Molecular Genetics and Metabolism 100 (2010) S97–S105
`
`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 ev i e r . c o m / l o c a t e / y m g m e
`
`Minireview
`Establishing a consortium for the study of rare diseases: The Urea Cycle
`Disorders Consortium
`Jennifer Seminara a, Mendel Tuchman a, Lauren Krivitzky a, Jeffrey Krischer b, Hye-Seung Lee b,
`Cynthia LeMons c, Matthias Baumgartner d, Stephen Cederbaum e, George A. Diaz f, Annette Feigenbaum g,
`Renata C. Gallagher h, Cary O. Harding i, Douglas S. Kerr j, Brendan Lanpher k, Brendan Lee l,
`Uta Lichter-Konecki a, Shawn E. McCandless j, J. Lawrence Merritt m, Mary Lou Oster-Granite q,
`Margretta R. Seashore n, Tamar Stricker d, Marshall Summar k, Susan Waisbren o, Marc Yudkoff p,
`Mark L. Batshaw a,*
`a Children’s National Medical Center, 111 Michigan Avenue, NW, Washington, DC 20010, USA
`b Data Management and Coordinating Center, University of South Florida, Tampa, FL, USA
`c National Urea Cycle Disorders Foundation, Pasadena, CA, USA
`d University Children’s Hospital, Zurich, Switzerland
`e University of California, Los Angeles, CA, USA
`f Mount Sinai School of Medicine, New York, NY, USA
`g Hospital for Sick Children, Toronto, Canada
`h The Children’s Hospital, Aurora, CO, USA
`i Oregon Health and Science University, Portland, OR, USA
`j Case Western Reserve University, Cleveland, OH, USA
`k Vanderbilt University Medical Center, Nashville, TN, USA
`l Baylor College of Medicine, Houston, TX, USA
`m Seattle Children’s Hospital, Seattle, WA, USA
`n Yale University, New Haven, CT, USA
`o Children’s Hospital, Boston, MA, USA
`p Children’s Hospital of Philadelphia, Philadelphia, PA, USA
`q National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Intellectual and Developmental Disabilities Branch,
`Bethesda, MD, USA
`
`a r t i c l e
`
`i n f o
`
`a b s t r a c t
`
`Article history:
`Received 7 December 2009
`Received in revised form 12 January 2010
`Accepted 12 January 2010
`Available online 10 February 2010
`
`The Urea Cycle Disorders Consortium (UCDC) was created as part of a larger network established by the
`National Institutes of Health to study rare diseases. This paper reviews the UCDC’s accomplishments over
`the first 6 years, including how the Consortium was developed and organized, clinical research studies
`initiated, and the importance of creating partnerships with patient advocacy groups, philanthropic foun-
`dations and biotech and pharmaceutical companies.
`
`Keywords:
`Urea cycle disorder
`Rare disease
`
`Introduction
`
`The Rare Diseases Clinical Research Network (RDCRN) was
`established by the National Institutes of Health (NIH) in 2003 to
`facilitate collaboration among experts in many different types of
`rare diseases of childhood and adulthood. Although research net-
`works or consortia have long served to advance our understanding
`of a number of rare diseases (e.g. PKU), such was not the case with
`
`* Corresponding author. Fax: +1 (202) 476 5988.
`E-mail address: mbatshaw@cnmc.org (M.L. Batshaw).
`
`1096-7192/$ - see front matter Published by Elsevier Inc.
`doi:10.1016/j.ymgme.2010.01.014
`
`Published by Elsevier Inc.
`
`Urea Cycle Disorders (UCD) before 2003. There had never been an
`attempt to develop a national collaborative approach to research-
`ing UCD. Funding of the Urea Cycle Disorders Consortium (UCDC)
`as part of the RDCRN over the past 6 years has addressed this
`gap. There is now a network of 15 clinical and research centers that
`provide state-of-the-art care and clinical research to patients with
`UCD.
`The UCDC has developed a website, which was visited over
`34,000 times by the lay public and by professionals in 2008. The re-
`sources available on the website include general information about
`UCD for lay and professional groups, diagnostic and treatment
`Horizon Exhibit 2035
`Lupin v. Horizon
`IPR2017-01159
`
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`
`guidelines, a registry, and information about clinical trials and out-
`come. In addition, the UCDC has trained 11 geneticists who have
`now entered the field of inborn errors of metabolism as clinical
`investigators. The UCDC has established partnerships with the Na-
`tional Urea Cycle Disorders Foundation (NUCDF), philanthropic
`foundations, and biotech and pharmaceutical companies, which
`have contributed to the UCDC’s success.
`
`Rare diseases clinical research network
`
`Ten consortia and a Data and Technology Coordinating Center
`(DTCC, now DMCC, Data Monitoring and Coordinating Center)
`were selected by the NIH to be a part of the original Rare Diseases
`Clinical Research Network, including the Urea Cycle Disorders Con-
`sortium (UCDC). In the re-competition held in 2008, this network
`has been expanded to 19 consortia. The RDCRN is governed by a
`steering committee, comprised of a principal investigator from
`each consortium, the director of the Data Monitoring and Coordi-
`nating Center (DMCC), NIH program and scientific officers, and a
`representative of the Coalition of Patient Advocacy Groups (CPAG).
`The steering committee and its standardization working groups
`develop policies, procedures, and standards for data collection,
`which reduces the effort each individual consortium must put
`forth in these efforts. The DTCC provides statistical, study imple-
`mentation, data management, and monitoring support for the
`network. It also acts as a liaison between the consortia and the
`NIH-led Protocol Review Committee (PRC), which provides in
`depth scientific review of protocols developed by the consortia,
`and the Data and Safety Monitoring Board (DSMB), which monitors
`study protocols, ensures the safety of study participants and the
`integrity of studies (Fig. 1).
`
`Urea Cycle Disorders Consortium
`
`When initially funded, the UCDC consisted of five sites: Chil-
`dren’s National Medical Center in Washington, DC (CNMC) (lead
`institution); Baylor College of Medicine in Houston, Texas; Chil-
`dren’s Hospital of Philadelphia (CHOP) in Pennsylvania; University
`of California Los Angeles in California; and Vanderbilt University
`
`Medical Center in Nashville, Tennessee. Subsequent to receiving
`NIH grant funding, the UCDC received a five year matching grant
`from the O’Malley Family Foundation. This gift permitted the addi-
`tion of two additional sites in 2004, one at Mount Sinai School of
`Medicine in New York City and a second at Yale University in
`New Haven, Connecticut. A grant from a second philanthropic
`foundation, the Kettering Fund, established a site at Case Western
`Reserve School of Medicine in Cleveland, Ohio in 2005. The UCDC
`consisted of these eight sites at the time the first study was acti-
`vated in February 2006. It soon became apparent that the most
`successful mode of recruitment was by internal referral, i.e. referral
`to the Longitudinal Study by one of the UCDC investigators. Thus,
`the UCDC sought to further expand the number of sites and inves-
`tigators. The O’Malley Family Foundation agreed to fund a site in
`Zurich, Switzerland which led to the addition of the UCDC’s first
`international site at the University of Zurich Kinderspital in 2007.
`That same year, the Hospital for Sick Children in Toronto, which
`is funded by a Canadian philanthropist, was added to the consor-
`tium. In 2008, The O’Malley Family Foundation helped support
`new UCDC sites at Seattle Children’s Hospital in Washington, Ore-
`gon Health & Science University in Portland, The Children’s Hospi-
`tal of Denver in Colorado, and the Children’s Hospital Boston in
`Massachusetts, bringing the UCDC to its current fourteen sites.
`The UCDC is working to activate its 15th site at University of Min-
`nesota in Minneapolis in late 2009, completing geographical cover-
`age of the contiguous United States plus Alaska, Ontario and
`Switzerland (Fig. 2).
`Each consortium site is led by a principal investigator, who is a
`board-certified metabolic specialist, with a team consisting of a
`study coordinator, a neuropsychologist, and at some sites a co-
`investigator, research fellow, and/or nutritionist. The UCDC also
`employs several staff members at CNMC for programmatic, grant
`management, administrative and biostatistical support. The UCDC
`currently consists of a total of 43 faculty investigators and 26 re-
`search staff members. The UCDC’s steering committee is composed
`of the UCDC directors, the principal investigator from each site, the
`executive director of the National Urea Cycle Disorders Foundation,
`the NIH scientific and program officers, the DMCC director, the pro-
`ject manager, and the grant manager (Fig. 3).
`
`NIH
`ORD, NCRR, NICHD, NIAMS,
`NHLBI, NIDDK, NINDS
`
`Steering Committee
`
`CPAG
`
`DSMB
`
`PRC
`
`Site
`
`Site
`
`NUCDF
`
`UCDC
`
`DMCC
`
`Public
`Website
`
`Database
`
`Industry
`
`Site
`
`Standardization
`Groups
`
`Contact
`Registry
`
`Patients
`
`Fig. 1. The Urea Cycle Disorders Consortium (UCDC) within the context of the Rare Diseases Clinical Research Network (RDCRN). DSMB-data safety and monitoring board;
`PRC-protocol review committee; CPAG-patient advocacy group; NUCDF-National Urea Cycle Disorders Foundation; DMCC-data monitoring and coordinating center.
`
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`S99
`
`UW
`
`OHSU
`
`UCLA
`
`CWRU
`
`UMN
`
`TCH
`
`BCM
`
`HSC
`
`CHB
`
`YSM
`MSSM
`CHOP
`CNMC
`
`VUMC
`
`UZH
`
`Fig. 2. UCDC Geographical Coverage CHB-Children’s Hospital, Boston; YSM-Yale School of Medicine; MSSM-Mt Sinai School of Medicine; CHOP-Children’s Hospital of
`Philadelphia; CNMC-Children’s National Medical Center; VUMC-Vanderbilt University Medical Center; CWRU-Case Western Reserve University; UMN-University of
`Minnesota; TCH-The Children’s Hospital; BCM - Baylor College of Medicine; UCLA-University of California, Los Angeles; OHSU-Oregon Health Sciences University; UW-
`University of Washington (Seattle Children’s Hospital); HSC-Hospital for Sick Children, Toronto; UZH-University of Zurich Kinderspital.
`
`NIH SCIENTIFIC
`and PROGRAM
`OFFICERS
`
`GRANT MANAGER
`and PROJECT
`MANAGER
`
`UCDC PI
`
`UCDC STEERING
`COMMITTEE
`
`NUCDF
`
`BIOSTATISTICS
`
`UCDC SITES
`
`TRAINING
`
`WEBSITE
`
`PILOT
`PROJECTS
`
`CLINICAL
`RESEARCH
`PROJECTS
`
`DTCC
`
`LONGITUDINAL STUDY
`BUPHENYL IN ASA
`STUDY
`NEUROIMAGING
`STUDY CARBAGLU
`STUDY
`
`Fig. 3. Organizational structure of the Urea Cycle Disorders Consortium.
`
`The Urea Cycle Disorders Consortium’s major goals are to: (1)
`develop better treatments and a deeper scientific understanding
`of the causes and outcomes of UCD; (2) conduct clinical trials of
`promising new therapies; (3) develop resources with information
`on UCD for clinicians, researchers, and patients; and (4) train the
`next generation of UCD investigators. Other objectives include pro-
`moting newborn screening for UCD to aid in identification and
`treatment of UCD and in establishing a research contact registry
`for the eight UCD under study.
`
`UCDC studies
`
`The UCDC initiated a research contact registry, four clinical pro-
`tocols, and two pilot studies during the initial 6-year funding per-
`iod. The Research Contact Registry and the Longitudinal Study of
`
`Urea Cycle Disorders are described in this review article. The other
`UCDC studies, which are described in separate articles in this sym-
`posium issue, include:
`
` Assessing Neural Mechanisms of Injury in Inborn Errors of
`Metabolism Using Structural MRI, Functional MRI and Magnetic
`Resonance Spectroscopy (MRS) (Gropman article in this supple-
`ment). This project studies cognitive and motor dysfunction in
`patients who are female carriers of ornithine transcarbamylase
`(OTC) deficiency or are males with late onset presentation of
`OTC deficiency, utilizing state of the art MRI (magnetic reso-
`nance imaging). This project seeks to improve our understand-
`ing of the underlying neural mechanisms that contribute to
`metabolic, cognitive, sensory and motor abnormalities in urea
`cycle disorders.
`
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`
` Measuring Urea Production in Patients with Urea Cycle Defects
`(Yudkoff article in this supplement). The overall purpose of this
`study is to develop a novel method to assess the in vivo rate of
`ureagenesis by administering [1-13C]acetate to humans and
`using mass spectrometry to measure the rate of appearance of
`label in [13C]urea.
` A Randomized, Double-Blind, Crossover Study of sodium phen-
`ylbutyrate and low-dose arginine (100 mg/kg/day) Compared
`to high-dose arginine (500 mg/kg/day) Alone on liver function,
`ureagenesis and subsequent nitric oxide production in patients
`with argininosuccinate lyase (AL) deficiency (Lee article in this
`supplement). This study focuses on determining if using sodium
`phenylbutyrate in the treatment of patients with AL deficiency
`improves outcome as measured by the frequency and severity
`of hyperammonemic crisis and transaminase levels. This is done
`by treating patients with sodium phenylbutyrate (Buphenyl-
`TM), an FDA-approved drug labeled for the treatment of other
`urea cycle disorders (ornithine transcarbamylase deficiency
`and citrullinemia).
` N-Carbamylglutamate treatment of N-Acetyl Glutamate Synthe-
`tase Deficiency (NAGS) (Tuchman article in this supplement).
`This study focuses on the effect of N-Carbamylglutamate on
`the incorporation of [15 N] ammonia into urea as a measure of
`restoration of ureagenesis capacity in patients with inherited
`NAGS deficiency diagnosed by DNA testing. The hypothesis is
`that N-Carbamylglutamate will restore deficient ureagenesis
`capacity and ameliorate the hyperammonemia in patients with
`inherited NAGS deficiency.
`
`Research contact registry
`
`In March 2005, the UCDC, in collaboration with the DTCC,
`launched an on-line research contact registry. As of July 31, 2009,
`295 individuals with UCD have self-registered. Of those, 250
`(85%) live in the U.S. Subjects enrolled in the registry receive infor-
`mation from the DTCC about UCDC studies via email bi-annually.
`The subject can then contact one of the UCDC sites to learn more
`about the studies and arrange for enrollment if they are deemed
`eligible to participate. March 2009 estimates show that 34% of
`the contact registrants are enrolled in one of the DSMB approved
`UCDC studies. About 45% of registrants that live within 200 miles
`of a UCDC site are enrolled in a study, and 51% of subjects who live
`
`within 100 miles of a UCDC site are enrolled in a study. This is
`slightly above average for the use of contact registries in general
`and for the RDCRN specifically [1].
`
`Longitudinal study of urea cycle disorders
`
`The longitudinal study follows the natural history of partici-
`pants with congenital deficiencies in any of the six enzymes and
`two membrane transporters involved in urea biosynthesis (see
`Fig. 4). The specific disorders and estimated prevalence [2,3] are
`noted below:
`
` Ornithine transcarbamylase deficiency (OTCD) (1:14,000)
` Argininosuccinate synthase (AS) deficiency (Citrullinemia)
`(1:57,000)
` Carbamyl phosphate synthase I (CPSI) deficiency (1:62,000)
` Argininosuccinate lyase (AL) deficiency (Argininosuccinic acidu-
`ria) (1:70,000)
` Arginase (ARG) deficiency (Argininemia) (1:350,000)
` N-acetylglutamate synthase (NAGS) deficiency (unknown)
` Citrullinemia type II (mitochondrial aspartate/glutamate carrier
`deficiency-CITR) (1 in 21,000 in Japan)
` Hyperornithinemia,
`homocitrullinuria
`hyperammonemia,
`(HHH) syndrome (or mitochondrial ornithine carrier defi-
`ciency-ORNT) (unknown)
`
`As of July 31, 2009, after 3.5 years of recruitment, the longitudi-
`nal study has enrolled 352 eligible participants (Fig. 5). The recruit-
`ment goal is to enroll 440 participants in the study by February
`2011. Recruitment from UCDC site metabolic clinic patient popula-
`tions has proven to be the most effective recruitment mechanism
`representing 69% of enrolled participants, followed by referrals
`from the patient advocacy group, NUCDF (13%), referrals from
`other physicians (8%) and referrals of small numbers of partici-
`pants from other study participants, the research contact registry,
`and the internet.
`In early publications [4,5] interim cross-sectional analysis of the
`first 183 participants enrolled during the initial 22 months of this
`study were presented. The current publication updates these find-
`ings for 352 eligible participants. Using the baseline assessment
`data provided at the time of enrollment through participant inter-
`view and review of medical records, characteristics of each type of
`
`MITOCHONDRION
`
`ammonia
`
`N-acetyl
`glutamate
`
`NAGS
`
`acetyl-CoA
`+
`glutamate
`
`CPS1
`
`carbamyl
`phosphate
`
`bicarbonate
`+
`ATP
`
`CYTOSOL
`
`ornithine
`
`ORNT
`
`ARG
`
`urea
`
`arginine
`
`fumarate
`
`Fig. 4. The urea cycle.
`
`oroticacid
`
`aspartate
`
`citrulline
`
`AS
`
`argininosuccinate
`
`AL
`
`CIT R
`
`citrulline
`OTC
`
`ornithine
`
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`J. Seminara et al. / Molecular Genetics and Metabolism 100 (2010) S97–S105
`
`S101
`
`Actual vs. Expected Accrual
`
`exp_cumulative
`act_cumulative
`
`400
`
`350
`
`300
`
`250
`
`200
`
`150
`
`100
`
`50
`
`Cumulative Accrual
`
`0
`Jul-06
`Jul-09
`Jul-07
`Jul-08
`Jan-09
`Jun-09
`Jun-06
`Jan-07
`Jun-07
`Jan-08
`Jun-08
`Mar-06
`Mar-09
`Nov-08
`Mar-07
`Nov-06
`Nov-07
`Mar-08
`Apr-09
`Oct-06
`Apr-06
`Apr-07
`Oct-07
`Oct-08
`Apr-08
`May-06
`May-07
`May-08
`Feb-06
`Aug-06
`Feb-09
`Sep-06
`Feb-07
`Aug-07
`Dec-06
`Sep-07
`Dec-08
`Dec-07
`Sep-08
`Aug-08
`Feb-08
`May-09
`Month
`
`Fig. 5. Actual accrual vs. expected accrual per longitudinal study. Data current as of July 31, 2009. Target enrollment to date: 294; enrolled to date: 352.
`
`UCD and associations with various factors were investigated. The
`questions posed included the following:
`What is the relative frequency of proximal vs. distal UCD defects
`and of neonatal onset vs. late onset disease? Table 1 illustrates the
`relative frequency of the various UCD among enrolled participants
`and those who have registered in the research contact registry. We
`examined relative frequencies in OTC deficiency (as a proximal de-
`fect) vs. AS/AL deficiencies (as distal defects). Thus far, the distribu-
`tion of
`frequency among eligible and registered participants
`appears to be consistent with prior estimates [6,7]. OTC deficiency
`is by far the most common disorder among the UCD, accounting for
`more than half of all participants, followed by AL and AS deficien-
`cies which together account for slightly less than a third of the par-
`ticipants. It is expected that the proportional frequency of these
`latter two disorders will increase in the near future as infants diag-
`nosed with AS/AL deficiencies by expanded newborn screening
`using tandem mass-spectrometry [8] are enrolled, while most
`other UCD, especially CPS1 and OTC deficiencies cannot yet be
`identified by this screening method.
`Among longitudinal study participants with OTC deficiency, 11%
`are neonatal onset, presenting clinically within the first month of
`life, and 89% are late onset, presenting after 1 month of age.
`Thirty-six percent are asymptomatic heterozygous females; 37%
`are manifesting heterozygous females; 24% are symptomatic
`males; and 3% are asymptomatic males. Although the neonatal on-
`set presentation comprises the smallest subgroup for OTC defi-
`
`Table 1
`Frequency of the various urea cycle disorders among eligible participants in the
`longitudinal study and those who have registered with the research contact registry.
`Data current as of July 31, 2009.
`
`Diagnosis
`
`OTC
`AL
`AS
`CPS
`Diagnosis pending
`ARG
`CITR
`HHH
`NAGS
`Total
`
`Registered in research
`contact registry
`
`Longitudinal study
`participants (eligible)
`
`162
`47
`31
`17
`13
`8
`6
`4
`4.
`265
`
`202
`55
`52
`8
`8
`12
`2
`3
`0
`352
`
`ciency, the majority of participants with AS and AL deficiencies
`(56%) are neonatal onset, possibly reflecting greater survival of
`these participants. Based on prior studies, it was assumed that
`the proportion of participants with neonatal onset OTC deficiency
`presentation would be at least equal to those with late onset dis-
`ease [9]. However, here the proportion of neonatal onset partici-
`pants is much smaller. This difference may be due to failure to
`recruit severely affected patients before they died or those who
`underwent liver transplantation soon after their initial presenta-
`tion. If this hypothesis is correct, as the study enrolls more partic-
`ipants soon after their initial clinical presentation, the proportion
`of neonatal cases should increase. As of July 31, 2009, only four
`out of 352 participants in the Longitudinal Study have died com-
`pared to a much higher proportion of deaths reported in earlier
`studies [10]. A retrospective analysis of data from deceased pa-
`tients, including those with OTC deficiency, has been added to
`the study to further evaluate this question.
`Are there ethnic/racial differences in UCD prevalence? Table 2
`shows the ethnic/racial origin of the participants. Although still
`preliminary, a marked difference is observed between the propor-
`tion of African–Americans enrolled in the study (4%) and their pro-
`portion in the general population (12%) [11]. Hispanics/Latinos
`who represent a similar proportion of the general population as
`African-Americans accounted for 15% of enrolled participants.
`While this could reflect a true difference in disease prevalence, it
`is more likely to be related to disparity in access to information
`about the study, location of UCDC sites, and/or mistrust of research
`due to past abuses [12].
`What are the triggers for hyperammonemic episodes? Previous
`studies show that the number and severity of hyperammonemic
`episodes impact outcome [13]. As of July 31, 2009, there were a to-
`tal of 1084 episodes of hyperammonemic crises reported in 189 of
`the 352 participants. The participants and/or guardians were asked
`to provide information on perceived triggers that preceded each
`recorded hyperammonemic episode. They identified several pre-
`cipitants, noted in Fig. 6. Not surprisingly, an intercurrent infection
`was the most frequently cited trigger, followed by a recent change
`in diet. There were several dozen other triggers listed, however,
`none of them was implicated in an appreciable frequency. In the
`majority of cases there was no specific precipitant identified. As
`these participants are followed prospectively in the Longitudinal
`Study triggers will be identified more clearly, which could lead to
`
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`

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`J. Seminara et al. / Molecular Genetics and Metabolism 100 (2010) S97–S105
`
`Table 2
`Longitudinal study participants by ethnicity and race. Data current as of July 31, 2009.
`
`Females Males Unknown/not
`reported
`
`Total
`
`34
`181
`10
`225
`
`20
`90
`8
`118
`
`0
`
`9
`9
`
`54
`271
`27
`352
`
`Sex/gender
`Category
`
`Ethnic categories
`Hispanic or Latino
`Not hispanic or Latino origin
`Unknown/not reported
`
`Racial categories
`American/Alaskan Native
`Asian
`Native Hawaiian/Pacific Islander
`Black/African-American
`White
`More than one race
`Unknown/not reported
`
`120
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`36
`
`5
`
`m
`u tis
`a
`n d is
`a ti o
`c
`
`D
`
`H
`
`n ic
`
`D
`
`u
`
`A
`
`m
`
`118
`
`95
`
`52
`
`47
`
`20
`
`23
`
`16
`
`7
`
`e r
`b r al p
`p
`el o
`
`v
`
`y
`als
`n t al d
`e
`a r n i n
`le
`
`m
`
`y
`ela
`g d is
`
`a
`
`m
`
`s
`
`p
`
`e r
`
`n t
`
`e
`
`air m
`
`e r
`p
`
`o r d
`g i m
`
`e r
`
`e
`
`0
`11
`0
`6
`196
`9
`3
`225
`
`0
`8
`0
`7
`86
`6
`11
`118
`
`0
`0
`0
`0
`0
`0
`9
`9
`
`0
`19
`0
`13
`282
`15
`23
`352
`
`592
`
`o r d
`e r e
`e
`d
`
`m
`
`o
`
`c
`
`b ilit y
`o r d
`o r d
`eiz u r e d is
`h ia tric d is
`d d is
`o
`o
`a ri n
`s
`c
`y
`n / h
`visi o
`
`Fig. 7. Self-reported developmental disabilities and psychiatric disorders in
`enrolled participants. Data current as of July 31, 2009.
`
`600
`
`500
`
`400
`
`300
`
`200
`
`100
`
`0
`
`327
`
`154
`
`46
`
`16
`
`11
`
`49
`
`D ie t
`
`n
`
`In fe c tio
`
`D r u
`
`s
`
`g
`
`n
`
`e
`
`M
`
`n
`
`n
`
`a tio
`
`a
`
`n
`
`g
`
`s tr u
`P r e
`
`eliv e r y
`
`c y/ D
`
`S tr e s s
`
`e r
`
`O t h
`
`Fig. 6. Hyperammonemic episode Triggers (n = 1084 episodes). Data current as of
`July 31, 2009.
`
`prevention or amelioration of these crises through early medical
`intervention.
`What is the frequency of developmental disabilities/neurological
`abnormalities in UCD? Baseline assessment includes self reporting
`and medical record review of neurodevelopmental parameters.
`Of the 352 participants, 177 reported at least one neurodevelop-
`mental disability. As seen in Fig. 7, global developmental delay
`(intellectual disability) was reported most frequently (47%), fol-
`lowed by learning disability (38%). The effects of recurrent hyper-
`ammonemia are known to cause irreversible damage to the brain
`[14], resulting in the effects reported here. Autism and mood disor-
`ders have been rarely reported in previous studies [15], as con-
`firmed by Longitudinal Study results.
`What is the pattern of neuropsychological deficits in adults with
`UCD and its relationship to hyperammonemic episodes? In a preli-
`minary analysis of 60 adult subjects, seven had neonatal onset
`UCD. This small number reflects the reported high mortality during
`childhood in this group and a failure to recruit the most severely
`affected patients. Three of these subjects could not be formally as-
`sessed because of the severity of their intellectual disability; 4
`were able to undergo neuropsychological testing. In the neonatal
`onset group, the overall mean IQ was in the range of mild intellec-
`tual disability (mean WASI Full Scale IQ (FSIQ)=57, sd = 11). In con-
`trast, the mean IQ of the late onset group (n = 56) was in the
`average range (mean FSIQ = 94, SD = 21). Given the substantial
`number of individuals in the adult group with either mild UCD
`or who are asymptomatic carriers, functioning based on a history
`
`120
`110
`100
`90
`80
`70
`60
`50
`40
`
`+ HA episodes (n=23)
`- HA episodes (n=34)
`
`FSIQ
`
`VIQ
`
`PIQ
`
`Fig. 8. IQ of adult participants (17+) experiencing hyperammonemic (HA) episodes
`vs. no hyperammonemic EPISODES (FSIQ – full scale IQ; VIQ – verbal IQ; PIQ –
`performance IQ).
`
`of hyperammonemic crises was also examined. Adults with no his-
`tory of a documented hyperammonemic episode (defined as hav-
`ing an ammonia level > 100uM and clinical symptoms requiring
`treatment) had overall intellectual abilities in the average range
`(n = 35, FSIQ = 100, SD = 18) while those with a history of at least
`one hyperammonemic episode had an overall intellectual quotient
`in the borderline range of functioning (n = 23, mean FSIQ = 78,
`SD = 22) (Fig. 8).
`What is the distribution of neuropsychological deficits in children
`with UCD? In a sample of 92 children ranging in age from 5 months
`to 16 years, 9 months (mean = 7.2 years; standard deviation = 4.7),
`the most prevalent diagnoses were OTCD, AL deficiency, and AS
`deficiency. Fifty-eight percent of the subjects were female, half of
`whom had partial OTC deficiency.
`Cognitive outcome was different based on late or early onset of
`disease, with early onset having more severe deficits; and by diag-
`nosis with AS deficiency being more severely affected (see Fig. 9).
`For children aged 3–16 years, eight (50%) of the neonatal onset
`group had FSIQ in the range of intellectual disability, five of whom
`fell into the moderate to profound classification. In contrast, 13
`(25%) of the late onset group were classified as having an intellec-
`tual disability, with two (4%) having moderate to profound
`disabilities.
`For the neonatal onset cases, there were greater percentages of
`impairment with age (Fig. 10). In children under three, two sub-
`
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`S103
`
`Neonatal Onset (n=16)
`
`Late Onset (n=52)
`4%
`
`31%
`
`19%
`
`21%
`
`19%
`
`10%
`
`31%
`
`65%
`
`Intellectual Function
`Average to Above Average
`Low Average to Borderline
`Mild Intellectual Disability
`Severe Intellectual Disability
`
`AL Deficiency (n=10) AS Deficiency (n=12) OTC Deficiency (n=36)
`6%
`
`14%
`
`40%
`
`40%
`
`33%
`
`33%
`
`14%
`
`66%
`
`20%
`
`17%
`
`17%
`
`Fig. 9. Cognitive range across all subjects ages 3–16: early vs. late onset and by diagnosis*. *includes estimated IQ scores for children unable to complete testing in their age
`range. Excludes lowest functioning children who were unable to complete the test battery in their age range.
`
`jects (8%) of the neonatal onset group and none of the late onset
`group presented with significant cognitive delay. No significant
`differences between the groups were evident in either develop-
`mental or adaptive functioning (p values ranged from 0.33 to
`0.89). However, there is a downward shift in scores, which were
`half to one standard deviation below the normative mean across
`all areas – cognitive development, language, motor skills, and
`adaptive functioning. This suggests that although most of the
`young children with UCD do not present with severe impairments,
`there is evidence that their development is mildly delayed.
`The overall level of developmental disabilities across both neo-
`natal and late onset groups is less than has been reported previ-
`ously. In studies of individuals with neonatal onset disease, the
`percentage with any level of intellectual disability was as high as
`80% in prior studies [16,17], as compared to the 50% noted in this
`study. Similarly, previous research has suggested a higher propor-
`tion of developmental disabilities in children with partial UCD. It
`was previously reported that > 50% of school age subjects with a
`partial UCD were in the range of intellectual disability [18]. Lower
`rates of intellectual impairment in this study may be attributable
`to methodological differences or reflect changes in outcomes due
`to medical advances of children with UCD. The overall sample size
`in this study is substantially larger and the range of diagnoses is
`much wider, including more mild presentations, than the sample
`sizes in previous studies. Improvements in cognitive outcome
`may also be due to earlier recognition and intervention, and im-
`proved treatment protocols. This is suggested by the fewer chil-
`dren with cognitive impairments who are under age three.
`
`However, the cross-sectional design is unable to rule out alterna-
`tive explanations. One possibility is that the majority of the chil-
`dren in this group were tested at either age 6 months or
`18 months of age. At those ages, the range of behaviors that can
`be measured are more limited and the variability of normal devel-
`opmental timeframes is large. A second possibility is that over
`time, children with UCD may plateau or even decline in abilities
`due to recurrent episodes of hyperammonemia. This would be con-
`sistent with prior studies [19] that demonstrated a decline in cog-
`nitive scores over time in a group of females with OTC deficiency.
`
`Partnerships
`
`The National Urea Cycle Disorders Foundation (NUCDF)
`
`NUCDF, the volunteer health organization for UCD, has been an
`integral partner and collaborator in the UCDC since its inception.
`The executive director of NUCDF serves as a voting member on
`the executive committee of the consortium. One of her key roles
`has been to continually challenge the existing paradigms and bar-
`riers to advancing research in UCD. NUCDF has been especially in-
`volved in the research contact registry and longitudinal study
`enrollment. In terms of study design, NUCDF had a direct involve-
`ment in the development of protocols, consents, content evalua-
`tions, progress reporting, website content and the training
`program. NUCDF brought the perspective of the UCD community’s
`needs into clinical protocols with its unique knowledge of the lim-
`
`110
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`<3
`
`3 to 5
`
`6 to 16
`
`17 to adult*
`
`Overall Cognitive- Late
`Onset
`Language-Late Onset
`
`Performance-Late Onset
`
`Overall Cognitive- Early
`Onset
`Language- Early Onset
`
`Performance-Early Onset
`
`Fig. 10. Possible age effects on IQ. *Cautionary note: 17+ age group has substantial # of asymptomatic subjects. **Data does not include very low functioning subjects.
`
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`
`itations of the affected community. NUCDF also partnered with the
`UCDC to develop content for the UCDC website.
`NUCDF has facilitated recruitment in UCDC studies in a number
`of ways, including serving as host for an annual conference during
`which educational presentations are given to patients and profes-
`sionals by UCDC investigators. Along with education, enrollment
`opportunities and information are provided to patients via exhibits
`and registration centers. NUCDF developed a patient survey to
`determine attitudes and barriers to study participation and re-
`cruited a genetic counseling student to conduct a survey via phone
`calls to NUCDF. NUCDF collaborated on development of UCDC bro-
`chures and distributed the brochures to families, patients and
`healthcare professionals. It expanded existing website content
`(www.nucdf.org) to educate patients and families on the impor-
`tance of participation in research and to inform potential partici-
`pants about open UCDC trials. NUCDF published focused articles
`on the UCDC studies in its quarterly newsletter. The UCDC’s expe-
`rience with the NUCDF points to the importance of engaging pa-
`tient advocacy groups, especially in studies of rare diseases
`wher