Molecular Genetics and Metabolism 110 (2013) 179–180
`
`Contents lists available at ScienceDirect
`
`Molecular Genetics and Metabolism
`
`j o u r n a l h o m e p a g e : w w w. e l s e v i e r . c o m/ l o c a t e / y m gm e
`
`Brief Communication
`The incidence of urea cycle disorders
`Marshall L. Summar a,⁎, Stefan Koelker b, Debra Freedenberg c, Cynthia Le Mons d, Johannes Haberle e,
`Hye-Seung Lee f, Brian Kirmse a, The European Registry and Network for Intoxication Type Metabolic
`Diseases (E-IMD) e, and The Members of the Urea Cycle Disorders Consortium (UCDC) f
`a Division of Genetics and Metabolism, Children's National Medical Center, 111 Michigan Ave. NW, Washington DC 20008, USA
`b University Children's Hospital, Dept. of General Pediatrics, Division of Inherited Metabolic Diseases, Im Neuenheimer Feld 430, D-69120 Heidelberg, Germany
`c Texas Department of State Health Services, 1100 W 49th Street — Mail code 1918, Austin, TX 78756, USA
`d National Urea Cycle Disorders Foundation, 75 South Grand Avenue, Pasadena, CA 91105, USA
`e Division of Metabolism, University Children's Hospital, Steinwiesstrasse 75, CH-8032 Zürich, Switzerland
`f Data Management and Coordinating Center, University of South Florida, Tampa, FL, USA
`
`a r t i c l e
`
`i n f o
`
`a b s t r a c t
`
`A key question for urea cycle disorders is their incidence. In the United States two UCDs, argininosuccinic syn
`thetase and lyase deficiency, are currently detected by newborn screening. We used newborn screening data
`on over 6 million births and data from the large US and European longitudinal registries to determine how
`common these conditions are. The incidence for the United States is predicted to be 1 urea cycle disorder pa
`tient for every 35,000 births presenting about 113 new patients per year across all age groups.
`© 2013 Published by Elsevier Inc.
`
`Article history:
`Received 6 May 2013
`Received in revised form 9 July 2013
`Accepted 10 July 2013
`Available online 18 July 2013
`
`Keywords:
`Incidence
`Urea cycle
`Inborn error of metabolism
`Newborn screening
`Hyperammonemia
`Ammonia
`
`1. Introduction
`
`A commonly asked question about almost all rare inborn errors
`of metabolism is: “How common is it?”. Most publications and web
`pages will provide an estimate that can range by orders of magnitude.
`With the advent of accountable care organizations, development and
`marketing of new treatments, and the creation of national registries
`and longitudinal studies, this question requires a more accurate an
`swer. Urea cycle disorders (UCDs) present a particular challenge
`since only two of the eight conditions, argininosuccinate synthetase
`(ASSD; or citrullinemia type 1) and lyase deficiency (ASLD) are reli
`ably detected and reported by tandem mass spectroscopy based new
`born screening in the United States [1]. The large natural history
`studies, i.e. the NIH sponsored Urea Cycle Disorders Consortium
`(UCDC) and the European Registry and Network for Intoxication
`Type Metabolic Diseases (E IMD) both give an idea of the proportions
`
`⁎ Corresponding author at: Division of Genetics and Metabolism, Children's National
`Medical Center, Suite 4800, 111 Michigan Ave. NW, Washington DC 20008, USA.
`E-mail addresses: msummar@childrensnational.org (M.L. Summar),
`Stefan.Koelker@med.uni-heidelberg.de (S. Koelker),
`debra.freedenberg@dshs.state.tx.us (D. Freedenberg), Cindy@nucdf.org (C. Le Mons).
`URL's: http://www.e-imd.org/en/index.phtml (E-IMD), http://rarediseasesnetwork.
`epi.usf.edu/ucdc/ (UCDC).
`
`1096-7192/$ – see front matter © 2013 Published by Elsevier Inc.
`http://dx.doi.org/10.1016/j.ymgme.2013.07.008
`
`for the different conditions but cannot be presumed to have enrolled
`all available patients [2]. We used a combination of data from US
`newborn screening programs and the ratios of individual conditions
`from the natural history studies to calculate an incidence for UCDs.
`Using those same datasets we were also able to estimate the number
`of UCD related patients that should present each year and the number
`with hyperammonemia in the United States.
`
`2. Material and methods
`
`We obtained open published data from the annual newborn
`screening (NBS) reports from the states of Texas (Dr. Freedenberg),
`New York (New York State Department of Health, Albany NY),
`Michigan (Michigan Newborn Screening Program, Michigan Depart
`ment of Community Health), California, Massachusetts, North Carolina,
`and Wisconsin (2011 Annual Report to Congress, Health and Human
`Services, Secretary's Advisory Committee on Heritable Disorders in
`Newborns and Children Committee Report) during periods where
`newborn screening was performed for ASSD and ASLD. To determine
`the ratios of ASSD and ASLD to the other UCDs we used data from the
`UCDC as a longitudinal registry generally corresponding to the same
`time frame as the newborn screening data (2004 present). UCDC
`data include asymptomatic and symptomatic patients distributed
`
`Horizon Exhibit 2003
`Lupin v. Horizon
`IPR2018-00459
`
`1 of 2
`
`

`

`180
`
`ML Sumrmr et 1!. / Molecular Genetics and Metabolism no (2013) 179— lm
`
`acros the United States. Data from the E IMD. and the National Urea
`Cycle Disorders Foundation (NUGJF) were used to check if the UCDC
`data were representative. E IMD data were not used to calculate the
`incidence since population differences in newborn screening candi
`dates exist between the two entities and it is still in a rapid patient
`enrollment phase. Data from the UCDC were used to determine the pro
`portion of patients who were symptomatic in the newborn period and
`the proportion of all patients who were symptomatic across the age
`spectrum of patients. UCDC data were also used to calculate the esti
`mated incidences for the individual enzyme defects Numbers were
`rounded to the nearest thousand for presentation
`
`3. Results
`
`Published NBS data from the states listed covered 6.077.736 births
`covering years from 2001 to 2012 for different states. In this cohort.
`there were 52 patients listed as having a confirmed diagnosis of ASSD
`or ASLD initially detected by NBS. The findings were consistent across
`this wide geographical sample. The inddence of A550 and ASID from
`this cohort is 1 in 117.000 newborns. Data from the UCDC longitudinal
`study of 590 patients (after 8 years of patient enrollment) showed that
`ASSD represented 14%and ASlD 16%of patients combining fora total of
`30%. Data from the E IMD sample of 224 patients (after 2 years of
`patient enrollment) showed a combined 30.5% and the NUCDl-‘s 661
`patients 31% for ASSDand ASLD combined.The UCDC and NUCDF regis
`tries contained data on all eight conditions. i.e. ASSD and ASLD as well
`as inherited deficiencies of: carbamyl phosphate synthetase l. omithine
`transcarbamylase. N acetyl glutamate syntlrase. mitochondrial omi
`thine transporter 1. arginase. and citrin. E IMD collects data for all
`urea cycle disorders except for citrin deficiency. Table 1 shows the rela
`tive frequencies of the individual diseases
`Using the UCDC's 30% as the fraction ofpatients with ASSD and ASLD
`in the UCD population the incidence for all UCDs should can be estirnat
`ed by multiplying the incidence ofASSD and ASLD patients in the new
`born screening cohort with the ratio ofASSD and ASLD to all ur- cycle
`disorders. ie. approx. 3:3. This gives an estimated curnulated incidence
`for all UCDs of 1 in 35.000. Table 1 shows estimates ofthe incidence for
`the individual disorders based on this overall incidence.
`Using an incidence of 1 in 35.000 and a birth rate of 3.954.000
`(US Census Bureau. 2011) live births per year in the US and of
`5.229.813 live births in EU member states (Eurostat. as of 2011) an
`average of 113 new UCD patients with urea cycle disorders per year
`in the US and
`assuming that the same incidence is also found in
`Europe
`149 new patients in EU member states can be expected. In the
`UCDC natural history study 26% of patients were symptomatic in the
`newborn period and 69% of all patients hell symptoms at some point.
`This should rsult in a minimum of30 newborns with hyperarnrnorremia
`per year in the [5.
`
`Table 1
`Distribution by group and estimated overall incidence.
`
`umc
`
`E—lMD'
`
`NUCDF
`
`All UCDs
`NAGS
`(PSI
`OTC
`ASS
`ASL
`ARG
`("min
`HHH
`
`59)
`3 (0.5%)
`16 (2.7%)
`363 (62%)
`83 (14%)
`93 (16%)
`D (3%)
`2 (< 1%)
`8 (1%)
`
`224
`2 (1%)
`10 (4.5%)
`133 (59%)
`43 (19%)
`26(115%)
`4 (2%)
`nla
`6 (3%)
`
`661
`6 (1%)
`53 (8%)
`377 (57%)
`86 (13%)
`119 (18%)
`14 (2%)
`0
`6 (1%)
`
`Incidence based on UCDC
`and newborn screening
`1:/35.ooo
`<1 :2.ooo.ooo
`1:130QIXX)
`1256.5“)
`”750.000
`1218.750
`1295011!)
`<1 :2.ooo.ooo
`<1 :2.ooo.ooo
`
`" As oprril 2013.
`
`20f2
`
`4. Discussion
`
`The study places the estimated incidence of urea cycle disorders at 1
`in 35.000 live births in the US or about 113 new patients per year. As
`suming that the sarrre incidence is found in Europe. 149 new patients
`are to be expected in EU member states. These calculations would be af
`fected by the sensitivity of NBS for ASSD and ASLD. These analytes are
`reasonably robust in NBS and the data was consistent across the differ
`ent states (data not shown). Dr. Freedenberg called all of the metabolic
`disease centers in the state of Taras to query about any ASSD or ASLD
`patients who might have been missed by NBS but were determined
`clinically during the period reported; none were found. The calculation
`would also be affected ifthere were a particular disease segment of the
`UCD community not enrolled in any ofthe natural history studies or the
`NUCDF. Given these caveats the overall incidence should provide a reli
`able working number in planning for these patients and diseases.
`The issue of prevalence is more complex and the UCDC and E lMD
`registries will be of some help in the future. Over the 8 years of
`enrollment of the UCDC there have been 6 deaths of 590 enrolled
`patients (1%). During this time there should have been 900 patients
`born with UCDs. There are most likely patients who passed away
`without diagnosis or before being enrolled (although the UCDC does
`capture deaths at the centers). Assuming the death rate is as high as
`10% one would still expect more than 800 patients in the population
`with urea cycle disorders from this time period not accounting for
`births in prior years. Prevalence data in EU member states cannot
`yet be estimated based on available data. since E IMD is still in the lin
`ear phase of patient enrollment (with about 9 10 newly registered
`UCD patients per month).
`This data will require further refinement but provide a sound basis
`for the disease incidence in the United States. Furtlrerrrrore. this effort
`represents the importance of data collection in both the NBS programs
`and natural history registries.
`
`Acknowledgments
`
`The Urea Cycle Disorders Consortium. is a part ofthe NIH Rare Dis
`eases Clinical Researdr Network (RDCRN). Funding and/or program
`matic support for this project has been provided by U54HD061221
`through collaboration between the NIH Office of Rare Diseases Re
`seardr (0RDR). the National Center for Advancing Translational Sci
`ence (NCATS). and the Eunice Kennedy Shriver National Institute of
`Child Health and Human Development (NICHD). The content is solely
`the responsibility of the authors and does not necessarily represent
`the official views of the National Institutes of Health
`This publication is also supported by the project “European regisz
`and network for intoxication type metabolic diseases" (E IMD. EAHC
`no. 2010 12 01) which has received funding from the European
`Union. in the framework of the Health Programme.
`The members of the UCDC consortium are: Mark L Batslraw. Mendel
`Tudrmarr. Marshall L Sumrrrar. Matthias R. Baumgartner. Susan A. Berry.
`Stephen Cederbaum. George A. Diaz. Annette Feigenbaurn. Renata C.
`Gallagher. Cary 0. Harding. Georg Hoffmann. Douglm S Kerr. Brendan
`lee. Uta lichter Konecld. Shawn E. McCandlss. J. [awrence Menitt ll.
`Andreas Sdrulze. Margretta R. Seashore. Tamar Stridcer. Susan Waisbren.
`Derek Wong. and Mark Yudkof'f.
`
`References
`
`[1] EW. Naylor. Newborn screening for urea cycle disorders, Adv. Exp. Med. Biol. 153
`(1982) 9-18.
`lemons. M.
`[2] ]. Seminara. M. Tuchman. L. Krivitzky. ]. Krischer. H.S. lee, C.
`Baumgartner. S. Cederbaurn. G.A. Diaz. A Feigenbaum. KC Gallagher. CO.
`Harding. 05. Kerr. B. lanpher. B. lee. U. Lichter-Konecki. SE McCandless. ].L
`Merritt. M.L Oster—Granite. M.R. Seashore. T. Stricker. M. Summar. S. Waisbren.
`M. Yudkofl', M.L Batshaw. Establishing a consortium for the study of rare diseases:
`The Urea Cycle Disorders Consortium. Mol. Genet. Metab. 100 (Suppl 1) (2010)
`597—5105.
`
`2 of 2
`
`