Spinocerebellar Ataxia Type 7 (SCA7): First Report of a Systematic Neuropathological Study of the Brain of a Patient with a Very Short Expanded CAG‐Repeat

Abstract

Spinocerebellar ataxia type 7 (SCA7) represents a very rare and severe autosomal dominantly inherited cerebellar ataxia (ADCA). It belongs to the group of CAG-repeat or polyglutamine diseases with its underlying molecular genetical defect on chromosome 3p12-p21.1. Here, we performed a systematic study of the neuropathology on unconventional thick serial sections of the first available brain tissue of a genetically confirmed late-onset SCA7 patient with a very short CAG-repeat expansion. Along with myelin pallor of a variety of central nervous fiber tracts, we observed i) neurodegeneration in select areas of the cerebral cortex, and ii) widespread nerve cell loss in the cerebellum, thalamus, nuclei of the basal ganglia, and brainstem. In addition, upon immunocytochemical analysis using the anti-polyglutamine antibody 1C2, immunopositive neuronal intranuclear inclusions bodies (NI) were observed in all cerebellar regions, in all parts of the cerebral cortex, and in telencephalic and brainstem nuclei, irrespective of whether they underwent neurodegeneration. These novel findings provide explanations for a variety of clinical symptoms and paraclinical findings of both our and other SCA7 patients. Finally, our immunocytochemical analysis confirms previous studies which described the presence of NI in obviously degenerated brain and retinal regions as well as in apparently well-preserved brain regions and retina of SCA7 patients.

SCA3: Neurological features, pathogenesis and animal models

“…In contrast to previous conventional neuropathological studies, recent pathoanatomical studies involving unconventional serial thick tissue sections demonstrated widespread damage to the cerebellum, thalamus, midbrain, pons, medulla oblongata, and spinal cord in SCA3 ( Figure 3) (63,64,(66)(67)(68)(69)(70)(71). This clearly exceeds the proposed 'olivopontocerebellar' pattern of neurodegeneration (2), is comparable to that commonly seen in terminal SCA2 and SCA7 patients (2,63,64,(66)(67)(68)70,(72)(73)(74) and provides suitable explanations for a variety of less understood clinical SCA3 symptoms. According to these studies the following gray matter components may be among the targets of the degenerative process of SCA3: nuclei of the motor cerebellothalamocortical loop (i.e., cerebellar dentate nucleus, pontine nuclei, thalamic ventral lateral nucleus) ( Figure 3A, C, D, I), and the basal ganglia-thalamocortical loop (i.e., pallidum, subthalamic nucleus, thalamic ventral anterior (63,65,68,70,75), the substantia nigra and ventral tegmental area ( Figure 3B) (63,65,75), select non-motor thalamic nuclei (thalamic reticular nucleus, lateral geniculate body, pulvinar) ( Figure 3A, B) (63,70), subcortical components of the somatosensory system (i.e., ventral posterior lateral and ventral posterior medial thalamic nuclei, trigeminal, cuneate, external cuneate, and gracile nuclei, Clarke's column) ( Figure 3A-C, F-H) (63,64,…”

Tensor-Based Morphometry and Stereology Reveal Brain Pathology in the Complexin1 Knockout Mouse

“…The involvement of the thalamus has also been reported previously in patients with spinocerebellar ataxias type 2, 3 and 7 [90], [91], [92] and [93], autosomal recessive ataxia [94] and patients with Wernicke-Korsakoff syndrome [89]. In addition, loss of granule cells in the cerebellum has been previously reported in siblings with ataxia-telangiectasia-like disorder [95] as well as in mouse models of ataxia [84], [82] and [83].…”

Brain pathology of spinocerebellar ataxias

“…Macroscopic post-mortem investigations reveal atrophy of the cerebellum and the brainstem (Fig. 6) [29,136]. Microscopy discloses widespread and severe neurodegeneration in the cerebral cortex, basal ganglia, thalamus, midbrain, pons, medulla oblongata and the cerebellum ( SCA7 is associated with a widespread occurrence of neuronal intranuclear ataxin-7 aggregates in affected and spared gray regions (Fig.…”