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Objective: To determine if remote administration of the Unified Batten Disease Rating Scale (UBDRS) Physical Impairment subscale by telemedicine is reliable and feasible across a broad range of disease severity. Methods: For the majority (n = 10) of subjects, the examination was performed by a nonphysician who had been trained to perform the examination but not to score the subjects. A trained rater scored the subjects via live video; a second trained rater performed a separate examination in person and scored that examination. For 3 telemedicine evaluations, examinations were performed and scored by a trained rater while a second trained rater simultaneously scored the subjects via live video. Reliability was determined by intraclass correlation coefficient (ICC). Results: Subjects (n = 13) represented a wide range of disease severity. Remote administration of the UBDRS Physical Impairment subscale had high interrater reliability across all subjects (ICC = 0.94). When only the subjects (n = 10) who had been examined by the nonphysician and scored remotely were included in the analysis, the reliability was unchanged (ICC = 0.95). Conclusions: The UBDRS Physical Impairment subscale is reliable and feasible for remote administration. Telemedicine has the potential to be a useful tool in rare neurologic disease research and clinical assessment.

Juvenile neuronal ceroid lipofuscinosis (JNCL; CLN3 disease; Batten disease) is an autosomal recessive neurodegenerative disease of childhood that typically presents at school age with vision loss followed by progressive cognitive decline, motor dysfunction, seizures, and behavior problems. No therapy has been shown to slow the progression of disease in JNCL patients, and all current treatments are symptomatic. Flupirtine has been shown in vitro to reduce apoptosis in CLN3 lymphocytes. Based on that preclinical study, several children with JNCL were given flupirtine by their parents. The purpose of this study was to determine if there was evidence of attenuated disease progression in any JNCL symptom domain. We administered a survey to parents of JNCL children to qualitatively assess flupirtine efficacy. We used the Unified Batten Disease Rating Scale (UBDRS) to determine specific aspects of disease progression and investigated three age-related factors: loss of independent ambulation, loss of intelligible speech, and loss of ability to perform independent activities of daily living. The median scores for the UBDRS physical, behavior, and capability subscales were determined in flupirtine-exposed subjects and compared to age-, sex-, and genotype-matched subjects who had never taken flupirtine. Twenty-one percent of survey responders reported administering flupirtine to their JNCL child, and 56% of these families perceived beneficial changes that they attributed to flupirtine. However, our quantitative, prospectively obtained data did not show any change in JNCL disease progression that could be attributed to flupirtine. This study highlights the need for prospective experimental therapeutic research.

Objective: To use the Unified Batten Disease Rating Scale (UBDRS) to measure the rate of decline in physical and functional capability domains in patients with juvenile neuronal ceroid lipofuscinosis (JNCL) or Batten disease, a neurodegenerative lysosomal storage disorder. We have evaluated the UBDRS in subjects with JNCL since 2002; during that time, the scale has been refined to improve reliability and validity. Now that therapies are being proposed to prevent, slow, or reverse the course of JNCL, the UBDRS will play an important role in quantitatively assessing clinical outcomes in research trials. Methods: We administered the UBDRS to 82 subjects with JNCL genetically confirmed by CLN3 mutational analysis. Forty-four subjects were seen for more than one annual visit. From these data, the rate of physical impairment over time was quantified using multivariate linear regression and repeated-measures analysis. Results: The UBDRS Physical Impairment subscale shows worsening over time that proceeds at a quantifiable linear rate in the years following initial onset of clinical symptoms. This deterioration correlates with functional capability and is not influenced by CLN3 genotype. Conclusion: The UBDRS is a reliable and valid instrument that measures clinical progression in JNCL. Our data support the use of the UBDRS to quantify the rate of progression of physical impairment in subjects with JNCL in clinical trials.

Juvenile neuronal ceroid lipofuscinosis (JNCL; CLN3 disease; Batten disease) is an autosomal recessive neurodegenerative disease of childhood. Symptoms typically present at school age with vision loss followed by progressive cognitive decline, motor dysfunction, seizures, and behavior problems. Studies on sex differences in JNCL have yielded mixed results, but parent anecdotes suggest that females experience a more precipitous disease course. Therefore, we sought to determine if sex-based differences exist in JNCL. We used data from the Unified Batten Disease Rating Scale (UBDRS), the Batten Disease Support and Research Association (BDSRA) database, and the PedsQL quality of life (QoL) survey to evaluate sex-based differences in functional independence and time from symptom onset to death. On average, females had JNCL symptom onset one year later and death one year earlier than did males. Despite a later age at onset, females had lower functional capability, earlier loss of independent function, and lower physical QoL. Future research in sex differences in JNCL may help to further understand the biological mechanisms underpinning the disease course and may point to targeted therapies.

Introduction Juvenile neuronal ceroid lipofuscinosis (JNCL; Batten disease) is a rare, inherited, fatal lysosomal storage childhood disorder. True for many rare diseases, there are no treatments that impact the course of JNCL. The University of Rochester Batten Center's (URBC) mission is to find treatments to slow, halt, or prevent JNCL. Objectives Our initial objective was to develop clinical research infrastructure preparatory to clinical trials, establish a JNCL research cohort, construct a disease-specific clinical outcome measure, and validate a non-invasive diagnostic sampling method. The long-term objective is to design and implement JNCL clinical trials. Methods The Unified Batten Disease Rating Scale (UBDRS) was developed. The Batten Disease Support and Research Association (BDSRA) referred participants; annual BDSRA meetings provided a mobile research setting for registry enrollment and UBDRS piloting. Neuropsychological examinations were performed, enabling external validation of the UBDRS. Buccal epithelial cell collection for genotyping was introduced. Telemedicine for remote UBDRS assessment was piloted. Results The registry enrolled 198 families representing 237 children with NCL. The UBDRS was piloted, was validated and has been used to collect natural history data from 120 subjects. Funding and regulatory approval were obtained for a recently launched phase II clinical trial. Several additional lines of inquiry were reported. Conclusion The registry and BDSRA collaboration have enabled development of a clinical rating scale, natural history and neuropsychological studies, and genetic studies for disease confirmation. This work highlights an approach for preparatory natural history research and infrastructure development needed to facilitate efficient implementation of clinical trials in rare diseases.

s for the Lysosomal Disease Network's WORLD Symposium Medical Comorbidities in Juvenile Neuronal Ceroid Lipofuscinosis (Batten Disease) Heather Adams a, , Erika Augustine , Samantha Potter , Jennifer Kwon , Fred Marshall , Nicole Newhouse , Amy Vierhile , Jonathan Mink , University of Rochester Medical Center, Rochester, NY, USA, Syracuse University, Syracuse, USA Juvenile neuronal ceroid lipofuscinosis (JNCL) is a childhoodonset neurodegenerative, lysosomal storage disease. JNCL causes vision loss, seizures, motor and mental decline, and premature death. Although neurological and psychiatric aspects of JNCL are wellcharacterized, little is known about systemic medical comorbidities. The University of Rochester Batten Center therefore reviewed medical history of 45 males and 41 females with genetically confirmed JNCL who had completed the Unified Batten Disease Rating Scale (UBDRS). Participants’ mean age was 15.1 years old (SD=5.2 years). Excluding neurologic and psychiatric symptoms, the five most commonly parent-reported medical comorbidities were constipation (N=23), incontinence (N=23), acne (N=18), ear infection (N=17), eczema or dry/itchy skin (N=14), and pain (N=13). Fourteen children were reported to have medication allergies. On average, children experienced approximately 4 comorbid health problems (M=3.9, SD=3.0; range=0 to 7). The total number of medical problems (“medical burden”) was positively correlated with age (r=.42, p< .01), psychosocial quality of life (r=.35, p

s for the lysosomal disease networks WORLD symposium 1. Update on longitudinal assessment of children with juvenile neuronal ceroid lipofuscinosis (Batten disease) Heather Adams, Nicole Newhouse, Erika J. Levy, Jennifer M. Kwon, Frederick J. Marshall, Elisabeth A. deBlieck, Amy Vierhile, Erika F. Augustine, Denia Ramirez, Jonathan W. Mink, University of Rochester Medical Center, Rochester, USA Objective: Juvenile neuronal ceroid lipofuscinosis (Batten disease; CLN3) is a progressive and fatal autosomal-recessive inherited lysosomal storage disorder of childhood. Core symptoms include vision loss, seizures, and mental and motor decline. Neurocognitive deficits are prominent and involve progressive decrements in attention, memory, verbal abilities and global IQ. Herein we report an update of our longitudinal study of neurocognitive function in JNCL/CLN3 disease and address some challenges in the assessment of this population. Method: Children with genetically confirmed JNCL/CLN3 disease who are participating in our Unified Batten Disease Rating Scale (UBDRS) project complete a brief neuropsychological battery. These evaluations are performed serially (per annum) whenever possible and include tests of auditory attention, verbal learning and recall, verbal fluency, fund of knowledge, vocabulary, and verbal reasoning. Results: We have completed 114 evaluations (N = 59 children); N = 28 have completed more than one exam. A summary score was calculated for general performance across all tests; test performance had a significant inverse relationship to age (r = .43, p < .01). Performance in individual domains showed similar patterns, except sentence repetition (r = .16, ns) consistent with our prior work. Conclusions: The longitudinal examination of this population presents several challenges, including selection of tests appropriate for visually impaired patients who must provide verbal responses yetalso experience motor speech decline, and selection of measures that can be administered consistently over time to patients experiencing progressive dementia. doi:10.1016/j.ymgme.2009.10.018 2. Visual aid skills and socioeconomic status in children with Batten disease Heather Adams, Nicole J. Newhouse, Erika J. Levy, Jonathan W. Mink, Jennifer M. Kwon, Frederick J. Marshall, Elisabeth de Blieck, Amy Vierhile, Erika F. Augustine, Denia Ramirez-Montealegre, Heather R. Adams, University of Rochester, Rochester, USA Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) is a childhood-onset autosomal recessive neurodegenerative disease, characterized by seizures and impaired vision, behavior, cognition, and motor control. Because vision loss is a prominent early feature, we sought to understand what methods children use to adapt to blindness. We also investigated the impact of family socioeconomic status (SES) on disability and the impact of the disease on the familys SES. We surveyed parents of 43 individuals with genetically confirmed CLN3 mutations. We ascertained parent education and employment status, the subjects physical activity, age of vision loss onset, and introduction of specific visual aid techniques. Parents rated how successfully these skills were learned and if they were retained. Visual aid skills were helpful for most subjects. Long Cane was taught most frequently (91%), closely followed by Guided Travel (84%) and Braille (84%). Braille was the earliest taught (mean = 7 years, SD = 1.9), but was the most difficult to learn. Guided Travel was easiest to learn and most likely to be retained (40%). Fifty percent of the parents had a high school diploma or less. Ninety-four percent of the fathers were employed. Sixty-three percent of the mothers were employed, of whom 35% worked part time. Visual aid techniques are helpful for children with JNCL, but vary in their acquisition and retention. It is possible that the age at which these aids are introduced influences their impact. SES may affect access, learning, and retention of these skills. doi:10.1016/j.ymgme.2009.10.019 3. Comparative analysis of lysosome quantity, size, and location in normal and GM1-affected ovine, canine, and human fibroblasts using fluorescence microscopy Amelia Ahern-Rindell, Lacey Boran, Thuan Chau, Troy Coady, Malia Harrison, University of Portland, Portland, USA The lysosome serves an important recycling function in normal cellular activity; however, mutations in the genes that code for necessary degradative enzymes can cause Lysosomal Storage Diseases (LSD). Gangliosidosis (GM1) is a LSD inherited as an autosomal recessive disorder caused by a deficiency of b-galactosidase, a lysosomal enzyme that catalyzes the hydrolysis of macromolecules containing terminal galactose residues. GM1 causing mutations have been identified in the GLB1 gene of several mammalian species. Qualitative differences have been observed in the size, quantity, and location of lysosomes, relative to the nucleus and each other, in GM1affected cells compared to normal cells. The purpose of this study was to gather quantitative data to statistically verify these differences. Intraspecies and interspecies comparisons were made using normal and GM1-affected human, canine, and ovine fibroblasts. Species-specific protocols were developed to optimize cold fixation of cells and fluorescent labeling of the lysosomes. Images were acquired with confocal and image restoration microscopy, while statistical data were analyzed using 3D image analysis software. Preliminary results indicate several significant differences between GM1-affected and normal fibroblast lysosomes, including a larger number, greater volumetric values, and an increase in localized density. The accumulation of stored, undegraded galactose-containing macromolecules in GM1-affected cells can account for the increase in lysosome size, but does not intuitively explain the altered localization that is present and how this manifestation might contribute to cell death. doi:10.1016/j.ymgme.2009.10.020 4. Preliminary data on quantitative MRI and neuropsychological function in the mild form of MPS II Alia Ahmed, Igor Nestrasil, Kyle Rudser, Kathleen Delaney, Elsa Shapiro, University of Minnesota, Minneapolis, MN, USA MPS II, (Hunter syndrome), an X linked disorder, has a mild and a severe form. The CNS natural history of mild MPS II is not well delineated and even clinical data is sparse with few neuropsychological studies. MRI abnormality has been investigated using clinical methods, indicating increased number and size of Virchow Robin spaces, increased signal in white matter and atrophy in severe cases. Goals: To explore quantitative MRI and neuropsychological data in attenuated MPS II to understand the neurological disease process. Methods: As part of a pilot study of MPS disorders, eight patients with attenuated MPS II, all on enzyme replacement had an unsedated MRI and neuropsychological testing. Manual tracing of hippocampus and amygdala was done with Brains2 and other volumes were obtained automatically using FreeSurfer. IQ, memory, attention, visual motor, and spatial ability testing was performed and compared with nine attenuated MPS I patients. Results: The mean age of the MPS II group was 15.3; for the MPS I group, 16.9; and for the controls, 15.4. Manual tracing was done for all participants, but FreeSurfer volumes could not be obtained for 2 of 8, because of the degree of structural abnormality. Manual tracing yielded larger MPS II hippocampal volumes than in MPS I (the entire group and males only) and still larger than normal controls. Amygdala volumes were normal and did not differ from FreeSurfer values. FreeSurfer volumes for some grey matter structures were larger than MPS I and controls (e.g. hippocampus, thalamus, caudate) as well as whole brain volumes. White matter hypointensities were considerably larger than MPS I and controls. IQ and memory scores were normal, considerably better than attenuated MPS I patients by a standard deviation. However, attention (vigilance) and consistency of processing were below average, worse than MPS I. Molecular Genetics and Metabolism 99 (2010) S8–S41