Light, corneal, gag, cough and deep tendon reflexes were all lost. There was no electrical activity on EEG.

He died of septic shock secondary to cholecystitis at the age of 32. Serum creatine kinase, lactic acid and pyruvic acid were within normal limits. Other peripheral hematology and blood chemistry were within normal limits. Lysosomal enzymes examined were all in normal ranges. Genetic analysis of SCA8 showed pathogenic CTA/CTG repeat of 23/127 (normal 16–91). Genes for SCA1, 2, 3, 6, 7, dentatorubral-pallidolluysian atrophy (DRPLA) and Huntington’s disease exhibited no pathological expansion. Abnormal fused in sarcoma (FUS) mutation was not confirmed. Thus we clinically diagnosed this case as marked psychomotor impairment, possibly related LY2835219 to the abnormal expansion of SCA8 mutation although other SCA8 cases reported up to now were quite distinct from the present case in clinical features. Autopsy was done 3 h after death. mTOR inhibitor The brain weighed 400 g. Macroscopic examination revealed diffuse atrophy of the whole brain, including the cerebellum,

brain stem and spinal cord. The cerebral cortex and white matter showed atrophy. The basal ganglia, thalamus, cerebellum, tegmentum of the brainstem, midbrain (Fig. 1A), pons, medulla oblongata and spinal cord were severely devastated, obscuring the details of their internal structures. On microscopic examination, the cerebral cortex showed diffuse neuronal loss and Thalidomide gliosis, and white matter atrophy was comparable to that of the gray matter (Fig. 1B). The degrees of neuronal loss and gliosis (graded into mild, moderate to severe) and the frequency of rNCIs are schematized (Fig. 2). Many remaining

neurons had round to oval rNCIs. The frequency of the neurons with rNCIs was variable between 5–30% of remaining neurons. It was low in areas with severe neuronal loss, such as the thalamus, cerebellum (Fig. 1C) and motor nucleus, such as the hypoglossal nucleus (Fig. 1D), while abundant in Ammon’s horn where neuronal cells were spared. It was moderate in the frontal and parietal cortices where neuronal loss was moderate in degree. This inverse relationship between neuronal loss and rNCI was similarly evident by contrasting the deep layers of the cerebral cortex where gliosis was mild with abundant rNCIs. The rNCIs were basophilic on HE (Fig. 3A) and KB (Fig. 3B) and argyrophilic with Bodian silver impregnation (Fig. 3C). The rNCIs were positive: Ub ≈ 25–35% (Fig. 3D, 1:200, Millipore, Tokyo, Japan); p62 ≈ 20–30% (Fig. 3E 1:500, Abnova, Walnut, CA, USA); and phosphorylated TDP43 ≈ 3–5% (Fig. 3F, 1:10 000, Cosmo Bio, Tokyo, Japan), then positive in a few rNCIs for expanded polyglutamine ≈ 0.5–1.0% (Fig. 3G, 1–2, 1:10 000, Millopore, Tokyo, Japan) and negative for Syn (Fig. 3H, 1:10 000, Wako, Tokyo, Japan), AT8 (Fig. 3I, 1:10 000, Innogenetics, Zwijndrecht, Belgium), FUS (Fig. 3J 1:100 gift of Dr Murayama), neurofilaments (Fig.