Abstracts for the lysosomal disease networks WORLD symposium

1. Update on longitudinal assessment of children with juvenile neuronal ceroidlipofuscinosis (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 pro-gressive and fatal autosomal-recessive inherited lysosomal storage disorder of child-hood. Core symptoms include vision loss, seizures, and mental and motor decline.Neurocognitive deficits are prominent and involve progressive decrements in atten-tion, memory, verbal abilities and global IQ. Herein we report an update of our longi-tudinal study of neurocognitive function in JNCL/CLN3 disease and address somechallenges in the assessment of this population.

Method: Children with genetically confirmed JNCL/CLN3 disease who are partici-pating in our Unified Batten Disease Rating Scale (UBDRS) project complete a briefneuropsychological 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 com-pleted more than one exam. A summary score was calculated for general performanceacross all tests; test performance had a significant inverse relationship to age(r = �.43, p < .01). Performance in individual domains showed similar patterns, exceptsentence repetition (r = �.16, ns) consistent with our prior work.

Conclusions: The longitudinal examination of this population presents severalchallenges, including selection of tests appropriate for visually impaired patientswho must provide verbal responses yetalso experience motor speech decline, andselection of measures that can be administered consistently over time to patientsexperiencing 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 autosomalrecessive neurodegenerative disease, characterized by seizures and impaired vision,behavior, cognition, and motor control. Because vision loss is a prominent early fea-ture, we sought to understand what methods children use to adapt to blindness. Wealso investigated the impact of family socioeconomic status (SES) on disability andthe impact of the disease on the familys SES.

We surveyed parents of 43 individuals with genetically confirmed CLN3 muta-tions. We ascertained parent education and employment status, the subjects physicalactivity, 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 fre-quently (91%), closely followed by Guided Travel (84%) and Braille (84%). Braillewas 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 percentof the fathers were employed. Sixty-three percent of the mothers were employed, ofwhom 35% worked part time.

Visual aid techniques are helpful for children with JNCL, but vary in their acqui-sition and retention. It is possible that the age at which these aids are introducedinfluences 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 andGM1-affected ovine, canine, and human fibroblasts using fluorescencemicroscopy

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 cancause Lysosomal Storage Diseases (LSD). Gangliosidosis (GM1) is a LSD inherited asan autosomal recessive disorder caused by a deficiency of b-galactosidase, a lyso-somal enzyme that catalyzes the hydrolysis of macromolecules containing terminalgalactose residues. GM1 causing mutations have been identified in the GLB1 geneof several mammalian species. Qualitative differences have been observed in the size,quantity, and location of lysosomes, relative to the nucleus and each other, in GM1-affected cells compared to normal cells. The purpose of this study was to gather quan-titative data to statistically verify these differences. Intraspecies and interspeciescomparisons were made using normal and GM1-affected human, canine, and ovinefibroblasts. Species-specific protocols were developed to optimize cold fixation ofcells and fluorescent labeling of the lysosomes. Images were acquired with confocaland image restoration microscopy, while statistical data were analyzed using 3Dimage analysis software. Preliminary results indicate several significant differencesbetween GM1-affected and normal fibroblast lysosomes, including a larger number,greater volumetric values, and an increase in localized density. The accumulation ofstored, undegraded galactose-containing macromolecules in GM1-affected cells canaccount for the increase in lysosome size, but does not intuitively explain the alteredlocalization 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 themild form of MPS II

Alia Ahmed, Igor Nestrasil, Kyle Rudser, Kathleen Delaney, Elsa Shapiro, University ofMinnesota, 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 datais sparse with few neuropsychological studies. MRI abnormality has been investigatedusing clinical methods, indicating increased number and size of Virchow Robinspaces, increased signal in white matter and atrophy in severe cases.

Goals: To explore quantitative MRI and neuropsychological data in attenuatedMPS II to understand the neurological disease process.

Methods: As part of a pilot study of MPS disorders, eight patients with attenuatedMPS II, all on enzyme replacement had an unsedated MRI and neuropsychologicaltesting. Manual tracing of hippocampus and amygdala was done with Brains2 andother volumes were obtained automatically using FreeSurfer. IQ, memory, attention,visual motor, and spatial ability testing was performed and compared with nineattenuated MPS I patients.

Results: The mean age of the MPS II group was 15.3; for the MPS I group, 16.9; andfor the controls, 15.4. Manual tracing was done for all participants, but FreeSurfer vol-umes 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 entiregroup and males only) and still larger than normal controls. Amygdala volumes werenormal and did not differ from FreeSurfer values. FreeSurfer volumes for some greymatter structures were larger than MPS I and controls (e.g. hippocampus, thalamus,caudate) as well as whole brain volumes. White matter hypointensities were consid-erably larger than MPS I and controls. IQ and memory scores were normal, consider-ably better than attenuated MPS I patients by a standard deviation. However,attention (vigilance) and consistency of processing were below average, worse thanMPS I.

Molecular Genetics and Metabolism 99 (2010) S8–S41

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Molecular Genetics and Metabolism

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