Intermuscular Coherence in Spinocerebellar Ataxias 3 and 6: a Preliminary Study.

Spinocerebellar ataxias (SCAs) are familial neurodegenerative diseases involving the cerebellum and spinocerebellar tracts. While there is variable involvement of corticospinal tracts (CST), dorsal root ganglia, and motor neurons in SCA3, SCA6 is characterized by a pure, late-onset ataxia. Abnormal intermuscular coherence in the beta-gamma frequency range (IMCßγ) implies a lack of integrity of CST or the afferent input from the acting muscles. We test the hypothesis that IMCßγ has the potential to be a biomarker of disease activity in SCA3 but not SCA6. Intermuscular coherence between biceps brachii and brachioradialis muscles was measured from surface EMG waveforms in SCA3 (N = 16) and SCA6 (N = 20) patients and in neurotypical subjects (N = 23). IMC peak frequencies were present in the ß range in SCA patients and in the γ range in neurotypical subjects. The difference between IMC amplitudes in the γ and ß ranges was significant when comparing neurotypical control subjects to SCA3 (p < 0.01) and SCA6 (p = 0.01) patients. IMCßγ amplitude was smaller in SCA3 patients compared to neurotypical subjects (p < 0.05), but not different between SCA3 and SCA6 patients or between SCA6 and neurotypical subjects. IMC metrics can differentiate SCA patients from normal controls.

Targeting the CACNA1A IRES as a Treatment for Spinocerebellar Ataxia Type 6.

We have discovered that the P/Q-type voltage-gated Ca2+ channel (VGCC) gene, CACNA1A, encodes both the α1A (Cav2.1) subunit and a newly recognized transcription factor, α1ACT, by means of a novel internal ribosomal entry site (IRES) within the α1A C-terminal coding region. α1ACT, when mutated with an expansion of the polyglutamine tract in the C-terminus, gives rise to spinocerebellar ataxia type 6 (SCA6). Because silencing of the entire CACNA1A gene would result in the loss of the essential Cav2.1 channel, the IRES controlling α1ACT expression is an excellent target for selective silencing of α1ACT as a therapeutic intervention for SCA6. We performed a high-throughput screen of FDA-approved small molecules using a dual luciferase reporter system and identified ten hits able to selectively inhibit the IRES. We identified four main candidates that showed selective suppression of α1ACT relative to α1A in HEK cells expressing a native CACNA1A vector. We previously pursued another avenue of molecular intervention through miRNA silencing. We studied three human miRNAs (miRNA-711, -3191-5p, -4786) that would potentially bind to sequences within the CACNA1A IRES region, based on an miRNA prediction program. Only miRNA-3191-5p was found to selectively inhibit the translation of α1ACT in cells. We developed a hyperacute model of SCA6 in mice by injecting a pathogenic form of the IRES-mediated α1ACT (AAV9-α1ACTQ33). Finally, we tested the effectiveness of the miRNA therapy by co-expressing either control miRNA or miRNA-3191-5p and found that miRNA-3191-5p decreased the levels of α1ACTQ33 and prevented the hyperacute disease in mice. These studies provide the proof of principle that a therapy directed at selectively preventing α1ACT expression could be used to treat SCA6.

Spinocerebellar [corrected] Ataxia Type 6: Molecular Mechanisms and Calcium Channel Genetics.

Spinocerebellar ataxia (SCA) type 6 is an autosomal dominant disease affecting cerebellar degeneration. Clinically, it is characterized by pure cerebellar dysfunction, slowly progressive unsteadiness of gait and stance, slurred speech, and abnormal eye movements with late onset. Pathological findings of SCA6 include a diffuse loss of Purkinje cells, predominantly in the cerebellar vermis. Genetically, SCA6 is caused by expansion of a trinucleotide CAG repeat in the last exon of longest isoform CACNA1A gene on chromosome 19p13.1-p13.2. Normal alleles have 4-18 repeats, while alleles causing disease contain 19-33 repeats. Due to presence of a novel internal ribosomal entry site (IRES) with the mRNA, CACNA1A encodes two structurally unrelated proteins with distinct functions within an overlapping open reading frame (ORF) of the same mRNA: (1) α1A subunit of P/Q-type voltage gated calcium channel; (2) α1ACT, a newly recognized transcription factor, with polyglutamine repeat at C-terminal end. Understanding the function of α1ACT in physiological and pathological conditions may elucidate the pathogenesis of SCA6. More importantly, the IRES, as the translational control element of α1ACT, provides a potential therapeutic target for the treatment of SCA6.

Resting-state functional connectivity and cognitive dysfunction correlations in spinocerebelellar ataxia type 6 (SCA6).

OBJECTIVE: The aim of this study is to evaluate the correlation between resting state functional MRI (RS-fMRI) activity and motor and cognitive impairment in spinocerebellar ataxia type 6 (SCA6). METHODS: Twelve patients with genetically confirmed SCA6 and 14 age matched healthy controls were imaged with RS-fMRI. Whole brain gray matter was automatically parcellated into 1000 regions of interest (ROIs). For each ROI, the first eigenvariate of voxel time courses was extracted. For each patient, Pearson correlation coefficients between each pair of ROI time courses were calculated across the 1000 ROIs. The set of average control correlation coefficients were fed as an undirected weighted adjacency matrix into the Rubinov and Sporns (2010) modularity algorithm. The intranetwork global efficiency of the thresholded adjacency sub-matrix was calculated and correlated with ataxia scores and cognitive performance. RESULTS: SCA6 patients showed mild cognitive impairments in executive function and visual-motor processing compared to control subjects. These neuropsychological impairments were correlated with decreased RS functional connectivity (FC) in the attention network. CONCLUSIONS: Mild cognitive executive functions and visual-motor coordination impairments seen in SCA6 patients correlate with decreased resting-state connectivity in the attention network, suggesting a possible metric for the study of cognitive dysfunction in cerebellar disease. Hum Brain Mapp 38:3001-3010, 2017. © 2017 Wiley Periodicals, Inc.

Progression of Dysphagia in Spinocerebellar Ataxia Type 6.

Spinocerebellar ataxia type 6 (SCA6), an autosomal dominant triplet repeat disease, predominantly affects the cerebellum with a late onset and generally good prognosis. Dysphagia is commonly associated with the outcomes of neurodegenerative diseases such as SCA6. Although the characteristics of dysphagia have been rarely reported in SCA6, our previous study indicated that dysphagia is generally milder in SCA6 than in SCA3, another inherited ataxia with multisystem involvement. However, abnormalities in the pharyngeal phase in SCA6 were indistinguishable from those in SCA3, with no explainable reason. To determine the reason, we repeatedly performed videofluoroscopic examinations (VF) in 14 patients with SCA6. The results showed that the gross progression of dysphagia was apparently slow, but four patients had progressive dysphagia at an early disease stage; dysphagia began within 10 years from the onset of ataxia and rapidly progressed. A common clinical feature of the four patients was a significantly older age at the onset of ataxia (74.0 vs. 60.3 years), associated with significantly shorter triplet repeats. This finding surprisingly indicated that patients who had shorter repeats and thereby later onset and potentially better prognoses were at risk for dysphagia-associated problems. Ischemic changes, homozygous mutation, and diabetes mellitus as well as aging might have contributed to the observed progressive dysphagia. We found that conventionally monitored somatosensory evoked potentials at least partly reflected progressive dysphagia. Despite the small study group, our findings suggest that clinicians should carefully monitor dysphagia in patients with SCA6 who are older at disease onset (>60 years).

Training balance with opto-kinetic stimuli in the home: a randomized controlled feasibility study in people with pure cerebellar disease.

OBJECTIVE: To investigate the feasibility of a randomized controlled trial of a home-based balance intervention for people with cerebellar ataxia. DESIGN: A randomized controlled trial design. SETTING: Intervention and assessment took place in the home environment. PARTICIPANTS: A total of 12 people with spinocerebellar ataxia type 6 were randomized into a therapy or control group. Both groups received identical assessments at baseline, four and eight weeks. INTERVENTIONS: Therapy group participants undertook balance exercises in front of optokinetic stimuli during weeks 4-8, while control group participants received no intervention. MAIN MEASURES: Test-retest reliability was analysed from outcome measures collected twice at baseline and four weeks later. Feasibility issues were evaluated using daily diaries and end trial exit interviews. RESULTS: The home-based training intervention with opto-kinetic stimuli was feasible for people with pure ataxia, with one drop-out. Test-retest reliability is strong (intraclass correlation coefficient >0.7) for selected outcome measures evaluating balance at impairment and activity levels. Some measures reveal trends towards improvement for those in the therapy group. Sample size estimations indicate that Bal-SARA scores could detect a clinically significant change of 0.8 points in this functional balance score if 80 people per group were analysed in future trials. CONCLUSIONS: Home-based targeted training of functional balance for people with pure cerebellar ataxia is feasible and the outcome measures employed are reliable.

Gait impairment precedes clinical symptoms in spinocerebellar ataxia type 6.

BACKGROUND: Spinocerebellar ataxia type 6 (SCA6) is an inherited ataxia with no established treatment. Gait ataxia is a prominent feature causing substantial disability. Understanding the evolution of the gait disturbance is a key step in developing treatment strategies. METHODS: We studied 9 gait variables in 24 SCA6 (6 presymptomatic; 18 symptomatic) and 24 controls and correlated gait with clinical severity (presymptomatic and symptomatic). RESULTS: Discrete gait characteristics precede symptoms in SCA6 with significantly increased variability of step width and step time, whereas a more global gait deficit was evident in symptomatic individuals. Gait characteristics discriminated between presymptomatic and symptomatic individuals and were selectively associated with disease severity. CONCLUSIONS: This is the largest study to include a detailed characterization of gait in SCA6, including presymptomatic subjects, allowing changes across the disease spectrum to be compared. Selective gait disturbance is already present in SCA6 before clinical symptoms appear and gait characteristics are also sensitive to disease progression. Early gait disturbance likely reflects primary pathology distinct from secondary changes. These findings open the opportunity for early evaluation and sensitive measures of therapeutic efficacy using instrumented gait analysis which may have broader relevance for all degenerative ataxias.

Abnormal saccade profiles in hereditary spinocerebellar degeneration reveal cerebellar contribution to visually guided saccades.

OBJECTIVE: To study how the pathophysiology underlying hereditary spinocerebellar degeneration (spinocerebellar ataxia; SCA) with pure cerebellar manifestation evolves with disease progression using saccade recordings. METHODS: We recorded visually- (VGS) and memory-guided saccade (MGS) task performance in a homogeneous population of 20 genetically proven SCA patients (12 SCA6 and eight SCA31 patients) and 19 normal controls. RESULTS: For VGS but not MGS, saccade latency and amplitude were increased and more variable than those in normal subjects, which correlated with cerebellar symptom severity assessed using the International Cooperative Ataxia Rating Scale (ICARS). Parameters with significant correlations with cerebellar symptoms showed an aggravation after disease stage progression (ICARS > 50). The saccade velocity profile exhibited shortened acceleration and prolonged deceleration, which also correlated with disease progression. The main sequence relationship between saccade amplitude and peak velocity as well as saccade inhibitory control were preserved. CONCLUSIONS: The cerebellum may be involved in initiating VGS, which was aggravated acutely during disease stage progression. Dysfunction associated with disease progression occurs mainly in the cerebellum and brainstem interaction but may also eventually involve cortical saccade processing. SIGNIFICANCE: Saccade recording can reveal cerebellar pathophysiology underlying SCA with disease progression.

The CCAS-scale in hereditary ataxias: helpful on the group level, particularly in SCA3, but limited in individual patients.

BACKGROUND: A brief bedside test has recently been introduced by Hoche et al. (Brain, 2018) to screen for the Cerebellar Cognitive Affective Syndrome (CCAS) in patients with cerebellar disease. OBJECTIVE: This multicenter study tested the ability of the CCAS-Scale to diagnose CCAS in individual patients with common forms of hereditary ataxia. METHODS: A German version of the CCAS-Scale was applied in 30 SCA3, 14 SCA6 and 20 FRDA patients, and 64 healthy participants matched for age, sex, and level of education. Based on original cut-off values, the number of failed test items was assessed, and CCAS was considered possible (one failed item), probable (two failed items) or definite (three failed items). In addition a total sum raw score was calculated. RESULTS: On a group level, failed items were significantly higher and total sum scores were significantly lower in SCA3 patients compared to matched controls. SCA6 and FRDA patients performed numerically below controls, but respective group differences failed to reach significance. The ability of the CCAS-Scale to diagnose CCAS in individual patients was limited to severe cases failing three or more items. Milder cases failing one or two items showed a great overlap with the performance of controls exhibiting a substantial number of false-positive test results. The word fluency test items differentiated best between patients and controls. CONCLUSIONS: As a group, SCA3 patients performed below the level of SCA6 and FRDA patients, possibly reflecting additional cerebral involvement. Moreover, the application of the CCAS-Scale in its present form results in a high number of false-positive test results, that is identifying controls as patients, reducing its usefulness as a screening tool for CCAS in individual patients.

Quantitative susceptibility mapping of basal ganglia iron is associated with cognitive and motor functions that distinguish spinocerebellar ataxia type 6 and type 3.

Background: In spinocerebellar ataxia type 3 (SCA3), volume loss has been reported in the basal ganglia, an iron-rich brain region, but iron content has not been examined. Recent studies have reported that patients with SCA6 have markedly decreased iron content in the cerebellar dentate, coupled with severe volume loss. Changing brain iron levels can disrupt cognitive and motor functions, yet this has not been examined in the SCAs, a disease in which iron-rich regions are affected. Methods: In the present study, we used quantitative susceptibility mapping (QSM) to measure tissue magnetic susceptibility (indicating iron concentration), structural volume, and normalized susceptibility mass (indicating iron content) in the cerebellar dentate and basal ganglia in people with SCA3 (n = 10) and SCA6 (n = 6) and healthy controls (n = 9). Data were acquired using a 7T Philips MRI scanner. Supplemental measures assessed motor, cognitive, and mood domains. Results: Putamen volume was lower in both SCA groups relative to controls, replicating prior findings. Dentate susceptibility mass and volume in SCA6 was lower than in SCA3 or controls, also replicating prior findings. The novel finding was that higher basal ganglia susceptibility mass in SCA6 correlated with lower cognitive performance and greater motor impairment, an association that was not observed in SCA3. Cerebellar dentate susceptibility mass, however, had the opposite relationship with cognition and motor function in SCA6, suggesting that, as dentate iron is depleted, it relocated to the basal ganglia, which contributed to cognitive and motor decline. By contrast, basal ganglia volume loss, rather than iron content, appeared to drive changes in motor function in SCA3. Conclusion: The associations of higher basal ganglia iron with lower motor and cognitive function in SCA6 but not in SCA3 suggest the potential for using brain iron deposition profiles beyond the cerebellar dentate to assess disease states within the cerebellar ataxias. Moreover, the role of the basal ganglia deserves greater attention as a contributor to pathologic and phenotypic changes associated with SCA.

Corrigendum: Assessment of cerebral and cerebellar white matter microstructure in spinocerebellar ataxias 1, 2, 3, and 6 using diffusion MRI.

[This corrects the article DOI: 10.3389/fneur.2020.00411.].

Assessment of Cerebral and Cerebellar White Matter Microstructure in Spinocerebellar Ataxias 1, 2, 3, and 6 Using Diffusion MRI.

Development of imaging biomarkers for rare neurodegenerative diseases such as spinocerebellar ataxia (SCA) is important to non-invasively track progression of disease pathology and monitor response to interventions. Diffusion MRI (dMRI) has been shown to identify cross-sectional degeneration of white matter (WM) microstructure and connectivity between healthy controls and patients with SCAs, using various analysis methods. In this paper, we present dMRI data in SCAs type 1, 2, 3, and 6 and matched controls, including longitudinal acquisitions at 12-24-month intervals in a subset of the cohort, with up to 5 visits. The SCA1 cohort also contained 3 premanifest patients at baseline, with 2 showing ataxia symptoms at the time of the follow-up scans. We focused on two aspects: first, multimodal evaluation of the dMRI data in a cross-sectional approach, and second, longitudinal trends in dMRI data in SCAs. Three different pipelines were used to perform cross-sectional analyses in WM: region of interest (ROI), tract-based spatial statistics (TBSS), and fixel-based analysis (FBA). We further analyzed longitudinal changes in dMRI metrics throughout the brain using ROI-based analysis. Both ROI and TBSS analyses identified higher mean (MD), axial (AD), and radial (RD) diffusivity and lower fractional anisotropy (FA) in the cerebellum for all SCAs compared to controls, as well as some cerebral alterations in SCA1, 2, and 3. FBA showed lower fiber density (FD) and fiber crossing (FC) regions similar to those identified by ROI and TBSS analyses. FBA also highlighted corticospinal tract (CST) abnormalities, which was not detected by the other two pipelines. Longitudinal ROI-based analysis showed significant increase in AD in the middle cerebellar peduncle (MCP) for patients with SCA1, suggesting that the MCP may be a good candidate region to monitor disease progression. The patient who remained symptom-free throughout the study displayed no microstructural abnormalities. On the other hand, the two patients who were at the premanifest stage at baseline, and showed ataxia symptoms in their follow-up visits, displayed AD values in the MCP that were already in the range of symptomatic patients with SCA1 at their baseline visit, demonstrating that microstructural abnormalities are detectable prior to the onset of ataxia.

Dopaminergic function in spinocerebellar ataxia type 6 patients with and without parkinsonism.

BACKGROUND: Although pure cerebellar ataxia is usually emphasized as the characteristic clinical feature of spinocerebellar ataxia type 6 (SCA6), parkinsonism has been repeatedly described in patients with genetically confirmed SCA6. METHODS: We conducted a positron emission tomography study using a combination of [18F]fluoro-L-dopa for dopamine synthesis and [11C]raclopride for dopamine D2 receptor function on six genetically confirmed SCA6 patients, both with and without parkinsonism. To the best of our knowledge, this is the first dopamine receptor imaging study of patients with SCA6. RESULTS: Most patients had somewhat decreased dopaminergic function, and this decrease was significant in the caudate nucleus. In addition, one SCA6 patient with parkinsonism had whole striatal dysfunction of both dopamine synthesis and dopamine D2 receptor function. CONCLUSIONS: The pathology of SCA6 may not be restricted to the cerebellum, but may also be distributed across various regions, including in both presynaptic and postsynaptic dopaminergic neurons to some degree. Patients with SCA6 may show apparent parkinsonism after the progression of neurodegeneration.

Quantifying iron deposition in the cerebellar subtype of multiple system atrophy and spinocerebellar ataxia type 6 by quantitative susceptibility mapping.

We used quantitative susceptibility mapping (QSM) to assess the brain iron deposition in 28 patients with the cerebellar subtype of multiple system atrophy (MSA-C), nine patients with spinocerebellar ataxia type 6 (SCA6), and 23 healthy controls. Two reviewers independently measured the mean QSM values in brain structures including the putamen, globus pallidus, caudate nucleus, red nucleus, substantia nigra, and cerebellar dentate nucleus. A receiver operating characteristics (ROC) analysis was performed to assess the diagnostic usefulness of the QSM measurements. The QSM values in the substantia nigra were significantly higher in the MSA-C group compared to the HC group (p = .007). The QSM values in the cerebellar dentate nucleus were significantly higher in MSA-C than those in the SCA6 and HC groups (p < .001), and significantly lower in the SCA6 patients compared to the HCs (p = .027). The QSM values in the cerebellar dentate nucleus were correlated with disease duration in MSA-C, but inversely correlated with disease duration in SCA6. In the ROC analysis, the QSM values in the cerebellar dentate nucleus showed excellent accuracy for differentiating MSA-C from SCA6 (area under curve [AUC], 0.925), and good accuracy for differentiating MSA-C from healthy controls (AUC 0.834). QSM can identify increased susceptibility of the substantia nigra and cerebellar dentate nucleus in MSA-C patients. These results suggest that an increase in iron accumulation in the cerebellar dentate nucleus may be secondary to the neurodegeneration associated with MSA-C.

Analysis of CACNA1A CAG repeat lengths in patients with familial ALS.

Intermediate-length ATXN2 CAG repeats are a risk factor for amyotrophic lateral sclerosis (ALS). Here we report on a female patient with heterozygous repeat expansion mutation in the CACNA1A gene presenting with a pure ALS syndrome while her father, who also carries that CACNA1A mutation, suffers from a classical spinocerebellar ataxia type 6. Hypothesizing that CACNA1A CAG repeat expansions could be a monogenic cause for familial ALS (fALS), we analyzed the CAG repeat lengths in CACNA1A in a large cohort of genetically unexplained patients with fALS. Our results indicate that CAG repeat expansion mutations in CACNA1A are not a frequent monogenic cause of fALS but could phenotypically present as ALS in rare instances.

Transcranial magnetic stimulation for diplopia in a patient with spinocerebellar ataxia type 6: a case report.

BACKGROUND: In Patients with spinocerebellar ataxia type 6 (SCA6) are often treated by transcranial magnetic stimulation (TMS) over the motor cortex and cerebellum. However, few reports have examined effective therapeutic modalities for diplopia in SCA6 patients. In the current case, we applied single-pulse TMS over the motor cortex and cerebellum to improve ataxia, and observed an unexpected improvement of diplopia. CASE PRESENTATION: A 62-year-old Japanese male with spinocerebellar ataxia type 6 (SCA6) was admitted to our hospital for exacerbation of ataxia. We administered single-pulse transcranial magnetic stimulation (TMS) over the hand motor area and the cerebellum with a circular coil to reduce ataxia. After the initiation of TMS, since diplopia unexpectedly improved, we started a quantitative assessment of diplopia by counting the number of fixation spots that he observed in his visual field. This assessment suggested that TMS had an immediate and cumulative effect on diplopia. We also delivered more localized stimulation only over the motor cortex with a Figure-8 coil, and diplopia improved immediately. Additionally, we administered a sham stimulation before the real stimulation over the motor cortex and the cerebellum. The sham stimulation improved diplopia, and greater improvement was observed with subsequent real stimulation. We also used a Hess chart examination and video recordings of binocular gross appearance to elucidate the changes in ocular movement objectively. However, these examinations did not reveal any obvious oculomotor changes. CONCLUSIONS: We applied single-pulse TMS to a SCA6 patient with diplopia, which improved without any adverse effects. TMS may have potential for the treatment of diplopia in SCA6 patients.

Cerebellar Degeneration Increases Visual Influence on Dynamic Estimates of Verticality.

Our perception of verticality relies on combining sensory information from multiple sources. Neuronal recordings in animals implicate the cerebellum in the process, yet disease of the human cerebellum was not found to affect this perception. Here we show that a perceptual disturbance of verticality is indeed present in people with a genetically determined and pure form of cerebellar degeneration (spinocerebellar ataxia type 6; SCA 6), but is only revealed under dynamic visual conditions. Participants were required to continuously orient a visually displayed bar to vertical while the bar angle was perturbed by a low-frequency random signal and a random dot pattern rotated in their visual periphery. The random dot pattern was rotated at one of two velocities (4°/s and 16°/s), traveling with either coherent or noisy motion. Perceived vertical was biased by visual rotation in healthy participants, particularly in a more elderly group, but SCA 6 participants were biased more than both groups. The bias was reduced by visual noise, but more so for SCA 6 participants than young controls. Distortion of verticality by visual rotation stems from the stimulus creating an illusion of self-rotation. We modeled this process using a maximum-likelihood sensory cue-combination model operating on noisy visual- and vestibular-rotation signals. The observed effects of visual rotation and visual noise could be compellingly explained by cerebellar degeneration, and to a lesser extent aging, causing an increase in central vestibular noise. This is consistent with the human cerebellum operating on dynamic vestibular signals to inform the process that estimates which way is up.

Bicistronic CACNA1A Gene Expression in Neurons Derived from Spinocerebellar Ataxia Type 6 Patient-Induced Pluripotent Stem Cells.

Spinocerebellar ataxia type 6 (SCA6) is an autosomal-dominant neurodegenerative disorder that is caused by a CAG trinucleotide repeat expansion in the CACNA1A gene. As one of the few bicistronic genes discovered in the human genome, CACNA1A encodes not only the α1A subunit of the P/Q type voltage-gated Ca2+ channel CaV2.1 but also the α1ACT protein, a 75 kDa transcription factor sharing the sequence of the cytoplasmic C-terminal tail of the α1A subunit. Isoforms of both proteins contain the polyglutamine (polyQ) domain that is expanded in SCA6 patients. Although certain SCA6 phenotypes appear to be specific for Purkinje neurons, other pathogenic effects of the SCA6 polyQ mutation can affect a broad spectrum of central nervous system (CNS) neuronal subtypes. We investigated the expression and function of CACNA1A gene products in human neurons derived from induced pluripotent stem cells from two SCA6 patients. Expression levels of CACNA1A encoding α1A subunit were similar between SCA6 and control neurons, and no differences were found in the subcellular distribution of CaV2.1 channel protein. The α1ACT immunoreactivity was detected in the majority of cell nuclei of SCA6 and control neurons. Although no SCA6 genotype-dependent differences in CaV2.1 channel function were observed, they were found in the expression levels of the α1ACT target gene Granulin (GRN) and in glutamate-induced cell vulnerability.

Spinocerebellar ataxia type 6 in eastern India: Some new observations.

INTRODUCTION: Spinocerebellar ataxias (SCAs) are hereditary, autosomal dominant progressive neurodegenerative disorders showing clinical and genetic heterogeneity. They are usually manifested clinically in the third to fifth decade of life although there is a wide variability in the age of onset. More than 36 different types of SCAs have been reported so far and about half of them are caused by pathological expansion of the trinucleotide, Cytosine Alanine Guanine (CAG) repeat. The global prevalence of SCA is 0.3-2 per 100,000 population, SCA3 being the commonest variety worldwide, accounting for 20-50 per cent of all cases, though SCA 2 is generally considered as the commonest one in India. However, SCA6 has not been addressed adequately from India though it is common in the eastern Asian countries like, Japan, Korea and Thailand. OBJECTIVE: The present study was undertaken to identify the prevalence of SCA6 in the city of Kolkata and the eastern part of India. MATERIALS AND METHODS: 83 consecutive patients were recruited for the study of possible SCAs and their clinical features and genotype were investigated. RESULTS: 6 of the 83 subjects turned out positive for SCA6, constituting therefore, 13.33% of the patient pool. DISCUSSION: SCA6 is prevalent in the eastern part of India, though not as frequent as the other common varieties. CONCLUSIONS: Further community based studies are required in order to understand the magnitude of SCA6 in the eastern part, as well as in other regions of India.