Heather Adams, PhD University of Rochester Batten Center Neurobehavioral Aspects of CLN3 (Juvenile Neuronal Ceroid Lipofuscinosis) Heather Adams, PhD University of Rochester Batten Center

Background – CLN3 Disease Juvenile Neuronal Ceroid Lipofuscinosis [“Batten Disease”] Autosomal-recessively inherited lysosomal storage disease Childhood onset Unique clinical features vision loss ▪ seizures ▪ dementia Motor decline ▪ speech impairment Rare disease: 1/12,500 to 1/40,000 live births. Males:Females = 1:1 Leads to severe disability and premature death

Neurobehavioral studies in CLN3 Cognition Behavior Adaptive Function Quality of Life Other projects… Visual aid skills (Newhouse) Socioeconomic Status / Demographic history (Newhouse) Knowledge and Attitudes – Genetic Testing (Rose) Sibling QoL and knowledge of Batten Disease (Agarwal)

IQ Measurements in JNCL (3 studies)

Further validation of UBDRS UBDRS “Clinician Global Impression” of cognitive Function (N = 28) CGI - Cognitive Function WISC-IV Vocabulary -0.41 (p < .05) WISC-IV Digit Span -0.45 (p < .05) WRAML Story Recall -0.59 (p < .01) WRAML Sentence Recall -0.58 (p < .01) FAS -0.10 (ns)

Cognition Digit Span Verbal Fluency

WISC-IV Vocabulary

Cognition and Sex Differences

Cognition & Sex Differences: WISC-IV Vocabulary

Immediate Recall (WRAML Story Memory) Means & 95% Confidence Intervals

Behavior Santavuori (1999) N = 42 .

Behavior CBCL Mean Scores

Unified Batten Disease Rating Scale: cross- validation with CBCL (N = 35) (Spearman Rank-Order Correlations)

Explore genotype / phenotype relationships

Behavior

Behavior in JNCL children & their sibs

Summary We have quantified neurobehavioral function in CLN3 disease There may be sex differences in some aspects of neurobehavioral function (cognition, quality of life). Neurobehavioral assessment can ‘talk to’ other data, expanding what we know about the disease. Rare disease challenges – small N, difficulties in reaching sample, inconsistency and LTFU in assessment, flexibility in measures and methods due to physical limitations of disease.

What’s next? Consider intervention study for behavioral management of dementia symptoms Closer study of speech & language in CLN3 disease Investigate late-stage CLN3 disease and end-of-life care issues Pursue roadmap for Phase III studies in CLN3 disease

NCL FAMILIES Neurologists Students Erika Augustine, MD Ankita Agarwal Joanna Blackburn, MD Leon Dure, MD Jennifer Kwon, MD, MPH Frederick Marshall, MD Jonathan Mink, MD, PhD Denia Ramirez, MD, MPH, PhD Neuropsychologist Heather Adams, PhD Julie Eisengart, PhD Biostatisticians Michael McDermott, PhD Chris Beck, PhD Research Coordinators Elisabeth de Blieck, MPA Nicole Newhouse Alyssa Thatcher Students Ankita Agarwal Jen Cialone Rachel Jordan Erika Levy, MD Tiffani McDonough Samantha Potter Jennifer Riehl Shayne Ragbeer Katherine Rose Sabrina Seehafer Erin Stachowski Melissa Wang Kim Worcester Molecular Genetics Paul Rothberg, PhD Instigator David Pearce, PhD Clinical Coordinator Amy Vierhile, RN, PNP NCL FAMILIES

Research sponsors: Current: Past support: NINDS: 5K23 NS058756-01 “Neurobehavioral Outcomes of Degenerative Neurologic Diseases” NINDS: 5R01NS060022-04 “Clinical and Neuropsychological Investigations in Batten Disease” NINDS/UMN: 5U54NS065768-02 “Longitudinal Studies in Batten Disease” Batten Disease Support & Research Association Food & Drug Administration Past support: Luke & Rachel Batten Foundation