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Aim The primary aim of this investigation was to examine genotype and clinical phenotype differences in individuals with juvenile neuronal ceroid lipofuscinosis (JNCL) who were homozygous for a common disease-causing deletion or compound heterozygous. The secondary aim was to cross-validate the Child Behavior Checklist (CBCL) and the Unified Batten Disease Rating Scale (UBDRS), a disease-specific JNCL rating scale. Method Sixty individuals (28 males, 32 females; mean age 15y 1mo, SD 4y 9mo, range 5y 8mo–31y 1mo) with JNCL completed the UBDRS. Results No significant genotype and clinical phenotype differences were identified when comparing individuals homozygous for the deletion with a heterogeneous group of compound heterozygous individuals. There were significant correlations among related behaviour items and scales on the CBCL and UBDRS (Spearman’s rho ranging from 0.39 [p

Background: Batten disease (juvenile neuronal ceroid lipofuscinosis [JNCL]) is an autosomal recessive neurodegenerative disorder characterized by blindness, seizures, and relentless decline in cognitive, motor, and behavioral function. Onset is in the early school years, with progression to death typically by late adolescence. Development of a clinical instrument to quantify severity of illness is a prerequisite to eventual assessment of experimental therapeutic interventions Objective: To develop a clinical rating instrument to assess motor, behavioral, and functional capability in JNCL. Methods: A clinical rating instrument, the Unified Batten Disease Rating Scale (UBDRS), was developed by the authors to assess motor, behavioral, and functional capability in JNCL. Children with verified JNCL were evaluated independently by three neurologists. Intraclass correlation coefficients (ICCs) were used to estimate the interrater reliability for total scores in each domain. Interrater reliability for scale items was assessed with weighted κ statistics Results: Thirty-one children with confirmed JNCL (10 boys, 21 girls) were evaluated. The mean age at symptom onset was 6.1 ± 1.6 years, and the mean duration of illness was 9.0 ± 4.4 years. The ICCs for the domains were as follows: motor = 0.83, behavioral = 0.68, and functional capability = 0.85. Conclusions: The Unified Batten Disease Rating Scale (UBDRS) is a reliable instrument that effectively tests for neurologic function in blind and demented patients. In its current form, the UBDRS is useful for monitoring the diverse clinical findings seen in Batten disease.

This paper describes 2 studies that evaluated a new instrument, the Perceived Ethnic Discrimination Questionnaire–Community Version (PEDQ-CV). The PEDQ-CV can be used across ethnic groups to assess perceived racism or ethnic discrimination. The scales measure several subdimensions of racism, permitting the examination of different forms of this race-related stressor. The first study evaluated the psychometric properties of the PEDQ-CV in a large sample of community-dwelling adults. The second evaluated psychometric properties of a brief version of the PEDQ-CV, developed for research protocols requiring a shorter administration time. Tests were made of reliability and several forms of construct validity. Both versions of the PEDQ-CV have good reliability and construct validity. The PEDQ-CV can facilitate the development of an integrative body of knowledge across different ethnic groups regarding the existence, determinants, and consequences of discrimination.

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.

The primary aim of this investigation was to examine genotype and clinical phenotype differences in individuals with juvenile neuronal ceroid lipofuscinosis (JNCL) who were homozygous for a common disease-causing deletion or compound heterozygous. The secondary aim was to cross-validate the Child Behavior Checklist (CBCL) and the Unified Batten Disease Rating Scale (UBDRS), a disease-specific JNCL rating scale.Sixty individuals (28 males, 32 females; mean age 15y 1mo, SD 4y 9mo, range 5y 8mo--31y 1mo) with JNCL completed the UBDRS.No significant genotype and clinical phenotype differences were identified when comparing individuals homozygous for the deletion with a heterogeneous group of compound heterozygous individuals. There were significant correlations among related behaviour items and scales on the CBCL and UBDRS (Spearman's rho ranging from 0.39 [p0.05] to 0.72 [p0.01]). Behaviour and physical function ratings were uncorrelated, supporting divergent validity of these two constructs in JNCL.Previous reports of genotype and clinical phenotype differences were unsupported in this investigation, which did not find differences between individuals homozygous or heterozygous for the CLN3 deletion. The CBCL, an already validated measure of behaviour problems, appears valid for use in JNCL and cross-validates well with the UBDRS.

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