Diagnostic slide session 2010American Association of

Neuropathologists

Case 2010-12

ContributorsArnulf 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 HistoryMain problem: Ataxia beginning at age 10Family history: Tremor in mother and maternal grandfatherGenetic testing: Normal for SCA 1, SCA-2, SCA-3, SCA-6, and Friedreich’s ataxiaNeurological 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 gyrus Globus pallidus; PAS

Thalamus

LAH Nucleus of Onuf

DRG

GM2 gangliosidosis :Sandhoff’s d.This case

What kind of lipidosis?

Systematic genetic analysis of possible GM2 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) GM2A: 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 257.220Unusual: 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.