The New England Journal of Medicine
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` From the NEJM Archive. Copyright © 2010 Massachusetts Medical Society. All rights reserved.
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`Page 1 of 6
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`Horizon Exhibit 2030
`Par v. Horizon
`IPR2017-01768
`
`

`

`The New England Journal of Medicine
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`Downloaded from nejm.org at STANFORD UNIVERSITY on June 29, 2015. For personal use only. No other uses without permission.
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` From the NEJM Archive. Copyright © 2010 Massachusetts Medical Society. All rights reserved.
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`

`

`1502
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`June 7, 1984
`
`died before one year of age and are notincludedinthis
`paper. Four additional patients who havesince died
`are included: one deficient
`in carbamyl phosphate
`synthetase, one in ornithine transcarbamylase, one in
`argininosuccinate synthetase, and one in argininosuc-
`cinase. ‘Twoof the deaths resulted from intercurrent
`hyperammonemic coma, one occurred after an acci-
`dental 10-fold overdose ofintravenous sodium benzo-
`ate and sodium phenylacetate during an episode of
`hyperammonemia, and one resulted from aspiration
`pneumonia. Postmortem examinations were not per-
`mitted in any ofthese children.
`
`Neurologic Function
`Table 3 shows that of the 24 children, 19 (79 per
`cent) had one or more developmental disabilities: 46
`per cent had cerebral palsy, 79 per cent were mentally
`retarded, 17 per cent hadseizure disorders, 54 percent
`had microcephaly, and one child was blind; 46 per
`cent had more thanone handicapping condition. The
`most recent IQ was 43+6 (mean +S.E.M.). Twenty-
`onepercent (five) of the children had an IQ above 70;
`broken down bytypeofdeficiency, the percentages of
`children with an IQ above 70 were as follows: carba-
`my! phosphate synthetase, 0 per cent; ornithine trans-
`carbamylase, 60 per cent; argininosuccinate synthe-
`tase, 12 per cent; and argininosuccinase, 12 per cent.
`Four ofthese five children had an attention-deficit
`disorder. A paired t-test was performed on the change
`between IQ at 12 months and the most recent 10
`(mean, 35+4 months; range, 19 to 74) in 19 children.
`‘The 1Q decreased by 8.62.5 points (P<0.01) during
`this period,
`Figure 3 shows the relation between duration of
`
`nium level versus C’l-scan rating. ‘The peak ammoniumlevel was
`defined as the highest recorded plasma ammoniumlevel during
`neonatal coma; peak values in the patients have been reported pre-
`viously.” Excluded fromthese analyses (other than C’'Tversus con-
`current IQ) were two patients who were in a coma for 12 and
`30 days.
`In addition, a paired t-test was usedto determinethesignificance
`of changes in 1Q from 12 months to follow-up at 19 to 74 months.
`Excludedfromthis analysis were the four children younger than 18
`months. Also excluded wasa child whohad an episodeof hyperam-
`monemic comaat 12 months, associated with Stage IV coma and
`increased intracranial pressure. ‘Vhis child’s 1Q fell from 78 to 10
`and was deemed outside the range we were considering clinically.
`This study was performed between 1978 and 1982 andinvolved a
`collaborative effort among 26 medical
`institutions in the United
`States and Europe. Parental consent was obtained, and the study
`was approved by the Joint Committee on Clinical Investigation at
`Johns Hopkins Hospital and by the institutional review boards of
`participating hospitals.
`
`REsuLts
`
`Mortality
`
`Six of 26 patients died during the study. Two male
`infants with ornithine transcarbamylase deficiency
`
`Stage III or IV neonatal hyperammonemic coma and
`
`Figure 2. CT Scans in Three Children with Complete Urea-Cycle EnzymeDeficiencies.
`Scan A shows mildly dilated ventricles (CT rating, 1.0) in a 24-month-old child with a deficiency of ornithine transcarbamylase. Scan B
`showsmild ventriculomegaly and patchy areas of parenchymallow density (CT rating, 2.5) in a six-month-old infant with argininosuccin-
`ase deficiency. Scan C showsventriculomegaly, prominent sulci, and subcortical low-density areas (CT rating, 5.0) in a 14-month-old
`child with argininosuccinase deficiency.
`The New England Journal of Medicine
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`Archive.
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`From the NEJM
`
`Page 3 of 6
`
`Table 2. Rating Scales for Cerebral Abnormalities Demonstrated
`by CT Scan.
`normal
`0
`minimally prominent
`moderately prominent
`markedly prominent
`normal
`minimally dilated
`moderately dilated
`markedly dilated
`normal
`subcortical low density
`scattered areas of low density
`confluent areas of low density
`
`Conical sulci
`
`Ventricles
`
`Brain substance
`
`huioud
`
`“oud
`
`0123
`
`0123
`
`

`

`The New England Journal of Medicine
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`Downloaded from nejm.org at STANFORD UNIVERSITY on June 29, 2015. For personal use only. No other uses without permission.
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`The New England Journal of Medicine
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`Downloaded from nejm.org at STANFORD UNIVERSITY on June 29, 2015. For personal use only. No other uses without permission.
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`

`The New England Journal of Medicine
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`Downloaded from nejm.org at STANFORD UNIVERSITY on June 29, 2015. For personal use only. No other uses without permission.
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`