`
`Prospective treatment of urea cycle
`disorders
`
`Nancy E. Maestri, PhD, Elizabeth R. Hauser, MHS,* Dennis Bartholomew, MD,"*
`and Saul W. Brusilow, MD
`From the Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore,
`Maryland
`
`Wepresent a diagnostic and therapeutic protocol designed to preventclinical
`expression of inborn errors of urea synthesis in the neonatalperiod, and discuss
`the long-term developmental outcomeof survivors. The families of 32 infants,
`among 43 identified prenataily as being af risk for a urea cycle disorder, chose
`to have their infants treated according to a diagnostic and therapeutic profo-
`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-
`cinate lyase deficiency. When treated prospectively, five of eight patients with
`ornithine transcarbamylase 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 outcomethan patients
`rescued from neonatal hyperammonemic coma. However, all of them require
`a burdensome medical regimen and may have handicapsthat 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 Pepiatr 1994;419:923-8)
`
`Hyperammonemia occurs with varying severity in all
`patients with inborn errors of urea synthesis; these errors
`
`Supported by the National Institutes of Health (grants HD11134,
`HD 26358, and RR-00052), the Kettering Family Foundation, the
`T. D. and M. A. O’Malley 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. 12, 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, Universily 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
`
`include deficiencies of carbamoyl phosphate synthetase,or-
`nithine transcarbamylase, argininosuccinate synthetase,
`argininosuccinate lyase, and arginase. There is considerable
`variability in severity within each enzyme deficiency, pre-
`sumably a function of genetic variability, and among the
`
`Ornithine transcarbamylase deficiency
`
`Argininosuccinate lyase deficiency
`Argininosuccinate synthetase deficiency
`Carbamoyl! phosphate synthetase deficiency
`
`enzymedeficiencies 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-
`
`
`
`Page 1 of 6
`
`Horizon Exhibit 2010
`
`Par v. Horizon
`IPR2017-01768
`
`923
`
`Page 1 of 6
`
`Horizon Exhibit 2010
`Par v. Horizon
`IPR2017-01768
`
`

`

`924 Maestri et al.
`
`The Journal of Pediatrics
`December 1991
`
`Table 1. Prospective neonatal treatment protocols for
`“at risk” infants as described in this study
`
`Diagnosis
`
`CPSD or
`OTCD
`
`ASD
`
`ALD
`
`1.5
`—
`120
`
`1.5
`—
`120
`
`
`
`20) chose to havetheir at-risk fetus treated prospectively at
`birth. Prenatal DNA analysis indicated that three at-risk
`male fetuses had OTCD. One patient with ALD andthree
`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
`performedin 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 I. 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 thereafterto
`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 synthetase. 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 ofa large
`line cannot be overemphasized. With blood flow of 50 ml/
`min, ammonium clearance maybe 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 HCI, 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
`
`0.7
`0.7
`120
`
`Diet (per kg per day)
`Natural protein (gm)
`Essential amino acids (gm)
`Calories (kcal)
`Medications (mg/kg/day)*
`700
`700
`170
`Arginine freebase
`—
`250
`250
`Sodium benzoate
`
`Sodium phenylacetatet —_— 250 _
`
`
`*Oral dosage.
`+Sodium phenylacetate was added to the protocol in 1984.
`
`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 hoursof 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 outcomeof affected
`survivors.
`
`Wepresent here the outcome of 32 at-risk infants who
`were treated prospectively at birth according to a therapeu-
`tie 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 burdensas-
`sociated with treatment were also explained. These include
`the requirementof anartificial diet, the need for medication
`for an indefinite period, and therisk 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 foror-
`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 (Intralipid, from
`KabiVitrum AB, Stockholm, Sweden [Franklin, Ohio]) if
`feasible, to minimize endogenous proteolysis.
`After 24 to 48 hoursoflife, if the infant’s plasma ammo-
`nium level is within normal limits, a 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
`
`

`

`Volume \19
`Number 6
`
`Prospective treatment of urea cycle disorders
`
`925
`
`
`
`logram. If argininosuccinate and its anhydrides do not ap-
`pear in plasmawithin 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 absenceof plasma
`citrulline, or its presence in trace concentrations, at 48 and
`72 hours of age was considered diagnosticof these disorders.
`A citrulline level greater than 5 umol/L at 48 hoursof age,
`unaccompanied by hyperammonemia or hyperglutamine-
`mia, was considered normal. Currently, percutaneousliver
`biopsy for assay of enzymeactivity is recommendedif 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.
`Thefirst-generation protocolincluded 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 benzoate’; patients
`were changedto 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 monthsoflife. So-
`dium phenylbutyrate is now recommendedas the drug of
`choice at a dosage of 450.to 500 mg/kg per day (9.9 to 13
`gm/m? per day).> Current protocols also include a higher
`intake of natural protein during thefirst few monthsoflife.3
`Follow-up study. The medical record of each affected in-
`fant was obtained periodically to collect metabolic, clinical,
`and developmental data. Long-term metabolic control was
`monitored by periodic measurementof plasma ammonium
`and plasma aminoacidlevels in conjunction with nutritional
`and anthropometric assessments. Long-term clinical con-
`trol was estimated by the numberofhospitalizations for in-
`tercurrent hyperammonemic episodes, duration ofthe 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
`standardizedtests.
`
`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 maybe increased
`to 1.2 gm/kg for the next 48 to 72-hour period.
`If the diagnosis of OTCD or CPSDis confirmed on the
`basis of plasma and urine substrate analysis,! oral medica-
`tions andenteral 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 mont-
`tored.
`Argininosuccinate synthetase deficiency. AS soon as pos-
`sible after birth, the infant at risk for ASD should receive
`the following intravenously: 10% arginine HCI, 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
`
`buffer the hydrochloride. Formula feeding may begin
`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 caloric intake of 110 to 120 kcal/kg. If
`plasmacitrulline 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-
`
`Page3 of 6
`
`RESULTS
`
`Implementation of therapy. Each of the pregnancies
`resulted in the birth of an infant with normal 1- and
`
`Page 3 of 6
`
`

`

`926 Maestri et al.
`
`The Journal of Pediatrics
`December 1991
`
`Table Ii. Survival history of prospectively treated patients with urea cycle disorders
`
`
`Age atstart of
`protocol’
`
`ID Diag- Birth
`
`No.
`nosis year Protocol 4 Protocol 2 Protocol 3 Status
`
`Survival
`(mo)
`
`Developmental
`assessment
`
`Other medical
`problems
`
`ALDT
`
`1982
`
`_
`
`_
`
`—_
`
`Alive
`
`102
`
`Significant delay;
`no expressive
`language
`Educable, mentally
`impaired
`Somespeech delay
`Mild delay in language,
`cognitive functioning
`Seizures (8 mo)
`Borderline functioning
`125
`Alive
`76 mo
`11 mo
`1981 At birth
`CPSD
`5
`
`
`6 CPSD=1987 Atbirth 5 mo Dead 46 Borderline functioning
`
`
`
`
`7
`CPSD
`1987
`At birth
`3 mo
`Alive
`49
`Low normal
`
`
`
`levels that remained at less than 50 wmol/L; the two other
`infants with CPSD had elevated ammoniumlevels (125 and
`219 »mol/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 ammoniumlevel (115
`pmol/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
`pmol/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*’ differ, it is
`likely that subtle differences in severity of disease in these
`patients affected their response to treatment and therefore
`the outcome.
`
`1
`
`2
`
`3.
`4
`
`ASD
`
`1984
`
`| wk
`
`5 mo
`
`ASD
`ASD
`
`1985
`1987
`
`At birth
`At birth
`
`37 mo
`
`37 mo
`12 mo
`
`Alive
`
`Alive
`Alive
`
`83
`
`69
`42
`
`Aortic stenosis,
`asthma, seizures
`
`Seizures (9 mo)
`
`8
`
`OTCD 1981 At birth
`
`Dead
`
`7
`
`intelligence
`
`Atbirth
`
`Language disorder
`33
`Dead
`OTCD 1983
`§
`21 (4+68)£ Within normal range
`Tx
`At birth
`OTCD 1984
`10
`47 (+5)
`Within normal range
`Tx
`At birth
`OTCD 1986
`11
`Seizures, after
`18 (+32) Within normal range
`Tx
`Atbirth
`OTCD 1987
`12
`transplant
`Tx, Received a liver transplant.
`*Protocol 1 consisted of administration of sodium benzoate and arginine orcitrulline; 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.
`Monthsof survival after liver transplant.
`
`14 mo
`
`5-minute Apgar scores and of normalsize. The therapeutic
`protocols were implemented successfully within 12 hoursof
`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 wereidentified on the basisof
`
`extremely elevated citrulline levels, ranging from 2692 to
`2893 pmol/L. Oneinfant at risk for ALD had an abnormal
`citrulline concentration of 262 wmol/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 chromatogramsthat showed no detectable peak
`at the retention timeof citrulline, indicating that they were
`affected. The mean (+SD) peak plasmacitrulline level in
`the first 72 hours among the remaining 17 unaffected
`infants in this study was 13.7 + 11.08 wmol/L (range | to
`51 umol/L; normal range for neonates, 9 to 29 pmol/L‘).
`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 wmol/L, compared with a meanlevel
`of 50.1 wmol/L in unaffected infants (range 5 to 112 wmol/
`L). One infant affected with CPSD had plasma ammonium
`
`Page 4 of 6
`
`Liver biopsy samples were obtained from three patients
`with OTCD for enzyme assay. Because plasmacitrulline
`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
`
`

`

`Volume 119
`Number 6
`
`Prospective treatment of urea cycle disorders
`
`927
`
`were discharged from the hospital on protein-restricted di-
`ets and medication regimensto stimulate excretion of waste
`nitrogen and to maintain nitrogen homeostasis (Table IT).
`Deaths. There have been three deaths among the 12 sur-
`vivors (Table II): CPSD patient 6, and OTCDpatients 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 oflife and had had fourprior hyper-
`ammonemic episodes.
`Two patients with OTCDalso 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 monthsoflife; 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.
`
`
`
`Thethree 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 commonviral or bacterial in-
`fections. Treatmentof these episodes has involved overnight
`hospitalizations for intravenous drug therapy and, in two
`cases,dialysis. Patients 1, 2, and 5 each hadseizures during
`a hyperammonemic episode and required long-term treat-
`ment with anticonvulsant agents.
`Thesingle 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 monthsof 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 monthsof age he lacks
`expressive language (Table IJ).
`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 | year of
`age,but thereis greater variability in the weightof patients
`with CPSD or OTCD.In most patients with CPSD,weight
`tracks between the 5th and 50th percentiles. The weight
`gain of patient 6 appearedtoleveloff in the months preced-
`ing his death.
`There was no apparent relationship between weight and
`
`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
`increasedto the 50th percentile before transplantation at 21
`months. Their most recent reported measurements (38
`months and 52 months) indicate that weightis below the 5th
`percentile after transplantation in both. There has beenless
`variability in height measurementsof these patients, which
`also track consistently. None of these patients has height
`measurements above the mean for age.
`Developmental progress. Treatmentof 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 appearedto 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, amongeight
`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 symptomsof
`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 werein-
`stituted immediately. This brief period of therapy does not
`appear to have had anyeffect on growth and development
`of the unaffected infants.
`
`Wereported previously that during thefirst 2 yearsoflife
`the overall survival rate for patients with CPSD and OTCD
`whosurvived 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, andliver trans-
`plantation in three patients with OTCD preclude direct
`comparison of survival times.
`All four of the prospectively treated patients with ASD
`
`Page 5 of 6
`
`Page 5 of 6
`
`

`

`928 Maestri etal.
`
`The Journal of Pediatrics
`December 1991
`
`
`
`or ALDare alive. Their survival rate can be compared with
`a survival rate of approximately 90% among patients with
`ASD or ALD whosurvive the neonatal period after being
`rescued from hyperammonemic coma (unpublished obser-
`vations), In general, patients with ALD whoare treated
`with dietary arginine and a protein-restricted diet rarely
`have intercurrent hyperammonemic episodes. The less
`favorable outcomeof this prospectively treated patient with
`ALD may be due to unknownfactors unrelated to his met-
`abolic disorder. Other patients with ALD who have been
`rescued from neonatal hyperammonemic comaandtreated
`with comparable dosesof argininefor as long as 8 years have
`made steady developmental progress and shown nosigns of
`neurodevelopmental deterioration.
`Anthropometric measurementsof 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.
`Msallet al.? described the neurologic outcomeof 26 chil-
`dren with inborn errors of urea synthesis. Seventy-nine per-
`cent had one or more developmental disabilities and a mean
`1Q of 43 + 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
`prospectively treated patients do have a more favorable
`neurologic outcome than patients rescued from neonatal
`hyperammonemic coma. Their overall 1Qs aresignificantly
`higher than those of rescued patients,’ fewer have seizure
`disorders, and none has cerebral palsy. The avoidance of
`neonatal hyperammonemic coma may be a major factor in
`these observed developmental differences. However,there is
`no clear correlation between the subsequent numberof ep-
`isodes of hyperammonemia and neurologic outcomein this
`small sample of patients. Although we were unable to ex-
`amine their siblings or parents to estimate these patients’
`expected IQ, their overall mean IQ is below the population
`mean, suggesting that either their disease or therapy does
`limit their intellectual development.
`Theresults of this clinical study indicate that prospective
`
`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 efficacy of
`sodium phenylacetate and phenylbutyrate in promoting
`survival beyond 2 years of age suggeststhatliver transplan-
`tation can be postponed until the patients achieve a b