We describe an exceptional spinocerebellar ataxia type 2 (SCA2) phenotype combining cerebellar ataxia, levodopa-responsive parkinsonism, and motor neuron symptoms. We conclude that motor neuron symptoms and signs may be a striking manifestation in SCA2, masking pre-existing cerebellar and extrapyramidal semeiology.
"This was in contrast to the second Flanders-Belgian patient carrying Q 33 who presented first with symptoms suggestive for a spinocerebellar disorder, but who several years later developed a rapidly progressive fatal motor neuron disease prompting a diagnosis of ALS. The rare association of Sca-2 and ALS has already been reported a few times before, but in patients who had longer ATXN2 alleles (Infante et al., 2004; Nanetti et al., 2009). Taken together, these results indicate that significant overlap exists between the ALS and Sca-2 phenotypes in patients with intermediate-length polyQ expansions in ATXN2 individuals may present with either ALS, Sca-2, or with overlapping pheno- types. "
[Show abstract][Hide abstract] ABSTRACT: There exists considerable clinical and pathological overlap between frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), which implies that these 2 neurodegenerative conditions share common pathogenic mechanisms. Recently, intermediate-length (27-33) polyglutamine (polyQ) expansions in ataxin-2 (ATXN2) have been associated with increased risk for ALS, while expansions of > 34 repeats are known to cause spinocerebellar ataxia type 2 (Sca-2). We identified in 72 ALS patients one patient with a 33 polyQ expansion that was absent in 810 control individuals. This allele was also found in one patient with concomitant ALS-Sca-2. In contrast, in a Flanders-Belgian series of 270 FTLD and 22 FTLD-ALS patients, we found no association with intermediate-length polyQ expansions nor did we observe patient-specific long expansions in agreement with the recent observation in a screening of a substantial sized cohort of patients with diverse neurodegenerative brain diseases. Our results provide further support to the notion that ATXN2 associated polyglutamine amplification is specific to the ALS-end of the FTLD-ALS disease spectrum.
Neurobiology of aging 10/2011; 33(5):1004.e17-20. DOI:10.1016/j.neurobiolaging.2011.09.025 · 5.01 Impact Factor
"Although SCA2 primarily presents with cerebellar Purkinje neuron degeneration, as in ALS, motor neurons can also degenerate, although these features are typically later than the cerebellar degeneration. In select cases, however, the motor neuron features can be sufficiently prominent to mimic an ALS presentation (Infante et al. 2004; Nanetti et al. 2009). These findings raise the potential for mechanistic overlap between SCA2 and ALS. "
[Show abstract][Hide abstract] ABSTRACT: Model organisms include yeast Saccromyces cerevisae and fly Drosophila melanogaster. These systems have powerful genetic approaches, as well as highly conserved pathways, both for normal function and disease. Here, we review and highlight how we applied these systems to provide mechanistic insight into the toxicity of TDP-43. TDP-43 accumulates in pathological aggregates in ALS and about half of FTD. Yeast and fly studies revealed an interaction with the counterparts of human Ataxin-2, a gene whose polyglutamine repeat expansion is associated with spinocerebellar ataxia type 2. This finding raised the hypothesis that repeat expansions in ataxin-2 may associate with diseases characterized by TDP-43 pathology such as ALS. DNA analysis of patients revealed that intermediate-length polyglutamine expansions in ataxin-2 are a risk factor for ALS, such that repeat lengths are greater than normal, but lower than that associated with spinocerebellar ataxia type 2 (SCA2), and are more frequent in ALS patients than in matched controls. Moreover, repeat expansions associated with ALS are interrupted CAA-CAG sequences as opposed to the pure CAG repeat expansions typically associated with SCA2. These studies provide an example of how model systems, when extended to human cells and human patient tissue, can reveal new mechanistic insight into disease.
"On the contrary, most SCAs are multisystemic disorders showing neurodegeneration not only in the spinocerebellar tracts but also in the basal ganglia and midbrain (Schols et al., 2000). Parkinsonism symptoms in SCA1 (Gilman et al., 1996), SCA2 (Infante et al., 2004; Simon-Sanchez et al., 2005), SCA3/MJD (Gwinn-Hardy et al., 2001), SCA6 (Khan et al., 2005), SCA17 (Gunther et al., 2004) and SCA27 (van Swieten et al., 2003) are indicative of possible impairment of striatonigral and/or striatopallidal projections in these spinocerebellar ataxia subtypes. "
[Show abstract][Hide abstract] ABSTRACT: The autosomal dominant spinocerebellar ataxias (SCAs) are a group of neurodegenerative diseases, clinically and genetically heterogeneous, characterized by loss of balance and motor coordination due to dysfunction of the cerebellum and its afferent and efferent connections. Despite a well-described clinical and pathological phenotype, the molecular and cellular events that underlie neurodegeneration are still poorly understood. Compelling evidence points to major aetiological roles for interference with transcriptional regulation, protein aggregation and clearance, the ubiquitin-proteasome system and alterations of calcium homeostasis in the neuronal loss observed during the neurodegenerative process. But novel molecular routes that might be disrupted during disease progression are also being identified. These pathways could act independently or, more likely, interact and enhance each other, triggering the accumulation of cellular damage that eventually leads to dysfunction and, ultimately, the demise of neurons through a series of multiple events. This suggests that simultaneous targeting of several pathways might be therapeutically necessary to prevent neurodegeneration and preserve neuronal function. Understanding how dysregulation of these pathways mediates disease progression is leading to the establishment of effective therapeutic strategies in vivo, which may prove beneficial in the treatment of SCAs. Herein, we review the latest evidence for the proposed molecular processes to the pathogenesis of dominantly inherited spinocerebellar ataxias and the current therapeutic strategies.
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