Long-term management of patients with
`urea cycle disorders
`Gerard T. Berry, MD, and Robert D. Steiner, MD
`
`The long-term treatment of patients with urea cycle disorders (UCDs)
`includes diet treatment and use of specific medications. Guidelines are
`provided for patients with a severe phenotype. However, treatment must be
`tailored for each individual, especially with regard to residual enzyme func-
`tion and in vivo metabolic capacity. This will be reflected in tests used for
`monitoring therapy that should be performed on a periodic basis. The goal
`of therapy is to eliminate chronic complications, a laudable but rarely at-
`tainable goal. Sick-day rules are discussed. Chronic management also in-
`cludes diverse services that are essential to the success of the metabolic pro-
`gram. These include neurologic and developmental evaluations, feeding
`team evaluation and therapy, physical and occupational therapies, speech
`therapy, school and educational services, social service intervention, psy-
`chologic services, and genetic counseling. (J Pediatr 2001;138:S56-S61)
`
`The long-term treatment of patients
`with urea cycle disorders involves the
`use of a low-protein diet, supplementa-
`tion with certain amino acids, and ad-
`ministration of organic compounds to
`augment waste nitrogen excretion.1-8
`Optimal care, however, necessitates
`the use of a comprehensive long-term
`management program that anticipates
`
`From the Divisions of Human Genetics and Molecular
`Biology and Endocrinology and Diabetes, Department
`of Pediatrics, University of Pennsylvania School of
`Medicine, The Children’s Hospital of Philadelphia,
`Pennsylvania, and the Metabolic Clinic, Child Develop-
`ment and Rehabilitation Center, Doernbecher Chil-
`dren’s Hospital, Oregon Health Sciences University,
`Portland, Oregon.
`Reprint requests: Gerard T. Berry, MD,
`Room 402 Abramson Research Center, De-
`partment of Pediatrics, The Children’s Hospi-
`tal of Philadelphia, 34th & Civic Center Blvd,
`Philadelphia, PA 19104-4399.
`Copyright © 2001 by Mosby, Inc.
`0022-3476/2001/$35.00 + 0 9/0/111837
`doi:10.1067/mpd.2001.111837
`
`and responds to a diverse array of
`needs and complications. The items
`covered in the treatment of the patients
`are outlined in Table I.
`The list of UCDs is shown in Table II.
`The most common UCD is ornithine
`transcarbamylase deficiency.1 Inherit-
`ed as an X-linked trait, it affects both
`males and females. The phenotype is
`extremely variable, not only because
`of random X chromosome inactivation
`in females but also because of many
`different types of OTC gene mutations
`and modifying factors such as puber-
`ty, pregnancy, labor and delivery, and
`environmental factors. The spectrum
`of disease expression ranges from the
`catastrophically ill 2-day-old boy with
`an extremely severe form of the dis-
`ease to the previously healthy adult
`woman with postpartum hyperam-
`monemia.1,9,10 The long-term manage-
`ment of each of these forms of OTC
`deficiency may be different. It is im-
`portant to be mindful that the type of
`
`S56
`
`low-protein diet and amount of med-
`ication must be tailored to each indi-
`vidual patient’s phenotype and needs.9
`However, in this article we restrict our
`discussion of treatment to the UCD
`with a severe phenotype. Also, be-
`cause the therapy for carbamylphos-
`phate synthetase deficiency is similar
`to that of OTC deficiency,1 treatment
`of both will be addressed as one. The
`rest of the UCDs will be addressed
`separately. CPS, argininosuccinate
`synthetase, argininosuccinate lyase,
`and arginase deficiencies are all inher-
`ited as autosomal recessive traits.1
`
`Argininosuccinic acid lyase
`ASL
`Argininosuccinic acid synthetase
`ASS
`Carbamyl phosphate synthetase I
`CPS
`OTC Ornithine transcarbamylase
`UCD Urea cycle disorder
`
`DIET
`
`The low-protein diet and medica-
`tions used in the treatment of infants
`with each of the UCDs are shown in
`Table III and are based on the recom-
`mended treatment as outlined, at least
`in part, in the book entitled Metabolic
`and Molecular Basis of Inherited Diseases.1
`However, it is important to note that
`these doses are recommended for se-
`verely affected patients and are not
`suitable for all patients. The treatment
`must be tailored to the needs of the
`patient as reflected in the growth rate,
`plasma ammonia, and amino acid lev-
`els and ancillary tests such as blood
`counts and serum albumin. The bio-
`chemical and nutritional rationales that
`are used for 2 representative patients
`are depicted in the flow diagrams in
`Horizon Exhibit 2014
`Lupin v. Horizon
`IPR2018-00459
`
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`THE JOURNAL OF PEDIATRICS
`VOLUME 138, NUMBER 1
`
`BERRY AND STEINER
`
`Fig 1. Maintenance therapy and whole body nitrogen economy in patients with severe UCDs. Six-month-old infant with OTC deficiency. *Forty percent
`to 45% used for waste nitrogen production. **Sixteen percent of protein and 11.5% of amino acids are nitrogen. ***Formula weight: sodium phenylbu-
`tyrate = 186. ✰This calculation does not take into account the fact that the nitrogen atom in glutamate derived from essential amino acid catabolism can
`be reused for synthesis of nonessential amino acids necessary for protein synthesis.
`
`Figs 1 and 2. Please note that the pa-
`tient whose treatment is depicted in
`Fig 2 is a 6-year-old child, not an in-
`fant. This child serves to illustrate how
`the protein intake, medication dosage,
`and partitioning of nitrogen differs ac-
`cording to disease type and age.
`In most instances only the broad
`ranges are given. The first principle is
`that the amount of whole protein that
`can be given to the patient will depend
`on the enzyme deficiency and age.
`With severe OTC deficiency, it is nec-
`essary to restrict dietary protein in-
`take to an amount that is inadequate to
`permit growth in infancy; the remain-
`ing amount of nitrogen must be deliv-
`ered as essential amino acids. This is
`analogous to increasing the biologic
`value of the protein. Therefore the
`total amount of nitrogen ingested per
`day can be reduced below the thresh-
`old necessary for growth. The types
`and amounts of medications will also
`vary but primarily are dependent on
`the enzyme defect. In OTC and CPS
`deficiencies, citrulline therapy is used
`to restore body arginine pools for pro-
`tein synthesis. Arginine may be used
`instead of citrulline, but the drawback
`is that the waste nitrogen atom from
`aspartate used in the ASS reaction is
`not used. However, in ASL deficiency
`
`arginine is exclusively used not only to
`maintain adequate arginine levels but
`also to increase production of argi-
`ninosuccinate and thereby enhance
`urinary excretion of waste nitrogen
`in the form of argininosuccinate. This
`works much better for ASL than for
`ASS deficiency, because argininosuc-
`cinate, unlike citrulline, is essentially
`filtered by the kidney and excreted in
`urine without being reabsorbed.
`
`CLINICAL AND
`LABORATORY
`MONITORING
`
`Clinical and laboratory monitoring
`of each patient is important to the suc-
`cess of the long-term management. The
`critical parameters in clinical monitor-
`ing of therapy are shown in Table IV.
`These include the growth parameters,
`weight, height, and head circumfer-
`ence, the developmental and neurolog-
`ic assessments, and the examination of
`the liver. In severe ASL deficiency the
`liver is usually chronically enlarged de-
`spite adequate treatment.1 Some pa-
`tients may even have cirrhosis. The
`key tests for laboratory monitoring
`of therapy are shown in Table V.
`This testing includes the quantitation
`
`Table I. Long-term treatment of
`patients with UCDs
`Low-protein diet and medications
`Acute episodes
`Elective surgery
`Neurologic and developmental
`evaluations
`Feeding team evaluation and therapy
`Physical and occupational therapies
`Speech therapy
`School and education services
`Social services
`Psychologic services
`Genetic counseling
`
`Table II. Urea cycle disorders
`
`OTC deficiency
`CPS deficiency
`ASS deficiency
`ASL deficiency
`Arginase deficiency
`N-acetylglutamate synthase
`deficiency
`
`of plasma ammonia, plasma amino
`acids, and in some instances, urine oro-
`tate. A complete blood count with a
`differential serum chemistry panel
`screen including liver function tests
`
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`THE JOURNAL OF PEDIATRICS
`JANUARY 2001
`
`Fig 2. Maintenance therapy and whole body nitrogen economy in patients with severe UCDs. Six-year-old child with ASL deficiency. *Molecular weight
`arginine = 174. ✰Assuming 100% of ASA is filtered and excreted.
`
`Table III. Treatment of infants with UCDs
`
`Diet
`
`Medications
`
`UCD
`
`OTC deficiency
`CPS deficiency
`
`Protein
`(g/kg/d)
`
`0.7
`
`ASS deficiency
`
`1.5 – 2.0
`
`ASL deficiency
`Arginase deficiency†
`
`1.5 – 2.0
`0.7
`
`Essential
`Amino
`Acids
`(g/kg/d)
`
`Sodium
`phenyl-
`butyrate
`(g/kg/d)
`
`Arginine
`(g/kg/d)
`
`Citrulline
`(g/kg/d)
`
`0.7
`
`—
`
`—
`0.7
`
`0.45-0.60
`(9.9-13.0)*
`0.45-0.60
`
`0.45-0.60
`0.30-0.60
`
`—
`0.4 – 0.7
`(8.8-15.4)*
`0.4 – 0.7
`—
`
`0.17
`(3.8)*
`—
`
`—
`—
`
`*(g/m2/d)
`†N.B. data on treatment of infants with arginase deficiency are not available, especially for
`prospective use in asymptomatic newborns.
`
`Table IV. Clinical monitoring of therapy.
`
`Weight, height, and head
`circumference
`Developmental assessment
`Neurologic assessment
`Liver examination
`
`Table V. Laboratory monitoring of
`therapy
`
`Plasma ammonia
`Plasma amino acid quantitation
`Urine orotate
`
`and urinalysis should be obtained on a
`yearly basis. Every 5 to 10 years each
`patient should be screened specifically
`for iron deficiency, vitamin B12 defi-
`ciency, or both, because of the low-
`protein, low-meat intake diet.
`The goal of treatment is to maintain
`normal levels of plasma ammonia
`
`through the use of the low-protein diet
`and medication while allowing for nor-
`mal growth. As the body’s burden
`of waste nitrogen increases, certain
`amino acid levels will rise, along with
`or preceding the rise in plasma ammo-
`nia. The most prominent is glutamine,
`the amino acid that is used to monitor
`
`S58
`
`the whole body waste nitrogen
`burden.1,11,12 The finding of both an
`elevated plasma ammonia and gluta-
`mine level indicates that body ammonia
`is elevated and the patient is at risk
`for hyperammonemic encephalopathy.1
`The other amino acids that may be
`elevated in plasma include alanine,
`glycine, glutamate, asparagine, aspar-
`tate, and lysine. Except in arginase de-
`ficiency, plasma arginine may be de-
`creased in the patient with inadequate
`treatment with arginine or citrulline.
`The latter may be low in some patients
`with OTC or CPS deficiency despite
`therapy. Occasionally, levels of the es-
`sential amino acids and, most impor-
`tant, the branched-chain amino acids,
`leucine, isoleucine, and valine, may fall
`below the normal range because of the
`use of a strict low-protein diet. It is
`important not to allow such deficiency
`to remain chronic and severe; other-
`wise, a nutritional deficiency state
`may ensue. Manifestations may in-
`clude poor growth, anemia, rash, and
`hypoalbuminemia.
`The biochemical targets for optimal
`UCD control are noted in Table VI.
`These include a plasma ammonia level
`of <40 µmol/L, a plasma glutamine
`level of <1000 µmol/L, normal plasma
`levels of alanine, glycine, lysine, and
`arginine, and no subnormal concentra-
`tion of any of the essential amino
`acids. When arginine therapy is used,
`the serum levels will vary, depending
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`THE JOURNAL OF PEDIATRICS
`VOLUME 138, NUMBER 1
`
`BERRY AND STEINER
`
`Table VI. Biochemical targets for optimal UCD control
`Plasma ammonia <40 µmol/L
`Plasma glutamine <1000 µmol/L
`Normal plasma levels of alanine, glycine, lysine, and arginine (except arginase
`deficiency)
`No subnormal concentrations of essential amino acids (eg, leucine, isoleucine,
`valine)
`Normal urinary orotate excretion (<3 µmol/mmol creatinine)
`Normal plasma protein concentrations (eg, albumin)
`
`These goals are not always attainable, or even appropriate in every patient. Treatment must be
`individualized.
`
`Table VII. Chronic complications in
`patients on UCD therapy
`
`Poor growth
`Developmental delay
`Learning problems
`Speech disorder
`ADHD
`Mental retardation
`Spasticity
`Seizure disorder
`Hepatomegaly
`
`ADHD, Attention deficit hyperactivity
`disorder.
`
`on the dosage schedule (usually 4-
`times daily) and timing of the blood
`sample, but the per-dose values should
`be <200 µmol/L. Some patients appear
`to maintain good metabolic control
`with higher glutamine levels, that is,
`>1000 µmol/L (personal communica-
`tion, J.V. Leonard). Ideally, the uri-
`nary orotate excretion will be <3
`µmol/mmol creatinine. Plasma con-
`centrations of proteins such as albu-
`min should be in the normal range.
`Measurement of plasma prealbumin
`may be necessary at times to ascertain
`the presence of an incipient protein
`deficiency. It is important to note that
`citrulline
`levels will always be
`markedly increased in patients with
`ASS deficiency, and both argininosuc-
`cinate and citrulline may be elevated
`in patients with ASL deficiency. It is
`almost impossible to achieve chronic
`normal levels of arginine in patients
`with arginase deficiency while on a
`protein-restricted diet, even when
`supplemented with an essential amino
`acid powder mixture.
`
`COMPLICATIONS OF
`UCD THERAPY
`
`The chronic complications that may
`be seen in patients receiving UCD
`therapy are shown in Table VII. These
`include poor growth, developmental
`
`delay, learning problems, speech disor-
`der, attention deficit hyperactivity dis-
`order, mental retardation, spasticity as
`in cerebral palsy, seizure disorder, and
`hepatomegaly with and without liver
`function test abnormalities.1,2,13,14 It is
`important to note that normal variant
`short stature such as genetic short
`stature and constitutional delay of
`growth and puberty may also occur in
`patients with UCDs. Whether the lat-
`ter condition is more prevalent in the
`UCD population is unknown. Many of
`the previously described complications
`may be a consequence of hyperam-
`monemic coma in the newborn period
`or later, after an acute intermittent ill-
`ness. In addition, some patients may
`have been chronically intoxicated be-
`cause of a delay in diagnosis. This type
`of patient can present in late infancy or
`childhood with progressive psychomo-
`tor retardation or with what appears to
`be a progressive neurodegenerative
`disease such as with arginase deficien-
`cy. After the hyperammonemia is cor-
`rected or the disease process is stabi-
`lized, all of the sequelae such as
`learning problems, speech defect, cere-
`bral palsy, and seizure disorders will
`need to be treated, as with any child
`without a UCD. Patients with ASL de-
`ficiency in particular may have devel-
`opmental delay and seizures despite
`adequate metabolic control and the ab-
`sence of a historical episode of hyper-
`ammonemic coma. Sometimes poor
`
`disease control may result in chronic
`hepatomegaly with increased accumu-
`lation of fat and glycogen in the liver,
`fibrosis, and abnormal liver function
`tests. It usually remits after stabiliza-
`tion of the hyperammonemia. As noted
`previously, this is not the case with
`ASL deficiency, especially with the
`neonatal-onset variety.
`The intercurrent illnesses or an acute
`episode of decompensation associated
`with hyperammonemia must be treat-
`ed as delineated by Brusilow et al.6
`This may include the use of intra-
`venous sodium phenylacetate, sodium
`benzoate, and arginine hydrochloride.
`Hemodialysis therapy may also be nec-
`essary. If the patient is not comatose,
`enteral administration of medications
`and cessation of protein intake may be
`effective. Parents are to be instructed in
`the signs and symptoms of hyperam-
`monemia such as anorexia, vomiting, al-
`tered behavior, headache, visual distur-
`bances, ataxia, lethargy, and seizures
`that may indicate acute hyperammone-
`mia. These may occur during a viral
`illness or after ingestion of a large
`amount of dietary protein. If a patient is
`ill because of an acquired illness but the
`plasma ammonia level is <100 µmol/L
`(approximately 3 times the upper range
`of normal), the family should introduce
`a sick-day routine.15 This consists of a
`decrease, or more commonly a cessa-
`tion, of protein intake while nonpro-
`tein calories are given often in the form
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`BERRY AND STEINER
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`of fruit juices, or even better, the Ross
`Prophree or Mead-Johnson 80056 for-
`mula suspensions. The ammonia scav-
`enging medications should be adminis-
`tered during these periods, and dosages
`can be increased by approximately 50%
`if warranted by the clinical findings.
`
`UCD AND SURGERY
`
`If patients require elective surgery,
`they should be admitted to the hospital
`on the day before surgery. At this time
`the plasma ammonia and amino acid
`levels should be checked to ensure that
`the patient is not in a decompensated
`state prior to surgery. Before surgery,
`when the patient is no longer allowed
`to eat or drink, an intravenous catheter
`should be placed to deliver fluids, glu-
`cose, and electrolytes at a maintenance
`rate. This will prevent fasting-induced
`catabolism and its associated hyperam-
`monemia. In older children and adoles-
`cents, the use of a 10% glucose solution
`may produce hyperglycemia to a de-
`gree sufficient to induce an osmotic di-
`uresis and volume contraction. For
`these instances a 5% glucose solution
`should be used. Patients may also need
`to receive the UCD medications be-
`fore, during, and after the procedure.
`Depending on the severity of the en-
`zyme deficiency and the nature of the
`surgery, plasma ammonia levels should
`be monitored before, during, and after
`the operation, even in the recovery
`room. If the procedure is a long one
`such as an orthopedic scoliosis repair,
`it may be necessary to administer glu-
`cose and Intralipid, with total par-
`enteral nutrition (the equivalent of a
`low-protein diet) along with intra-
`venous sodium phenylacetate, sodium
`benzoate, and arginine hydrochloride
`during the operation.
`The rest of the services outlined in
`Table I should be delivered to the pa-
`tients and their families. There are ex-
`ceptions, but the broad and compre-
`hensive approach to care is especially
`important for the patient with neona-
`
`S60
`
`tal-onset disease. Many of the patients
`with OTC and CPS deficiencies are so
`severely affected that the medical ther-
`apies outlined previously are only tem-
`porizing measures until liver trans-
`plantation can be performed in the first
`year of life.16,17 The delivery of chron-
`ic care to a patient with this kind of
`special needs requires a multidiscipli-
`nary approach.
`
`REFERENCES
`1. Brusilow SW, Horwich AL. Urea cycle
`enzymes. In: Scriver CR, Beaudet AL,
`Sly WS, Valle D, editors. The metabol-
`ic and molecular bases of inherited dis-
`ease. 7th ed. New York: McGraw-Hill
`Information Services Co; 1995. p.
`1187-232.
`2. Brusilow SW, Maestri NE. Urea cycle
`disorders: diagnosis, pathophysiology,
`and therapy. Adv Pediatr 1996;43:127-
`70.
`3. Bachmann C. Urea cycle disorders. In:
`Fernandes J, Saudubray J-M, Tada
`K, editors. Inborn metabolic diseases.
`1990. p. 211-28.
`4. Batshaw ML, Thomas GH, Brusilow
`SW. New approaches to the diagnosis
`and treatment of inborn errors of urea
`synthesis. Pediatrics 1981;68:290-7.
`5. Batshaw ML, Brusilow S, Waber L,
`Blom W, Brubakk AM, Burton BK, et
`al. Treatment of inborn errors of urea
`synthesis: activation of alternative
`pathways of urea synthesis. N Engl J
`Med 1982;306:1387-92.
`6. Brusilow SW, Danney M, Waber LJ, Bat-
`shaw M, Burton B, Levitsky L, et al. Treat-
`ment of episodic hyperammonemia in chil-
`dren with inborn errors of urea synthesis.
`N Engl J Med 1984,310:1630-4.
`7. Maestri NE, Brusilow SW, Clissold
`DB, Bassett SS. Long-term treatment of
`girls with ornithine transcarbamylase
`deficiency. N Engl J Med 1996;335:
`855-9.
`8. Feillet F, Leonard JV. Alternative path-
`way therapy for urea cycle disorders. J
`Inherit Metab Dis 1998;21:101-11.
`9. Brusilow SW, Finkelstein J. Restora-
`tion of nitrogen homeostasis in a man
`with ornithine transcarbamylase defi-
`ciency. Metabolism 1993;42:1336-9.
`10. Arn PH, Hauser ER, Thomas GH,
`Herman G, Hess D, Brusilow SW.
`Hyperammonemia in women with a
`mutation at the ornithine carbamyl-
`transferase locus. A cause of postpar-
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`THE JOURNAL OF PEDIATRICS
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`tum coma. N Engl J Med 1990;322:
`1652-5.
`11. Maestri NE, McGowan KD, Brusilow
`SW. Plasma glutamine concentration: a
`guide to the management of urea cycle
`disorders. J Pediatr 1992;121:259-61.
`12. Tuchman M, Yudkoff M. Blood levels
`of ammonia and nitrogen scavenging
`amino acids in patients with inherited
`hyperammonemia. Mol Genet Metab
`1999;66:10-5.
`13. Msall M, Batshaw ML, Suss R,
`Brusilow SW, Mellits ED. Neurologic
`outcome in children with inborn errors
`of urea synthesis: outcome of urea-
`cycle enzymyopathies. N Engl J Med
`1984;310:1500-5.
`14. Uchino T, Endo F, Matsuda I. Neu-
`rodevelopmental outcome of long-term
`therapy of urea cycle disorders in
`Japan. J Inherit Metab Dis 1998;21:
`151-9.
`15. Dixon MA, Leonard JV. Intercurrent
`illness in inborn errors of intermediary
`metabolism. Arch Dis Child 1992;67:
`1387-91.
`16. Whitington PF, Alonso EM, Boyle JT,
`Molleston JP, Rosenthal P, Emond
`JC, et al. Liver transplantation for the
`treatment of urea cycle disorders. J In-
`herit Metab Dis 1998;21:112-8.
`17. Saudubray JM, Touati G, Delonlay P,
`Jouvet P, Narcy C, Laurent J, et al.
`Liver transplantation in urea cycle disor-
`ders. Eur J Pediatr 1999;158:S55-9.
`
`LONG-TERM
`MANAGEMENT
`DISCUSSION
`Coordinator Role
`It was agreed that there is a need to
`establish a coordinator to oversee all
`aspects of the treatment of a patient
`with UCD, so that progress over time
`is properly reviewed.
`
`Amino Acid Levels
`Maintenance is aimed at balancing the
`amino acid pools. To achieve this, a range
`of proteins from different sources should
`be taken by the patient. Determination of
`amino acid levels should be made with a
`blood sample taken 2 hours after a meal.
`The amino acid levels should be as low as
`possible without being subnormal, pro-
`viding growth is not compromised.
`
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`THE JOURNAL OF PEDIATRICS
`VOLUME 138, NUMBER 1
`
`BERRY AND STEINER
`
`Management of the Febrile Child
`All protein intake should be discon-
`tinued for 24 hours, but no longer than
`48 hours (protein-free diets are nutri-
`tionally inadequate and potentially dan-
`
`gerous). Ibuprofen can be given for the
`fever, and the use of acetaminophen
`should be avoided because this drug
`could be hepatoxic, especially in large
`doses. Extreme caution should be exer-
`
`cised in the use of any antiemetics, be-
`cause they could mask the signs of
`hyperammonemia and induce other
`neurologic symptoms.
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