Rare Diseases Clinical Research Network Research Articles

Multiple system atrophy: the case for an international collaborative effort.

“United we stand divided we fall.” — Alexandre Dumas, The Three Musketeers Multiple system atrophy (MSA) is a rare neurodegenerative disease that affects both men and women and has no clear ethnic or racial susceptibilities. Cases are geographically spread throughout the world. Age of onset is typically in the mid-50s. Based on MSA prevalence rates [6] and 32% of Americans being over 50, estimates suggest there are around 5,200 Americans suffering from MSA. The rarity of the disease in combination with the geographical spread of the cases is the biggest obstacle when it comes to enrolling patients in clinical trials. It is thought that with so few cases, no single treatment center -and probably no single country- has enough patients to perform well-powered translational research. MSA is an orphan disease – because it affects less than 200,000 Americans. Orphan diseases are surprisingly common, with an estimated 7,000 different orphan diseases affecting around 30 million Americans. Awareness of rare diseases is growing fast. The National Institutes of Health (NIH) released a position piece recommending that each rare disease has a dedicated global registry and data repository. They emphasized the importance of collecting de-identified clinical data in a standardized fashion overtime and making this information linkable to tissue stored in bio-specimen banks [2]. Gathering specific information from a large pool of patients has obvious advantages when it comes to defining true rates of disease progression as well as the impact of common treatment interventions. Well-defined patient cohorts also lay the foundation for future biomarker research. This strength in numbers approach requires an international collaborative effort that brings together clinical centers conducting research on MSA. Fortunately, in the case of MSA, these collaborative consortia working on the disease already exist. MSA is a central focus of the North American Autonomic Disorders Consortium, created in 2009, as part of the Rare Diseases Clinical Research Network (RDCRN) – a partnership between several NIH Programs [3]. The Consortium has an ongoing prospective natural history study of MSA. The Consortium recently completed a controlled trial to test the neuroprotective potential of the old antibiotic rifampicin. Although the trial ultimately proved negative, the undertaking showed that it was possible to enroll 100 early MSA patients in little under a year [4]. The European counterpart is the European MSA Study Group (EMSA-SG), founded in 1999, from sites in Austria, Denmark, France, Germany, Italy, Portugal, Sweden, Spain and Great Britain. The European MSA Study Group published a report of it’s prospective MSA cohort that had been followed for 2-years [5], which defines much of what we know about the motor progression rates in MSA. They have also completed several clinical trials. In 2013, the MSA Coalition, a patient and caregiver advocacy group, provided support for an initiative to form a transatlantic alliance that would unite US and European MSA Centers. The organization and structure are now in place and a standardized dataset has been agreed upon. Sites in Europe, the US and South America have signed agreements to contribute the standardized data set that will be used to follow the motor and autonomic features of MSA overtime (Figure). Figure Collaborating sites in the Global MSA Natural History Study include: New York University Medical Center (Coordinating site: Horacio Kaufmann), Vanderbilt University Medical Center (PI Autonomic RDCRC: David Robertson & Italo Biaggioni), Beth Israel ... On a day-to-day basis, natural history studies are not the most exciting and require endless hours pouring through case report forms and entering data, but the efforts pay off in the long-term. Large and well-thought natural history studies can provide valuable information for drug development. They are the only way to understand the variability in disease severity amongst patients and reliably estimate the sample size necessary to sufficiently power a study with a clinically meaningful endpoint [1]. They also define rates of progression of affected patients outside a clinical trial. By describing the natural course of the disease, an international prospective study in MSA should help to also define guidelines for clinical care. The argument for an international registry and natural history study is convincing, Sharing data across academic institutions and international boundary lines requires understanding of local rules and regulations, but is possible. The continued support of the MSA Coalition and the NIH’s Rare Diseases Clinical Research Network will make the project feasible.

Secured web-based video repository for multicenter studies.

We developed a novel secured web-based dystonia video repository for the Dystonia Coalition, part of the Rare Disease Clinical Research network funded by the Office of Rare Diseases Research and the National Institute of Neurological Disorders and Stroke. A critical component of phenotypic data collection for all projects of the Dystonia Coalition includes a standardized video of each participant. We now describe our method for collecting, serving and securing these videos that is widely applicable to other studies. Each recruiting site uploads standardized videos to a centralized secured server for processing to permit website posting. The streaming technology used to view the videos from the website does not allow downloading of video files. With appropriate institutional review board approval and agreement with the hosting institution, users can search and view selected videos on the website using customizable, permissions-based access that maintains security yet facilitates research and quality control. This approach provides a convenient platform for researchers across institutions to evaluate and analyze shared video data. We have applied this methodology for quality control, confirmation of diagnoses, validation of rating scales, and implementation of new research projects. We believe our system can be a model for similar projects that require access to common video resources.

A longitudinal study of urea cycle disorders

The Urea Cycle Disorders Consortium (UCDC) is a member of the NIH funded Rare Diseases Clinical Research Network and is performing a longitudinal study of 8 urea cycle disorders (UCDs) with initial enrollment beginning in 2006. The consortium consists of 14 sites in the U.S., Canada and Europe. This report summarizes data mining studies of 614 patients with UCDs enrolled in the UCDC's longitudinal study protocol. The most common disorder is ornithine transcarbamylase deficiency, accounting for more than half of the participants. We calculated the overall prevalence of urea cycle disorders to be 1/35,000, with 2/3rds presenting initial symptoms after the newborn period. We found the mortality rate to be 24% in neonatal onset cases and 11% in late onset cases. The most common precipitant of clinical hyperammonemic episodes in the post-neonatal period was intercurrent infections. Elevations in both blood ammonia and glutamine appeared to be biomarkers for neurocognitive outcome. In terms of chronic treatment, low protein diet appeared to result in normal weight but decreased linear growth while N-scavenger therapy with phenylbutyrate resulted in low levels of branched chain amino acids. Finally, we found an unexpectedly high risk for hepatic dysfunction in patients with ornithine transcarbamylase deficiency. This natural history study illustrates how a collaborative study of a rare genetic disorder can result in an improved understanding of morbidity and disease outcome.

The Rare Diseases Clinical Research Network's organization and approach to observational research and health outcomes research.

Established in 2003 by the Office of Rare Diseases Research (ORDR), in collaboration with several National Institutes of Health (NIH) Institutes/Centers, the Rare Diseases Clinical Research Network (RDCRN) consists of multiple clinical consortia conducting research in more than 200 rare diseases. The RDCRN supports longitudinal or natural history, pilot, Phase I, II, and III, case-control, cross-sectional, chart review, physician survey, bio-repository, and RDCRN Contact Registry (CR) studies. To date, there have been 24,684 participants enrolled on 120 studies from 446 sites worldwide. An additional 11,533 individuals participate in the CR. Through a central data management and coordinating center (DMCC), the RDCRN's platform for the conduct of observational research encompasses electronic case report forms, federated databases, and an online CR for epidemiological and survey research. An ORDR-governed data repository (through dbGaP, a database for genotype and phenotype information from the National Library of Medicine) has been created. DMCC coordinates with ORDR to register and upload study data to dbGaP for data sharing with the scientific community. The platform provided by the RDCRN DMCC has supported 128 studies, six of which were successfully conducted through the online CR, with 2,352 individuals accrued and a median enrollment time of just 2months. The RDCRN has built a powerful suite of web-based tools that provide for integration of federated and online database support that can accommodate a large number of rare diseases on a global scale. RDCRN studies have made important advances in the diagnosis and treatment of rare diseases.

Quality-of-life in Charcot–Marie–Tooth disease: The patient’s perspective

This study determines the impact of symptoms associated with Charcot–Marie–Tooth disease on quality-of-life. Charcot–Marie–Tooth patients in the Inherited Neuropathies Consortium Rare Diseases Clinical Research Network Contact Registry were surveyed. The survey inquired about 214 symptoms and 20 themes previously identified as important to Charcot–Marie–Tooth patients through patient interviews. Symptom population impact was calculated as the prevalence multiplied by the relative importance of each symptom identified. Prevalence and symptom impact were analyzed by age, symptom duration, gender, Charcot–Marie–Tooth type, and employment status. 407 participants returned the survey, identifying foot and ankle weakness (99.7%) and impaired balance (98.6%) as the most prevalent themes. Foot and ankle weakness and limitations with mobility were the themes with the highest impact. Both symptom prevalence and impact gradually increased with age and symptom duration. Several themes were more prevalent in women with Charcot–Marie–Tooth, including activity limitations, pain, fatigue, hip–thigh weakness, and gastrointestinal issues. All of the themes, except emotional or body image issues, were more prevalent among unemployed individuals. There were minimal differences in symptom prevalence between Charcot–Marie–Tooth types. There are multiple symptoms that impact Charcot–Marie–Tooth quality-of-life in adults. These symptoms have different levels of importance, are readily recognized by patients, and represent critical areas of Charcot–Marie–Tooth health.

William L. Young, MD

William L. Young, MD

A model for collaborative clinical research in rare diseases: experience from the Rare Disease Clinical Research Network program

To overcome a lack of interest in research of rare diseases and an insufficient number of patients who can be recruited into clinical studies of rare diseases and potential diagnostics and treatments, the Rare Diseases Clinical Research Network (RDCRN) was established with the services of a centralized Data Management and Coordinating Center. The RDCRN has been very successful at recruiting patients, initiating clinical studies and trials, meeting patient recruitment milestones, training the next generation of research investigators and developing an active role for patient advocacy groups as research patnerships. The RDCRN has fostered international collaborations at multiple research sites that have led to regulatory approval of several drug products and expanded the knowledgebase for diseases included in the RDCRN. Rare disease research continues to evolve and considerable emphasis is placed on the translational research of discoveries from basic and clinical research activities, leading to the possibl...

Frequency of Prader–Willi syndrome in births conceived via assisted reproductive technology

PurposePrader-Willi syndrome (PWS) is an imprinting disorder characterized by typical facial, physical and cognitive/behavioral features, resulting from lack of paternally-expressed genes on chromosome 15q11.2-q13. Studies have suggested an increased risk of other imprinting disorders in children conceived by assisted reproductive techniques (ART). This study was designed to determine the association between ART and PWS.MethodsData on individuals with PWS were collected from three distinct sources and the proportion of ART-births analyzed.ResultsThe proportion of ART-births in the Prader-Willi Syndrome Association [PWSA (USA)], Rare Diseases Clinical Research Network (RDCRN), and University of California, Irvine Medical Center (UCIMC) populations was 1.0% (18/1,736), 1.0% (1/98), and 2.0% (1/50), respectively (overall 1.1%; population frequency for the U.S was 1.0%). Interestingly, 2.4% (45/1,898) of participants were co-twins (eleven born after ART procedures); U.S. twin frequency is 1.6% (p=0.007). The proportion of individuals with maternal disomy 15/imprinting defects born after ART was higher than in the total sample, 55.6% (10/18) and 34.5% (431/1,250), respectively.ConclusionThis study found no association between ART and PWS. There was an increased frequency of twinning. The number of individuals with maternal disomy 15/imprinting defect was nearly double in the ART group compared to the total PWS participants.

Non-dystrophic myotonia: prospective study of objective and patient reported outcomes

Non-dystrophic myotonias are rare diseases caused by mutations in skeletal muscle chloride and sodium ion channels with considerable phenotypic overlap between diseases. Few prospective studies have evaluated the sensitivity of symptoms and signs of myotonia in a large cohort of patients. We performed a prospective observational study of 95 participants with definite or clinically suspected non-dystrophic myotonia recruited from six sites in the USA, UK and Canada between March 2006 and March 2009. We used the common infrastructure and data elements provided by the NIH-funded Rare Disease Clinical Research Network. Outcomes included a standardized symptom interview and physical exam; the Short Form-36 and the Individualized Neuromuscular Quality of Life instruments; electrophysiological short and prolonged exercise tests; manual muscle testing; and a modified get-up-and-go test. Thirty-two participants had chloride channel mutations, 34 had sodium channel mutations, nine had myotonic dystrophy type 2, one had myotonic dystrophy type 1, and 17 had no identified mutation. Phenotype comparisons were restricted to those with sodium channel mutations, chloride channel mutations, and myotonic dystrophy type 2. Muscle stiffness was the most prominent symptom overall, seen in 66.7% to 100% of participants. In comparison with chloride channel mutations, participants with sodium mutations had an earlier age of onset of stiffness (5 years versus 10 years), frequent eye closure myotonia (73.5% versus 25%), more impairment on the Individualized Neuromuscular Quality of Life summary score (20.0 versus 9.44), and paradoxical eye closure myotonia (50% versus 0%). Handgrip myotonia was seen in three-quarters of participants, with warm up of myotonia in 75% chloride channel mutations, but also 35.3% of sodium channel mutations. The short exercise test showed ≥10% decrement in the compound muscle action potential amplitude in 59.3% of chloride channel participants compared with 27.6% of sodium channel participants, which increased post-cooling to 57.6% in sodium channel mutations. In evaluation of patients with clinical and electrical myotonia, despite considerable phenotypic overlap, the presence of eye closure myotonia, paradoxical myotonia, and an increase in short exercise test sensitivity post-cooling suggest sodium channel mutations. Outcomes designed to measure stiffness or the electrophysiological correlates of stiffness may prove useful for future clinical trials, regardless of underlying mutation, and include patient-reported stiffness, bedside manoeuvres to evaluate myotonia, muscle specific quality of life instruments and short exercise testing.

An overview of the rare diseases clinical research network

An overview of the rare diseases clinical research network

Rare disease clinical research network's urea cycle consortium delivers a successful clinical trial to improve alternate pathway therapy

Rare disease clinical research network's urea cycle consortium delivers a successful clinical trial to improve alternate pathway therapy

Hopes for intractable and rare diseases research.

Hopes for intractable and rare diseases research.

Growth failure and outcome in Rett syndrome

Prominent growth failure typifies Rett syndrome (RTT). Our aims were to 1) develop RTT growth charts for clinical and research settings, 2) compare growth in children with RTT with that of unaffected children, and 3) compare growth patterns among RTT genotypes and phenotypes. A cohort of the RTT Rare Diseases Clinical Research Network observational study participants was recruited, and cross-sectional and longitudinal growth data and comprehensive clinical information were collected. A reliability study confirmed interobserver consistency. Reference curves for height, weight, head circumference, and body mass index (BMI), generated using a semiparametric model with goodness-of-fit tests, were compared with normative values using Student's t test adjusted for multiple comparisons. Genotype and phenotype subgroups were compared using analysis of variance and linear regression. Growth charts for classic and atypical RTT were created from 9,749 observations of 816 female participants. Mean growth in classic RTT decreased below that for the normative population at 1 month for head circumference, 6 months for weight, and 17 months for length. Mean BMI was similar in those with RTT and the normative population. Pubertal increases in height and weight were absent in classic RTT. Classic RTT was associated with more growth failure than atypical RTT. In classic RTT, poor growth was associated with worse development, higher disease severity, and certain MECP2 mutations (pre-C-terminal truncation, large deletion, T158M, R168X, R255X, and R270X). RTT-specific growth references will allow effective screening for disease and treatment monitoring. Growth failure occurs less frequently in girls with RTT with better development, less morbidity typically associated with RTT, and late truncation mutations.

Gastrointestinal and nutritional problems occur frequently throughout life in girls and women with Rett syndrome.

We conducted a nationwide survey to determine the prevalence of common gastrointestinal and nutritional disorders in Rett syndrome (RTT) based on parental reporting and related the occurrence of these problems to age and methyl-CpG-binding protein 2 (MECP2) gene status. We designed a questionnaire that probed symptoms, diagnoses, diagnostic tests, and treatment interventions related to gastrointestinal and nutritional problems in RTT. The International Rett Syndrome Foundation distributed the questionnaire to 1666 family-based members and forwarded their responses for our review. We interrogated the Rare Disease Clinical Research Network database to supplement findings related to medications used to treat gastrointestinal problems in RTT. Parents of 983 female patients with RTT (59%) responded and identified symptoms and diagnoses associated with gastrointestinal dysmotility (92%), chewing and swallowing difficulties (81%), weight deficits or excess (47%), growth deficits (45%), low bone mineral content or fractures (37%), and biliary tract disorders (3%). Height-for-age, weight-for-age, and body mass index z scores decreased significantly with age; height- and weight-, but not body mass index-for-age z scores were significantly lower in female subjects with MECP2 mutations than in those without. Vomiting, nighttime awakening, gastroesophageal reflux, chewing difficulty, and choking with feeding were significantly less likely to occur with increasing age. Short stature, low bone mineral content, fractures, and gastrostomy placement were significantly more likely to occur with increasing age. Chewing difficulty, choking with feeding, and nighttime awakening were significantly less likely to occur, whereas short stature was significantly more likely to occur, in female subjects with MECP2 mutations than in those without. Diagnostic evaluations and therapeutic interventions were used less frequently than the occurrence of symptoms or diagnoses in the RTT cohort. Gastrointestinal and nutritional problems perceived by parents are prevalent throughout life in girls and women with RTT and may pose a substantial medical burden for their caregivers. Physician awareness of these features of RTT may improve the health and quality of life of individuals affected with this disorder.

Establishing a Charcot-Marie-Tooth (CMT) Induced Pluripotent Stem Cell Bank: Towards a Human Disease Model for CMT (S27.001)

Objective: To establish a Charcot-Marie-Tooth Induced pluripotent stem cell (iPS) bank as a human platform for mechanistic and drug screening studies. Background Induced pluripotent stem cells are derived from somatic cells after the forced expression of defined transcription factors. Like embryonic stem cells, they are capable of being differentiated into cell types from the three embryonic germ layers. Previous studies have demonstrated the feasibility of differentiating iPS cells from patients with neurological diseases into functional neurons. This approach could be particularly useful in the pathophysiological study of distinct forms of inherited neuropathies where a basic biological understanding is already available. Design/Methods: We have performed skin biopsies and developed iPS cell lines by retroviral transduction with Klf-3/4, Sox-2, Oct-4, and c-Myc of fibroblasts from 12 CMT patients, including 4 with CMT 1A (PMP22 duplication), two with CMT 1X (GJB1), 2 with CMT4J (FIG4) and one each for the following types: CMT1B (MPZ), CMT2A (MFN2), CMT2E (NEFL) and CMT4A (GDAP1). Results: All iPS CMT lines have a normal karyotype, carry the respective disease causing mutation and express pluripotency factors, as determined by immunostaining and gene expression profiling. These cells can also be spontaneously differentiated into cell types from the three embryonic germ layers. More importantly, these cells can be directed to differentiate into ventral spinal cord motor neurons that express appropriate antigens, including the transcription factors ISLET1 and HB9, the intermediate filaments peripherin and internexin and the enzyme Choline acetyltransferase. They also present ultrastructural features of neurons and demonstrate spontaneous and induced calcium channel transients. Conclusions: Human motor neurons can be consistently derived from patient-specific CMT iPS cells and can be used in multiple assays including gene expression studies, time lapse microscopy and electrophysiological studies, providing an authentic human model for mechanistic and drug screening studies of different types of inherited neuropathies. Supported by: M.S. was funded by a Rare Disease Clinical Research Network Fellowship from the National Institutes of Health. This study was also supported by iPierian Inc. Disclosure: Dr. Saporta has nothing to disclose. Dr. Shy has nothing to disclose. Dr. Dimos has received personal compensation for activities with iPierian Inc. as an employee.Dr. Dimos has received research support from iPierian Inc.

Update - Inherited Neuropathies Consortium (P05.144)

Objective: To describe the progress of the Inherited Neuropathy Consortium (INC) in promoting translational research in the inherited peripheral neuropathies. Background The INC is a Rare Disease Clinical Research Consortium (RDCRC) that is a member of the Rare Disease Clinical Research Network (RDCRN), funded by various NIH Institutes and the Office of Rare Diseases. Over the past year the North American CMT Network has merged with INC. There are currently 10 international sites with several others in queue. Design/Methods: Projects include (1) the natural history of CMT, with particular emphasis on CMT1B, CMT2A, CMT4A, and CMT4C, (2) genetics of CMT, including genetic modifiers of CMT1A and new forms of CMT, (3) pediatric evaluation of CMT, and (4) creation and validation of a disability severity index (DSI). There is also a patient Contact Registry and a training program for new investigators. Results: Over 1550 patients are currently enrolled the sub-projects. More than 622 patients from 20 countries have signed up for the Contact Registry directly through the web. Our exome sequencing project has found three new CMT genes or loci. We have created a CMT pediatric scoring scale that has been submitted for publication. A CMT pediatric quality of life questionnaire has been developed. The natural history study is ongoing with the goal of laying the groundwork for clinical trials in the near future. We have recently added our third fellow to the training program. Conclusions: The INC RDCRC is actively pursuing a multidisciplinary approach to develop rational therapies for patients with inherited neuropathies. We are actively recruiting patients with all forms of CMT to be involved in the consortium as well as recruiting talented young investigators for training to become the next generation of investigators in the inherited neuropathies. Supported by: NINDS, ORD, MDA. Disclosure: Dr. Siskind has nothing to disclose. Dr. Feely has nothing to disclose. Dr. Burns has nothing to disclose. Dr. Zuchner has received license fee payments from Athena Diagnostics. Dr. Pareyson has nothing to disclose. Dr. Herrmann has received personal compensation for activities with Pfizer Inc as consultant. Dr. Scherer has received personal compensation with Lundbeck for activities as a consultant. Dr. Bird has received personal compensation for activities with Athena Diagnostics for speakers bureau and licensing fees.Dr. Bird has received liscensing payments from Athena Diagnostics. Dr. Lloyd has nothing to disclose. Dr. Sumner has nothing to disclose. Dr. Croker has nothing to disclose. Dr. Krischer has nothing to disclose. Dr. Muntoni has received personal compensation for activities with AVI BioPharma. Dr. Muntoni has received research support from PTC Therapeutics, AVI BioPharma, and Prosensa/GlaxoSmithKline, Inc. Dr. Finkel has nothing to disclose. Dr. Neal has nothing to disclose. Dr. Reilly has nothing to disclose. Dr. Shy has nothing to disclose.

Abnormal Mitochondrial Trafficking and Cytoskeletal Organization in a Human Induced Pluripotent Stem Cell and a Mouse Model of Charcot-Marie-Tooth Disease Type 2E (IN7-2.001)

Objective: To characterize human neuronal cells derived from induced pluripotent stem cells of a patient with CMT2E and a mouse model of the same mutation. Background Induced pluripotent stem cells (iPS) offer an alternative human model for the study of neurogenetic conditions. Previous studies have demonstrated the feasibility of generating and differentiating iPS cells from patients with neurological diseases into functional neurons and glia. This approach could be particularly useful in the pathophysiological study of distinct forms of inherited neuropathies. Charcot-Marie-Tooth disease type 2E (CMT2E) is caused by heterozygous point mutations in the NEFL gene, which encodes the intermediate filament neurofilament light chain, an essential component of the neuronal cytoskeleton. Design/Methods: We developed iPS cell lines from skin fibroblasts of a patient with a N98S NFL point mutation. Knockin mice carrying the same N98S mutation were also generated. Following a differentiation protocol for generating spinal cord motor neurons, we obtained human CMT2E neuronal cultures consisting of at least 50% ISLET1 immunoreactive cells. These neuronal cultures were characterized by time-lapse microscopy and axonal mitochondrial kinetics was analyzed. Results: Immunostaining for intermediate filaments revealed an increased content of these proteins in the neuronal body of CMT2E spinal cord motor neurons. Immunostaining of both the spinal cord and brain of a N98S mouse shows abundant NFL positive aggregates in the cell bodies and axons of the motor neurons, as well as in the cerebellum. Multiple filamentous spheroid-like structures were also observed in the brain stem of the mice. An increased proportion of paused mitochondria was found in axons from human CMT2E neurons, compared to an age-matched control. Conclusions: This study demonstrates disease relevant phenotypes in human CMT2E motor neurons that were supported by a mouse model of the same mutation, demonstrating the potential of iPS cell technology to model neurogenetic diseases. Supported by: M.S. was funded by a Rare Disease Clinical Research Network Fellowship from the National Institutes of Health. This study was also supported by iPierian Inc. Disclosure: Dr. Saporta has nothing to disclose. Dr. Volfson has received personal compensation for activities with iPierian Inc. Dr. Volfson has received research support from iPierian Inc. Dr. Liem has nothing to disclose. Dr. Shy has nothing to disclose. Dr. Liem has nothing to disclose. Dr. Dimos has received personal compensation for activities with iPierian Inc. as an employee.Dr. Dimos has received research support from iPierian Inc.

The Rare Diseases Clinical Research Network Contact Registry update: Features and functionality

The Rare Diseases Clinical Research Network (RDCRN) Contact Registry has grown in size and scope since it was first reported in this journal in 2007. In this paper, we reflect on our seven years' experience developing and expanding the RDCRN Contact Registry to include many more rare diseases. We present the functional and data requirements that motivated this registry, and the new features and policies that have been developed since. Given the high costs and long-term commitment required to build patient registries, the RDCRN Contact Registry experience represents a reasonable approach for identifying and cultivating potential research populations, with minimal resources and patient burden. The basic model of a patient-reported registry has not changed since our 2007 report, but the number of diseases has grown from 42 to 201, and the types of information that are exchanged with participants has expanded. A patient-directed information-sharing feature has been added to reduce barriers to communication between investigators and patients affected by rare and genetic diseases. As specific data and research needs arise, the Contact Registry can be leveraged to access needed data or to solicit patients for particular research opportunities. This multiple-disease registry is scalable, expandable, and standards-driven, and has become a model for clinical and translational research across rare and many other diseases.

Analysis of EEG patterns and genotypes in patients with Angelman syndrome

We prospectively analyzed EEGs from participants in the ongoing NIH Rare Diseases Clinical Research Network Angelman Syndrome Natural History Study. Of the one-hundred-sixty enrolled patients (2006–2010), 115 had complete data (58 boys, median age 3.6years). Distinct EEG findings were intermittent rhythmic delta waves (83.5%), interictal epileptiform discharges (74.2%), intermittent rhythmic theta waves (43.5%), and posterior rhythm slowing (43.5%). Centro-occipital and centro-temporal delta waves decreased with age (p=0.01, p=0.03). There were no specific correlations between EEG patterns and genotypes. A classification tree allowed the prediction of deletions class-1 (5.9Mb) in patients with intermittent theta waves in <50% of EEG and interictal epileptiform abnormalities; UPD, UBE3A mutation or imprinting defects in patients with intermittent theta in <50% of EEG without interictal epileptiform abnormalities; deletions class-2 (5.0Mb) in patients with >50% theta and normal posterior rhythm; atypical deletions in patients with >50% theta but abnormal posterior rhythm. EEG patterns are important biomarkers in Angelman syndrome and may suggest the underlying genetic etiology.

Patient Registries to Support Research in Rare Diseases – Experience from the Rare Diseases Clinical Research Network

Patient Registries to Support Research in Rare Diseases – Experience from the Rare Diseases Clinical Research Network