15
`
`.S
`
`28
`
`C
`
`v
`
`SYMPTOMS
`
`GENETIC
`
`CONDITIONS
`
`A HANDBOOK
`
`x
`
`Page 1 of 26
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`Horizon Exhibit 2029
`Lupin v. Horizon
`IPR2016-00829
`
`

`

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

`

`
`
`A HANDBOOK
`
`EDITED BY LOUANNE HUDGINS
`
`HELGA V. TORIELLO
`
`GREGORY M. ENNS
`
`H. EUGENE HOYME
`
`Page 3 of 26
`
`
`UN'1VERSI']'.‘Y PRESS
`
`Page 3 of 26
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`

`

`OXFORD
`U'NIVERSITY PRESS
`
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`Library of Congress Cataloging-in~Publication Data
`Signs and symptoms of genetic conditions : a handbook / edited by Louanne I-Iudgins, Helga V. Toriello,
`Gregory M. Enns, H. Eugene Hoyme.
`p. ,- cm.
`Includes bibliographical references.
`ISBN 97s~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—«I-Iandbool<s.
`2. Genetic Diseases, Inborn——diagnosis--Handbooks.
`Diiferential—Handbooks.
`4. Genetic T‘esting~—-Handbooks.
`5. Signs and Symptoms-Handbooks. WS 39]
`RB 1 5 5 .5
`616’.042—~dc2.3
`
`III. Enns,
`
`2013048866
`_........V__M,.......
`
`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 eflicacy of the drug dosages mentioned in the material. The authors and the publisher do not
`accept, an.d 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 5 4 3 2 1.
`Printed in the United States ofAmerica
`
`on acid—free paper
`
`Page 4 of 26
`
`Page 4 of 26
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`

`

`Contents
`
`Preface ix
`About the Editors 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. Micmcephaly 63
`CYNTHIA J. CURRY
`
`7. Macrocephaly 78
`HELGA V. TORIELLO AND MARGARET P. ADAM
`
`8. Altéarations in Cran1’alShape 94
`MICHAEL J. LYONS
`
`9. Brain Mahcorrnafionss 106
`
`ANNE SLAVOTINEK
`
`Page 5 of 26
`
`V
`
`Page 5 of 26
`
`

`

`vi
`
`CONTENTS
`
`10. Intellectual Disability 122
`AGATINO BATTAGLIA
`
`11. Autism Spectrum Disorders 136
`MARWAN SHINAWI
`
`12.. Hypotonia 145
`ELLIOTT H. SHERR AND GREGORY M. ENNS
`
`13. Weakness 164
`
`AMY l<AO 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 251
`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 Cletting 355
`MARILYN C. JONES
`
`Page 6 of 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 327
`
`DAVID B.EVERMAN AND LESLIE(L 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 I<WAN AND H. EUGENE HOYME
`
`Index 509
`
`Page 7 of 26
`
`Page 7 of 26
`
`

`

`
`
`Hyperammonemia
`
`GREGORY M. ENNS AND TINA M. COWAN
`
`Definition
`
`Hyperarnmonemia is defined as a blood ammonia concentration greater than about
`100 p.I\/I in neonates or 50 yl\/I in children and adults (precise cutoffs vary depend-
`ing on individual laboratory normative levels). A common cause of an apparently high
`aminonia level is iniproper specimen handling, leading to a factitiously increased value.
`Blood samples should be obtained frorn 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 ulvl), 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.
`
`Ctinical Assessment
`
`Although inborn errors of metabolism that are associated with significant hyperamrno—
`nernia often rnanifest for the first time in neonates and young children, rnetabolic 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 X~linl<ed,- hyperarnrnonenaia hyperinsulinisrn syndrome, which is autosoinal
`doininant; and sonne disorders of Initochondrial respiratory chain function, which may
`exhibit rnaternal inheritance. A detailed family history .may reveal the existence of an
`
`Page 8 of 26
`
`251
`
`Page 8 of 26
`
`

`

`262
`
`SIGNS AND SYMPTOMS OF GENETIC CONDITIONS
`
`Table 1 8. 1
`
`inborn Errors nfls/iietaboiisni with Associated Hyperarnnionenaia
`
`
`Urea cycle defects:
`lV—Acetylglutam.ate synthetase deficiency
`
`Carbanioyl phosphate synthetase deficiency:
`Ornithine transcarbaniylase 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:
`D/Iethylinalonic acidemia
`Propionic acidemia
`Isovaleric acidemia
`
`l\/Iultiple carboxylase deficiency
`Multiple acyl-COA dehydrogenase deficiency
`3~Hydroxy;methylglutaryl— COA. dehydrogenase deficiency
`3—Methylcrotonyl—CoA carboxylase deficiency
`3—Oxothiolase deficiency
`
`L—2~HydroXyglutaric acidemia
`3—lVlethylglutaconyl—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 dehyclrogenase deficiency
`Very—long~chain acyl~CoA dehydrogenase deficiency
`
`Pyruvate carboxylase deficiency
`lvlitochondrial disorders
`
`Hyperammonemia~hyperinsulinism syndrome (glutamate dehydrogenase mutations)
`A1—pyrroline—5—carboxylate synthase deficiency
`
`affected relative with a similar illness, 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—linl<ed disease. Some disorders are caused by mitochondrial DNA mutations,
`therefore maternal transrnission 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. l\/laternal 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 of 26
`
`Page 9 of 26
`
`

`

`Table 1 8.2 Acquired Hyperarninonemia
`
`
`Hyperammonemia
`
`263
`
`Sampling artifact
`Cardiovascular:
`
`Patent ductus venosus
`
`Portocaval shuntl
`
`I-Iypovolemia
`Congestive heart failure
`
`Perinatal asphyxia
`Liver failure:
`
`Infectious hepatitis (e.g., HSV) »
`
`Bacterial colonization (urease positive organisms):
`Neurogenic bladder
`Prune belly syndrome
`Blind loop syndroine
`Ureterosigmoidostomy
`
`Iatrogenic:
`Valproate
`Asparaginase cheniotherapy
`High~dose cytoreductive chemotherapy
`Bone rnarrow transplantation
`
`Arginine deficiency
`Total parenteral nutrition
`
`1 Hyperaminoneinia has been seen in patients with hepatic arteriovenous inalforinations, 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
`rnother carrying a fetus with long~chain 3—hydroxyacyl~CoA dehydrogenase (LCI-IAD)
`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 sonie 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, <:aus~
`ing progressive obtundation, and perrnanent brain damage may ensue.
`In the case of significant and progressive hyperarnmoneinia in a neonate, the
`acid—base status may provide a clue to the underlying diagnosis. Tachypnea with an
`associated respiratory alkalosis coinmonly occurs in urea cycle disorders "because of
`
`Page 10 of 26
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`Page 10 of 26
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`

`

`264
`
`SIGNS AND SYMPTOMS OF GENETIC CONDITIONS
`
`Table 18.3 Frequent Signs and Synnptoms of Hyperanirnoneniia
`
`
`
`Neonates/infants
`Feeding difficulty
`
`Vomiting
`Lethargy, progressing to coma
`Tachypnea
`Hypotherinia/hypertherrnia
`
`Hypotoiiia
`Seizures
`
`Pulmonary heinorrhage
`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
`allcalosis (secondary to ernesis) and even metabolic acidosis (frorn circulatory failure
`and poor peripheral perfusion) niay 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 allcalosis (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 hyperamrnonernia; it inay 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 acidernias are associated
`with severe metabolic acidosis, and urea cycle disorders are more commonly associated
`with respiratory alkalosis.
`Inborn errors of inetabolism often present in the neonatal period with extreinely
`high levels of arnrnonia (>l,OOO uM), although initial symptoins 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 hyperarnmonemia solely based on the degree of
`
`Page 11 of 26
`
`
`
`Page 11 of 26
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`

`

`Hyperammonemia
`
`265
`
`ammonia elevation. Organic acidemias may be associated with arnrnonia 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, TI-1Al\T
`tends to present Within the first day of life in a pre~term infant, whereas inborn errors of
`nnetabolisrn usually have initial symptoms after the first 24 hours (Figure 18.1
`Organic acidemias cause approximately one—third of cases of neonatal. hyperamrno—
`nemia secondary to inborn errors of metabolism, and urea cycle defects are respon-
`sible for the remaining two~third.s of cases. Fatty acid oxidation disorders, including
`carnitine-acylcarnitine translocase (CACT) deficiency, mediurn—chain .acyl—CoA
`dehydrogenase
`deficiency,
`long~cha.in 3-hydroXyacylCoA dehydrogenase
`(LCPIAD) deficiency, very~long-chain acyl—CoA dehydrogenase (VLCAD) deficiency,
`and acyl~CoA dehydrogenase—9 (ACAD—9) deficiency may also cause neonatal hyper-
`aminonernia, although the level of elevation is typically not as high as that encountered
`
`
`
`
`Sample on ice
`
`
`I-Iyperammonemia
`Sampling
`
`confirmed on repeat
`testing
`
`
`
`HYPERAMMONEMIA
`
`
`
`
`
`Hyperammonemia
`of the Newborn
`
`Transient
`
`
`Symptoms <24 h
`Preterm delivery
`
`Metabolic acidosis
`
`
`
`Organic aciduria
`+/— Lactic acidemia
`
`
`
`
`Organic
`
`acidemias
`
`
`
`Fatty acid oxidation
`disorders
`
`
`
`
`
`
`
`Mitochondrial disease
`
`
`
`Pyruvate carboxylase
`deficiency
`
`
`
`Figure 1 8. 1 Metabolic acidosis. It is most important to ensure that the ainmonia levels
`are obtained using proper sainpling and laboratory techniques (sample obtained from
`free—flowing vein or a.rtery and placed immediately on ice), in order to avoid false
`elevations. Transient hyperammonemia of the newborn (TPIALN) typically presents on
`day of life 1 in pre—terin infants with extremely high levels of ammonia (> 1,000 ulvl) . 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: Hyperammoneinia
`
`diagnostic algorithrns. A variety of factors influence the levels of metabolites encountered in metabolic
`disorders associated With hyperarnmonernia, including clinical status, nutritional intake, and the severity
`of a given mutation. In addition, non—classical or Variant forms of inborn errors ofrnetabolisrn exist in
`most cases. Therefore, these algoritlims are useful general guides, but not all patients will fit neatly into
`
`simple diagnostic paradigms.
`
`Page 12 of 26
`
`Page 12 of 26
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`

`

`266
`
`SIGNS AND SYMPTOMS OF GENETIC CONDITIONS
`
`in urea cycle disorders and organic acideniia. In addition, other laboratory findings,
`especially hypoketotic hypoglycernia, may provide a clue to the existence of an under-
`lying fatty acid oxidation disorder. Rarer causes of hyp eranimonemia include the
`hyperornith.inernia~hyperammoneinia-homocitrullinuria (lrll-ll—l) syndrorne, lysinuric
`protein intolerance, hyperainrnonernia liyperinsulinism syndrorne, and some mito-
`chondrial d.isorders (Table 1 8.1). These latter conditions are usually not associated with
`aminonia levels higher than about 300
`Expanded newborn screening using tandem inass spectrornetry (MS/MS) is
`becoming the standard in developed countries. MS /MS screening is effective in detect-
`ing coinmon organic acidemias, such as methylrnalonic acidemia, propionic acidemia,
`and isoval.eric acidernia, but does not yet detect some urea cycle disorders, including
`ornithine transcarbarnylase deficiency, carbarnoyl 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 frorn perforrning a complete
`metabolic evaluation in patients who have signs and symptoms suggestive of an inborn
`error of nietabolism.
`
`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 stirnulant, a respiratory alkalo-
`sis is common. Although these conditions present rnost dramatically in neonates, ini-
`tial syrnptoms 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
`edenia 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. Insidiously progressive spasticity
`and developmental delay are niore common findings in arginase deficiency, although
`rare cases of neonatal hyperamrnonemia have been reported. Hyperainmonemia may
`be mild or even absent in arginase deficiency. Individuals affected by urea cycle defects
`rnay selflrestrict protein intake, and this may provide an imp ortant clue to the underly-
`ing diagnosis. Synlptoms are typically interinittent, appearing during times of physi-
`ological stress, such as illness severe enough to cause catabolisin, prolonged fasting,
`or childbirth. Although significant liver disease isyrelatively uncoininon in urea cycle
`disorders, transarninase 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 arnrnonia level, otherwise late~onset urea
`cycle defects may be missed.
`
`Page 13 of 26
`
`Page 13 of 26
`
`

`

`/-/yperammonezmicz
`
`267
`
`ORGANIC ACIDEMIAS
`
`Organic acidemias may cause significant hyperatnmonemia in neonates and infants by
`secondary inhibition of the urea cycle. Conimon neonatal syrnptoms 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 rnetabolism that are
`associated with non— or hyp oketotic hypoglycemia and sudden~ons et rnultisystem organ
`failure (Reye~like syndrome). Fasting during an intercurrent illness often precipitates a
`metabolic crisis characterized by encephalopathy, coma, sudden infant death syndronie
`(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 i.n 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 hyperarnmonemia.
`
`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-II-II-I syndrome is caused by
`defective ornithine transport into mitochondria from the cytosol, leading to dirnin—
`ished intramitochondrial ornithine concentration and secondary urea cycle inhibition.
`The mitochondrial ornithine transporter is encoded by the gene SLCZSAIS. Clinical
`features are similar to priinary urea cycle enzyme disorders, although the associated
`I hyperanimonemia 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 d.ibasic arnino 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 asymptornatic wh.en breastfed, but
`develop symptorns upon weaning. Common features include growth failure, von1i.t—
`ing, diarrhea, and hyperarnrnonemic encephalopathy following high protein ingestion.
`Protein aversion is often present in older children. Other signs of LP]. include sparse
`hair, hepatosplen ornegaly, 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. Some patients develop pulmonary alveolar proteinosis and acute or chronic
`pulmonary comprornise, which may be fatal.
`I
`Type II citrullinemia or citrin deficiency is caused by a defect in the Initochondrial
`aspartate-glutamate transporter citrin, encoded by the SLC25./L13 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 rnay resolve with supportive care. More coinmonly, citrullinernia type II
`presents in older children or adults with hyperarnrnonemia and neurological signs that
`resemble hepatic encephalopathy. This is a severe, progressive disorder, and death from
`cerebral herniation often occurs Within several years of in.itial diagnosis. Both presenta~
`tions appear to occur more commonly in Asians.
`
`OTHER INBORN ERRORS OF METABOLISM
`
`Pyruvate carboxylase deficiency and disorders of the rnitochondrial respiratory chain
`may also be associated with hyperaminonemia. 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 inore severe phenotype
`with early demise, hyperammonemia and elevations of plasma citrulline and lysine.
`I\/Iitochondrial disorders are often multisystemic conditions. I-lyperammonemia, and
`even fulrnin ant hepatic failure, may occur in mitochond.rial disease, but other laboratory
`findings, such as lactic acidemia, tend to predominate.
`T-Iyperinsulinism and hyperammonemia syndrome (I-II-IS) is characterized by rela~
`tively mild hyperammonemia (90-2OO
`and moderately severe hyperinsulinism.
`PH-IS is an unusual inborn error of rnetabolism because it is inherited in an autosomal
`
`dominant fashion. The main clinical manifestations are secondary to hypoglycemia
`encountered in the neonatal period or infancy. I-lypoglycernic seizures are usually the ini-
`tial presenting sign. Macrosomia may be present at birth, but m.ost patients have nornial
`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 HI-IS is excessive
`glutamate dehydrogenase (GDI-I) activity secondary to decreased sensitivity to guanosine
`triphosphate (GT1?) , a compound that normally exerts feedback inhibition ofthis enzyine.
`In theory, increased GDH activity leads to an increased forination of cL—l<etoglutarate (and
`decreased glutamate), which results in an increased ATP/ADP ratio in pancreatic B cells
`and subsequent insulin secretion. Because glutaniate is a precursor to 1\7~acetylglutarnate,
`a decreased arnount of the latter compound could lead to iinpaired urea cycle function
`(l\f—acetylglutamate is essential in the activation of carbamyl phosphate synthetase).
`A1—pyr_roline—5~carboXylate is a precursor of ornithine. /.\1—pyrroline—5—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, ernesis, hypotonia, and
`intellectual disability. Hyperarnmonernia is mild.
`
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`

`Hyperammonemia
`
`269
`
`IATROGENIC HYPERAMMONEMIA
`
`latrogenic causes ofhyp eramrnonemia include treatment with valproate and cancer che-
`motherapy with L—aspara.ginase or high—dose cytoreductive therapy. The onset of val-
`proic acid—induced hyperainmonernic encephalopathy is heralded by acute~onset altered.
`mental status, focal or bilateral neu.rological 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~acety'lgluta1na‘te, leading to a
`decrease in u.rea cycle activity. Patients undergoing chemotherapy for leukemia with
`L-asparaginase may develop a hyperarnmonemic encephalopathy. Asparaginase hydro-
`lyzes the arnido group of asparagine, causing release of animonia. Idiopathic hyper—
`ammonemia has been described following high—dose cytotoxic chernotherapy with a
`variety of agents and following bone marrow transplantation.
`Iiyperammonemia has also been documented in infants receiving total parenteral
`nutrition (TPN). The pathogenesis of TPN~associated hyperamnionernia is unclear,
`but is possibly related to hepatic immaturity in pre~terrn 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 hyperornithinernia associated with gyrate atrophy has
`also been associated with hyperarnmonemia.
`Surgical procedures that directly divert urine into the gastrointestinal tract, such
`as an ureterosigmoidostomy, may lead to increased urea absorption and hyperamrno—
`neniia. Portal—systemic shunt encephalopathy may occur if blood from the portal vein
`(relatively high animonia 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 froin the
`portal system into the systemic. venous system through previously unidentified. cbnor—
`mal vascular connections.
`
`UREASE—POSITlVE BACTERIA
`
`Bacteria that possess the ability to split urea, such as diptheroids or Proteus mirczlailis, can
`cause systemic hyperamrnonernia, 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, pru.ne belly syndrome)
`may predispose to bacterial colonization and hyp erammonemia.
`
`LIVER FAILURE
`
`I-lyperarnrnonernia may also occur secondary to liver failure from any cause, acquired
`or inherited. In the neonatal period, perinatal asphyxia and disserninated 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 rnetabolism that cause acute liver failure, such as transaldolase
`
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`270
`
`SIGNS AND SYMPTOMS OF GENETIC CONDITIONS
`
`deficiency, hepatorenal tyrosinernia, Wilsoii disease, Nien1ann—Picl< disease type C, or
`rnitochondrial DNA depletion syndromes, may also be associated with hyperarnmo—
`nemia, although the level of elevation is typically mild to inoderate (<5OO uh/I). Severe
`liver failure inay also occur in neonatal hernochroniatosis, a condition that is heteroge-
`neous in etiology.
`
`Diagnostic Evaluation
`
`Unless the clinical circurnstances clearly point to the underlying etiology of hyper~
`ammonemia (e.g., asparaginase chemotherapy, bacterial infection with urea—splitting
`organism), a comprehensive inetabolic evaluation should be performed to determine
`the cause of the abnormal elevation (Table 18.4). l\/lost of the relatively commonly
`encountered rnetabolic disorders, such as urea cycle defects, organic acidemias, and
`fatty acid oxidation defects, can be detected by performing studies on blood for quanti~
`tative arnino 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 rnetabo~
`lite in the diagnostic evaluation of hyperainrnonemiav 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 cl1romatography/
`mass spectrometry or high~per