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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`Page 1 of 6
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`Horizon Exhibit 2030
`Par v. Horizon
`IPR2017-01768
`
`

`

`The New England Journal of Medicine
`
`Downloaded from nejm.org at STANFORD UNIVERSITY on June 29, 2015. For personal use only. No other uses without permission.
`
` From the NEJM Archive. Copyright © 2010 Massachusetts Medical Society. All rights reserved.
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`Page 2 of 6
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`

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`l5ll2
`
`'I'III". NEW ENGLANDJUURNAI. OF MEDICINE
`
`June 7, HIM
`
`Table 2. Rating Scales for Cerebral Abnormalities Demonstrated
`by CT Scan.
`nomtal
`(i
`minimally prominent
`moderately prominent
`markedly prominent
`normal
`minimally diluted
`moderately dilated
`markedly dilated
`nomad
`witcortical low density
`scattered areas of low density
`confluent areas of low demity
`
`Conical sulci
`
`Vcntricles
`
`Brain substance
`
`IIIIIIil
`
`0
`
`123
`
`fll1llll
`
`0l2 3
`
`died before one year ofage and are not included in this
`paper. Four additional patients who have since died
`are included: one deficient
`in carbamyl phosphate
`synthctasc, one in ornithine transcarbamylasc, one in
`argininosuccinate synthetase, and one in argininosuc—
`cinase. Two of the deaths resulted from intercurrcnt
`
`hyperammonemic coma, one occurred after an acci-
`dental 10-fold overdose ofintravenous sodium benzo—
`
`ate and sodium phenylacetate during an episode of
`hyperammoncmia, and one resulted from aspiration
`pneumonia. Postmortem examinations were not per-
`mitted in any of these children.
`
`Neurologlc 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, I7 per cent had seizure disorders, 54 per cent
`had microcephaly, and one child was blind; 46 per
`cent had more than one handicapping condition. The
`most recent IQ was 43:6 (mean tS.E.M.). Twenty-
`one per cent (live) ofthe children had an IQ above 70;
`broken down by type ofdeliciency, the percentages of
`children with an IQ above 70 were as follows: carba-
`myl phosphate synthctase, 0 per cent; ornithine trans-
`carbamylase, 60 per cent; argininosuccinate synthe-
`tase, I2 per cent; and argininosuccinase, 12 per cent.
`Four of these 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 IQ
`(mean, 35:4 months; range, 19 to 74) in 19 children.
`The. IQ decreased by 8.6125 points (I’<0.0I) during
`this period.
`Figure 3 shows the relation between duration of
`Stage III or IV neonatal hyperammoncmic coma and
`
`niutn level versus (IT-scan rating. The peak ammoniunt level was
`defined as the highest recorded plasma ammonium level during
`neonatal coma; peak values in the patients have been reported pre-
`viously.2 Excluded frotn these analyses (other than CT versus con-
`current IQ) were two patients wlto were in a coma for
`l2 and
`30 days.
`In addition, a paired t-test was used to determine the significance
`ol‘changcs in IQ frotn l2 months to follow-up at 19 to 74 months.
`Excluded from this analysis were the four children younger than Ill
`months. Also excluded was a child who had an episode ofhypt-ram-
`tnonetnie coma at I2 months, associated with Stage IV (‘t)lll:l and
`increased intracranial pressure. This child's IQ fell from 78 to If)
`and was deemed outside the range we were considering clinically.
`This study was performed between I978 and |982 and involved 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 hoards of
`participating hospitals.
`
`RESULTS
`
`Mortality
`
`Six of 26 patients died during the study. Two male
`infants with ornithine transcarbamylasc deficiency
`
`
`
`Figure 2. CT Scans in Three Children with Complete Urea-Cycle Enzyme Deficiencies.
`Sean A shows mildly dilated ventricles (CT rating. 1.0) in a 24-month-old child with a deficiency of ornithine transcarbamylase. Scan B
`shows mild ventriculomegaly and patchy areas of parenchymal low density (CT rating, 2.5) in a six-month—old infant with argininosuccin-
`ase deficiency. Scan C shows ventriculomegaly, prominent sulci. and subcortical low-density areas (CT rating. 5.0) in a 14-month-old
`child with argininosuccinase deficiency.
`mmmmumm
`WmmaflmWmmmfl.ml5.mmflmufl.mflwmmm
`memm.womtuumwsm.umm.
`
`Page 3 of 6
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`

`The New England Journal of Medicine
`
`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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`

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

`

`The New England Journal of Medicine
`
`Downloaded from nejm.org at STANFORD UNIVERSITY on June 29, 2015. For personal use only. No other uses without permission.
`
` From the NEJM Archive. Copyright © 2010 Massachusetts Medical Society. All rights reserved.
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`Page 6 of 6
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`