2. Visual aid skills and socioeconomic status in children with Batten disease

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