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.

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. Neurology The neuronal ceroid lipofuscinoses (NCLs) are degenerative, autosomal recessive storage diseases with common clinical and pathologic features, including blindness, seizures, dementia, motor decline, and lysosomal accumulation of autofluorescent material (ceroid and lipofuscin).1 The NCLs are categorized by genetic etiology. The juvenile form of neuronal ceroid lipofuscinosis (JNCL), also called Batten disease, is the most prevalent NCL. Clinically, JNCL begins with progressive visual loss between 4 and 8 years of age, followed by seizures, then loss of motor coordination and dementia between 10 and 12 years. Death occurs by the third or fourth decade. 1,2 JNCL is due to mutations of the CLN3 3 gene that encodes a ubiquitously expressed protein of unknown function localized to the lysosomal membrane 4,5 ; modeling studies suggest a role in substrate trafficking. 5,6 Most cases of JNCL are caused by an approximately 1-kb deletion in the CLN3 3,7 gene, encompassing exons 7 and 8. Approximately 74% of patients with JNCL are homozygous for this common deletion, and 22% are compound heterozygotes for this deletion and another CLN3 mutation.8 There are no mutations consistently associated with better prognosis. 8 -10 From the University of Rochester (J.M.K., H.A., P.G.R., E. With biological advances, there is hope for rational therapies to prevent, slow, or reverse the course of JNCL. We developed the Unified Batten Disease Rating Scale (UBDRS) to measure disease progression in JNCL.11 We used the UBDRS to evaluate and quantify disease burden in 82 subjects with JNCL from 2002 through 2010...

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, 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.

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 ϭ 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 ϭ 13) represented a wide range of disease severity. Remote administration of the UBDRS Physical Impairment subscale had high interrater reliability across all subjects (ICC ϭ 0.94). When only the subjects (n ϭ 10) who had been examined by the nonphysician and scored remotely were included in the analysis, the reliability was unchanged (ICC ϭ 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; Batten disease; CLN3 disease) is an autosomal recessive neurodegenerative disorder of childhood. The disease course is characterized by vision loss, seizures, dementia, behavioral difficulties, and motor impairment. Symptoms typically begin around age 5 years and the disease progresses to severe disability and then death in the late second or third decade of life. [1][2][3] We have characterized the clinical and neurobehavioral aspects of JNCL and designed the Unified Batten Disease Rating Scale (UBDRS) to assess multiple aspects of JNCL and its progression.4 -6 The UBDRS encompasses 4 subscales: physical impairment, seizures, behavior, and functional capability. For physical impairment, the UBDRS has required in-person assessment. Because JNCL is rare (0.7-7 per 100,000 live births) 7 and affected individuals are spread throughout the United States, participating families often travel long distances for evaluation. This travel imposes substantial burdens on families, including lost time at work, travel with a physically disabled blind child, and cost. A feasible and reliable method for remote physical assessment could reduce these burdens.We hypothesized that telemedicine administration of the UBDRS Physical Impairment subscale would be reliable across a broad range of disease severity. We further hypothesized that remote sites could employ a nonphysician to perform the examination with a trained rater observing and scoring without loss of reliability.From the University of Rochester, Rochester, NY.

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.