labo(cid:173)
`ratory evaluation. The laboratory workload should not be underestimated.
`ratory evaluation. The laboratory workload should not be underestimated.
`Besides the initial diagnostic studies, frequent monitoring is required dur—
`Besides the initial diagnostic studies, frequent monitoring is required dur(cid:173)
`ing treatment. In a UCD, treatment consists of measures for reducing the
`ing treatment. In a UCD, treatment consists of measures for reducing the
`nitrogen load (restricting natural protein intake, gut acidification with lac—
`nitrogen load (restricting natural protein intake, gut acidification with lac(cid:173)
`tulose) and providing the substrates which are rate limiting due to the re—
`tulose) and providing the substrates which are rate limiting due to the re(cid:173)
`striction: of natural nutrients or due to the enzyme block. These would be
`striction of natural nutrients or due to the enzyme block. These would be
`arginine or citrulline, citric acid in the case of ASA, essential amino acids
`in calculated amounts, and adequate calcium, phosphate,
`iron,
`trace ele—
`arginine or citrulline, citric acid in the case of ASA, essential amino acids
`ments and vitamins. Also if needed, substrates for alternate pathways such
`in calculated amounts, and adequate calcium, phosphate, iron, trace ele(cid:173)
`as benzoate, with proper controls in neonates. One must be very cautious
`ments and vitamins. Also if needed, substrates for alternate pathways such
`with the chronic use of phenylbutyrale because of it’s long term side ef—
`as benzoate, with proper controls in neonates. One must be very cautious
`fects, which include its interference with cell replication and farnesylation.
`with the chronic use of phenylbutyrale because of it's long term side ef(cid:173)
`The above treatment should only be instituted after a definite diagnosis is
`fects, which include its interference with cell replication and farnesylation.
`made and it would be contraindicated in an organic aciduria. Whatever
`The above treatment should only be instituted after a definite diagnosis is
`treatment variation is used, it must be carefully controlled, especially in or—
`made and it would be contraindicated in an organic aciduria. Whatever
`der to avoid chronic malnutrition due to a deficiency of essential amino
`treatment variation is used, it must be carefully controlled, especially in or(cid:173)
`acids. Dietary management
`is actually more of a challenge,
`in practice,
`der to avoid chronic malnutrition due to a deficiency of essential amino
`than is
`the hyperammonemia. Because of the expertise and experience
`acids. Dietary management is actually more of a challenge, in practice,
`than is the hyperammonemia. Because of the expertise and experience
`
`
`
`Par Pharmaceutical, Inc. Ex. 1006
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 6 of 20
`
`

`

`263
`
`Introduction
`
`263
`
`Introduction
`needed in managing patients with UCD's, the transfer of patients into a
`center with experienced clinicians and a laboratory is recommended.
`needed in managing patients with UCD’s,
`the transfer of patients into a
`Brain ammonia toxicity depends upon the level of blood ammonia,
`center with experienced clinicians and a laboratory is recommended.
`which crosses membranes in its undissociated form (pK 9.05 at 3rC). In(cid:173)
`Brain ammonia toxicity depends upon the level of blood ammonia,
`creased brain ammonia is considered to augment the synthesis of gluta(cid:173)
`which crosses membranes in its undissociated form (pK 9.05 at 37 °C}.
`In—
`mate and glutamine, the intercellular transport moiety. This in turn in(cid:173)
`creased brain ammonia is considered to augment the synthesis of gluta-
`creases the transport capacity of large neutral amino acids (including tryp(cid:173)
`mate and glntamine,
`the intercellular transport moiety. This in turn in-
`tophan) at the blood brain barrier (yGT dependant) and elicits an in(cid:173)
`creases the transport capacity of large neutral amino acids (including tryp-
`creased serotonin secretion [2]. The increased glutamate released by neu(cid:173)
`tophan) at
`the blood brain barrier (yGT dependant) and elicits an in—
`creased serotonin secretion [2]. The increased glutamate released by neu—
`rons and its decreased re-uptake is probably exotoxic. The accumulation of
`rons and its decreased rewuptake is probably exotoxic. The accumulation of
`glutamine in astrocytes has been shown, under extreme conditions, to lead
`glutamine in astrocytes has been shown, under extreme conditions. to lead
`to astrocytic swelling which may be responsible for terminal brain edema.
`to astrocytic swelling which may be responsible for terminal brain edema.
`The mechanisms affecting the energy pathways in brain are still controver(cid:173)
`The mechanisms affecting the energy pathways in brain are still controver-
`sial. Since the major portion of brain glutamate is synthesized within the
`sial. Since the major portion of brain giutamate is synthesized within the
`brain, it is not at all clear if plasma glutamine plays any pathogenic role in
`brain,
`it is not at all clear if plasma glutamine piays any pathogenic role in
`the brain's toxicity. It is, however, an indicator of ammonia detoxification
`the brain's toxicity. It is, however. an indicator of ammonia detoxification
`in the peri-central part of the hepatic lobules (urea cycle enzymes are peri(cid:173)
`in the perivcentral part of the hepatic lobules (urea cycle enzymes are peri-
`portal), or of its release by muscle or other tissues. When managing pa(cid:173)
`portal), or of its release by muscle or other tissues. When managing pa-
`tients, one must also know that arginine, a semi-essential amino acid,
`is
`tients, one must also know that arginine, a semi-essential amino acid, is
`mainiy synthesized in the kidneys from citrulline, which in turn is formed
`mainly synthesized in the kidneys from citrulline, which in turn is formed
`predominantly in the intestine {see Table 11.2). Argininosuccinaie synthe-
`predominantly in the intestine (see Table 11.2). Argininosuccinate synthe(cid:173)
`tase and lyase and the arginine transporters (CAT), additionally, play a role
`tase and lyase and the arginine transporters (CAT), additionally, play a role
`in the recycling of citrulline to arginine (e.g. for NO synthesis in kidneys,
`in the recycling of citrulline to arginine (e.g. for NO synthesis in kidneys,
`intestine and brain [3].
`intestine and brain [3].
`The inherited enzyme deficiencies listed in Table 11.2 lead to the accur
`The inherited enzyme deficiencies listed in Table 11.2 lead to the accu(cid:173)
`mulation of substrates and deficiencies of products. For correct interpreta—
`mulation of substrates and deficiencies of products. For correct interpreta(cid:173)
`tion of laboratory results, one need be aware that substrate accumulation
`can affect the prior enzyme in the pathway (eg. increased carbamyl phos
`tion of laboratory results, one need be aware that substrate accumulation
`phate inhibits CPS). A deficiency of urea cycle intermediates (transport or
`can affect the prior enzyme in the pathway (e.g. increased carbamyl phos(cid:173)
`enzyme products or dietary substances] e.g. arginine or ornithine. is often
`phate inhibits CPS). A deficiency of urea cycle intermediates (transport or
`rate limiting. It can initiate a vicious cycle, which worsens the urea syn
`enzyme products or dietary substances) e.g. arginine or ornithine, is often
`thetic capacity in the cytosol (eg. by limiting protein synthesis), or in the
`rate limiting. It can initiate a vicious cycle, which worsens the urea syn(cid:173)
`mitochondria (deficient stimulation of NAGS and of substrate for OTC).
`thetic capacity in the cytosol (e.g. by limiting protein synthesis), or in the
`Measured plasma values reflect cytosolic metabolite concentrations, not
`mitochondria (deficient stimulation of NAGS and of substrate for OTC).
`those of mitochondria. Protein catabolism contributes to the plasma amino
`Measured plasma values reflect cytosolic metabolite concentrations, not
`acid values. Thus, the interpretation of results for plasma arginine, proline
`those of mitochondria. Protein catabolism contributes to the plasma amino
`and iysine must be done within the context of the pattern found for all of
`acid values. Thus, the interpretation of results for plasma arginine, proline
`the amino acids. Urea concentrations depend upon the arginine in the cyto—
`sol originating from protein catabolism, urea cycle synthesis, and therapeu—
`and lysine must be done within the context of the pattern found for all of
`tic applications.
`the amino acids. Urea concentrations depend upon the arginine in the cyto(cid:173)
`sol originating from protein catabolism, urea cycle synthesis, and therapeu(cid:173)
`tic applications.
`
`_
`
`1
`
`-
`
`
`
`
`
`Par Pharmaceutical, Inc. Ex. 1006
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 7 of 20
`
`;'
`
`:
`
`
`I.
`
`
`
` -‘2v....r;-,~.r-p.-u-v.v_
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`f
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`3:
`
`
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`

`

`264
`
`Inherited Hyperammonemias
`
`11 .2 Nomenclature
`264
`1nherited Hyper-ainmonemias
`
`
`Chromo· MIM
`13.2 Nomenclature
`Expression
`No. Disorder
`some
`
`
`2q35
`
`2311300
`
`311250
`
`szm
`
`311250
`
`215700
`
`2157110
`
`
`
`
`
`
`
`
`
`
`
`MIM
`No. Disorder
`Expression
`Cbromo-
`SOIRC
`237300
`2q35
`ll.l Carbamylphosphate Mitochondrial: liver (periportal -t
`
`synthetase (CPS 1) pericentral; all urea cycle enzymes)
`and much less intestine (enzyme not
`11.1 Carbamylphosphate Mitochondrial: liver (periportal 7»
`expressed in red or white blood cells
`synthetase (CPS 1)
`pericentral; all urea cycle enzymes)
`and much less intestine (enzyme not
`or fibroblasts)
`
`Xp2l.l
`expressed in red or white blood cells
`11.2 Ornithine transcar- Mitochondrial: liver and much less
`
`or fibroblasts)
`
`intestine. Mosaicism in heterozygote
`bamylase
`11,2 Drnitltine transcar- Mitochondrial: liver and much less
`females (not expressed in red or white
`
`(OTC, OCT)
`barnylase
`intestine. Mosal'cisrn in betcrozygote
`blood cells or flbroblasts)
`
`(OTC, OCT)
`females (not expressed in red or white
`
`11.3 Argininosuccinate Cytosolic: Liver, kidney (cortical prox· 9q34
`blood cells or fibroblasts)
`
`imal tubule); intestine, myenteric neu·
`synthetase (AS);
`11.3 Argininosuccinale
`Cytosolic: Liver, kidney (cortical prox- 9q34
`
`rons, ileal and colonic muscles; CNS:
`Citrullinemia
`syntbctase (AS);
`imal tubule); intestine, myenteric neu-
`
`not in astrocytes (selective neurons in
`Citrullinemia
`rons, ileal and colonic muscles; CNS:
`Type I
`
`neocortex, and midbrain), brainstem,
`not in astrocytes (selective neurons in
`Type 1
`
`neocortex, and midbrain), brainstem,
`diencephalon, cerebellar molecular
`
`diencephalon, cerebellar molecular
`and granular layer; eye. Fibroblasts
`
`and granular layer; eye. Fibroblasts
`11.4 Argininosuccinate Cytosolic: Liver; kidney (cortical prox- 7cen-q11.2 207900
`
`1L4 Argininosuccinate
`Cytosolic: Liver; kidney{corticalprox- 7cen—-qll.2
`2031900
`imal tubule); intestine, myenteric neu-
`lyase (AL); Argini-
`
`lyase (AL); Arginie
`imal tubule); intestine, myenteric neu—
`nosuccinic aciduria rons, ileal and colonic muscles; CNS:
`
`nosuccinic acicluria tons, ileal and colonic muscles; CNS:
`
`cerebrum ubiquitous, cerebellum (not
`cerebruin ubiquitous, cerebellum (not
`
`in cerebellar white matter); eye: Red
`in cerebellar white matter); eye: Red
`
`cells, fibroblasts
`cells, fibroblasts
`
`6q23
`Arginase 1 cytosol (liver)
`Arginase l cytosul (liver)
`
`Arginase 2 (mitochondria: small intes-
`Arginase 2 (mitochondria: small intes·
`
`tine, kidney {outer medulla and partly
`tine, kidney (outer medulla and partly
`
`cortex), CNS: ubiquitous; eye: solely
`cortex), CNS: ubiquitous; eye: solely
`
`retina. Red cells, Fibroblasts
`
`retina. Red cells, Fibroblasts
`unknown
`11.6 N-Acetylglutamate Mitochondrial: liver >> intestine
`2373111
`237310
`unknown
`
`11.6 N-Acetylglutamate Mitochondrial: liver ~intestine
`synthetase WAGS)
`>> spleen. Intestine (enzyme not ex-
`synthetase (NAGS) »spleen. Intestine (enzyme not ex-
`
`pressed in red or white blood cells or
`
`pressed in red or white blood cells or
`fibroblasts)
`
`fibroblasts)
`Solute carrier fami- Basolateral membrane
`11.7
`
`11.7 Solute carrier fami- Basolateral membrane
`ly 7 A7 (SLC7AT);
`Liver, intestine, kidney
`
`ly 7 A7 (SLC7 A7); Liver, intestine, kidney
`Lysinuric protein
`
`intolerance
`Lysinuric protein
`11.8 Solute carrier fainir Mitochondrial membrane: Fibroblasts
`l3ql4
`
`intolerance
`by 25 A15
`l3ql4
`11.8 Solute carrier fami- Mitochondrial membrane: Fibroblasts
`
`(SLCZSAlS,
`
`ly 25 Al5
`ORNTI); Hyperor—
`
`(SLC25Al5,
`nitltinemia—hyper—
`
`ammonemia-homoe
`ORNTl); Hyperor-
`
`citi‘ullinuria (HHH)
`nithinemia-hyper-
`
`syndrome
`ammonemia-homo-
`
`11.9 A’-Pyrroline-5~car— Mitochondrial
`citrullinuria (HHH)
`
`boxylate synthe-
`syndrome
`
`tase, PYCS
`/).' -Pyrroline-5-car- Mitochondrial
`11.9
`boxylate synthe·
`tase, PYCS
`
`11.5 Arginase 1
`11.5 Arginase 1
`
`6q23
`
`207800
`201300
`
`1414112
`14qll.2
`
`22.2?00
`222700
`
`238970
`238970
`
`10q24.3
`
`138251)
`
`10q24.3
`
`138250
`
`
`
`Par Pharmaceutical, Inc. Ex. 1006
`I
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 8 of 20
`
`

`

`F,
`.- it?
`"E
`
`'-
`
`
`
`I"
`
`
`
`Metabolic Pathway
`
`265
`
`265
`Metabolic Pathway
`Chromo(cid:173)
`MIM
`Expression
`No. Disorder
`
`some
`MIM
`Chromo-
`Expression
`No. Disorder
`some
`10q23.3
`138130
`Mitochondrial
`11.10 Glutamate dehydro(cid:173)
`
`genase 1, GTP
`11.10 Glutamate dehydro— Mitochondrial
`binding site muta(cid:173)
`genase 1, GT]?
`tions (GLUDl);
`binding site muta-
`Hyperinsulinism(cid:173)
`tions (GLUDI);
`Hyperammonemia
`Hyperinsulinism-
`syndrome
`Hypetammonemia
`7q21.3
`Mitochondrial membrane, liver (not
`syndrome
`11.11 Citrullinemia type
`kidney) with secondary AS deficiency
`11.11 Citrullinemia type Mitochondrial membrane, liver (not
`7q21.3
`2 (SLC25Al3 gene)
`2 (SLCZSMB gene) kidney) with secondary AS deficiency
`Citrin deficiency
`
`Citrin deficiency
`
`10q23.3
`
`138130
`
`603471
`603471
`
`11.3 Metabolic Pathway
`11.3 Metabolic Pathway
`
`
`GLU
`
`GLN
`
`Mitochondrion
`Mitochondrial)
`ototic acid
`-----~~- Orotic acid
`l
`~
`0MP —. croridine
`OMP -