Proceedings of a Consensus Conference for the
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`Management of Patients with Urea Cycle Disorders
`Mart1halL Summar, MD, an'J Men'JeL Tuchman, MD
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`Urea cycle disorders are each caused by
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`inherited defects in genes encoding en­
`In an effort to develop standards for the treatment of patients with urea
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`zymes or membrane transporters in­
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`cycle disorders, a consensus conference was held in Washington, DC, from
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`volved in ureagenesis (Fig 1). Their
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`April 27-29, 2000. Conference participants included physicians, scientists,
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`overall prevalence is considered to be
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`nurses, dieticians, and a genetic counselor, all experts in their various med­
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`approximately 1:30,000 births; howev­
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`ical fields in these diseases. Representatives from the Food and Drug Ad­
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`er, there are no population studies to
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`ministration and the National Urea Cycle Disorders Foundation, a parents
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`support this frequency. The lack of
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`support group, also participated in the conference. The goals set forth for
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`newborn mass screening programs tar­
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`the conference were to (1) reach a consensus on diagnostic and therapeutic
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`geted at these disorders prevents us
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`guidelines for urea cycle disorders with the most up-to-date information and
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`from obtaining prevalence data. Urea
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`the experience of experts in the field, (2) establish a collaborative network
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`cycle disorders are a common cause of
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`of health care professionals to advance the cause of patients with urea cycle
`hype rammonemia, but be­
`inherited
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`disorders in the areas of clinical management and research, and (3) provide
`cause of the severe consequences of
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`help to health care providers in the recognition and management of these
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`these disorders for the patient, they
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`complex disorders by publishing the proceedings of the conference in a
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`should be distinguished from other in­
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`born errors of metabolism with sec­
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`widely read journal. The articles that follow this introduction represent the
`ondary hyp erammonemia such as fatty
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`current state of knowledge on the topics addressed in the conference and a
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`acid oxidation disorders, organic
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`summary of the discussions that followed each of the presentations. With
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`acidurias, nonketotic hyp erglycinemia,
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`input from all the participants, we tried to cover those topics that were be­
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`and congenital lactic acidoses. Acq uired
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`As the lieved to be the most relevant both to the experts and to patients.
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`hyperammonemia can frequently be
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`reader will appreciate, many unresolved and controversial issues pertaining
`seen in liver disease of various causes
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`methods. On the scientific to treatment have yet to be studied by rigorous
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`and after chemotherapy and organ
`other hand, there are many issues on which the panel agreed. In many in­
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`transplantation. Finally, there is a rare
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`stances the availability of reliable information on the respective topics deter­
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`and severe condition termed transient
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`mined whether consensus could be reached. (J Pediatr 2001;138:S6-S10)
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`found hyp erammonemia of the neonate,
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`predominantly in premature infants, the
`cause of which remains obscure.
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`A short summary on inherited urea
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`ment. Some of the content of this sum­
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`cycle disorders follows to provide the
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`mary was adapted from Tuchman M,
`CPS Carbamy l phosphate
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`synthetase I
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`reader with a succinct: background to
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`Batshaw ML: Urea cycle and related
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`HHH Hyperornithinemia, hyperammonemia,
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`the specific topics on diagnosis and
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`disorders in Rudolph's Textbook of
`homocitrullinemia
`management that make up this supple-
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`Pediatrics (in press).
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`LPI Lysinuric protein intolerance
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`NAGS N-acecyt glutamate synthase
`OTC Omithine transcarbamytase
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`The urea cycle disorders are caused
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`Reprint requests: Mendel Tuchman, MD , Children's National Medical Center, 111 M;chigan
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`by defects in the enzymes carbamyl
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`phosphate synthetase I, ornit:hine trans­
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`carbamylase, argininosuccinate syn­
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`thetase (citrullinemia), argininosucci-
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`S6
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`Page 1 of 5
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`Horizon Exhibit 2023
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`Par v. Horizon
`IPR2017-01769
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`;lf,J. From tlu Divi,ion of Jlfe.iJical Centtiu, VaniJerl,i/t Uni1,e.r;ity, N11Jbvill4 Tenne.,;u, and Chi/Jre.n '., National
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`ical Cente.r, tbe Ge;,rge WOJhington Univer;ity, lfl11Jbington, DC.
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`This conference was funded by an educational grant from Ucydyd Pharma, a subsidiary of
`SPECIFIC DISORDERS
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`Medicis Pharmaceutical Corpo ration.
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`Dr Tuchman is a paid consultant of Ucyclyd Pharma.
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`Ave, NW; Washington, DC20010.
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`Copyright© 2001 by Mosby, Inc.
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`0022-3476/2001/$35.00 + 0 9/0/111831
`doi:I0.1067/mpd.2001.111831
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`

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`THE JOURNAL OF PEDIATRICS
`VOLUME 138, NUMBER 1
`
`SUMMAR AND TUCHMAN
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`Fig 1. Complete urea cycle pathway that resides in liver is illustrated. Also shown are alternative pathways used to elimi-
`nate nitrogen in patients with urea cycle defects. CPS, Carbamyl phosphate synthetase; OTC, ornithine transcarbamylase;
`ASS, argininosuccinate synthetase, ASL, argininosuccinate lyase; ARG, arginase; NAGS, N-acetylglutamate synthase.
`
`nate lyase (argininosuccinic aciduria),
`arginase (hyperargininemia), and N-
`acetylglutamate synthase. Defects in the
`membrane transporter of dibasic amino
`acids (lysine, arginine, and ornithine)
`called hyperdibasic aminoaciduria or
`lysinuric protein intolerance, the mito-
`chondrial membrane ornithine transporter
`called hyperornithinemia, hyperammone-
`mia, homocitrullinuria syndrome, and the
`mitochondrial calcium-dependent trans-
`porter called citrullinemia type II should
`also be included in urea cycle disorders.
`Awareness by health care professionals
`of these genetic disorders is very impor-
`tant, because failure to recognize hyper-
`ammonemia often leads to brain damage
`or death and because these disorders
`
`frequently affect more than one family
`member.
`Ammonia is almost exclusively toxic
`to the brain. The pathophysiology is not
`well understood, but several hypotheses
`have been formulated based on bio-
`chemical and structural changes that
`are observed. Interference with energy
`metabolism or neurotransmitter metab-
`olism has been postulated. Brain edema
`rapidly develops during hyperammone-
`mic coma, and swelling of astrocytes
`has been observed on postmortem
`analysis. Plasma ammonia levels as low
`as 100 to 200 µmol/L are usually associ-
`ated with clinical symptoms of lethargy,
`confusion, and vomiting, and higher
`levels usually result in coma.
`
`The entire urea cycle resides exclu-
`sively in periportal hepatocytes. It is an
`essential biochemical pathway for
`waste nitrogen excretion. A cascade of
`enzymatic transformations converts the
`toxic ammonia molecule to nontoxic
`water-soluble urea containing 2 amino
`groups (one deriving from free ammo-
`nia and the other from aspartate) and is
`eliminated in the urine (Fig 1). Ammo-
`nia is also taken up by “scavengers”
`(eg, glutamate, pyruvate, and aspar-
`tate) and is also used in the synthesis of
`nitrogen-containing compounds (eg,
`glycine and pyrimidines including orot-
`ic acid). A block of the urea cycle can
`result either from an enzyme deficiency
`(CPS, OTC, NAGS, argininosuccinic
`
`S7
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`Page 2 of 5
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`SUMMAR AND TUCHMAN
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`acid synthetase, arginosuccinic acid
`lyase, or arginase) or depletion of an
`amino acid essential to the normal func-
`tion of the cycle resulting from a trans-
`port defect (HHH syndrome and LPI).
`A recently identified separate mito-
`chondrial transporter, the function of
`which is unknown, causes citrullinemia
`type II and is seen in Japanese adults.
`Except for OTC deficiency, which is
`transmitted as a partially dominant X-
`linked trait, all other known urea cycle
`disorders are transmitted as autosomal
`recessive traits. The gene associated
`with the enzyme deficiency has been
`identified in each of these disorders ex-
`cept NAGS, and deleterious mutations
`have been found in the respective
`genes of affected patients. Thus DNA
`analysis for mutation detection is pos-
`sible for each, enhancing both prenatal
`and postnatal diagnosis and carrier de-
`tection in affected families. The degree
`of the deleterious effect the mutation
`has on the respective protein’s function
`tends to correlate with the severity
`of the clinical course. However, the
`milder the mutation, the more hetero-
`geneous the resulting clinical picture.
`Unfortunately, newborn mass screen-
`ing is not currently available for the
`early diagnosis of these disorders.
`
`CLINICAL
`PRESENTATION
`
`In general, the more proximal the en-
`zyme defect, the more severe and resis-
`tant to treatment is the hyperammone-
`mia (ie, CPS and OTC deficiencies are
`the most severe). However, as noted
`previously, there is considerable het-
`erogeneity in the magnitude of hyper-
`ammonemia and age of initial presen-
`tation based not only on the position of
`the block within the urea cycle but also
`on the degree of the enzyme deficien-
`cy. The most severe cases have no en-
`zyme activity and present with hyper-
`ammonemic coma in the first week of
`life, whereas patients with the milder
`forms have some residual enzyme ac-
`
`S8
`
`tivity, and their clinical presentation
`occurs later in life (ranging from infan-
`cy to adulthood) with recurrent
`episodes of hyperammonemia. Ap-
`proximately 15% of OTC-deficient
`heterozygous female patients have
`symptoms of hyperammonemia some-
`time in their lives, presumably as a re-
`sult of skewed liver X-inactivation.
`Conversely, adults with no symptoms
`occasionally have been found with the
`same genetic defect that causes symp-
`toms in a family relative.
`
`Neonatal-onset Urea Cycle
`Disorders
`Infants with complete enzyme defi-
`ciencies are usually born at term with
`no prenatal complications, because the
`maternal circulation detoxifies the
`accumulating ammonia. Between 1 to
`5 days of age, however, they start feed-
`ing poorly, vomit frequently, become
`lethargic and hypotonic, and may hy-
`perventilate. The diagnosis of sepsis is
`frequently considered, and workup fails
`to detect evidence of infection. These
`babies will progressively have tremor,
`stupor, seizures, apnea, coma, increased
`intracranial pressure, and death if the
`hyperammonemia is not diagnosed and
`treated effectively. Plasma ammonia
`levels on acute neonatal presentation
`may reach levels higher than 1000
`µmol/L (normal <35). Other clinical
`findings may include hepatomegaly,
`mild serum liver enzyme elevations, and
`a coagulopathy, but liver function is fre-
`quently normal except for hyperam-
`monemia. Initial blood gas measure-
`ment typically shows a respiratory
`alkalosis (caused by hyperventilation).
`Pulmonary bleeding has been reported
`as a terminal event, but more frequently
`the cause of death is vascular compro-
`mise of the central nervous system.
`
`Late-onset Urea Cycle Disorders
`In patients with partial enzyme defi-
`ciencies, the first recognized clinical
`episode may be delayed for months or
`years; the hyperammonemia is less se-
`vere, and the symptoms are more sub-
`
`THE JOURNAL OF PEDIATRICS
`JANUARY 2001
`
`tle. The clinical abnormalities vary
`somewhat with the specific disorder. In
`most urea cycle disorders, the hyper-
`ammonemic episode is marked by loss
`of appetite, cyclical vomiting, lethargy,
`and behavioral abnormalities. Sleep
`disorders, delusions, hallucinations,
`and psychosis have also been reported.
`An encephalopathic (slow wave) elec-
`troencephalogram pattern may be ob-
`served during hyperammonemia, and
`nonspecific brain atrophy may be seen
`subsequently on magnetic resonance
`imaging.
`
`Associated Clinical
`Abnormalities
`In addition to the symptoms of hy-
`perammonemia, a number of hyperam-
`monemic disorders have other, more
`specific clinical abnormalities. In hy-
`perargininemia there is a progressive
`spastic diplegia, or quadriplegia that
`has also been observed in HHH syn-
`drome. Tremor, ataxia, and choreo-
`athetosis have also been reported in
`hyperargininemia, whereas retinal
`depigmentation and chorioretinal thin-
`ning have been observed in HHH syn-
`drome. Interstitial pneumonia caused
`by pulmonary alveolar proteinosis is
`seen in LPI, as are glomerulonephritis
`and osteoporosis; there may also be an
`underlying immune deficiency in this
`disorder. Trichorrhexis nodosa, a node-
`like appearance of fragile hair, is pathog-
`nomonic for argininosuccinic aciduria.
`
`DIFFERENTIAL
`DIAGNOSIS
`
`The diagnosis of congenital hyper-
`ammonemia should be considered on
`finding an elevated plasma ammonia
`level in association with only mild or
`no liver dysfunction and in the absence
`of ketoacidosis. A precipitating cata-
`bolic event such as an infection, trau-
`matic
`injury,
`ingestion of
`large
`amounts of protein, or other yet un-
`known metabolic stresses can precipi-
`tate hyperammonemia in these pa-
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`Page 3 of 5
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`THE JOURNAL OF PEDIATRICS
`VOLUME 138, NUMBER 1
`
`SUMMAR AND TUCHMAN
`
`Fig 2. Flow chart for differential diagnosis of congenital hyperammonemia. LPI, Lysinuric protein intolerance; HHH, hyperor-
`nithinemia hyperammonemia and homocitrullinuria syndrome.
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`tients. Valproate and haloperidol have
`unmasked previously undiagnosed urea
`cycle defects in some patients, whereas
`other patients have erroneously been
`given the diagnosis of Reye syndrome.
`The flow diagram for the differen-
`tial diagnosis of a urea cycle defect
`(Fig 2) shows that the first task is to
`obtain a plasma ammonia level. The
`blood sample should be placed on ice
`and ideally run within 15 minutes of
`collection. Most hospitals now have
`automated analyzers that measure a
`plasma ammonia level in <30 minutes
`
`in <1 mL of blood. Normal plasma
`ammonia levels are <35 µmol/L (63
`µg/dL). In symptomatic hyperam-
`monemia, levels are usually >100
`µmol/L. Other routine laboratory
`tests may be useful in making the di-
`agnosis. A low blood urea nitrogen
`and a respiratory alkalosis in a severe-
`ly ill child are characteristic of urea
`cycle disorders. On the other hand, a
`metabolic acidosis or ketoacidosis is
`more commonly seen in hyperam-
`monemia caused by an organic aci-
`demia or congenital lactic acidosis.
`
`These can be further discriminated by
`measuring urinary organic acids for
`the former condition and plasma lac-
`tate/pyruvate for the latter. Organic
`acidemias and fatty acid oxidation de-
`fects can be distinguished by measur-
`ing acylcarnitine esters in blood.
`Quantitative plasma and urinary
`amino acids are most helpful in estab-
`lishing a specific diagnosis of a defect in
`urea synthesis (Fig 2). Levels of gluta-
`mine, alanine, and asparagine, which
`serve as storage forms of waste nitrogen,
`are frequently elevated. Plasma arginine
`
`S9
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`Page 4 of 5
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`

`

`SUMMAR AND TUCHMAN
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`may be reduced in all urea cycle disor-
`ders, except in hyperargininemia, where
`it is 10- to 20-fold higher than normal.
`In partial defects, however, it is fre-
`quently normal. Plasma citrulline levels
`help discriminate between the proximal
`and distal urea cycle defects, because
`citrulline is the product of OTC and
`CPS activity and a substrate for the dis-
`tal enzymes. Consequently, plasma cit-
`rulline is absent or present only in trace
`amounts in neonatal-onset CPS and
`OTC deficiencies and is present in low
`to low-normal levels in late-onset dis-
`ease, whereas it is markedly elevated in
`blood and urine in citrullinemia and
`argininosuccinic aciduria. To distinguish
`CPS from OTC deficiency, urinary
`orotic acid is measured; it is significantly
`elevated in OTC deficiency and normal
`or low in CPS deficiency. As in OTC de-
`ficiency, urinary orotic acid excretion
`can also be increased in hyperarginin-
`emia, citrullinemia, HHH syndrome,
`and LPI. Patients with citrullinemia
`have up to a 100-fold elevation in plas-
`ma citrulline, whereas those with
`argininosuccinic aciduria show a more
`moderate increase in citrulline of ap-
`proximately 10-fold, associated with the
`presence in large amounts of the nor-
`mally absent argininosuccinic acid. The
`argininosuccinate
`chromatographic
`peak may co-elute with leucine or
`isoleucine, resulting in an apparent in-
`crease in one of these amino acids, but
`its anhydrides eluting later in the run
`should allow the correct identification
`of argininosuccinate. In HHH syn-
`drome, plasma ornithine and urine ho-
`mocitrulline levels are elevated, where-
`as in LPI urinary lysine, arginine and
`ornithine levels are elevated and blood
`levels may be normal or low.
`Citrullinemia, argininosuccinic acid-
`uria, hyperargininemia, and LPI and
`HHH syndrome can be diagnosed on
`the basis of the amino acid pattern.
`NAGS deficiency requires enzymatic
`diagnosis with hepatic tissue. In OTC
`deficiency approximately 75% of pa-
`tients have an identifiable mutation by
`DNA studies, and mutation analysis can
`
`S10
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`be done for the other disorders as well.
`A definitive diagnosis of CPS or OTC
`deficiency depends on enzyme determi-
`nation from a liver biopsy specimen.
`Therapy for these disorders is dis-
`cussed in detail in the articles that follow.
`
`OUTCOME
`
`Before alternate pathway therapy
`was developed, virtually all children
`with neonatal-onset disease died rapid-
`ly. Approximately half of affected
`neonates still die of hyperammonemic
`coma. However, long-term survival has
`improved, with approximately half of
`the infants who survive neonatal hyper-
`ammonemic coma living 5 years or
`more. Survival is obviously better in
`partial defects, but these children still
`remain at risk for intercurrent life-
`threatening hyperammonemic crises.
`Although mortality has improved, mor-
`bidity remains high. There is a signifi-
`cant risk for multiple developmental
`disabilities including mental retarda-
`tion, cerebral palsy, and seizure disor-
`ders in children with a neonatal-onset
`disorder. Children with partial defects
`and those who have been treated
`prospectively from birth because of a
`previously affected sibling have a better
`outcome, although there is a high inci-
`dence of more subtle cognitive deficits
`including learning disabilities and atten-
`tion deficit hyperactivity disorder.
`
`SELECTED READING
`LIST
`
`Batshaw ML. Arginase deficiency. In:
`Gilman S, Goldstein GW, Waxman SG, ed-
`itors. Neurobase. La Jolla (CA): CD-
`ROM 1998.
`
`Batshaw ML. Argininosuccinic acidemia.
`In: Gilman S, Goldstein GW, Waxman SG
`editors. Neurobase. La Jolla (CA): CD-
`ROM 1998.
`
`Batshaw ML. Carbamyl phosphate syn-
`thetase I deficiency. In: Gilman S, Gold-
`stein GW, Waxman SG, editors. Neu-
`robase. La Jolla (CA): CD-ROM 1999.
`
`THE JOURNAL OF PEDIATRICS
`JANUARY 2001
`
`Batshaw ML. Citrullinemia. In: Gilman S,
`Goldstein GW, Waxman SG, editors. Neu-
`robase. La Jolla (CA): CD-ROM 1998.
`
`Batshaw ML. Inborn errors of urea syn-
`thesis: a review. Ann Neurol 1994;35:133-
`41.
`
`Batshaw ML. N-acetylglutamate synthase
`deficiency. In: Gilman S, Goldstein GW,
`Waxman SG, editors. Neurobase. La Jolla
`(CA): CD-ROM 1998.
`
`Batshaw ML. Ornithine transcarbamylase
`deficiency. In: Gilman S, Goldstein GW,
`Waxman SG, editors. Neurobase. La Jolla
`(CA): CD-ROM 1998.
`
`Batshaw ML, Brusilow SW. Treatment of
`hyperammonemic coma caused by inborn
`errors or urea synthesis. Pediatrics 1980;
`97:893-900.
`
`Brusilow SW, Batshaw ML, Waber L.
`Neonatal hyperammonemic coma. Adv Pe-
`diatr 1982;29:69-103.
`
`Brusilow SW, Horwich AL. Urea cycle
`enzymes. In: Scriver CR, Beaudet AL,
`Sly WS, Valle D, editors. The metabolic
`and molecular basis of inherited disease.
`7th ed. New York: McGraw-Hill; 1995. p.
`1187-232.
`
`Cederbaum SD. The treatment of urea
`cycle disorders. Int Pediatr 1992;7:61-6.
`
`Jackson MJ, Beaudet AL, O’Brien WE.
`Mammalian urea cycle enzymes. Ann Rev
`Genet 1986;20:431-64.
`
`Maestri NE, Hauser ER, Bartholomew D,
`Brusilow SW. Prospective treatment of
`urea cycle disorders. J Pediatr 1991;119:
`923-8.
`
`Tuchman M. Inherited hyperammonemia.
`In: Blau N, Duran M, Blaskovics ME, edi-
`tors. Physician’s guide to the laboratory di-
`agnosis of metabolic diseases. London:
`Chapman & Hall Medical; 1996. p. 209-22.
`
`Tuchman M. The clinical biochemical and
`molecular spectrum of ornithine transcar-
`bamylase deficiency. J Lab Clin Med 1992;
`120:836-50.
`
`Tuchman M, Sharp HL. An approach to the
`diagnosis and management of inherited
`metabolic liver disorders. In: Liebenthal E,
`editor. Textbook of gastroenterology and
`nutrition in infancy. 2nd ed. New York:
`Raven Press; 1989. p. 969-1003.
`
`Urea Cycle Symposium, part 1 and part 2.
`Pediatrics 1981;68:271-97, and Pediatrics
`1981;68:446-62.
`
`Page 5 of 5
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