`
`15
`
`.8
`
`24
`
`CHpy
`
`SYMPTOMS
`GENETIC
`CONDITIONS
`
`A HANDBOOK
`
`x
`
`EDITED BY
`
`Louanne Hudgins
`Helga V. Toriello
`Gregory M. Enns
`H. Eugene Hoyme
`
` Page 1 of 26
`
`Horizon Exhibit 2029
`Par v. Horizon
`IPR2017-01768
`
`Page 1 of 26
`
`Horizon Exhibit 2029
`Par v. Horizon
`IPR2017-01768
`
`

`

`Signs and Symptoms of
`Genetic Conditions
`
`Page 2 of 26
`
`Page 2 of 26
`
`

`

`
`
`A HANDBOOK
`
`EDITED BY LOUANNE HUDGINS
`
`HELGA V. TORTELLO
`
`GREGORY M. ENNS
`
`H. EUGENE HOYME
`
`Page 3 of 26
`
`
`UNIVERSITY PRESS
`
`Page 3 of 26
`
`

`

`OXFORD
`UNIVERSITY PRESS
`
`Oxford University Press is a department of the University of
`Oxford.It furthers the University’s objective of excellence in research,
`scholarship, and education by publishing worldwide.
`
`Oxford New York
`Auckland Cape Town DaresSalaam HongKong Karachi
`KualaLumpur Madrid Melbourne Mexico City Nairobi
`New Delhi
`Shanghai
`‘Taipei Toronto
`
`Withoffices in
`France Greece
`Czech Republic
`Argentina Austria Brazil Chile
`Poland
`Portugal
`Singapore
`Guatemala Hungary
`Italy Japan
`South Korea
`Switzerland Thailand Turkey Ukraine Vietnam
`
`Oxford is a registered trademark of Oxford University Press
`in the UKandcertain other countries.
`
`Published in the United States of America by
`Oxford University Press
`198 Madison Avenue, New York, NY 10016
`
`© Oxford University Press 2014
`
`All rights reserved. No part of this publication may be reproduced, stored in
`a retrieval system, or transmitted, in any form or by any means, withoutthe prior
`permissionin writing of Oxford University Press, or as expressly permitted by law,
`by license, or under terms agreed with the appropriate reproductionrights organization.
`Inquiries concerning reproduction outside the scope of the above shouldbe sent to the
`Rights Department, Oxford University Press, at the address above.
`
`You must not circulate this work in any other form
`and you must imposethis same condition on any acquirer.
`
`Library of Congress Cataloging-in-Publication Data
`Signs and symptomsofgenetic conditions : a handbook/ edited by Louanne Hudgins, HelgaV. Toriello,
`Gregory M.Enns, H. Eugene Hoyme,
`p.jcm.
`Includes bibliographical references.
`ISBN 978-0-19--993097-S(alk. paper)
`UL. Toriello, Helga V., editor of compilation.
`I. Hudgins, Louanne, editor of compilation.
`Gregory M., editor of compilation.
`IV. Hoyme, H. Eugene, editor of compilation.
`3. Diagnosis,
`[DNLM:1. Child—-Handbooks.
`2. Genetic Diseases, Inborn-—diagnosis-—-Handbooks.
`Differential—Handbooks.
`4. Genetic Testing--Handbooks.
`S$. Signs and Symptoms—-Handbooks. WS 39]
`RBIS55.5
`616’.042-—dce23
`
`II. Enns,
`
`2013048866
`eeeees
`
`This material is not intended to be, and should not be considered, a substitute for medical or other professional
`advice. Treatment for the conditions described in this material is highly dependent onthe individual
`circumstances. And, while this material is designed to offer accurate information with respect to the subject
`matter covered and to be currentas of the time it was written, research and knowledge about medical and health
`issues is constantly evolving and dose schedules for medications are being revised continually, with new side
`effects recognized and accountedforregularly. Readers must therefore always check the product information
`andclinical procedures with the most up-to-date published product information and data sheets provided by
`the manufacturers and the most recent codes of conduct andsafety regulation. The publisher and the authors
`make no representations or warranties to readers, express or implied, as to the accuracy or completeness of this
`material. Without limiting the foregoing, the publisher and the authors make no representations or warranties as
`to the accuracy or efficacy of the drug dosages mentionedin the material. The authors and the publisher do not
`accept, and expressly disclaim, any responsibility for any liability, loss or risk that may be claimedorincurred as a
`consequenceofthe use and/orapplication of any ofthe contents of this material.
`
`987654321
`Printed in the United States ofAmerica
`on acid-free paper
`
`Page 4 of 26
`
`Page 4 of 26
`
`

`

`Contents
`
`Preface ix
`About the Editors xi
`Contributors xiti
`
`1. Genetic Testing 1
`GREGORY M. ENNS, LOUANNE HUDGINS,
`
`AND TINA M. COWAN
`
`. Short Stature 9
`
`MELANIE A. MANNING
`
`. Obesity 22
`DAVID J. AUGHTON
`
`. Overgrowth Syndromes 34
`MARGARET P. ADAM
`
`. Asymmetry 50
`OMAR A. ABDUL-RAHMAN
`
`. Microcephaly 63
`CYNTHIA J. CURRY
`
`. Macrocephaly 7s
`HELGA V. TORTELLO AND MARGARET P. ADAM
`
`. Alterations in Cranial Shape 94
`MICHAEL J. LYONS
`
`. Brain Malformations 106
`
`ANNE SLAVOTINEK
`
`Page 5 of 26
`
`Page 5 of 26
`
`

`

`vi
`
`CONTENTS
`
`10.
`
`Intellectual Disability 128
`AGATINO BATTAGLIA
`
`11.
`
`Autism Spectrum Disorders 136
`MARWAN SHINAWI
`
`12.
`
`Hypotonia 145
`ELLIOTT H. SHERR AND GREGORY M. ENNS
`
`13.
`
`Weakness 164
`AMY KAO AND ROBERT D. STEINER
`
`. Ataxia 190
`CHING H. WANG AND GREGORY M. ENNS
`
`15.
`
`Seizures 209
`RANDALL A. HEIDENREICH
`
`16.
`
`Metabolic Acidosis 235
`TINA M. COWAN AND GREGORY M. ENNS
`
`17.
`
`Hypoglycemia 248
`DIVYA VATS AND SEYMOUR PACKMAN
`
`18.
`
`Hyperammonemia 261
`GREGORY M. ENNS AND TINA M. COWAN
`
`19.
`
`Hepatosplenomegaly 280
`RENATA C. GALLAGHER
`
`20.
`
`Hearing Loss 305
`ELOISE PRIJOLES
`
`21.
`
`Malformations of the External Ear 322
`CHAD HALDEMAN-ENGLERT AND HELGA V. TORIELLO
`
`C2.
`
`Anomalies of the Eye 335
`GRAEME C. BLACK AND RACHEL GILLESPIE
`
`23.
`
`Facial Clefting 355
`MARILYN C. JONES
`
`Page6 of 26
`
`Page 6 of 26
`
`

`

`Contents
`
`vii
`
`24.
`
`Congenital Heart Defects 368
`TOM CUSHING AND JOSEPH T. C. SHIEH
`
`25.
`
`Genetics of Renal Malformations 380
`JOSEPH T. C. SHIEH
`
`26.
`
`Limb Anomalies 387
`DAVID B. EVERMAN AND LESLIE G. BIESECKER
`
`27.
`
`Congenital Contractures: Emphasizing Multiple Congenital
`Contractures—Arthrogryposis 420
`JUDITH G. HALL
`
`28.
`
`Disorders of Sexual Development 440
`CHRISTOPHER CUNNIFF
`
`29.
`
`Alterations in Skin Pigmentation 459
`ANNA L. BRUCKNER
`
`30.
`
`Skin Malformations 475
`MARY BETH PALKO DINULOS
`
`31.
`
`Spontaneous Abortion and Intrauterine Fetal Death 497
`ANDREA KWAN AND H. EUGENE HOYME
`
`Index s09
`
`Page7 of 26
`
`Page 7 of 26
`
`

`

`
`
`Hyperammonemia
`
`GREGORY M. ENNS AND TINA M. COWAN
`
`Definition
`
`Hyperammonemiais defined as a blood ammonia concentration greater than about
`100 uM in neonates or SO uM in children and adults (precise cut-offs vary depend-
`ing on individual laboratory normative levels). A commoncause of an apparently high
`ammonialevelis improper specimen handling, leadingto a factitiously increased value.
`Blood samples should be obtained from a free-flowing vein or artery and placed onice
`immediately after being drawn in order to avoid spurious elevations. Inborn errors of
`metabolism, especially urea cycle defects and organic acidemias, are often associated
`with very high elevations of blood ammonia (> 1,000 uM),particularly in the newborn
`period. More mild to moderate elevations of blood ammonia may occur in these or
`other metabolic disorders, such as fatty acid oxidation defects and aminoacid trans-
`porter disorders, or in the context of a numberof acquired conditions, such as a porto-
`caval shunt, bacterial overgrowth with organismsthat can split urea, or the use of certain
`medications (Tables 18.1 and 18.2). Finally, any condition, either inherited or acquired,
`that causesliver failure may be associated with hyperammonemia.
`
`Clinical Assessment
`
`Although inborn errors of metabolism that are associated with significant hyperammo-
`nemia often manifest for the first time in neonates and young children, metabolic disor-
`ders can present for thefirst time at any age. Signs and symptomswill vary depending
`on the age of presentation (Table 18.3). A thorough history and physical examination
`are crucial and may yield important clues. The clinician should pay particular atten-
`tion to voluntary dietary restrictions, especially protein avoidance; family history; and
`neurological status, including the presence of seizures or mental deterioration.
`The majority of metabolic disorders that cause hyperammonemia are autosomal
`recessive traits, with the notable exceptions of ornithine transcarbamylase deficiency,
`whichis X-linked; hyperammonemia hyperinsulinism syndrome, which is autosomal
`dominant; and some disorders of mitochondrial respiratory chain function, which may
`exhibit maternal inheritance. A detailed family history may reveal the existence of an
`
`Page 8 of 26
`
`264
`
`Page 8 of 26
`
`

`

`262
`
`STGNS AND SYMPTOMS OF GENETIC CONDITIONS
`
`Table 18.1 Inborn Errors ofMetabolism with Associated Hyperammonemia
`
`
`Urea cycle defects:
`N-Acetylglutamate synthetase deficiency
`Carbamoyl phosphate synthetase deficiency:
`Ornithine transcarbamylase deficiency
`Argininosuccinate synthetase deficiency (citrullinemia)
`Argininosuccinate lyase deficiency
`Arginase deficiency
`Amino acid transporter deficiencies:
`Hyperornithinemia-hyperammonemia-homocitrullinemia (HHH) syndrome
`Lysinuric protein intolerance
`Citrin deficiency (citrullinemia type II)
`Organic acidemias:
`Methylmalonic acidemia
`Propionic acidemia
`Isovaleric acidemia
`Multiple carboxylase deficiency
`Multiple acyl-CoA dehydrogenase deficiency
`3-Hydroxymethylglutaryl-CoA dehydrogenase deficiency
`3-Methylcrotonyl-CoA carboxylase deficiency
`3-Oxothiolase deficiency
`L-2-Hydroxyglutaric acidemia
`3-Methylglutaconyl-CoA hydratase deficiency
`Fatty acid oxidation defects:
`Carnitine uptake deficiency
`Carnitine palmitoyl transferase 2 deficiency
`Carnitine acylcarnitine translocase deficiency
`Medium-chain acyl-CoA dehydrogenase deficiency
`Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency
`Very-long-chain acyl-CoA dehydrogenase deficiency
`Pyruvate carboxylase deficiency
`Mitochondrial disorders
`Hyperammonemia-hyperinsulinism syndrome (glutamate dehydrogenase mutations)
`A'-pyrroline-5-carboxylate synthase deficiency
`
`affected relative with a similarillness, and is of great diagnostic importance. This rela-
`tive will typically be a sibling of either sex in the case of an autosomal recessive condi-
`tion, but can be a maternal uncle, a brother, or a mildly affected mother or other female
`in X-linked disease. Some disorders are caused by mitochondrial DNA mutations,
`therefore maternal transmission may occur. Special attention should be givento family
`history of stillbirths, unexplained deaths, and neurological diseases or delayed develop-
`ment of any degree or severity. Maternalillness in pregnancy has also been associated
`with specific metabolic disorders and may yield a clue to the presence of an inborn error
`
`Page 9 of 26
`
`Page 9 of 26
`
`

`

`Table 18.2 Acquired Hyperammonemia
`
`Sampling artifact
`Cardiovascular:
`
`Hyperammonemia
`
`263
`
`Patent ductus venosus
`Portocaval shunt?
`Hypovolemia
`Congestive heart failure
`Perinatal asphyxia
`Liver failure:
`Infectious hepatitis (e.g., HSV) -
`Bacterial colonization (urease positive organisms):
`Neurogenic bladder
`Prunebelly syndrome
`Blind loop syndrome
`Ureterosigmoidostomy
`
`latrogenic:
`Valproate
`Asparaginase chemotherapy
`High-dose cytoreductive chemotherapy
`Bone marrow transplantation
`Arginine deficiency
`Total parenteral nutrition
`
`1 Hfyperammonemia has been seenin patients with hepatic arteriovenous malformations, including
`those who have Osler-Weber-Rendu syndrome.
`
`ofmetabolism in a neonate. For example, acute fatty liver ofpregnancyor the hemolysis,
`elevated liver enzymes, low platelets (HELLP) syndrome may occur in a heterozygous
`mothercarrying a fetus with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)
`deficiency or otherfatty acid oxidation disorders.
`
`NEONATAL HYPERAMMONEMIA
`
`Any neonate presenting with nonspecific signs ofdistress, such as poorfeeding,lethargy,
`or abnormalrespiratory pattern,is typically evaluated for sepsis. However, hyperammo-
`nemia may cause similar symptoms. Because urea cycle disorders and organic acidemias
`in someinstancesyieldlittle in the way of diagnostic clues whenroutine laboratorytests
`(i.e., complete blood count and electrolytes) are checked, somecases will undoubtedly
`be missed or the diagnosis delayed, unless a blood ammonia level is also checked upon
`initial presentation. If diagnosis is delayed, the ammonialevel will continueto rise, caus-
`ing progressive obtundation, and permanent brain damage may ensue.
`In the case of significant and progressive hyperammonemia in a neonate, the
`acid-base status may provide a clue to the underlying diagnosis. Tachypnea with an
`associated respiratory alkalosis commonly occurs in urea cycle disorders because of
`
`Page 10 of 26
`
`Page 10 of 26
`
`

`

`264
`
`SIGNS AND SYMPTOMS OF GENETIC CONDITIONS
`
`Table 18.3 Frequent Signs and Symptoms of Hyperammonemia
`
`
`
`Neonates/infants
`Feeding difficulty
`Vomiting
`Lethargy, progressing to coma
`Tachypnea
`Hypothermia/hyperthermia
`Hypotonia
`Seizures
`Pulmonary hemorrhage
`Cardiovascular collapse
`Liver disease (elevated transaminases, synthetic defect, fibrosis)
`Brittle hair (trichorrhexis nodosa)
`Developmental delay
`Children/adults
`Intellectual disability
`Ataxia
`
`Asterixis
`
`Hypotonia
`Hypertonia/progressive spasticity (arginase deficiency)
`Psychiatric disorders
`Protein aversion/malnutrition
`Vomiting
`Liver disease (elevated transaminases, synthetic defect, fibrosis)
`Failure to thrive
`
`the stimulatory effect of hyperammonemia on the respiratory center, but metabolic
`alkalosis (secondary to emesis) and even metabolic acidosis (from circulatory failure
`and poor peripheral perfusion) may occur. Because significant metabolic acidosis is
`frequently encountered in organic acidemias (see Chapter 16), the clinician often sus-
`pects an inborn error of metabolism as a diagnostic possibility in such cases. However,
`organic acidemias also may be associated with relatively normal electrolyte levels ini-
`tially, or even a metabolic alkalosis (more rarely). Therefore, the presence or absence of
`a metabolic acidosis does not always reliably distinguish a urea cycle disorder from an
`organic acidemia in a neonate with hyperammonemia; it may be difficult to distinguish
`between the two types of metabolic disorders before the results of specialized tests are
`available. Despite these considerations, in general, organic acidemias are associated
`with severe metabolic acidosis, and urea cycle disorders are more commonly associated
`with respiratory alkalosis.
`Inborn errors of metabolism often present in the neonatal period with extremely
`high levels of ammonia (>1,000 uM), although initial symptoms may occur at lower
`levels (>200 uM). In neonates, prominent hyperammonemia is commonly caused
`by metabolic disease, especially urea cycle disorders and organic acidemias. It is not
`possible to determine the cause of hyperammonemia solely based on the degree of
`
`Page 11 of 26
`
`
`
`Page 11 of 26
`
`

`

`Hyperammonemia
`
`265
`
`ammonia elevation. Organic acidemias may be associated with ammonia levels just as
`high as those encountered in urea cycle defects. Extremely high ammonialevels also
`can be seen in transient hyperammonemiaof the newborn (THAN). However, THAN
`tends to present within the first day oflife in a pre-term infant, whereas inborn errors of
`metabolism usuallyhaveinitial symptomsafter the first 24 hours (Figure 18.1).
`Organic acidemias cause approximately one-third of cases of neonatal hyperammo-
`nemia secondary to inborn errors of metabolism, and urea cycle defects are respon-
`sible for the remaining two-thirds of cases. Fatty acid oxidation disorders, including
`carnitine-acylearnitine translocase (CACT) deficiency, medium-chain acyl-CoA
`dehydrogenase (MCAD) deficiency,
`long-chain 3-hydroxyacylCoA dehydrogenase
`(LCHAD)deficiency, very-long-chain acyl-CoA dehydrogenase (VLCAD)deficiency,
`and acyl-CoA dehydrogenase-9 (ACAD-9) deficiency may also cause neonatal hyper-
`ammonemia, although the level of elevation is typically not as high as that encountered
`
`
`
`HYPERAMMONEMIA
`
`Sampling
`Artifact
`
`
`
`
`
`
`Hyperammonemia
`
`confirmed on repeat
`
`
`testing
`
`
`
`Transient
`
`Hyperammonemia
`of the Newborn
`
`
`Metabolic acidosis
`Organic aciduria
`+/- Lactic acidemia
`
`Organic
`acidemias
`
`
`
`Page 12 of 26
`
`
`
`Fatty acid oxidation
`disorders
`
`
`
`
`
`
`Mitochondrial disease
`
`Pyruvate carboxylase
`deficiency
`Figure 18.1 Metabolic acidosis. It is most important to ensure that the ammonialevels
`are obtained using proper sampling and laboratory techniques (sample obtained from
`free-flowing vein or artery and placed immediately on ice), in order to avoid false
`elevations. Transient hyperammonemia of the newborn (THAN)typically presents on
`day oflife 1 in pre-term infants with extremely high levels of ammonia (>1,000 uM). The
`ammonia levels associatedwith organic acidemias are often higher than levels seen in fatty
`acid oxidation defects, pyruvate carboxylase deficiency, or mitochondrial disorders. Fatty
`acid oxidation disorders also feature absence or decreased generation of ketone bodies,
`in contrast to other causes of metabolic acidosis (see Chapter 16). Note: Hyperammonemia
`diagnostic algorithms. A variety of factors influence the levels of metabolites encountered in metabolic
`disorders associated with hyperammonemia, including clinical status, nutritional intake, and the severity
`of a given mutation. In addition, non-classical or variant forms ofinborn errors of metabolism exist in
`most cases. Therefore, these algorithmsare useful general guides, but not all patients will fit neatly into
`simple diagnostic paradigms.
`
`Page 12 of 26
`
`

`

`266
`
`SIGNS AND SYMPTOMS OF GENETIC CONDITIONS
`
`in urea cycle disorders and organic acidemia. In addition, other laboratory findings,
`especially hypoketotic hypoglycemia, may provide a clue to the existence of an under-
`lying fatty acid oxidation disorder. Rarer causes of hyperammonemia include the
`hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, lysinuric
`protein intolerance, hyperammonemia hyperinsulinism syndrome, and some mito-
`chondrial disorders (Table 18.1). These latter conditions are usually not associated with
`ammonia levels higher than about 300 uM.
`Expanded newborn screening using tandem mass spectrometry (MS/MS) is
`becoming the standard in developed countries. MS/MSscreeningis effective in detect-
`ing commonorganic acidemias, such as methylmalonic acidemia, propionic acidemia,
`and isovaleric acidemia, but does not yet detect some urea cycle disorders, including
`ornithine transcarbamylase deficiency, carbamoyl phosphate synthase deficiency, and
`N-acetylglutamate synthase deficiency. On the other hand, argininosuccinate synthase
`deficiency (citrullinemia), argininosuccinate lyase deficiency, and arginase deficiency
`have been detected by MS/MS newbornscreening. The presence of a normal MS/MS
`expanded newborn screen should not deter the clinician from performing a complete
`metabolic evaluation in patients who have signs and symptoms suggestive of an inborn
`error of metabolism.
`
`UREA CYCLE DISORDERS
`
`Urea cycle disorders are an important cause of hyperammonemia. The blood urea
`nitrogen level is often, but not invariably low, suggesting the underlying difficulty with
`ureagenesis. Because ammonia is a central respiratory stimulant, a respiratory alkalo-
`sis is common. Although these conditions present most dramatically in neonates, ini-
`tial symptoms can occurat any age. Indeed, only about one-third of urea cycle disease
`patients initially present in the neonatal period. Common signs and symptomsinclude
`poor feeding, increased respiratory rate, and lethargy progressing to coma. Cerebral
`edema andseizures may also occur. Children and adults may have alterations in behav-
`ior, psychiatric symptoms, and ataxia. Gastrointestinal symptoms are also common
`(Table 18.3). Trichorrhexis nodosa (dull, brittle hair) surrounded by partial alopecia
`may occur in argininosuccinic acid lyase deficiency. Insidiously progressive spasticity
`and developmental delay are more commonfindings in arginase deficiency, although
`rare cases of neonatal hyperammonemia have been reported. Hyperammonemia may
`be mild or even absent in arginase deficiency. Individuals affected by urea cycle defects
`mayself-restrict protein intake, and this may provide an important clue to the underly-
`ing diagnosis. Symptomsare typically intermittent, appearing during times of physi-
`ological stress, such as illness severe enough to cause catabolism, prolonged fasting,
`or childbirth. Although significant liver disease is relatively uncommonin urea cycle
`disorders, transaminase elevations, hepatic fibrosis, and even acute liver failure with
`coagulopathy may occur. Amongthe urea cycle disorders, argininosuccinic acid lyase
`deficiency in particular is associated with hepatic involvement that ranges from hepa-
`tomegaly to progressive liver fibrosis. Altered mental status without evidence of liver
`damage should alert the clinician to check an ammonia level, otherwise late-onset urea
`cycle defects may be missed.
`
`Page 13 of 26
`
`Page 13 of 26
`
`

`

`Hyperammonemia
`
`267
`
`ORGANIC ACIDEMIAS
`Organic acidemias may cause significant hyperammonemia in neonates and infants by
`secondary inhibition of the urea cycle. Common neonatal symptomsare poor feeding
`and lethargy that may progress to coma. Developmental delay, intellectual disability,
`episodic vomiting, and failure to thrive are often encounteredin older children with
`organic acidemias. Further details of the clinical presentation are given in Chapter 16.
`
`FATTY ACID OXIDATION DISORDERS
`Fatty acid oxidation disorders (FAOD) are disorders of energy metabolism that are
`associated with non- or hypoketotic hypoglycemia and sudden-onset multisystem organ
`failure (Reye-like syndrome). Fasting during an intercurrent illness often precipitates a
`metabolic crisis characterized by encephalopathy, coma, suddeninfant death syndrome
`(SIDS), near-SIDS, or an acute life-threatening event (ALTE).Chronically ill patients
`have failure to thrive, recurrent vomiting and infections, cardiomyopathy, liver disease,
`and skeletal myopathy. Severe elevations in creatine phosphokinase may occur during
`crises, especially in the disorders oflong-chain fat catabolism (e.g., VLCAD deficiency).
`Cardiomyopathy is also more commonly encountered in long-chain disorders; both
`cardiac and skeletal muscle use long-chain fats as fuel. Hyperammonemiais typically
`not a major manifestation ofFAOD,but on occasion may be significant andlead to con-
`fusion with urea cycle defects or organic acidemias. Carnitine-acylcarnitine translocase
`deficiency, in particular, may be associated with significant hyperammonemia.
`
`AMINO ACID TRANSPORTER DISORDERS
`The urea cycle may be affected in a secondary fashion by defects in transporters respon-
`sible for providing essential components for its function. HHHsyndromeis caused by
`defective ornithine transport into mitochondria from the cytosol, leading to dimin-
`ished intramitochondrial ornithine concentration and secondary urea cycle inhibition.
`The mitochondrial ornithine transporter is encoded by the gene SLC2SAI1S. Clinical
`features are similar to primary urea cycle enzyme disorders, although the associated
`hyperammonemiatendsto berelatively mild. Patients present with growthdeficiency,
`episodic lethargy, vomiting, ataxia, hypotonia or hypertonia, developmental delay, and
`intellectual disability.
`Lysinuric protein intolerance (LPI) is caused by a defect in a dibasic amino acid
`transporter (system y*L) coded for by the SLC7A7 gene and expressed in the kidney,
`small intestine, lung, and white blood cells. Renal loss ofthe dibasic amino acids lysine,
`ornithine, and arginine results in decreased concentrations of substrates essential for
`urea cycle function. Affectedinfants are typically asymptomatic when breastfed, but
`develop symptoms upon weaning. Common features include growth failure, vomit-
`ing, diarrhea, and hyperammonemic encephalopathy following high protein ingestion.
`Protein aversion is often present in older children. Other signs of LPI include sparse
`hair, hepatosplenomegaly, hypotonia, delayed bone maturation, and osteoporosis. Most
`patients have abnormal chest radiographs, showing interstitial changes suggestive of
`
`Page 14 of 26
`
`Page 14 of 26
`
`

`

`268
`
`SIGNS AND SYMPTOMS OF GENETIC CONDITIONS
`
`fibrosis. Sore patients develop pulmonary alveolar proteinosis and acute or chronic
`pulmonary compromise, which may befatal.
`,
`Type Il citrullinemia or citrin deficiency is caused by a defect in the mitochondrial
`aspartate-glutamate transporter citrin, encoded by the SLC2SA13 gene. There is a
`decrease of function of argininosuccinate synthase by an unknown mechanism leading
`to elevated citrulline levels. There are two main clinical presentations of this disorder.
`The neonatalillness is associated with cholestasis and liver disease, with absent or only
`mild hyperammonemia and elevated citrulline. The clinical course is often mild, and
`symptoms may resolve with supportive care. More commonly, citrullinernia type IH
`presents in older children or adults with hyperammonemia and neurological signs that
`resemble hepatic encephalopathy. This is a severe, progressive disorder, and death from
`cerebral herniation often occurs within several years of initial diagnosis. Both presenta-
`tions appear to occur more commonly in Asians.
`
`OTHER INBORN ERRORS OF METABOLISM
`
`Pyruvate carboxylase deficiency and disorders of the mitochondrial respiratory chain
`may also be associated with hyperammonemia. Pyruvate carboxylase deficiency exists
`in two forms. The more commontype features lactic acidosis, seizures, severe intellec-
`tual disability, andearly death. A rare form is characterized by a more severe phenotype
`with early demise, hyperammonemia and elevations of plasmacitrulline and lysine.
`Mitochondrial disorders are often multisystemic conditions. Hyperammonemia, and
`even fulminanthepatic failure, may occur in mitochondrial disease, but other laboratory
`findings, such as lactic acidemia, tend to predominate.
`Hyperinsulinism and hyperammonemia syndrome (HHS) is characterized by rela-
`tively mild hyperammonemia (90-200 uM) and moderately severe hyperinsulinism.
`HHS is an unusual inborn error of metabolism because it is inherited in an autosomal
`dominant fashion. The main clinical manifestations are secondary to hypoglycemia
`encountered in the neonatal periodor infancy. Hypoglycemic seizures are usually theini-
`tial presenting sign. Macrosomia may be presentat birth, but most patients have normal
`birth weights. Continuous oral or intravenous glucose is typically needed to control the
`hypoglycemiainitially. Patients respond to medical treatment consisting of diazoxide, a
`leucine-restricted diet, and cornstarch supplementation. The cause of HHS is excessive
`glutamate dehydrogenase (GDH)activity secondary to decreased sensitivity to guanosine
`triphosphate (GTP), a compoundthat normally exerts feedback inhibition ofthis enzyme.
`In theory, increased GDH activity leads to an increased formation of a-ketoglutarate (and
`decreased glutamate), which results in an increased ATP/ADPratio in pancreatic B cells
`and subsequentinsulin secretion. Because glutamate is a precursor to N-acetylglutamate,
`a decreased arnountof the latter compound could lead to impaired urea cycle function
`(N-acetylglutamateis essential in the activation of carbamyl phosphate synthetase).
`A}-pyrroline-5-carboxylate is a precursor of ornithine. A’-pyrroline-S-carboxylate
`synthase (P5CS) deficiency leads to decreased ornithine levels and secondary inhibi-
`tion of the urea cycle. Affected individuals have progressive neurodegeneration,bilat-
`eral subcapsular cataracts, joint laxity, and hyperelastic skin. Nonspecific signs and
`symptomsoccurin early infancy and include failure to thrive, emesis, hypotonia, and
`intellectual disability. Hyperammonemiais mild.
`
`Page 15 of 26
`
`Page 15 of 26
`
`

`

`Hyperammonemia
`
`269
`
`TATROGENIC HYPERAMMONEMIA
`Iatrogenic causes ofhyperammonemia include treatment with valproate and cancer che-
`motherapy with L-asparaginase or high-dose cytoreductive therapy. The onset of val-
`proic acid-induced hyperammonemic encephalopathyis heraldedby acute-onset altered
`mental status, focal or bilateral neurological symptomsor signs, and increased seizure
`frequency. A number of neurological signs, such as stupor, coma, behavioral changes,
`and psychiatric illness, may occur. An underlying urea cycle defect or carnitine defi-
`ciency maypredispose to these valproate side effects. Elevated levels of valproyl-CoA
`or one of its metabolites may inhibit the synthesis of N-acetylglutamate, leading to a
`decrease in urea cycle activity. Patients undergoing chemotherapy for leukemia with
`L-asparaginase may develop a hyperammonemic encephalopathy. Asparaginase hydro-
`lyzes the amido group of asparagine, causing release of ammonia. Idiopathic hyper-
`ammonemia has been described following high-dose cytotoxic chemotherapy with a
`variety of agents and following bone marrowtransplantation.
`Hyperammonemia has also been documented in infants receiving total parenteral
`nutrition (TPN). The pathogenesis of TPN-associated hyperammonemiais unclear,
`but is possibly related to hepatic immaturity in pre-term infants, deficient arginine, an
`excess protein load, or a combination of these factors. Over-restriction of dietary argi-
`nine in an attempt to treat the hyperornithinemia associated with gyrate atrophy has
`also been associated with hyperammonemia.
`Surgical procedures that directly divert urine into the gastrointestinal tract, such
`as an ureterosigmoidostomy, may lead to increased urea absorption and hyperammo-
`nemia. Portal-systemic shunt encephalopathy may occurif blood from the portal vein
`(relatively high ammonia concentration) bypasses the liver and enters the systemic
`circulation. Portal-systemic venous shunts have been identified after the initiation of
`hemodialysis; a rapid decrease in systemic intravenous blood pressure following the
`institution of dialysis may lead to the flow of relatively ammonia-rich blood from the
`portal system into the systemic venous system through previously unidentified abnor-
`mal vascular connections.
`
`UREASE-POSITIVE BACTERIA
`Bacteria that possess the ability to split urea, such as diptheroids or Proteus mirabilis, can
`cause systemic hyperammonemia, although the level of ammonia elevation tends to be
`considerably lower than that encountered in metabolic disease. Urinary stasis as a con-
`sequence of a dysfunctional bladder (e.g., neurogenic bladder, prune belly syndrome)
`may predisposeto bacterial colonization and hyperammonemia.
`
`LIVER FAILURE
`Hyperammonemia may also occur secondary toliver failure from any cause, acquired
`or inherited. In the neonatal period, perinatal asphyxia and disseminated herpes sim-
`plex infection may lead to severe liver dysfunction and hyperammonemia. In adults,
`cirrhosis is a relatively common predisposing factor that leads to hepatic encephalo-
`pathy. Inborn errors of metabolism that cause acuteliverfailure, such as transaldolase
`
`Page 16 of 26
`
`Page 16 of 26
`
`

`

`270
`
`SIGNS AND SYMPTOMS OF GENETIC CONDITIONS
`
`deficiency, hepatorenal tyrosinemia, Wilson disease, Niemann-Pick disease type C, or
`mitochondrial DNA depletion syndromes, may also be associated with hyperammo-
`nemia, althoughthelevel of elevation is typically mild to moderate (<500 uM). Severe
`liver failure may also occur in neonatal hemochromatosis, a condition thatis heteroge-
`neous in etiology.
`
`Diagnostic Evaluation
`
`Unless the clinical circumstances clearly point to the underlying etiology of hyper-
`ammonemia (e.g., asparaginase chemotherapy, bacterial infection with urea-splitting
`organism), a comprehensive metabolic evaluation should be performed to determine
`‘the cause of the abnormal elevation (Table 18.4). Most of the relatively commonly
`encountered metabolic disorders, such as urea cycle defects, organic acidemias, and
`fatty acid oxidation defects, can be detected by performing studies on blood for quanti-
`tative amino acids; total, free, and esterified carnitine levels; and an acylcarnitine profile
`and urine for organic acids and for quantitative orotic acid. Orotic acid is a key metabo-
`lite in the diagnostic evaluation of hyperammonemia and is typically highly elevated in
`males with OTC deficiency; it can be easily seen on organic acid analysis. However, cer-
`tain cases, such as OTC heterozygote fernales, may require obtaining a true quantitative
`orotic acid value by a methodology suchas stable isotope dilution gas chromatography/
`mass spectrometry or high-performance liquid chromatography, because elevations
`
`Table 18.4 Ynitial Metabolic Investigations in Hyperammonemia
`
`First-line studies
`Liver transaminases, alkaline phosphatase, bilirubin, prothrombin time
`Plasma amino acids
`Urine organic acids
`Urine quantitative orotic acid level
`Plasma carnitine levels (total, free, esterified)
`Plasmaacylcarnitine profile
`Other analyses
`Urine amino acids
`Urine homocitrulline level
`Ornithine transcarbamylase deficiency
`Citrullinemia (argininosuccinic aci