Diagnostic slide session 2010 American Association of Neuropathologists Case

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

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.

Diagnosis?

20 μm

Dentate nucleus

Substantia nigra

100 μm Oculomotor nucleus; HE Oculomotor nucleus; PAS

Parahippocampal gyrusGlobus pallidus; PAS Thalamus

LAH Nucleus of Onuf

DRG

GM 2 gangliosidosis :Sandhoff’s d.This case

What kind of lipidosis?

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

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)

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

There is more!

Hippocampus

20 μm Cortex; filipin

…..and more

Thank you

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.