`
`15
`
`.S
`
`26
`
`C
`
`v
`
`SYMPTOMS
`
`GENETIC
`
`CONDITIONS
`
`A HANDBOOK
`
`x
`
`EDITED BY
`
`Louanne Hudgins
`
`Helga V. Toriello
`
`Gregory M. Enns
`
`H. Eugene Hoyme
`
`________m
`
`Page 1 of 26
`
`Horizon Exhibit 2029
`Lupin v. Horizon
`IPR2017—01159
`
`Page 1 of 26
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`

`

`Signs and Symptoms of
`Genetic Conditions
`
`Page 2 0f 26
`
`Page 2 of 26
`
`

`

`
`
`A HANDBOOK
`
`EDITED BY LOUANNE HUDGINS
`
`HELGA V. TORIELLO
`
`GREGORY M. ENNS
`
`H. EUGENE HOYME
`
`Page 3 0f 26
`
`
`UNIVERSITY PRESS
`
`Page 3 of 26
`
`

`

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`UNIVERSITY PRESS
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`Library of Congress Cataloging-in~Publication Data
`Signs and symptoms of genetic conditions : a handbook / edited by Louanne Hudgins, Helga V. Toriello,
`Gregory M. Enns, H. Eugene Hoyme.
`p. ; cm.
`Includes bibliographical references.
`ISBN 978~O—19~993097—S (alk. paper)
`II. 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 'I‘estinngandbooks.
`5. Signs and Syinptomstandbooks. WS 39]
`RB 1 5 5 .5
`616’.O42-dc23
`
`III. Enns,
`
`2013048866
`.c.....-wa
`
`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 on the individual
`circumstances. And, while this material is designed to offer accurate information with respect to the subject
`matter covered and to be current as 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 accounted for regularly Readers must therefore always check the product information
`and clinical procedures with the most up—to—date published product information and data sheets provided by
`the manufacturers and the most recent codes of conduct and safety 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 mentioned in the material. The authors and the publisher do not
`accept, and expressly disclaim, any responsibility for any liability, loss or risk that may be claimed or incurred as a
`consequence of the use and/ or application of any of the contents of this material.
`
`9 8 7 6 S 4 3 2 1.
`Printed in the United States ofAmerica
`
`on acid—free paper
`
`Page 4 0f 26
`
`Page 4 of 26
`
`

`

`Contents
`
`Preface ix
`About theEditors xi
`
`Contributors xiii
`
`1. Genetic Testing 1
`GREGORY M. ENNS, LOUANNE HUDGINS,
`
`AND TINA M. COWAN
`
`2. Short Stature 9
`
`MELANIE A. MANNING
`
`3. Obesity 22
`DAVID J. AUGHTON
`
`4. Overgrowth Syndromes 34
`MARGARET P. ADAM
`
`5. Asymmetry 50
`OMAR A. ABDUL—RAHMAN
`
`6. Microcephaly 63
`CYNTHIA J. CURRY
`
`7. Macmcephaly 78
`HELGA V. TORIELLO AND MARGARET P. ADAM
`
`8. Alterations in Cranial Shape 94
`MICHAEL J. LYONS
`
`9. Brain Malformations 106
`
`ANNE SLAVOTINEK
`
`Page 5 0f 26
`
`V
`
`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
`
`14. 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
`
`22. Anomalies of the Eye 335
`GRAEME C. BLACK AND RACHEL GILLESPIE
`
`23. Facial Clefting 355
`MARILYN C. JONES
`
`Page 6 0f 26
`
`Page 6 of 26
`
`

`

`Contents
`
`vfi
`
`. 24. Congenital Heart Defects 368
`TOM CUSHING AND JOSEPH E C.SHIEH
`
`25. Genetics of Renal Malformations 380
`
`JOSEPH P C.SHIEH
`
`26. Limb Anomalies 387
`
`DAVID B. EVERMAN AND LESLIE G. BIESECKER
`
`27. Congenital Contractures: Emphasizing Multiple Congenital
`Contracturesw—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 509
`
`Page 7 0f 26
`
`Page 7 of 26
`
`

`

`
`
`Hyperammonemia
`
`GREGORY M. ENNS AND TINA M. COWAN
`
`Definition
`
`Hyperammonemia is defined as a blood ammonia concentration greater than about
`100 pM in neonates or 50 M in children and adults (precise cut—offs vary depend-
`ing on individual laboratory normative levels). A common cause of an apparently high
`ammonia level is improper specimen handling, leading to a factitiously increased value.
`Blood samples should be obtained from a free—flowing vein or artery and placed on ice
`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 9M), 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 amino acid trans—
`porter disorders, or in the context of a number of acquired conditions, such as a porto~
`caval shunt, bacterial overgrowth with organisms that can split urea, or the use of certain
`medications (Tables 18.1 and 18.2). Finally, any condition, either inherited or acquired,
`that causes liver failure may be associated with hyperammonemia.
`
`Clinical Assessment
`
`Although inborn errors of metabolism that are associated with significant hyperarnmo—
`nernia often manifest for the first time in neonates and young children, metabolic disor—
`ders can present for the first time at any age. Signs and symptoms will 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,
`which is Xelinked; 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 0f 26
`
`261
`
`Page 8 of 26
`
`

`

`262
`
`SIGNS AND SYMPTOMS OF GENETIC CONDITIONS
`
`Table 1 8. l
`
`inborn Errors ot’Metabolisrn with Associated Hyperanimonemia
`
`
`Urea cycle defects:
`N—Acetylglutamate synthetase deficiency
`
`Carbanioyl phosphate synthetase deficiency:
`Ornithine transcarbainylase deficiency
`Argininosuccinate synthetase deficiency (citrullinemia)
`Argininosuccinate lyase deficiency
`Arginase deficiency
`
`Amino acid transporter deficiencies:
`I-{yperornithinemia~hyperammonemia-homocitrullinemia
`
`syndrome
`
`Lysinuric protein intolerance
`Citrin deficiency (citrullinemia type II)
`Organic acidemias:
`Methylrnalonic acidemia
`Propionic acidemia
`Isovaleric acidemia
`
`Multiple carboxylase deficiency
`Multiple acyl—CoA dehydrogenase deficiency
`3~Hydroxy1nethylglutaryl—CoA dehydrogenase deficiency
`3—Methylcrotonyl-C0A 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—hydr0xyacyl—COA dehydrogenase deficiency
`Very—longchain acyleoA dehydrogenase deficiency
`
`Pyruvate carboxylase deficiency
`Mitochondrial disorders
`
`Hyperammonemia—hyperinsulinism syndrome (glutamate dehydrogenase mutations)
`Al—pyrroline-S—carboxylate synthase deficiency
`
`affected relative with a similar illness, and is of great diagnostic importance. This relaw
`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 given to family
`history of stillbirths, unexplained deaths, and neurological diseases or delayed develop~
`ment of any degree or severity. Maternal illness in pregnancy has also been associated
`with specific metabolic disorders and may yield a clue to the presence of an inborn error
`
`Page 9 0f 26
`
`Page 9 of 26
`
`

`

`Table 1 8.2 Acquired Hyperaminonemia
`
`
`Hyperammonemia
`
`263
`
`Sampling artifact
`Cardiovascular:
`
`Patent ductus venosus
`
`Portocaval shuntl
`
`Hypovolemia
`Congestive heart failure
`
`Perinatal asphyxia
`Liver failure:
`
`Infectious hepatitis (e.g., HSV) »
`
`Bacterial colonization (urease positive organisms):
`Neurogenic bladder
`Prune belly syndrome
`Blind loop syndrome
`Ureterosigmoidostomy
`
`Iatrogenic:
`Valproate
`Asparaginase chemotherapy
`High~dose cytoreductive chemotherapy
`Bone marrow transplantation
`
`Arginine deficiency
`Total parenteral nutrition
`
`1 Hyperaminoneinia has been seen in patients with hepatic arteriovenous malformations, including
`those who have Osler—Weber~Rendu syndrome.
`
`of metabolism in a neonate. For example, acute fatty liver of pregnancy or the hemolysis,
`elevated liver enzymes, low platelets (HELLP) syndrome may occur in a heterozygous
`mother carrying a fetus with long—chain 3—hydroxyacyl—COA dehydrogenase (LCHAD)
`deficiency or other fatty acid oxidation disorders.
`
`NEONATAL HYPERAMMONEMIA
`
`Any neonate presenting with nonspecific signs of distress, such as poor feeding, lethargy,
`or abnormal respiratory pattern, is typically evaluated for sepsis. However, hyperammo—
`nemia may cause similar symptoms. Because urea cycle disorders and organic acidemias
`in some instances yield little in the way of diagnostic clues when routine laboratory tests
`(i.e., complete blood count and electrolytes) are checked, some cases will undoubtedly
`be missed or the diagnosis delayed, unless a blood ammonia level is also checked upon
`initial presentation. If diagnosis is delayed, the ammonia level will continue to rise, caus»
`ing progressive obtundation, and permanent brain damage may ensue.
`In the case of significant and progressive hyperammoneinia 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 0f 26
`
`Page 10 of 26
`
`

`

`264
`
`SIGNS AND SYMPTOMS OF GENETIC CONDITIONS
`
`Table 18.3 Frequent Signs and Synnptems of Hyperammonemia
`
`
`
`Neonates/infant‘s
`Feeding difficulty
`
`Vomiting
`Lethargy, progressing to coma
`Tachypnea
`Hypotherinia/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 transarninases, 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 hyperammonernia; it lnay 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.
`lnborn errors of metabolism often present in the neonatal period with extremely
`high levels of ammonia (>1,000 9M), although initial symptoms may occur at lower
`levels (>200
`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 0f 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 ammonia levels also
`can be seen in transient hyp erarnrnonemia of the newborn (TI—IAN). However, THAN
`tends to present Within the first day of life in a pre~term infant, whereas inborn errors of
`metabolism usually have initial symptoms after the first 24 hours (Figure 18.1
`Organic acidemias cause approximately one—third of cases of neonatal. hyperamnio—
`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—acylcarnitine translocase (CACT) deficiency, mediuin—chain .acyl—COA
`dehydrogenase
`deficiency,
`long~chain 3-hydroxyacleoA dehydrogenase
`(LCHAD) deficiency, very~long—chain acyl—COA dehydrogenase (VLCAD) deficiency,
`and acyl~CoA dehydrogenase~9 (ACAD—Q) deficiency may also cause neonatal hyper—
`aminonemia, although the level of elevation is typically not as high as that encountered
`
`
`HYPERAMMONEMIA
`
`
`
`
`Hyperammonemia
`Sampling
`
`
`
`Sample on ice
`confirmed on repeat
`
`testing
`
`
`
`
`
`
`Symptoms <24 h
`Hyperammonemia
`
`
`Preterm delivery
`of the Newborn
`
`
`Metabolic acidosis
`
`
`
`
`
`Transient
`
`Organic
`
`acidemias
`
`
`
`
`
`Fatty aCid ox1dation
`disorders
`
`Organic aciduria
`+/— Lactic acidemia
`
`
`
`
`
`
`
`Mitochondrial disease
`
`
`
`Pyruvate carboxylase
`deficiency
`
`
`
`Figure l 8. 1 Metabolic acidosis. It is most important to ensure that the ammonia levels
`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 (TPIAN) typically presents on
`day of life 1 in pre—terin infants with extremely high levels of ammonia (> 1,000 ELM) . The
`ammonia levels associated-With organic acidernias 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 hyperammonernia, including clinical status, nutritional intake, and the severity
`of a given mutation. In addition, non—classical or variant forms of inborn errors of metabolism exist in
`most cases. Therefore, these algorithms are useful general guides, but not all patients will fit neatly into
`
`simple diagnostic paradigms.
`
`Page 12 0f 26
`
`Page 12 of 26
`
`

`

`266
`
`SIGNS AND SYMPTOMS 0F GENETIC CONDITIONS
`
`in urea cycle disorders and organic acideniia. 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 hyp erammonemia include the
`hyperornithinernia~hyperammoneinia-homocitrullinuria (lrll-ll—l) syndrome, lysinuric
`protein intolerance, hyperamrnonemia hyperinsulinism syndrome, and some mito-
`chondrial disorders (Table 1 8.1). These latter conditions are usually not associated with
`ammonia levels higher than about 300
`Expanded newborn screening using tandem mass spectrometry (MS/MS) is
`becoming the standard in developed countries. MS /MS screening is effective in detect—
`ing ceinmon organic acidemias, such as methylrnalonic acidemia, propionic acidemia,
`and isovaleric acidernia, 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 newborn. screening. 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 occur at any age. Indeed, only about one—third of urea cycle disease
`patients initially present in the neonatal period. Common signs and symptoms include
`poor feeding, increased respiratory rate, and lethargy progressing to coma. Cerebral
`edema and seizures 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. lnsidiously progressive spasticity
`and developmental delay are nlore conlmon findings 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
`may self-restrict protein intake, and this may provide an important clue to the underly~
`ing diagnosis. Symptoms are typically intermittent, appearing during times of physi—
`ological stress, such as illness severe enough to cause catabolisrn, prolonged fasting,
`or childbirth. Although significant liver disease isrelatively uncommon in urea cycle
`disorders, transaminase elevations, hepatic fibrosis, and even acute liver failure with
`coagulopathy may occur. Among the 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 0f 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 symptoms are poor feeding
`and lethargy that may progress to coma. Developmental delay, intellectual disability,
`episodic vomiting, and failure to thrive are often encountered. in older children with
`organic acidernias. 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 hyp oketotic hypoglycemia and sudden~ons et multisystem organ
`failure (Reye—like syndrome). Fasting during an intercurrent illness often precipitates a
`metabolic crisis characterized by encephalopathy, coma, sudden infant death syndrome
`(SIDS), near—SIDS, or an acute life-threatening event
`Chronically ill patients
`have failure to thrive, recurrent vomiting and infections, cardiomyopathy, liver disease,
`and skeletal inyopathy. 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. I-Iyperainmonemia is typically
`not a major manifestation of PAOD, but on occasion may be significant and. lead 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 maybe affected in a secondary fashion by defects in transporters respon—
`sible for providing essential components for its function. I-lI-IH syndrome is caused by
`defective ornithine transport into mitochondria from the cytosol, leading to dirnin~
`ished intramitochondrial ornithine concentration and secondary urea cycle inhibition.
`'Ihe mitochondrial ornithine transporter is encoded by the gene SLCZSAlS. Clinical
`features are similar to primary urea cycle enzyme disorders, although the associated
`' hyperarnmonemia tends to be relatively mild. Patients present with growth deficiency,
`episodic lethargy, vomiting, ataxia, hypotonia or hyp ertonia, 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 of the dibasic amino acids lysine,
`ornithine, and arginine results in decreased concentrations of substrates essential for
`urea cycle function. Affected infants are typically asymptomatic when breastfed, but
`develop symptoms upon weaning. Common features include growth failure, voniit—
`ing, diarrhea, and hyperammonemic encephalopathy following high protein ingestion.
`Protein aversion is often present in older children. Other signs of LP]. include sparse
`hair, hepatosplen omegaly, hypotonia, delayed bone maturation, and osteoporosis. Most
`patients have abnormal chest radiographs, showing interstitial changes suggestive of
`
`Page 14 0f 26
`
`Page 14 of 26
`
`

`

`268
`
`SIGNS AND SYMPTOMS OF GENETIC CONDITIONS
`
`fibrosis. Some patients develop pulmonary alveolar proteinosis and acute or chronic
`pulmonary compromise, which may be fatal.
`I
`Type II citrullinemia or citrin deficiency is caused by a defect in the mitochondrial
`aspartate-glutamate transporter citrin, encoded by the SLC25A13 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 neonatal illness is associated with cholestasis and liver disease, with absent or only
`mild hyperarnmonemia and elevated citrulline. The clinical course is often mild, and
`symptoms may resolve with supportive care. More commonly, citrullinemia type IT
`presents in older children or adults with hyperamrnonemia 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 common type features lactic acidosis, seizures, severe intellec—
`tual disability, and early death. A rare form is characterized by a more severe phenotype
`with early demise, hyperammonemia and elevations of plasma citrulline and lysine.
`Mitochondrial disorders are often multisystemic conditions. Hyperammonemia, and
`even fulrnin ant hepatic failure, may occur in mitochondrial disease, but other laboratory
`findings, such as lactic acidemia, tend to predominate.
`l-Iyperinsulinism and hyperammonemia syndrome (HHS) is characterized by relaw
`tively mild hyperammonemia (90w200
`and moderately severe hyperinsulinism.
`PIT-IS 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 period or infancy. Hypoglycernic seizures are usually the ini—
`tial presenting sign. Macrosomia may be present at birth, but most patients have normal
`birth weights. Continuous oral or intravenous glucose is typically needed to control the
`hypoglycemia initially. 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 compound that 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/ADP ratio in pancreatic B cells
`and subsequent insulin secretion. Because glutamate is a precursor to N~acetylglutarnate,
`a decreased amount of the latter compound could lead to impaired urea cycle function
`(N-acetflglutamate is essential in the activation of carbamyl phosphate synthetase).
`Al-pyrroline—5~carboxylate is a precursor of ornithine. Al—pyrroline—S-carboxylate
`synthase (PSCS) 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
`symptoms occur in early infancy and include failure to thrive, emesis, hypotonia, and
`intellectual disability. Hyperammonemia is mild.
`
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`Hyperammonemia
`
`269
`
`IATROGENIC HYPERAMMONEMIA
`
`Iatrogenic causes ofhyp erammonemia include treatment with valproate and cancer che—
`motherapy with L—asparaginase or high-dose cytoreductive therapy. The onset of val—
`proic acid—induced hyperanimonemic encephalopathy is heralded by acute~onset altered.
`mental status, focal or bilateral neurological symptoms or 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 may predispose 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 marrow transplantation.
`I~Iyperammonemia has also been documented in infants receiving total parenteral
`nutrition (TPN). The pathogenesis of TPN~associated hyperammonemia is unclear,
`but is possibly related to hepatic immaturity in preterm 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—
`neniia. Portal—systemic shunt encephalopathy may occur if 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 frein the
`portal system into the systemic venous system through previously unidentified. cbnor—
`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 predispose to bacterial colonization and hyp erammonemia.
`
`LIVER FAILURE
`
`l—lyperammoneinia may also occur secondary to liver 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 hyperaininoneniia. In adults,
`cirrhosis is a relatively common predisposing factor that leads to hepatic encephalo—
`pathy. lnborn errors of metabolism that cause acute liver failure, such as transaldolase
`
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`270
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`SIGNS AND SYMPTOMS OF GENETIC CONDITIONS
`
`deficiency, hepatorenal tyrosinemia, Wilson disease, Niernann—Pick disease type C, or
`mitochondrial DNA depletion syndromes, may also be associated with hyperammo—
`nemia, although the level of elevation is typically mild to moderate (<SOO uM). Severe
`liver failure may also occur in neonatal hemochrornatosis, a condition that is 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 hyperanimonemia 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 females, may require obtaining a true quantitative
`orotic acid value by a methodology such as stable isotope dilution gas chromatography/
`mass spectrometry or high»performance liquid chromatography, because elevations
`
`Table 1 8 .4 Initial Metabolic Investigations in Hyp erammoneinia
`
`
`First~line studie