Prospeotive treatment of urea cycle
`
`disorders
`
`Nancy E. Maestri, PhD, Elizabeth R. Hauser, MHS,* Dennis Bartholomew, MD,”
`andSauHN.&uwow,MD
`From the Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore,
`Maryland
`
`H erammoncmia occurs with var 'in
`Y
`3 3
`patients with inborn errors of urea synthesis; these errors
`
`severit '
`
`include deficiencies of carbamoyl phosphate synthetase, or-
`nithine transcarbamylase, argininosuccinatc synthctasc,
`argininosuccinate lyase, and arginasc. There is considerable
`variability in severity within each enzyme deficiency, pre-
`sumably a function of genetic variability, and among the
`
`Argininosuccinate lyase deficiency
`Argininosuccinate synthetase deficiency
`Carbamoyl phosphate synthetase deficiency
`Ornithine transcarbamylase deficiency
`
`enzyme deficiencies as a result of their different metabolic
`consequences. The most severe expression of these diseases,
`excluding arginase deficiency, is neonatal hyperammone-
`mic coma, the consequences of which include death, if un-
`treated, or mental retardation and cerebral palsy in the
`surviving treated infants.
`Prenatal diagnosis of at-risk fetuses, by DNA or bio-
`
`We present a diagnostic and therapeutic protocol designed to prevent clinical
`expression of inborn errors of urea synthesis in the neonatal period, and discuss
`the long-term developmental outcome of survivors. The families of 32 infants,
`among 43 identified prenatally as being at risk for a urea cycle disorder, chose
`to have their infants treated according to a diagnostic and therapeutic proto-
`col, beginning at birth. the therapy was effective in avoiding neonatal hyper-
`ammonemic coma and death in seven patients with carbamoyl phosphate syn-
`thetase deficiency, argininosuccinate synthetase deficiency, and argininosuc-
`cinote lyase deficiency. When treated prospectively, five of eight patients with
`ornithine transcarbamylclse deficiency avoided severe hyperammonemia and
`survived the neonatal period. Two patients with carbamoyl phosphate syn-
`thetase deficiency and two with ornithine transcarbamylase deficiency have
`subsequently died; three additional patients with the latter disorder have
`received orthotopic liver transplants. Our experience suggests that these
`surviving patients have had a more favorable neurologic outcome than patients
`rescued from neonatal hyperammonemic coma. However, all of them require
`a burdensome medical regimen and may have handicaps that include impair-
`ment of development and recurrent episodes of hyperammonemia. Further,
`those with deficiency of carbamoyl phosphate synthetase or ornithine transcar-
`bamylase have a high mortality rate. (J Psomnz 1991;119:923-8)
`
`
`
`in all
`
`Supported by the National Institutes of Health (grants HDl1134,
`HD 26358, and RR,-00052), the Kettering Family Foundation, the
`T. D. and M. A. O’Ma1ley Foundation, and the National Organi-
`zation for Rare Disorders.
`The opinions expressed in this article are those of the authors and
`do not necessarily reflect those of the United States Air Force or
`the Department of Defense.
`Submitted for publication Feb. I2, 1991; accepted June 24, 1991.
`Reprint requests: Nancy E. Maestri, PhD, Department of Pediat-
`rics, Johns Hopkins Hospital, Park 336, 600 North Wolfe St., Bal-
`timore, MD 21205.
`*Now at the Department of Biostatistics, University of Michigan,
`Ann Arbor, MI 48109-2029.
`**Now at Air Force Medical Genetics Center, U.S. Air Force
`Medical Center, Keesler Air Force Base, Biloxi, MS 39534-5300.
`9/20/32004
`
`Page 1 of 6
`
`Horizon Exhibit 2010
`Lupin v. Horizon
`IPR2016-00829
`
`

`

`9 2 4 Maestri et al.
`
`The Journal of Pediatrics
`December 1991
`
`Table I. Prospective neonatal treatment protocols for
`“at risk” infants as described in this study
`
`Diagnosis
`
`CPSD or
`OTCD
`
`ASD
`
`ALD
`
`Diet (per kg per day)
`Natural protein (gm)
`Essential amino acids (gm)
`Calories (kcal)
`Medications (mg/kg/day)*
`Arginine freebase
`Sodium benzoate
`
`0.7
`0.7
`120
`
`170
`250
`
`l.5
`—-
`120
`
`700
`250
`
`l.5
`—
`l20
`
`700
`—
`
`--
`
`
`
`20) chose to have their at-risk fetus treated prospectively at
`birth. Prenatal DNA analysis indicated that three at-risk
`male fetuses had OTCD. One patient with ALD and three
`patients with ASD were identified after amniocentesis and
`enzyme analysis of cultured cells. The genotype of the re-
`maining fetuses was unknown at birth. Parental consent was
`granted under procedures approved by the Johns Hopkins
`Joint Committee on Clinical Investigation. This study was
`performed in collaboration with physicians enrolled in the
`trials of sodium benzoate, sodium phenylacetate, and
`sodium phenylbutyrate approved by the U.S. Food and
`Drug Administration.
`Prospective therapeutic protocols. Therapeutic protocols
`were designed to prevent hyperammonemia in neonates
`known to be at risk for a urea cycle defect. The original
`protocols for patients in this study are summarized in Ta-
`ble 1. The most recent modifications of these protocols are
`described below. For all patients, the protocol included im-
`plementing therapy within 2 hours of birth and obtaining
`cord blood and plasma samples every 12 hours thereafter to
`monitor levels of urea, ammonium, and amino acids. Blood
`pH and partial pressure of carbon dioxide should also be
`measured at least daily.
`Deficiency of ornithine transcarbamylase or carbamoyl
`phosphate synthelase. Hemodialysis is occasionally neces-
`sary to control the plasma ammonium level of infants with
`OTCD or CPSD if medical therapy should fail to do so.
`Promptly after birth, size 7F or larger catheters should be
`placed in an artery and in a vein. The importance of a large
`line cannot be overemphasized. With blood flow of 50 ml/
`min, ammonium clearance may be similar to the blood flow
`through the dialyzer; virtually all the ammonium may be
`removed in a single pass. Because the clearances of ammo-
`nium by peritoneal dialysis and continuous arteriovenous
`hemofiltration are only 10% of the hemodialysis clearance
`of ammonium, the latter is the procedure of choice.
`Within 2 hours of birth, a priming infusion of sodium
`benzoate and sodium phenylacetate, 250 mg/kg each, and
`of 10% arginine HCl, 2 ml/kg, in 10% glucose, 35 ml/kg,
`should be given for a period of 2 hours. After this priming
`dose is completed, a sustaining infusion containing the same
`doses of each drug in 10% glucose, 60 ml/ kg, should be ad-
`ministered for 24 hours and continued until the medications
`
`Sodium phenylacetatet
`*0ral dosage.
`‘(Sodium phenylacetate was added to the protocol in 1984.
`
`250
`
`——
`
`chemical analysis, and subsequent termination of the preg-
`nancies can prevent these diseases. However, termination is
`not an option for all patients, either because of ethical con-
`cerns or because of a lack of 100% specificity of fetal diag-
`nosis. We have developed a prospective therapeutic proto-
`col as an alternative for parents who do not wish to abort
`an affected fetus; it is implemented within 12 hours of birth,
`before a definitive diagnosis is possible. The goal of this
`therapy is to prevent the development of hyperammonemia
`and its dire consequences in the neonatal period and thus
`improve the long-term developmental outcome of affected
`survivors.
`
`We present here the outcome of 32 at-risk infants who
`were treated prospectively at birth according to a therapeu-
`tic protocol.
`
`METHODS
`
`Subjects. From 1981 to 1988, a total of 43 fetuses were
`identified as being at risk for a urea cycle defect on the ba-
`sis of the diagnosis of a previously affected sibling with
`neonatal onset. Before conception or delivery, parents were
`counseled regarding three options available after the birth
`of an at-risk infant: the experimental prospective diagnos-
`tic and therapeutic protocol described below; no therapy
`unless hyperammonemia occurred; and comfort care with-
`out therapy after the development of hyperammonemia. As
`part of the counseling procedure, the medical burdens as-
`sociated with treatment were also explained. These include
`the requirement of an artificial diet, the need for medication
`for an indefinite period, and the risk of subsequent episodes
`of hyperammonemia, brain damage, and death. Parents
`were encouraged to discuss these concerns with other par-
`ents who were familiar with the therapy. The option for or-
`thotopic liver transplantation when the child reaches an ap-
`propriate age was also discussed.
`Thirty-two parents (ALD, 2; ASD, 4; CPSD, 6; OTCD,
`
`Page 2 of 6
`
`can be given orally. A generous caloric intake should be
`provided as glucose and a lipid emulsion (lntralipid, from
`KabiVitrum AB, Stockholm, Sweden [Franklin, Ohio]) if
`feasible, to minimize endogenous proteolysis.
`After 24 to 48 hours of life, if the infant’s plasma ammo-
`nium level is within normal limits, 2. 0.5 gm infusion (per
`kilogram) of a nitrogen—amino acid—protein combination
`(Trophamine, from Kendall-McGaw Laboratories, Santa
`Ana, Calif.) may be administered daily, supplemented daily
`
`Page 2 of 6
`
`

`

`
`
`logram. If argininosuccinate and its anhydrides do not ap-
`pear in plasma within 48 hours, a diagnosis of normalcy may
`be made and therapy discontinued.
`Diagnosis. The diagnostic algorithm for urea cycle disor-
`ders, as previously described} was employed for these
`at—risk neonates with the following modifications. For
`infants at risk for CPSD and OTCD, the absence of plasma
`citrulline, or its presence in trace concentrations, at 48 and
`72 hours of age was considered diagnostic of these disorders.
`A citrulline level greater than 5 pmol/ L at 48 hours of age,
`unaccompanied by hyperammonemia or hyperglutamine-
`mia, was considered normal. Currently, percutaneous liver
`biopsy for assay of enzyme activity is recommended if these
`substrate levels are ambiguous. For neonates at risk for
`ASD and ALD, the appearance of a high plasma level of
`citrulline in the former, or of argininosuccinate lyase in the
`latter, was considered diagnostic of the disease. Normal
`levels of these amino acids at 48 hours of age were consid-
`ered diagnostic of normalcy of the infant.
`Long-term therapy. The disease-specific protocols were
`modified during the 10-year period of this study as a con-
`sequence of the availability of investigational new drugs.
`The first-generation protocol included the administration of
`sodium benzoate and arginine or citrulline; patients born
`before 1984 were maintained on this protocol. The second-
`generation protocol added sodium phenylacetate; it was
`first used to treat patients in 1984. The third-generation
`protocol included high doses of sodium phenylacetate or
`phenylbutyrate and excluded sodium benzoatez; patients
`were changed to this protocol as it became available in 1987.
`New patients were usually converted from standard to
`high-dose therapy within the first 3 to 6 months of life. So-
`dium phenylbutyrate is now recommended as the drug of
`choice at a dosage of 45010 500 mg/kg per day (9.9 to 13
`gm/m2 per day).3 Current protocols also include a higher
`intake of natural protein during the first few months of life.3
`Follow-up study. The medical record of each alfected in-
`fant was obtained periodically to collect metabolic, clinical,
`and developmental data. Long-term metabolic control was
`monitored by periodic measurement of plasma ammonium
`and plasma amino acid levels in conjunction with nutritional
`and anthropometric assessments. Long-term clinical con-
`trol was estimated by the number of hospitalizations for in-
`tercurrent hyperammonemic episodes, duration of the epi-
`sode, and the peak plasma ammonium level. Developmen-
`tal progress and intelligence after 6 months of age were
`evaluated by private physicians or psychologists, who used
`standardized tests.
`
`with at least 80 kcal/kg from glucose and Intralipid. If
`plasma ammonium levels remain within normal limits or
`nearly so, the daily intake of Trophamine may be increased
`to 1.2 gm/kg for the next 48 to 72-hour period.
`If the diagnosis of OTCD or CPSD is confirmed on the
`basis of plasma and urine substrate analysis,1 oral medica-
`tions and enteral nutrition may continue. The recommended
`diet for neonates on the protocol described above consists of
`natural protein (from standard infant formula), no more
`than 2 gm/kg per day, supplemented with Mead Johnson
`product No. 80056 (4.9 kcal/gm) to supply a total daily
`caloric intake of 120 to 130 kcal/kg. This protein intake
`should be attained in staged increments of 0.25 to 0.5 gm/kg
`per day. The plasma levels of ammonium, glutamine,
`branched-chain amino acids, and protein should be moni-
`tored.
`
`Argininosuccinate synthetase deficiency. As soon as pos-
`sible after birth, the infant at risk for ASD should receive
`
`the following intravenously: 10% arginine HCl, 6 ml /kg per
`day (3 mmol/kg per day), sodium benzoate, 250 mg/ kg per
`day, and sodium phenylacetate, 250 mg/kg per day, in 10%
`glucose to provide as high a caloric intake as is practicable.
`Sodium bicarbonate should be added to the infusate to
`
`the hydrochloride. Formula feeding may begin
`bufi'er
`shortly after birth, starting with protein, 0.5 g/ kg per day;
`Mead Johnson product No. 80056, made up to contain 0.7
`kcal/ml, may be given orally as a caloric supplement. If
`plasma ammonium levels remain normal, protein intake
`may be gradually increased up to 2.0 gm/kg per day, sup-
`plemented with Mead Johnson product No. 80056 to sup-
`ply a total daily calorie intake of 110 to 120 kcal/ kg. If
`plasma citrulline levels remain normal for 48 hours, a diag-
`nosis of normalcy may be made and therapy discontinued.
`Argininosuccinate lyase deficiency. Within 2 hours of
`birth, all infants at risk for ALD should be fed (by gavage,
`if necessary) a mixture of arginine freebase, 600 mg/kg per
`day, plus normal formula feeding, starting with protein, 0.5
`gm/kg per day. If oral feeding is not tolerated, it is essen-
`tial that the infant promptly be treated intravenously with
`10% arginine hydrochloride at a dosage of 6 ml /kg per day
`(3 mmol/ kg per day), with generous amounts of sodium bi-
`carbonate to buffer the hydrochloride. As he or she is able
`to tolerate oral feedings, the intravenous administration of
`arginine may be discontinued in favor of arginine (free-
`base).
`Additional calories can be supplied by using Mead
`Johnson product No. 80056 to provide the infant with a to-
`tal of 110 to 120 kcal/kg per day. Water should be added
`as tolerated. The formula must be adjusted so that the in-
`fant receives a full day’s dose of arginine each day. For a
`period of several days,
`the formula may be gradually
`increased to provide no more than 2.0 gm of protein per ki-
`
`Volume 1 19
`Number 6
`
`Prospective treatment of urea cycle disorders
`
`925
`
`RESULTS
`
`Implementation of therapy. Each of the pregnancies
`resulted in the birth of an infant with normal 1- and
`
`Page 3 of 6
`
`Page 3 of 6
`
`

`

`926 Maestri et al.
`
`The Journal of Pediatrics
`December 1991
`
`Table 11. Survival history of prospectively treated patients with urea cycle disorders
`
`ID
`No.
`
`Diog— Birth
`nosis year Protocol 1 Protocol 2 Protocol 3
`
`status
`
`survival
`(mo)
`
`Developmental
`assessment
`
`other medical
`problems
`
`Age of start of
`prolocol'
`
`1
`
`2
`
`3
`4
`
`5
`6
`7
`
`8
`
`9
`10
`11
`12
`
`ALDT
`
`1982
`
`—-
`
`——
`
`—
`
`Alive
`
`102
`
`ASD
`
`1984
`
`1 wk
`
`5 mo
`
`ASD
`ASD
`
`1985
`1987
`
`CPSD
`CPSD
`CPSD
`
`1981 At birth
`1987
`1987
`
`OTCD 1981 At birth
`
`OTCD 1983 At birth
`OTCD 1984
`OTCD 1986
`OTCD 1987
`
`At birth
`At birth
`
`11 mo
`At birth
`At birth
`
`At birth
`At birth
`At birth
`
`37 mo
`
`37 mo
`12 mo
`
`76 mo
`5 mo
`3 mo
`
`14 mo
`
`Alive
`
`Alive
`Alive
`
`Alive
`Dead
`Alive
`
`Dead
`
`Dead
`Tx
`TX
`Tx
`
`83
`
`69
`42
`
`125
`46
`49
`
`7
`
`
`
`umol,’ L) was moderately elevated for a brief period, and
`they survived the neonatal period. However, three infants
`had ammonium levels that remained greater than 500
`umol / L despite aggressive therapy, including intravenous
`infusion of arginine, sodium benzoate, and sodium pheny-
`lacetate; exchange transfusion in one patient; and hemodi-
`alysis in the second. These three infants died at days 4, 5,
`and 12, respectively. Inasmuch as the 13 mutations identi-
`fied at the ornithine transcarbamylase locus-5'7 differ, it is
`likely that subtle differences in severity of disease in these
`patients affected their response to treatment and therefore
`the outcome.
`
`Aortic stenosis,
`asthma, seizures
`
`Seizures (9 mo)
`
`Seizures (8 mo)
`
`Significant delay;
`no expressive
`language
`Educable, mentally
`impaired
`Some speech delay
`Mild delay in language,
`cognitive functioning
`Borderline functioning
`Borderline functioning
`Low normal
`
`intelligence
`
`Language disorder
`33
`21 (+68)i Within normal range
`47 (+5)
`Within normal range
`18 (+32) Within normal range
`
`Seizures, after
`transplant
`
`Tx, Received a liver transplant.
`*Protocol 1 consisted of administration of sodium benzoate and arginine or citrulline; protocol 2 consisted of protocol 1 plus administration of sodium phenylac-
`etate; protocol 3 consisted of high doses of sodium phenylacetate or phenylbutyrate plus arginine or citrulline (sodium benzoate is excluded).
`TReceived arginine from birth.
`iMonths of survival after liver transplant.
`
`5-minute Apgar scores and of normal size. The therapeutic
`protocols were implemented successfully within 12 hours of
`birth. Cord blood and serial plasma samples were obtained
`for the measurement of ammonium and amino acids.
`
`Diagnostic protocol and neonatal outcome. Three of the
`four infants at risk for ASD were identified on the basis of
`
`extremely elevated citrulline levels, ranging from 2692 to
`2893 umol / L. One infant at risk for ALD had an abnormal
`citrulline concentration of 262 umol / L at 120 hours; this
`level is typical of patients with ALD. Elevated levels of
`argininosuccinate and its anhydrides were also present in
`this patient. Of 26 infants at risk for OTCD or CPSD, 11
`had plasma chromatograms that showed no detectable peak
`at the retention time of citrulline, indicating that they were
`affected. The mean (:SD) peak plasma citrulline level in
`the first 72 hours among the remaining 17 unaffected
`infants in this study was 13.7 1 11.08 umol/L (range 1 to
`51 ;:.mol/ L; normal range for neonates, 9 to 29 umol/L4).
`Plasma ammonium levels measured between 48 and 72
`
`hours after birth showed considerable variability, reflecting
`diagnostic category, efficacy of treatment, and differing
`normal reference values at various institutions. The infants
`
`affected with ASD or ALD had peak ammonium levels that
`ranged from 29 to 82 umol / L, compared with a mean level
`of 50.1 umol/L in unaffected infants (range 5 to 112 um0l/
`L). One infant affected with CPSD had plasma ammonium
`
`Page 4 of 6
`
`levels that remained at less than 50 urnol / L; the two other
`infants with CPSD had elevated ammonium levels (125 and
`
`219 umol / L) but no symptoms of hyperammonemia. All of
`these infants survived the neonatal period.
`Hyperammonemia developed in the eight patients with
`OTCD. In five infants the mean peak ammonium level (115
`
`Liver biopsy samples were obtained from three patients
`with OTCD for enzyme assay. Because plasma citrulline
`and ammonium levels remained within the normal range for
`3 to 5 days, a urea cycle defect was ruled out in 17 infants
`and the therapeutic protocol was discontinued.
`Long-term follow-up study. Twelve prospectively treated
`affected infants survived the neonatal period, free of symp-
`toms of hyperammonemia and developmental delay. All
`
`Page 4 of 6
`
`

`

`outcome in patients with OTCD. The weight of patient 9
`was between the 5th and 10th percentiles up to the time of
`his death. Patient 12 had weight measurements below the
`5th percentile preceding his liver transplantation at 18
`months of age, whereas the weight of patient 10 had
`increased to the 50th percentile before transplantation at 21
`months. Their most recent reported measurements (38
`months and 52 months) indicate that weight is below the 5th
`percentile after transplantation in both. There has been less
`variability in height measurements of these patients, which
`also track consistently. None of these patients has height
`measurements above the mean for age.
`Developmental progress. Treatment of these patients was
`not part of a strictly controlled clinical trial. Many differ-
`ent standardized tests were used to assess development; the
`timing and type of tests were at the discretion of parents and
`private physicians. Children who appeared to be developing
`normally were tested less frequently than children who
`showed evidence of developmental delay. Most patients
`have had some developmental delay (Table II), and almost
`all are reported to have problems with expressive or recep-
`tive language resulting in referral for speech therapy, occu-
`pational therapy, and /or physical therapy in structured
`preschool programs.
`
`
`
`DISCUSSION
`
`The protocols were successful in averting neonatal hy-
`perammonemic coma and death in all patients (n = 7) af-
`fected with ALD, ASD, and CPSD. However, among eight
`patients affected with OTCD, three died as a result of hy-
`perammonemic coma. The remaining five had moderately
`elevated levels of plasma ammonium but no symptoms of
`hyperammonemia.
`Therapy did not interfere with the diagnosis of normalcy
`in 17 unaffected infants. Their medications were discontin-
`
`ued within 96 hours, and regular formula feedings were in-
`stituted immediately. This brief period of therapy does not
`appear to have had any effect on growth and development
`of the unaffected infants.
`
`We reported previously that during the first 2 years of life
`the overall survival rate for patients with CPSD and OTCD
`who survived rescue from neonatal hyperammonemic coma
`is approximately 73%‘; the one prospectively treated patient
`who died before 2 years of age in this study had been treated
`with sodium benzoate alone. Survival after age 2 years ap-
`pears to be comparable in the rescue and prospectively
`treated groups; both have a mortality rate of approximately
`29%. However, small numbers of patients, changes in
`treatment protocol during the study period, and liver trans-
`plantation in three patients with OTCD preclude direct
`comparison of survival times.
`All four of the prospectively treated patients with ASD
`
`Volume 119
`Number 6
`
`Prospective treatment of urea cycle disorders
`
`927
`
`were discharged from the hospital on protein-restricted di-
`ets and medication regimens to stimulate excretion of waste
`nitrogen and to maintain nitrogen homeostasis (Table II).
`Deaths. There have been three deaths among the 12 sur-
`vivors (Table II): CPSD patient 6, and OTCD patients 8
`and 9. Patient 6 died at 46 months of age during a hyper-
`ammonemic episode that did not respond to peritoneal di-
`alysis or hemodialysis. He had been maintained on protocol
`3 since his fifth month of life and had had four prior hyper-
`ammonemic episodes.
`Two patients with OTCD also died as a result of hyper-
`ammonemia that did not respond to treatment at 7 months
`and 33 months, respectively. Patient 8 had been treated with
`protocol 1 and had had nine hyperammonemic episodes in
`his 7 months of life; although his physicians reported that
`his development was normal, the frequency of hyperam-
`monemic episodes suggests that his nitrogen metabolism
`was not adequately controlled. Patient 8 was also treated
`with protocol 1. He had had four hyperammonemic epi-
`sodes, each associated with a viral infection, before his
`death.
`
`The three surviving OTCD patients have received ortho-
`topic liver transplants at. ages 18, 21, and 47 months,
`respectively; they are on normal diets and are no longer
`maintained on these therapeutic protocols.
`All patients have had intercurrent hyperammonemic ep-
`isodes, often associated with common viral or bacterial in-
`
`fections. Treatment of these episodes has involved overnight
`hospitalizations for intravenous drug therapy and, in two
`cases, dialysis. Patients 1, 2, and 5 each had seizures during
`a hyperammonemic episode and required long-term treat-
`ment with anticonvulsant agents.
`The single patient with ALD has had developmental de-
`lay despite having had arginine supplementation since birth
`and no severe episode of hyperammonemic encephalopathy.
`At 10 weeks of age he had excessive regurgitation, poor
`weight gain, and possible neurologic deterioration. Aortic
`stenosis was diagnosed when he was 35 months of age. He
`has had five hyperammonemic episodes, and a seizure dis-
`order that developed at 35 months of age has required
`treatment with carbamazepine. Repeated testing has indi-
`cated psychomotor delay, and at 87 months of age he lacks
`expressive language (Table II).
`Anthropometric measurements. The weight of most of the
`patients appears to have tracked consistently. The weight of
`patients with ASD is at or above the mean after 1 year of
`age, but there is greater variability in the weight of patients
`with CPSD or OTCD. In most patients with CPSD, weight
`tracks between the 5th and 50th percentiles. The weight
`gain of patient 6 appeared to level off in the months preced-
`ing his death.
`There was no apparent relationship between weight and
`
`Page 5 of 6
`
`Page 5 of 6
`
`

`

`or ALD are alive. Their survival rate can be compared with
`a survival rate of approximately 90% among patients with
`ASD or ALD who survive the neonatal period after being
`rescued from hyperammonemic coma (unpublished obser-
`vations). In general, patients with ALD who are treated
`with dietary arginine and a protein-restricted diet rarely
`have intercurrent hyperammonemic episodes. The less
`favorable outcome of this prospectively treated patient with
`ALD may be due to unknown factors unrelated to his met-
`abolic disorder. Other patients with ALD who have been
`rescued from neonatal hyperammonemic coma and treated
`with comparable doses of arginine for as long as 8 years have
`made steady developmental progress and shown no signs of
`neurodevelopmental deterioration.
`Anthropometric measurements of these patients indicate
`that in the majority of patients with CPSD or OTCD, mea-
`surements are below the mean for their age, possibly
`reflecting their low protein diets. In those with ASD or
`ALD, weight is closer to the mean but height remains less
`than average.
`Msall et al.9 described the neurologic outcome of 26 chil-
`dren with inborn errors of urea synthesis. Seventy-nine per-
`cent had one or more developmental disabilities and a mean
`IQ of 43 i 6. A significant negative correlation existed be-
`tween the duration of stage 3 or 4 hyperammonemic coma
`and IQ at
`1 year of age. The authors concluded that
`prevention of, or early intervention in, neonatal hyperam-
`monemia might avoid the severe neurologic handicaps
`characteristic of these disorders. Our results indicate that
`
`
`
`therapy is effective in avoiding neonatal hyperammonemia
`in patients with CPSD, ALD, or ASD. Approximately 65%
`of prospectively treated patients with OTCD avoid severe
`hyperammonemia and survive the neonatal period. Not-
`withstanding the greatly improved status of patients who
`are treated prospectively in comparison with those rescued
`from coma, in the former group, handicaps impair develop-
`ment, a burdensome medical regimen must be followed, ep-
`isodes of hyperammonemia are recurrent, and there is a
`high mortality rate. Orthotopic liver transplantation repre-
`sents an option for patients whose parents are informed of
`the risks and burdens of surgical therapy. The efiicacy of
`sodium phenylacetate and phenylbutyrate in promoting
`survival beyond 2 years of age suggests that liver transplan-
`tation can be postponed until the patients achieve a body
`size associated with reduced surgical risk.
`
`REFERENCES
`
`l. Brusilow SW, Horwich AL. Urea cycle enzymes. In: Scribner
`C, Beaudet A, Sly W, Valle D, eds. The metabolic basis of in-
`herited disease. 6th ed. New York: McGraw-Hill, 1989:629-
`63.
`2. Brusilow SW. Phenylacetylglutamine may replace urea as a
`vehicle for waste nitrogen excretion. Pediatr Res 1991;29:147-
`50.
`
`3. Brusilow SW. Treatment of urea cycle disorders. In: Desnick
`R, ed. Treatment of genetic diseases. New York: Churchill-
`Livingstone, l991:79-94.
`4. Dickinson JC, Rosenblurn H, Hamilton PB. Ion exchange
`chromatography of the free amino acids in the plasma of the
`newborn infant. Pediatrics l965;36:2-13.
`5. Castens RP, Fenton WA, Rosenberg LE. Identification of
`RNA splicing errors resulting in ornithine transcarbamylase
`deficiency