1. Diagnostic slide session 2010 American Association of Neuropathologists Case 2010-12

2. Contributors Arnulf H. Koeppen, Ashley N. Davis, Jennifer A. Morral, Edward S. Johnson, Jiang Qian, Kinuko Suzuki, Uta Gölnitz, Matthias Wittstock, Arndt Rolfs, and Richard Camicioli

4. Clinical History Main problem: Ataxia beginning at age 10 Family history: Tremor in mother and maternal grandfather Genetic testing: Normal for SCA 1, SCA-2, SCA-3, SCA-6, and Friedreich’s ataxia Neurological findings: Normal mental status; saccadic intrusions into ocular pursuit movements; ataxia; dysmetria; dysarthria; hearing loss; modest hyperreflexia; and a right Babinski sign. Course: Relentless progression to intense rigidity of her extremities; dystonia; leg spasticity; and sustained ankle clonus; death at 39 Imaging: Magnetic resonance imaging unrevealing. Autopsy findings: Pulmonary congestion and an angiomyolipoma of the right kidney; brain weight 1321 g; substantia nigra pale.

9. Diagnosis?

10. 20 μm

12. Dentate nucleus

13. Substantia nigra

14. 100 μm Oculomotor nucleus; HE Oculomotor nucleus; PAS

15. Parahippocampal gyrusGlobus pallidus; PAS Thalamus

16. LAH Nucleus of Onuf

17. DRG

18. GM 2 gangliosidosis :Sandhoff’s d.This case

19. What kind of lipidosis?

20. Systematic genetic analysis of possible GM 2 gangliosidosis (Institute of Molecular Diagnostics, Rostock, Germany) Patient’s DNA: (1) Hex A: normal, excluding Tay-Sachs disease (2) Hex B: normal, excluding Sandhoff’s disease (3) GM 2 A: normal, excluding Tay-Sachs variant

21. Systematic analysis of Niemann-Pick type C1 disease (NPC1) Father’s DNA: R935Q ( known pathogenic mutation) Mother’s DNA: G992R (known pathogenic mutation) Patient’s DNA: R934Q/G992R (compound heterozygote of two known pathogenic mutations)

22. Genetic diagnosis: Niemann-Pick disease, type C1, OMIM 257.220 Unusual: compound heterozygosity

23. There is more!

24. Hippocampus

25. 20 μm Cortex; filipin

27. …..and more

30. Thank you

31. Acknowledgment. The neuropathological work was completed in the laboratories of VA Medical Center in Albany, N.Y. (AHK); Albany Medical College (JQ); and WC Mackenzie Health Sciences Center, Edmonton, AB, Canada (ESJ). The mutations were identified at Centogene and University of Rostock, Rostock, Germany (UG, MW, AR). RC contributed the clinical data.