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 g m 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
`
`Page 1 of 2
`
`Horizon Exhibit 2035
`Par v. Horizon
`IPR2017-01769
`
`

`

`180
`
`M.L Summaret al. / Molecular Genetics and Metabolism 110 (2013) 179-180
`
`4. Discussion
`
`The study places the estimated incidenceofurea cycle disordersat 1
`in 35,000 live births in the US or about 113 new patients per year. As
`suming that the same incidence is found in Europe, 149 new patients
`are to be expected in EU memberstates. 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 consistentacross thediffer
`ent states (data not shown). Dr. Freedenbergcalled all of the metabolic
`disease centers in the state of Texas to query about any ASSD or ASLD
`patients who might have been missed by NBS but were determined
`clinically during the period reported; none werefound. The calculation
`would also be affected ifthere were a particular disease segmentof the
`UCD community not enrolled in any ofthe natural history studies or the
`NUCDF.Giventhese caveats the overall incidence should provide a reli
`able working numberin planning for these patients and diseases.
`The issue of prevalence is more complex and the UCDC and E IMD
`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 deathrate is as high as
`10% one wouldstill 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 memberstates cannot
`yet be estimated based onavailable data, since E IMDis still in the lin
`ear phase ofpatient enrollment (with about 9 10 newly registered
`UCDpatients per month).
`This data will require further refinementbut provide a sound basis
`for the disease incidence in the United States. Furthermore,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 Research 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
`search (ORDR), the National Center for Advancing Translational Sci
`ence (NCATS), and the Eunice Kennedy Shriver National Institute of
`Child Health and Human Development(NICHD). The contentis 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 registry
`and network for intoxication type metabolic diseases” (E IMD, EAHC
`no. 2010 12 01) which has received funding from the European
`Union, in the frameworkof the Health Programme.
`The members of the UCDC consortium are: Mark L Batshaw, Mendel
`Tuchman, Marshall L. Summar, Matthias R. Baumgartner, Susan A. Berry,
`Stephen Cederbaum, George A. Diaz, Annette Feigenbaum, Renata C.
`Gallagher, Cary O. Harding, Georg Hoffmann, Douglas S. Kerr, Brendan
`Lee, Uta Lichter Konecki, Shawn E. McCandless, J. Lawrence Merritt Il,
`Andreas Schulze, Margretta R. Seashore, Tamar Stricker, Susan Waisbren,
`Derek Wong, and Mark Yudkoff.
`
`References
`
`across the United States. Data from the E IMD, and the National Urea
`Cycle Disorders Foundation (NUCDF) wereused to check if the UCDC
`data were representative. E IMD data werenotused 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
`enrollmentphase. Data from the UCDC were used to determinethe 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 thousandfor 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 incidence of ASSD and ASLD from
`this cohort is 1 in 117,000 newborns.Data from the UCDClongitudinal
`study of 590 patients (after 8 years of patient enrollment) showed that
`ASSDrepresented 14% and ASLD 16% of patients combining for a 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 NUCDF's 661
`patients 31% for ASSD and ASLD combined. The UCDC and NUCDFregis
`tries contained data on all eight conditions, i.e. ASSD and ASLD as well
`as inherited deficiencies of: carbamyl phosphate synthetase I, ornithine
`transcarbamylase, N acetyl glutamate synthase, mitochondrial orni
`thine transporter 1, arginase, and citrin. E IMD collects data for all
`urea cycle disorders exceptforcitrin deficiency. Table 1 showsthe rela
`tive frequencies of the individual diseases.
`Using the UCDC's 30% as the fraction ofpatients with ASSD and ASLD
`inthe UCD populationthe incidence forall UCDs should can be estimat
`ed by multiplying the incidence ofASSD and ASLD patients in the new
`born screening cohort with the ratio ofASSD and ASLD to all urea cycle
`disorders, i.e. approx. 3:3. This gives an estimated cumulated 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 memberstates (Eurostat, as of 2011) an
`average of 113 new UCDpatients with urea cycle disorders per year
`in the US and
`assumingthat the sameincidenceis also found in
`Europe
`149 new patients in EU memberstates can be expected. In the
`UCDC natural history study 26% of patients were symptomatic in the
`newborn period and 69% ofall patients had symptoms at some point.
`This should result in a minimum of30 newborns with hyperammonemia
`per year in the US.
`
`Table 1
`Distribution by group andestimated overall incidence.
`
`ucpc
`
`E-IMD™
`
`NUCDF
`
`* As of April 2013.
`
`Page 2 of 2
`
`Incidence based on UCDC
`and newborn screening
`1:/35,000
`661
`224
`590
`AllUCDs
`<1:2,000,000
`6 (1%)
`2(1%)
`3(0.5%)
`NAGS
`1:1,300,000
`53 (8%)
`10 (4.5%)
`16 (2.7%)
`CPSI
`[1] EW. Naylor, Newborn screeningfor urea cycle disorders, Adv. Exp. Med. Biol. 153
` 1:56,500
`377(57%)
` 133(59%)
`363 (62%)
`oTc
`(1982) 9-18.
`[2] J. Seminara, M. Tuchman, L. Krivitzky, J. Krischer, H.S. Lee, C. Lemons, M.
`
`
`ASS 86 (13%)—1:/250,00083 (14%) 43 (19%)
`
`Baumgartner, S. Cederbaum, G.A. Diaz, A. Feigenbaum, R.C. Gallagher, CO.
`ASL
`93(16%)
` 26(115%)
`119(18%)
` 1:218,750
`Harding, D.S. Kerr, B. Lanpher, B. Lee, U. Lichter-Konecki, S.E. McCandless, J.L
`ARG
`22 (3%)
`4 (2%)
`14 (2%)
`1:950,000
`Merritt, M.L. Oster-Granite, M.R. Seashore, T. Stricker, M. Summar, S. Waisbren,
`Citrin
`2 (<1%)
`n/a
`0
`<1:2,000,000
`M. Yudkoff, M.L. Batshaw,Establishing a consortium for the study of rare diseases:
`HHH
`8 (1%)
`6 (3%)
`6 (1%)
`<1:2,000,000
`The Urea Cycle Disorders Consortium, Mol. Genet. Metab. 100 (Suppl 1) (2010)
`$97-S105.
`
`