Autonomic function testing in spinocerebellar ataxia type 2.
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ABSTRACT:
SUBMITTER: Indelicato E
PROVIDER: S-EPMC5995979 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Microsatellite expansions cause a number of dominantly-inherited neurological diseases. Expansions in coding-regions cause protein gain-of-function effects, while non-coding expansions produce toxic RNAs that alter RNA splicing activities of MBNL and CELF proteins. Bi-directional expression of the spinocerebellar ataxia type 8 (SCA8) CTG CAG expansion produces CUG expansion RNAs (CUG(exp)) from the ATXN8OS gene and a nearly pure polyglutamine expansion protein encoded by ATXN8 CAG(exp) transcripts expressed in the opposite direction. Here, we present three lines of evidence that RNA gain-of-function plays a significant role in SCA8: 1) CUG(exp) transcripts accumulate as ribonuclear inclusions that co-localize with MBNL1 in selected neurons in the brain; 2) loss of Mbnl1 enhances motor deficits in SCA8 mice; 3) SCA8 CUG(exp) transcripts trigger splicing changes and increased expression of the CUGBP1-MBNL1 regulated CNS target, GABA-A transporter 4 (GAT4/Gabt4). In vivo optical imaging studies in SCA8 mice confirm that Gabt4 upregulation is associated with the predicted loss of GABAergic inhibition within the granular cell layer. These data demonstrate that CUG(exp) transcripts dysregulate MBNL/CELF regulated pathways in the brain and provide mechanistic insight into the CNS effects of other CUG(exp) disorders. Moreover, our demonstration that relatively short CUG(exp) transcripts cause RNA gain-of-function effects and the growing number of antisense transcripts recently reported in mammalian genomes suggest unrecognized toxic RNAs contribute to the pathophysiology of polyglutamine CAG CTG disorders.
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Project description:A 58-year-old man consulted our hospital due to a 2-year history of dysarthria and a 1-month history of blepharospasm. In addition to the ataxic dysarthria and blepharospasm, a neurological examination demonstrated slight ataxia of the trunk and lower limbs. Brain MRI demonstrated atrophy of the upper portion of the cerebellar vermis. Gene analysis established a diagnosis of spinocerebellar ataxia type 31 (SCA31). Single photon emission computed tomography (SPECT) with the three-dimensional stereotaxic ROI template (3DSRT) software program demonstrated hyperperfusion in the lenticular nucleus and thalamus. Although the association between SCA31 and blepharospasm in our patient remains unclear, we considered that this combination might be more than coincidental.
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Project description:PurposeTo analyze the relation between ophthalmologic and motor changes in spinocerebellar ataxia type 7 (SCA7).Patients and methodsThis was a case series study. Sixteen SCA7 patients underwent a comprehensive ophthalmic examination, including ocular extrinsic motility testing, color vision test, and optical coherence tomography of the optic nerve and macula. Changes in the corneal endothelium, electroretinographic patterns, and a complete neurologic evaluation using the Scale for the Assessment and Rating of Ataxia (SARA) were evaluated. Correlations of endothelial cell density (ECD) with number of CAG repetitions and the SARA scores were estimated.ResultsAll patients showed various degrees of visual impairment mainly due to macular deterioration. Notably, they also presented decreased ECD. Pairwise correlations of ECD with number of CAG repeats and severity of motor symptoms quantified with the SARA scores were inverse (r=-0.46, P=0.083 and r=-0.64, P=0.009, respectively). Further analyses indicated an average ECD decrease of 48 cells/mm2 (P=0.006) per unit of change on the number of CAG repeats, and of 75 cells/mm2 (P=0.001) per unit of change on the SARA scores.ConclusionsThe results agree with previous ophthalmological findings regarding the widespread effect of SCA7 mutation on the patient's visual system. However, the results also show a significant negative correlation of decreased ECD with both CAG repetitions and SARA scores. This suggests that motor systems could degenerate in parallel with visual systems, although more research is needed to determine whether the degeneration is caused by the same mechanisms.
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Project description:Dominantly inherited GAA repeat expansions in FGF14 are a common cause of spinocerebellar ataxia (GAA-FGF14 ataxia; spinocerebellar ataxia 27B). Molecular confirmation of FGF14 GAA repeat expansions has thus far mostly relied on long-read sequencing, a technology that is not yet widely available in clinical laboratories. We developed and validated a strategy to detect FGF14 GAA repeat expansions using long-range PCR, bidirectional repeat-primed PCRs, and Sanger sequencing. We compared this strategy to targeted nanopore sequencing in a cohort of 22 French Canadian patients and next validated it in a cohort of 53 French index patients with unsolved ataxia. Method comparison showed that capillary electrophoresis of long-range PCR amplification products significantly underestimated expansion sizes compared to nanopore sequencing (slope, 0.87 [95% CI, 0.81 to 0.93]; intercept, 14.58 [95% CI, - 2.48 to 31.12]) and gel electrophoresis (slope, 0.84 [95% CI, 0.78 to 0.97]; intercept, 21.34 [95% CI, - 27.66 to 40.22]). The latter techniques yielded similar size estimates. Following calibration with internal controls, expansion size estimates were similar between capillary electrophoresis and nanopore sequencing (slope: 0.98 [95% CI, 0.92 to 1.04]; intercept: 10.62 [95% CI, - 7.49 to 27.71]), and gel electrophoresis (slope: 0.94 [95% CI, 0.88 to 1.09]; intercept: 18.81 [95% CI, - 41.93 to 39.15]). Diagnosis was accurately confirmed for all 22 French Canadian patients using this strategy. We also identified 9 French patients (9/53; 17%) and 2 of their relatives who carried an FGF14 (GAA)≥250 expansion. This novel strategy reliably detected and sized FGF14 GAA expansions, and compared favorably to long-read sequencing.
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Project description:Spinocerebellar ataxia type 10 (SCA10; OMIM #603516) is an autosomal dominant cerebellar ataxia with variably associated extracerebellar signs.(1,2) SCA10 is caused by an expanded noncoding pentanucleotide repeat in ATXN10, which normally ranges from 9 to 32 repeats(3,4); pathogenic alleles have as many as 4,500 repeats.(4) To date, SCA10 has been found exclusively on American continents. In this report, we describe a Chinese Han family with autosomal dominant cerebellar ataxia caused by an SCA10 expansion.
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Project description:Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder that affects one or two individuals per 100,000. The disease is caused by an extended CAG repeat in exon 8 of the ATXN1 gene and is characterized mostly by a profound loss of cerebellar Purkinje cells, leading to disturbances in coordination, balance, and gait. At present, no curative treatment is available for SCA1. However, increasing knowledge on the cellular and molecular mechanisms of SCA1 has led the way towards several therapeutic strategies that can potentially slow disease progression. SCA1 therapeutics can be classified as genetic, pharmacological, and cell replacement therapies. These different therapeutic strategies target either the (mutant) ATXN1 RNA or the ataxin-1 protein, pathways that play an important role in downstream SCA1 disease mechanisms or which help restore cells that are lost due to SCA1 pathology. In this review, we will provide a summary of the different therapeutic strategies that are currently being investigated for SCA1.
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Project description:Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), may be the most common dominantly inherited ataxia in the world. Here I will review historical, clinical, neuropathological, genetic, and pathogenic features of MJD, and finish with a brief discussion of present, and possible future, treatment for this currently incurable disorder. Like many other dominantly inherited ataxias, MJD/SCA3 shows remarkable clinical heterogeneity, reflecting the underlying genetic defect: an unstable CAG trinucleotide repeat that varies in size among affected persons. This pathogenic repeat in MJD/SCA3 encodes an expanded tract of the amino acid glutamine in the disease protein, which is known as ataxin-3. MJD/SCA3 is one of nine identified polyglutamine neurodegenerative diseases which share features of pathogenesis centered on protein misfolding and accumulation. The specific properties of MJD/SCA3 and its disease protein are discussed in light of what is known about the entire class of polyglutamine diseases.
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Project description:There is increasing appreciation for the role of the neurovascular unit in neurodegenerative diseases. We showed previously that the angiogenic and neurotrophic cytokine, vascular endothelial growth factor (VEGF), is suppressed to abnormally low levels in spinocerebellar ataxia type 1 (SCA1), and that replenishing VEGF reverses the cerebellar pathology in SCA1 mice. In that study, however, we used a recombinant VEGF, which is extremely costly to manufacture and biologically unstable as well as immunogenic. To develop a more viable therapy, here we test a synthetic VEGF peptide amphiphile that self-assembles into nanoparticles. We show that this nano-VEGF has potent neurotrophic and angiogenic properties, is well-tolerated, and leads to functional improvement in SCA1 mice even when administered at advanced stages of the disease. This approach can be generalized to other neurotrophic factors or molecules that act in a paracrine manner, offering a novel therapeutic strategy for neurodegenerative conditions.
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Project description:Spinocerebellar ataxia type 6 (SCA6) is a genetic disease that causes degeneration of Purkinje cells, and recent evidence points to degeneration of Betz cells in the motor cortex. The relation between functional activity of motor cortex and symptom severity during a hand-grip motor control in vivo has not yet been investigated. This study explored both functional changes in the sensorimotor cortex and cerebellar regions and structural alterations in the cerebellum for SCA6 patients as compared to age-matched healthy controls using a multimodal imaging approach (task-based fMRI, task-based functional connectivity, and free-water diffusion MRI). Further, we tested their relation with the severity of ataxia symptoms. SCA6 patients had reduced functional activity in the sensorimotor cortex, supplementary motor area (SMA), cerebellar vermis, and cerebellar lobules I-VI (corrected P < 0.05). Reduced task-based functional connectivity between cortical motor regions (i.e., primary motor cortex and SMA) and cerebellar regions (i.e., vermis and lobules I-VI) was found in SCA6 (corrected P < 0.05). SCA6 had elevated free-water values throughout the cerebellum as compared with controls (corrected P < 0.05). Importantly, reduced functional activity in the sensorimotor cortex and SMA and increased free-water in the superior cerebellar peduncle and cerebellar lobule V were related to more severe symptoms in SCA6 (all pairs: R 2 ≥ 0.4 and corrected P < 0.05). Current results demonstrate that impaired functional activity in sensorimotor cortex and SMA and elevated free-water of lobule V and superior cerebellar peduncle are both related to symptom severity, and may provide candidate biomarkers for SCA6.
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