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`Megapagnd
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`cae eeLop tO aae
`Laboratory r)
`Pe Drteaalense
`of Metabolic
`Dera
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`SecondEdition
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`\@y;) Springer
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`Page1of 20
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`n, IPR ofPatent Nos.9,264oe.8095,380,3nd9,ozs,966
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`Page 2 of 20
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`Py
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`metabolic diseases mayhave devastating con-
`To use the CD-ROM youneedonly
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`Gipson tered and clinical descriptionsofrare conditions are hard plethefargihre!operatingIles
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`cal values for crucial metabolites. Relevant metabolic joktae PY traeecaei
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`index. ThePhysician’s GuidepaseoCCH eeCeleWee(acheeaeDaresehieeeendaoe
`other physicians with a unique aidto help them select the
`some Unixversions
`eyeageleeueleMaiglCoattHeelofEe eeradsvetmcee
`hitp://wwwadabe.com
`clinical and laboratory data.
`This book includes a bonus CD-ROMcnn facilitat
`menioees
`ing access to the content bymeansofa full-oe search
`RipariancaegearchOTE
`Cry eit
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`D-69121Heidelberg
`site
`BisystNgClutefoteyae
`http://www.springer.defhelpdesk-fe
`Phone (German customers):
`Oe Ltn iMoby
`Phone (international);
`+49 62 21 487 82.35
`Fax:
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`Physician’s Guide
`to the Laboratory Diagnosis
`of Metabolic Diseases
`
`SS
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`:
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`ISBN 3-540-42542-x
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`Wl HU
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`ae
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`>
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`http://www.springer.de
`
` ii
`Par Pharmaceutical, Inc. Ex. 1006
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`
`

`

`
`
`N. Blau · M. Duran
`M. E. Blaskovics · K. M. Gibson
`N. Blau - M. Duran
`(Eds.)
`M.E. Blaskovics - 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 C.R. Scriver
`
`With 100 Figures and 270 Tables
`With 100 Figures and 270 Tables
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`Se
`4) Springer
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`'
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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
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`

`

`>I o vY\ e.vL caJ
`~!) Nenad Blau
`Marinus Duran
`
`~ 1 Division of Clinical Chemistry
`Academic Medical Center
`Dept. of Pediatrics
`Marinus Duran
`and Biochemistry
`Nenad Blau
`)~l ~ University Children's Hospital
`and Clinical Chemistry
`Academic Medical Center
`Division of Clinical Chemistry
`Meibergdreef 9
`Dept. of Pediatrics
`Stein~iesstrasse 75
`and Biochemistry
`-DO'j 8032 Zurich
`and Clinical Chemistry
`) University Children’s Hospital
`1105 AZ Amsterdam
`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.duran@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
`Dept. of Molecular and Med. Genetics
`USA
`Los Angeles, CA 90027
`USA
`2525 SW 3rd Avenue, Suite 350
`Oregon Health & Science University
`e-mail: blaskk@earthlink.net
`2525 SW 3rd Avenue, Suite 350
`e-mail: blaskk@earthlink.net
`Portland, Oregon 97201, USA
`Portland, Oregon 97201, USA
`e-mail: gibsonm@ohsu.edu
`e-mail: gibsonm@ohsu.edu
`
`ISBN 3-540-42542-X 2nd Edition Springer-Verlag Berlin Heidelberg Ne~ York
`ISBN 3-540-42542-X 2nd Edition Springer-Verlag Berlin Heidelberg New York
`Title of the Ist Edition:
`Title of the 1st Edition:
`N. Blau, M. Duran, M. E. Blaskovics
`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
`© 1996 Chapman & Hall
`Library of Congress Cataloging-in-Publication 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
`. fetal]. - 2nd ed.
`ps cm,
`. . [et al.). - 2nd ed. p.; em.
`Includes bibliographical references and index.
`Includes bibliographical references and index.
`ISBN 3-540-42542-X (hd.: alk.paper)
`ISBN 3-540-42542-X (hd.: alk.paper)
`1, Metabolism — Disorders - Diagnosis - Handbooks, manuals, ete. 2. Metabolism,
`l. Metabolism - Disorders - Diagnosis - Handbooks, manuals, etc. 2. Metabolism,
`Inborn errors of - Diagnosis - Handbooks, manuals,etc. 3. Diagnosis,
`Inborn errors of- Diagnosis - Handbooks, manuals, etc. 3. Diagnosis,
`Laboratory - Handbooks, manuals, etc. I. Blau, N. (Nenad), 1946 -
`Laboratory- Handbooks, manuals, etc. I. Blau, N. (Nenad), 1946-
`[DNLM:1. Metabolism, Inborn Errors - diagnosis. 2. Diagnosis, Differential.
`[DNLM: l. Metabolism, Inborn Errors - diagnosis. 2. Diagnosis, Differential.
`3. Laboratory Techniques and Procedures. WD 205 P578 2002]
`RB147.P476 2002
`616.3°9075-de21
`2002021642
`3. Laboratory Techniques and Procedures. ~D 205 P578 2002)
`RB147.P476 2002 616.3'9075-dc21 2002021642
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`II
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`Par Pharmaceutical, Inc. Ex. 1006
`Parv. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 4 of 20
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`Printed on acid-free paper
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`SPIN 10764999
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`

`
`II Inherited Hyperammonemias
`
`
`
`i
`
` 4iji”7
`
`iF
`ida
`iq
`a|
`
`Inherited Hyperammonemias
`CLAUDE BACHMANN
`CLAUDE BACHMANN
`
`11.1
`Introduction
`11.1
`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 pmol/L 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 urease 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 en-
`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 ora pat-
`portal blood does not reach the hepatocytes (a portacaval bypass or a pat(cid:173)
`ent ductus), which can cause “transient hyperammonemia of the prema-
`ent ductus), which can cause "transient hyperammonemia of the prema(cid:173)
`ture’. 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
`conditions where glutamate or acetyl CoA is decreased (valproate therapy
`zymes, transport proteins (estimated incidence 1:30000 newborns, [1]) in
`and organic acidurias), with carnitine and CoA (sequestered by pathologi-
`conditions where glutamate or acetyl CoA is decreased (valproate therapy
`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 NAGSdeficiency. 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 Syndromeis dis-
`fects of an acetyl CoA deficiency lead to a Reye syndrome. Today, because
`appearing.
`The actual enzymeactivity in urea cycle disorders (UCD) in vivo is only
`more specific etiological diagnoses can be made, the Reye Syndrome is dis-
`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 gut 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-
`
`sa
`
`26
`- rnicianeeeare aera eeree
`
`
`
`Par Pharmaceutical, Inc. Ex. 1006
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 5 of 20
`
`

`

`Hi,
`
`262
`
`Inherited Hyperammonemias
`
`ity) may lead to severe hyperammonemic crises if protein catabolism pre(cid:173)
`Inherited Hyperammonemias
`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 pre-
`toninergic) and irreversible effects. Blood ammonia (NH3} concentrations
`dominates (e.g. major weight loss in newborns, viral infections etc.).
`exceeding 180 ~unol/L, or a coma lasting more than 2-3 days appear to be
`Hyperammonemia 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 (NH;) concentrations
`coma. Thus, ammonia should be assayed in any sick newborn as a "stat"
`exceeding 180 jtmol/L, or a coma lasting more than 2-3 days appear to be
`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. Thus, ammonia should be assayed in any sick newborn as a “stat”
`cerebral hemorrhage which is not confirmed. If hyperammonemia is found,
`analysis together with a sepsis work-up, or with the suspicion of anintra-
`it should be confirmed by a second "stat" assay with samples obtained for
`cerebral hemorrhage whichis not confirmed. If hyperammonemiais 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 madeas rapidly as possible and notlater than 12-24h
`monemias, 2/3 are due to urea cycle defects, and 1/3 to organic acidemias
`in order to initiate specific treatment. Among the non-artefactual 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 1/3 to organic acidemias
`perammonemia. Blood gas analyses and anion gap determinations are of(cid:173)
`and other defects which can not be distinguished by the extent of the hy-
`ten not helpful since secondary lactic acidosis is often present in UCD pa(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-
`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)
`versa), a rapid diagnosis is necessary. If a 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 beyond 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 heme(cid:173)
`risks and complications (coagulation problems, hemodialysis and or hemo-
`filtration). This can be avoided or minimized by a rapid and complete labo(cid:173)
`filtration). This can be avoided or minimized by a rapid and complete labo-
`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
`arginine or citrulline, citric acid in the case of ASA, essential amino acids
`in calculated amounts, and adequate calcium, phosphate,
`iron,
`trace ele-
`in calculated amounts, and adequate calcium, phosphate, iron, trace ele(cid:173)
`ments and vitamins. Also if needed, substrates for alternate pathways such
`ments and vitamins. Also if needed, substrates for alternate pathways such
`as benzoate, with proper controls in neonates. One must be very cautious
`with the chronic use of phenylbutyrate because ofit’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
`Parv. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 6 of 20
`
`

`

`
`BeaSereareas
`
`Introduction
`
`263
`
`needed in managing patients with UCD's, the transfer of patients into a
` Introduction 263
`
`center with experienced clinicians and a laboratory is recommended.
`Brain ammonia toxicity depends upon the level of blood ammonia,
`needed in managing patients with UCD’s,
`the transfer of patients into a
`which crosses membranes in its undissociated form (pK 9.05 at 3rC). In(cid:173)
`center with experienced clinicians and a laboratory is recommended.
`creased brain ammonia is considered to augment the synthesis of gluta(cid:173)
`Brain ammonia toxicity depends upon the level of blood ammonia,
`mate and glutamine, the intercellular transport moiety. This in turn in(cid:173)
`which crosses membranes in its undissociated form (pK 9.05 at 37°C), In-
`creases the transport capacity of large neutral amino acids (including tryp(cid:173)
`creased brain ammonia is considered to augment the synthesis of gluta-
`tophan) at the blood brain barrier (yGT dependant) and elicits an in(cid:173)
`mate and glutamine,
`the intercellular transport moiety. This in turn in-
`creased serotonin secretion [2]. The increased glutamate released by neu(cid:173)
`creases the transport capacity of large neutral amino acids (including tryp-
`rons and its decreased re-uptake is probably exotoxic. The accumulation of
`tophan) at
`the blood brain barrier (yGT dependant) and elicits an in-
`glutamine in astrocytes has been shown, under extreme conditions, to lead
`creased serotonin secretion [2]. The increased glutamate released by neu-
`to astrocytic swelling which may be responsible for terminal brain edema.
`rons and its decreased re-uptake is probably exotoxic. The accumulation of
`glutamine in astrocytes has been shown, under extreme conditions, to lead
`The mechanisms affecting the energy pathways in brain are still controver(cid:173)
`to astrocytic swelling which may be responsible for terminal brain edema.
`sial. Since the major portion of brain glutamate is synthesized within the
`The mechanismsaffecting the energy pathways in brain are still controver-
`brain, it is not at all clear if plasma glutamine plays any pathogenic role in
`sial, Since the major portion of brain glutamate is synthesized within the
`the brain's toxicity. It is, however, an indicator of ammonia detoxification
`brain, it is not at all clear if plasma glutamine plays any pathogenic role in
`in the peri-central part of the hepatic lobules (urea cycle enzymes are peri(cid:173)
`the brain’s toxicity. It is, however, an indicator of ammonia detoxification
`portal), or of its release by muscle or other tissues. When managing pa(cid:173)
`in the peri-central part of the hepatic lobules (urea cycle enzymes are peri-
`tients, one must also know that arginine, a semi-essential amino acid, is
`portal), or of its release by muscle or other tissues. When managing pa-
`mainly synthesized in the kidneys from citrulline, which in turn is formed
`tients, one must also know that arginine, a semi-essential amino acid,
`is
`predominantly in the intestine (see Table 11.2). Argininosuccinate synthe(cid:173)
`mainly synthesized in the kidneys from citrulline, which in turn is formed
`predominantly in the intestine (see Table 11.2), Argininosuccinate synthe-
`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 ofcitrulline 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 accu(cid:173)
`The inherited enzyme deficiencies listed in Table 11.2 lead to the accu-
`mulation of substrates and deficiencies of products. For correct interpreta(cid:173)
`mulation of substrates and deficiencies of products. For correct interpreta-
`tion of laboratory results, one need be aware that substrate accumulation
`tion of laboratory results, one need be aware that substrate accumulation
`can affect the prior enzyme in the pathway (e.g. increased carbamyl phos(cid:173)
`can affect the prior enzyme in the pathway (e.g, increased carbamyl phos-
`phate inhibits CPS). A deficiency of urea cycle intermediates (transport or
`phate inhibits CPS). A deficiency of urea cycle intermediates (transport or
`enzyme products or dietary substances) e.g. arginine or ornithine, is often
`enzyme products or dietary substances) e.g. arginine or ornithine, is often
`rate limiting. It can initiate a vicious cycle, which worsens the urea syn-
`rate limiting. It can initiate a vicious cycle, which worsens the urea syn(cid:173)
`thetic capacity in the cytosol (e.g. by limiting protein synthesis), or in the
`thetic capacity in the cytosol (e.g. by limiting protein synthesis), or in the
`mitochondria (deficient stimulation of NAGS and of substrate for OTC).
`mitochondria (deficient stimulation of NAGS and of substrate for OTC).
`Measured plasma values reflect cytosolic metabolite concentrations, not
`Measured plasma values reflect cytosolic metabolite concentrations, not
`those of mitochondria. Protein catabolism contributes to the plasma amino
`those of mitochondria. Protein catabolism contributes to the plasma amino
`acid values. Thus, the interpretation of results for plasma arginine, proline
`acid values. Thus, the interpretation of results for plasma arginine, proline
`and lysine must be done within the context of the pattern found for all of
`and lysine must be done within the context of the pattern found for all of
`the amino acids, Urea concentrations depend uponthe arginine in the cyto-
`the amino acids. Urea concentrations depend upon the arginine in the cyto(cid:173)
`sol originating from protein catabolism, urea cycle synthesis, and therapeu-
`sol originating from protein catabolism, urea cycle synthesis, and therapeu(cid:173)
`tic applications,
`tic applications.
`
`
`
`eno
`ra
`
`
`
`hatenes=
`
`ee
`
`
`
`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
`
`

`

`Chromo· MIM
`Expression
`11.2 Nomenclature
`No. Disorder
`some
`
`MIM
`No. Disorder
`Expression
`Chromo-
`237300
`2q35
`some
`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 >
`2q35
`237300
`expressed in red or white blood cells
`synthetase (CPS 1)
`pericentral, all urea cycle enzymes)
`or fibroblasts)
`and muchless intestine (enzyme not
`Xp2l.l
`expressed in red or white bloodcells
`11.2 Ornithine transcar- Mitochondrial: liver and much less
`or fibroblasts)
`intestine. Mosaicism in heterozygote
`bamylase
`11.2 Ornithine transcar- Mitochondrial: liver and muchless
`females (not expressed in red or white
`(OTC, OCT)
`bamylase
`intestine. Mosaicism in heterozygote
`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. Argininosuccinate
`Cytosolic: Liver, kidney (cortical prox- 9q34
`rons, ileal and colonic muscles; CNS:
`Citrullinemia
`synthetase (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 granularlayer; eye. Fibroblasts
`11.4 Argininosuccinate Cytosolic: Liver; kidney (cortical prox- 7cen-q11.2 207900
`11.4 Argininosuccinate
`Cytosolic: Liver; kidney (cortical prox- 7cen-ql1.2 207900
`imal tubule); intestine, myenteric neu-
`lyase (AL); Argini-
`lyase (AL); Argini-
`imal tubule); intestine, myenteric neu-
`nosuccinic aciduria rons, ileal and colonic muscles; CNS:
`nosuccinic aciduria rons, ileal and colonic muscles; CNS:
`cerebrum ubiquitous, cerebellum (not
`cerebrum 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 1 cytosol (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
`237310
`237310
`unknown
`11.6 N-Acetylglutamate Mitochondrial: liver ~intestine
`synthetase (NAGS) >>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)
`Solute carrier fami- Basolateral membrane
`11.7.
`fibroblasts)
`11.7 Solute carrier fami- Basolateral membrane
`ly 7 AT (SLC7A7);
`Liver, intestine, kidney
`ly 7 A7 (SLC7 A7); Liver, intestine, kidney
`Lysinuric protein
`intolerance
`Lysinuric protein
`11.8 Solute carrier fami- Mitochondrial membrane: Fibroblasts
`13q14
`intolerance
`l3ql4
`ly 25 ALS
`11.8 Solute carrier fami- Mitochondrial membrane: Fibroblasts
`(SLC25A15,
`ly 25 Al5
`ORNT1); Hyperor-
`(SLC25Al5,
`nithinemia-hyper-
`ORNTl); Hyperor-
`ammonemia-homo-
`nithinemia-hyper-
`citrullinuria (HHH)
`ammonemia-homo-
`syndrome
`11.9 A’-Pyrroline-5-car- Mitochondrial
`citrullinuria (HHH)
`boxylate synthe-
`syndrome
`138250
`tase, PYCS
`10q24.3
`/).' -Pyrroline-5-car- Mitochondrial
`
`boxylate synthe·
`tase, PYCS
`
`11.9
`
`10q24.3
`
`138250
`
`264
`
`Inherited Hyperammonemias
`
`11 .2 Nomenclature
`264
`Inherited Hyperammonemias
`
`311250
`
`Xp21.1
`
`311250
`
`215700
`215700
`
`11.5 Arginase 1
`11.5 Arginase 1
`
`6q23
`
`207800
`207800
`
`14q11.2
`14qll.2
`
`222700
`222700
`
`238970
`238970
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Par Pharmaceutical, Inc. Ex. 1006
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 8 of 20
`
`

`

`
`
`Metabolic Pathway
`
`265
`
`cae
`
`Se
`
`
`
`ar
`
`
`
`Metabolic Pathway 265
`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, GTP
`tions (GLUDl);
`binding site muta-
`Hyperinsulinism(cid:173)
`tions (GLUD1);
`Hyperammonemia
`Hyperinsulinism-
`syndrome
`Hyperammonemia
`7q21.3
`Mitochondrial membrane, liver (not
`11.11 Citrullinemia type
`syndrome
`kidney) with secondary AS deficiency
`11.11 Citrullinemia type Mitochondrial membrane, liver (not
`—7q21.3
`2 (SLC25Al3 gene)
`2 (SLC25A13 gene) kidney) with secondary AS deficiency
`Citrin deficiency
`Citrin deficiency
`
`10q23.3
`
`138130
`
`603471
`603471
`
`
`
`
`
`_
`"3
`
`·
`
`11.(
`
`IT
`
`c
`
`NAGOY
`1
`·
`
`Carb.-P
`OTC
`112
`
`AcCoA
`11.2
`{
`AcCarnitine
`
`ORN
`
`11.3 Metabolic Pathway
`11.3 Metabolic Pathway
`
`Cytosol
`
`
`Mitochondrion
`Mitechondrion
`Orotic acid
`-----~~- Orotic acid
`
`
`GLN
`GLN
`|
`GLU
`~
`OMP —> Orotidine
`Glutamine synthetase
`OMP - Orotidine
`ASP
`~
`
`
`NH3 UMP—,Uridi
`
`ASP
`~,
`Uridine
`NH3
`
`
`UMP -........ Uridine
`sree
`ae
`Uracil
`
`OT~arrb.-P CIT r CIT
`A~
`NAG .. ·•01 CPS
`Uracil
`
`
`ASA
`a4
`t 11
`FUM
`AL
`ASA ~FUM
`NAGS
`NO
`114
`x
`11.6
`1
`N~~S
`“
`ARG
`
`cr
`NOS
`n
`
`..
`NO
`11.4 ARG
`UREA
`|
`sacha)
`
`NOS
`ORN +-...Y.-----URE:R::1.J or 2
`ORN
`ARG! or 2
`zs
`
`1 r CAT
`:
`ORNT1
`2-0xoGiuuActoA
`\
`8
`CAT
`O~~Jl
`1oasic
`Dibasi
`on
`
`" "
`...._.-::..--- A_c_c_ar_n_it-in_e_
`
`
`YGLU-