Neurobehavioral Aspects of CLN3 (Juvenile Neuronal Ceroid Lipofuscinosis)

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

2. 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

3. 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)

4. IQ Measurements in JNCL (3 studies)

5. Further validation of UBDRS UBDRS “Clinician Global Impression” of cognitive Function (N = 28)

6. Cognition Digit Span Verbal Fluency

7. WISC-IV Vocabulary

8. Cognition and Sex Differences

9. Cognition & Sex Differences: WISC-IV Vocabulary

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

11. Behavior Santavuori (1999) N = 42

12. Behavior CBCL Mean Scores

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

14. Explore genotype / phenotype relationships

15. Behavior

16. Behavior in JNCL children & their sibs

17. 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.

18. 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

19. Neurologists • Erika Augustine, MD • 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

20. Research sponsors: Current: • 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: • Batten Disease Support & Research Association • Luke & Rachel Batten Foundation