Genotype-specific spinal cord damage in spinocerebellar ataxias: an ENIGMA-Ataxia study.

BACKGROUND: Spinal cord damage is a feature of many spinocerebellar ataxias (SCAs), but well-powered in vivo studies are lacking and links with disease severity and progression remain unclear. Here we characterise cervical spinal cord morphometric abnormalities in SCA1, SCA2, SCA3 and SCA6 using a large multisite MRI dataset. METHODS: Upper spinal cord (vertebrae C1-C4) cross-sectional area (CSA) and eccentricity (flattening) were assessed using MRI data from nine sites within the ENIGMA-Ataxia consortium, including 364 people with ataxic SCA, 56 individuals with preataxic SCA and 394 nonataxic controls. Correlations and subgroup analyses within the SCA cohorts were undertaken based on disease duration and ataxia severity. RESULTS: Individuals in the ataxic stage of SCA1, SCA2 and SCA3, relative to non-ataxic controls, had significantly reduced CSA and increased eccentricity at all examined levels. CSA showed large effect sizes (d>2.0) and correlated with ataxia severity (r<-0.43) and disease duration (r<-0.21). Eccentricity correlated only with ataxia severity in SCA2 (r=0.28). No significant spinal cord differences were evident in SCA6. In preataxic individuals, CSA was significantly reduced in SCA2 (d=1.6) and SCA3 (d=1.7), and the SCA2 group also showed increased eccentricity (d=1.1) relative to nonataxic controls. Subgroup analyses confirmed that CSA and eccentricity are abnormal in early disease stages in SCA1, SCA2 and SCA3. CSA declined with disease progression in all, whereas eccentricity progressed only in SCA2. CONCLUSIONS: Spinal cord abnormalities are an early and progressive feature of SCA1, SCA2 and SCA3, but not SCA6, which can be captured using quantitative MRI.

The longitudinal progression of MRI changes in pre-ataxic carriers of SCA3/MJD.

BACKGROUND: The natural history of magnetic resonance imaging (MRI) in pre-ataxic stages of spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is not well known. We report cross-sectional and longitudinal data obtained at this stage. METHODS: Baseline (follow-up) observations included 32 (17) pre-ataxic carriers (SARA < 3) and 20 (12) related controls. The mutation length was used to estimate the time to onset (TimeTo) of gait ataxia. Clinical scales and MRIs were performed at baseline and after a median (IQR) of 30 (7) months. Cerebellar volumetries (ACAPULCO), deep gray-matter (T1-Multiatlas), cortical thickness (FreeSurfer), cervical spinal cord area (SCT) and white matter (DTI-Multiatlas) were assessed. Baseline differences between groups were described; variables that presented a p < 0.1 after Bonferroni correction were assessed longitudinally, using TimeTo and study time. For TimeTo strategy, corrections for age, sex and intracranial volume were done with Z-score progression. A significance level of 5% was adopted. RESULTS: SCT at C1 level distinguished pre-ataxic carriers from controls. DTI measures of the right inferior cerebellar peduncle (ICP), bilateral middle cerebellar peduncles (MCP) and bilateral medial lemniscus (ML), also distinguished pre-ataxic carriers from controls, and progressed over TimeTo, with effect sizes varying from 0.11 to 0.20, larger than those of the clinical scales. No MRI variable showed progression over study time. DISCUSSION: DTI parameters of the right ICP, left MCP and right ML were the best biomarkers for the pre-ataxic stage of SCA3/MJD. TimeTo is an interesting timescale, since it captured the longitudinal worsening of these structures.

Redox Imbalance Associates with Clinical Worsening in Spinocerebellar Ataxia Type 2.

BACKGROUND: Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease presenting with redox imbalance. However, the nature and implications of redox imbalance in SCA2 physiopathology have not been fully understood. OBJECTIVE: The objective of this study is to assess the redox imbalance and its association with disease severity in SCA2 mutation carriers. METHODS: A case-control study was conducted involving molecularly confirmed SCA2 patients, presymptomatic individuals, and healthy controls. Several antioxidant parameters were assessed, including serum thiol concentration and the superoxide dismutase, catalase, and glutathione S-transferase enzymatic activities. Also, several prooxidant parameters were evaluated, including thiobarbituric acid-reactive species and protein carbonyl concentrations. Damage, protective, and OXY scores were computed. Clinical correlates were established. RESULTS: Significant differences were found between comparison groups for redox markers, including protein carbonyl concentration (F = 3.30; p = 0.041), glutathione S-transferase activity (F = 4.88; p = 0.009), and damage (F = 3.20; p = 0.045), protection (F = 12.75; p < 0.001), and OXY (F = 7.29; p = 0.001) scores. Protein carbonyl concentration was positively correlated with CAG repeat length (r = 0.27; p = 0.022), while both protein carbonyl concentration (r = -0.27; p = 0.018) and OXY score (r = -0.25; p = 0.013) were inversely correlated to the disease duration. Increasing levels of antioxidants and decreasing levels of prooxidant parameters were associated with clinical worsening. CONCLUSIONS: There is a disruption of redox balance in SCA2 mutation carriers which depends on the disease stage. Besides, redox changes associate with markers of disease severity, suggesting a link between disruption of redox balance and SCA2 physiopathology.

Volumetric MRI Changes in Spinocerebellar Ataxia (SCA3 and SCA10) Patients.

Spinocerebellar ataxias type 3 (SCA3) and type 10 (SCA10) are the most prevalent in southern Brazil. To analyze the relationships between volumetric MRI changes and clinical and genetic findings in SCA3 and SCA10 patients. All patients in the study had a confirmed genetic diagnosis. Demographic data, ataxia severity (SARA score), and the size of the expanded alleles were evaluated. Nineteen SCA3 and 18 SCA10 patients were selected and compared with a similar number of healthy controls. Patient and control groups underwent the same MRI protocol. The standard FreeSurfer pipeline was used for the morphometric data. Our results show more affected brain structures (volume reductions) in SCA3 patients than in SCA10 patients (15 vs. 5 structures). Volume reductions in brain structures were also greater in the former. The main areas with significant volumetric reductions in the former were the cerebellum, basal ganglia, brain stem, and diencephalon, whereas in the latter, significant volume reductions were observed in the cerebellum and pallidum. While SARA scores and disease duration were more correlated with volume reduction in SCA10, in SCA3, the expansion length (CAGn) correlated positively with cerebellar WM, thalamus, brain stem, and total GM volumes. There was no correlation between expansion length (ATTCTn) and neuroimaging findings in SCA10. Neuroimaging results differed significantly between SCA3 and SCA10 patients and were compatible with the differences in clinical presentation, disease progression, and molecular findings.

Neuroradiological Findings in the Spinocerebellar Ataxias.

Background: The spinocerebellar ataxias (SCAs) are a group of autosomal dominant degenerative diseases characterized by cerebellar ataxia. Classified according to gene discovery, specific features of the SCAs - clinical, laboratorial, and neuroradiological (NR) - can facilitate establishing the diagnosis. The purpose of this study was to review the particular NR abnormalities in the main SCAs. Methods: We conducted a literature search on this topic. Results: The main NR characteristics of brain imaging (magnetic resonance imaging or computerized tomography) in SCAs were: (1) pure cerebellar atrophy; (2) cerebellar atrophy with other findings (e.g., pontine, olivopontocerebellar, spinal, cortical, or subcortical atrophy; "hot cross bun sign", and demyelinating lesions); (3) selective cerebellar atrophy; (4) no cerebellar atrophy. Discussion: The main NR abnormalities in the commonest SCAs, are not pathognomonic of any specific genotype, but can be helpful in limiting the diagnostic options. We are progressing to a better understanding of the SCAs, not only genetically, but also pathologically; NR is helpful in the challenge of diagnosing the specific genotype of SCA.

Extensive cerebellar and thalamic degeneration in spinocerebellar ataxia type 10.

INTRODUCTION: Spinocerebellar ataxia type 10 (SCA10) is a hereditary neurodegenerative disorder caused by repeat expansions in the ATXN10 gene. Patients present with cerebellar ataxia frequently accompanied by seizures. Even though loss of cerebellar Purkinje neurons has been described, its brain degeneration pattern is unknown. Our aim was to characterize the gray and white matter degeneration patterns in SCA10 patients and the association with clinical features. METHODS: We enrolled 18 patients with molecular diagnosis of SCA10 and 18 healthy individuals matched for age and sex. All participants underwent brain MRI including high-resolution anatomical and diffusion images. Whole-brain Tract-Based Spatial Statistics (TBSS) and Voxel-Based Morphometry (VBM) were performed to identify white and grey matter degeneration respectively. A second analysis in the cerebellum identified the unbiased pattern of degeneration. Motor impairment was assessed using the SARA Scale. RESULTS: TBSS analysis in the patient group revealed white matter atrophy exclusively in the cerebellum. VBM analysis showed extensive grey matter degeneration in the cerebellum, brainstem, thalamus, and putamen. Significant associations between cerebellar degeneration and SARA scores were found. Additionally, degeneration in thalamic GM and WM in the cerebellar lobule VI were significantly associated with the presence of seizures. CONCLUSION: The results show that besides cerebellum and brainstem, brain degeneration in SCA10 includes predominantly the putamen and thalamus; involvement of the latter is strongly associated with seizures. Analysis of the unbiased degeneration pattern in the cerebellum suggests lobules VIIIb, IX, and X as the primary cerebellar targets of the disease, which expands to the anterior lobe in later stages.

Structural signature of SCA3: From presymptomatic to late disease stages.

OBJECTIVE: Machado-Joseph disease (SCA3/MJD) is the most frequent spinocerebellar ataxia worldwide and characterized by brainstem, basal ganglia, and cerebellar damage. However, little is known about the natural history of the disease. This motivated us to determine the extension and progression of central nervous system involvement in SCA3/MJD using multimodal magnetic resonance imaging (MRI)-based analyses in a large cohort of patients (n = 79) and presymptomatic subjects (n = 12). METHODS: All subjects underwent MRI in a 3T device to assess gray and white matter. To evaluate the cerebral and cerebellar cortices, we used measures from FreeSurfer and SUIT. T1-multiatlas assessed deep gray matter. Diffusion tensor imaging multiatlas was used to investigate cerebral white matter (WM) and SpineSeg to assess the cervical spinal cord. RESULTS: There was widespread WM and cerebellar damage, in contrast to the restricted motor cortex involvement when all patients are compared to age- and sex-matched controls. Presymtomatic patients showed WM microstructural abnormalities mainly in the cerebellar and cerebral peduncles and volumetric reduction of midbrain, spinal cord, and substantia nigra. To assess the disease progression, we divided patients into four subgroups defined by time from ataxia onset. There was a clear pattern of evolving structural compromise, starting in infratentorial structures and progressing up to the cerebral cortex. CONCLUSION: Structural damage in SCA3/MJD begins in the spinal cord, cerebellar peduncles, as well as substantia nigra and progresses to cerebral areas in the long term. These structural differences reveal some insights into the pathogenesis of SCA3/MJD and suggest a staging scheme to map the progression of the disease. Ann Neurol 2018;84:401-408.

The progression rate of spinocerebellar ataxia type 2 changes with stage of disease.

BACKGROUND: Spinocerebellar ataxia type 2 (SCA2) affects several neurological structures, giving rise to multiple symptoms. However, only the natural history of ataxia is well known, as measured during the study duration. We aimed to describe the progression rate of ataxia, by the Scale for the Assessment and Rating of Ataxia (SARA), as well as the progression rate of the overall neurological picture, by the Neurological Examination Score for Spinocerebellar Ataxias (NESSCA), and not only during the study duration but also in a disease duration model. Comparisons between these models might allow us to explore whether progression is linear during the disease duration in SCA2; and to look for potential modifiers. RESULTS: Eighty-eight evaluations were prospectively done on 49 symptomatic subjects; on average (SD), study duration and disease duration models covered 13 (2.16) months and 14 (6.66) years of individuals' life, respectively. SARA progressed 1.75 (CI 95%: 0.92-2.57) versus 0.79 (95% CI 0.45 to 1.14) points/year in the study duration and disease duration models. NESSCA progressed 1.45 (CI 95%: 0.74-2.16) versus 0.41 (95% CI 0.24 to 0.59) points/year in the same models. In order to explain these discrepancies, the progression rates of the study duration model were plotted against disease duration. Then an acceleration was detected after 10 years of disease duration: SARA scores progressed 0.35 before and 2.45 points/year after this deadline (p = 0.013). Age at onset, mutation severity, and presence of amyotrophy, parkinsonism, dystonic manifestations and cognitive decline at baseline did not influence the rate of disease progression. CONCLUSIONS: NESSCA and SARA progression rates were not constant during disease duration in SCA2: early phases of disease were associated with slower progressions. Modelling of future clinical trials on SCA2 should take this phenomenon into account, since disease duration might impact on inclusion criteria, sample size, and study duration. Our database is available online and accessible to future studies aimed to compare the present data with other cohorts.

Spinocerebellar ataxia type 10: common haplotype and disease progression rate in Peru and Brazil.

BACKGROUND AND PURPOSE: Spinocerebellar ataxia type 10 is a neurodegenerative disorder that is due to an expanded ATTCT repeat tract in the ATXN10 gene. Our aim was to describe clinical characteristics and intragenic haplotypes of patients with spinocerebellar ataxia type 10 from Brazil and Peru. METHODS: Expanded alleles were detected by repeat-primed polymerase chain reaction. Disease progression was measured by the Scale for the Assessment and Rating of Ataxia, and the Neurological Examination Score for Spinocerebellar Ataxias when possible. Haplotypes were constructed based on polymorphic markers within and outside the gene. RESULTS: Thirteen new families were diagnosed (three from Peru). Patients from three Brazilian families diagnosed previously were also reassessed. In total, 25 individuals (16 families) were evaluated. Mean (± SD) age at onset and disease duration were 34.8 ± 10.2 and 12 ± 8 years, respectively. Common findings were ataxia, dysarthria/dysphagia, nystagmus, pyramidal signs, ophthalmoparesis and seizures. No associations were found between clinical findings and geographical origins. Twelve patients living in remote regions were examined only once. In the remaining individuals, the Scale for the Assessment and Rating of Ataxia score, and Neurological Examination Score for Spinocerebellar Ataxias worsened by 0.444 (95% CI, -0.088 to 0.800) and 0.287 (95% CI, -0.061 to 0.635) points/year, respectively. A common haplotype, 19CGGC14, was found in 11/13 of Brazilian and in 1/3 of Peruvian families. CONCLUSIONS: The progression rate was slower than in other spinocerebellar ataxias. A consistently recurrent intragenic haplotype was found, suggesting a common ancestry for most, if not all, patients.

Analysis of a fully penetrant spinocerebellar ataxia type 8 Brazilian family.

Spinocerebellar ataxia type 8 (SCA8) is a progressive neurological disorder caused by the expanded repeat CTA/CTG of two overlapping genes, ATXN8OS and ATXN8, expressed bidirectionally. Normal alleles have 15-50 repeats, and pathogenic alleles range from 71 to 1300 repeats. The disorder is relatively rare, accounting for about 2%-5% of the autosomal dominant forms of hereditary ataxia worldwide. However, the prevalence of disease-causing ATXN8OS/ATXN8 expansions is higher than the disease because of the reduced penetrance of the expanded allele. The aim of this study was to describe the first fully penetrant SCA8 family showing mixed Brazilian African and Amerindian origin. Eight members of this family were evaluated-the mother and seven offspring-through a complete neurological examination conducted at the Neurogenetics Clinic, HCFMRP-USP in Brazil. The number of CTA/CTG repeats was obtained after polymerase chain reaction (PCR) and fragment analysis. The haplotype analysis was conducted using a microsatellite marker, D13S1296, and four single nucleotide polymorphisms (SNPs), rs1831189, rs8002227, rs11841483, and rs72284461, all spanning a 70.1 Mb region on chromosome 13q21.3. The molecular analysis showed that the expansions ranged from 104 to 109 CTA/CTG repeats in the six affected individuals and were absent in two asymptomatic daughters (aged 53 and 40 years). Three SNPs cosegregate with the expanded alleles, confirming the connection between expansion and disease in this family. As the SCA8 diagnosis demands careful interpretation, we suggest the use of linkage analysis to observe segregation of the mutation, making more accurate its genotyping.

Parahippocampal gray matter alterations in Spinocerebellar Ataxia Type 2 identified by voxel based morphometry.

Spinocerebellar Ataxia Type 2 (SCA2) is a genetic disorder causing cerebellar degeneration that result in motor and cognitive alterations. Voxel-based morphometry (VBM) analyses have found neurodegenerative patterns associated to SCA2, but they show some discrepancies. Moreover, behavioral deficits related to non-cerebellar functions are scarcely discussed in those reports. In this work we use behavioral and cognitive tests and VBM to identify and confirm cognitive and gray matter alterations in SCA2 patients compared with control subjects. Also, we discuss the cerebellar and non-cerebellar functions affected by this disease. Our results confirmed gray matter reduction in the cerebellar vermis, pons, and insular, frontal, parietal and temporal cortices. However, our analysis also found unreported loss of gray matter in the parahippocampal gyrus bilaterally. Motor performance test ratings correlated with total gray and white matter reductions, but executive performance and clinical features such as CAG repetitions and disease progression did not show any correlation. This pattern of cerebellar and non-cerebellar morphological alterations associated with SCA2 has to be considered to fully understand the motor and non-motor deficits that include language production and comprehension and some social skill changes that occur in these patients.

Comprehensive study of early features in spinocerebellar ataxia 2: delineating the prodromal stage of the disease.

The prodromal phase of spinocerebellar ataxias (SCAs) has not been systematically studied. Main findings come from a homogeneous SCA type 2 (SCA2) population living in Cuba. The aim of this study was to characterize extensively the prodromal phase of SCA2 by several approaches. Thirty-seven non-ataxic SCA2 mutation carriers and its age- and sex-matched controls underwent clinical assessments, including standardized neurological exam, structured interviews and clinical scales, and looking for somatic and autonomic features, as well as a neuropsychological battery, antisaccadic recordings, and MRI scans. Main clinical somatic features of non-ataxic mutation carriers were cramps, sensory symptoms, sleep disorders, and hyperreflexia, whereas predominating autonomic symptoms were pollakiuria/nocturia, constipation, and frequent throat clearing. Cognitive impairments included early deficits of executive functions and visual memory, suggesting the involvement of cerebro-cerebellar-cerebral loops and/or reduced cholinergic basal forebrain input to the cortex. Antisaccadic task revealed impaired oculomotor inhibitory control but preserved ability for error correction. Cognitive and antisaccadic deficits were higher as carriers were closer to the estimated onset of ataxia, whereas higher Scale for the Assessment and Rating of Ataxia (SARA) scores were associated most notably to vermis atrophy. The recognition of early features of SCA2 offers novel insights into the prodromal phase and physiopathological base of the disease, allowing the assessment of its progression and the efficacy of treatments, in particular at early phases when therapeutical options should be most effective.

Progression of early features of spinocerebellar ataxia type 2 in individuals at risk: a longitudinal study.

BACKGROUND: The effects of ATXN2 expansion on the nervous system arise before the cerebellar syndrome can be diagnosed; however, progression of the underlying early clinical manifestations is unknown. We aimed to assess progression of the main clinical features in early stages of the spinocerebellar ataxia type 2 (SCA2). METHODS: We did this longitudinal study between Aug 12, 1986, and Sept 3, 2013, in carriers and non-carriers of the SCA2 mutation. We enrolled participants aged 6-60 years who were asymptomatic offspring or siblings of patients with SCA2. Participants were repeatedly assessed (two to seven times) until they presented definite cerebellar syndrome. All participants underwent standardised neurological examinations and electrophysiological (nerve conduction tests and somatosensory evoked potentials) and genetic assessments. FINDINGS: We enrolled 40 (73%) of 55 eligible participants to the baseline assessment, of whom 21 (13 women and eight men) were carriers of the SCA2 mutation, and 19 (14 women and five men) were non-carriers. Muscle cramps and sensory abnormalities were the most common clinical features in carriers (n=17 [81%] for both features) compared with controls (n=3 [16%] and n=4 [21%], respectively; χ(2)=84·58; p<0.0001, and χ(2)=72·03; p<0·0001, respectively) Both features showed a notable worsening over time and, in 17 (81%) carriers, age at onset was inversely correlated to CAG repeats (cramps: r -0·76, p=0·0004; sensory abnormalities: r -0·77, p=0·0004). Hyper-reflexia was associated with long time to ataxia onset (mean 5·71 years [SD 5·03]), whereas hyporeflexia was associated with short time (median 1·29 years [range 1-3]). Electrophysiological recordings obtained between 5 and 8 years before ataxia in 11 (52%) carriers showed reduced sensory amplitudes for median nerve (10·34 uV [SD 5·07]) and prolonged mean P40 latency (39·31 ms [2·40]) compared with age-matched and sex-matched controls (20·72 uV [9·08 uV]; p=0·0085, and 35·60 ms [2·05]; p=0·0023, respectively). INTERPRETATION: Early features of SCA2 are detectable before the onset of the cerebellar syndrome, and are associated with expanded CAG repeats and the time to onset of cerebellar syndrome. These findings could aid early diagnosis and genetic counselling, and also offer physiopathological insights that could help in the implementation of clinical trials in early stages of the disease. FUNDING: Cuban Ministry of Public Health.

Huntington disease and Huntington disease-like in a case series from Brazil.

The aim of this study was to identify the relative frequency of Huntington's disease (HD) and HD-like (HDL) disorders HDL1, HDL2, spinocerebellar ataxia type 2 (SCA2), SCA17, dentatorubral-pallidoluysian degeneration (DRPLA), benign hereditary chorea, neuroferritinopathy and chorea-acanthocytosis (CHAC), in a series of Brazilian families. Patients were recruited in seven centers if they or their relatives presented at least chorea, besides other findings. Molecular studies of HTT, ATXN2, TBP, ATN1, JPH3, FTL, NKX2-1/TITF1 and VPS13A genes were performed. A total of 104 families were ascertained from 2001 to 2012: 71 families from South, 25 from Southeast and 8 from Northeast Brazil. There were 93 HD, 4 HDL2 and 1 SCA2 families. Eleven of 104 index cases did not have a family history: 10 with HD. Clinical characteristics were similar between HD and non-HD cases. In HD, the median expanded (CAG)n (range) was 44 (40-81) units; R(2) between expanded HTT and age-at-onset (AO) was 0.55 (p=0.0001, Pearson). HDL2 was found in Rio de Janeiro (2 of 9 families) and Rio Grande do Sul states (2 of 68 families). We detected HD in 89.4%, HDL2 in 3.8% and SCA2 in 1% of 104 Brazilian families. There were no cases of HDL1, SCA17, DRPLA, neuroferritinopathy, benign hereditary chorea or CHAC. Only six families (5.8%) remained without diagnosis.

Abordagem fisioterapêutica da ataxia espinocerebelar: uma revisão sistemática / Physical therapy approach to spinocerebellar ataxia: a systematic review / El abordaje fisioterapéutico de la ataxia espinocerebelosa: una revisión sistemática

A ataxia espinocerebelar (SCA) é uma afecção hereditária que cursa com a degeneração progressiva do cerebelo e suas vias, causando alterações do equilíbrio e de outras funções. O efeito das abordagens da fisioterapia no tratamento da SCA e a qualidade metodológica desses estudos foram analisados. Foi investigado ainda se os benefícios alcançados com o tratamento são retidos. As intervenções encontradas incluem treino do equilíbrio, marcha e coordenação; fortalecimento; caneleiras nos membros durante exercícios e aplicação de estimulação magnética transcraniana. A retenção das melhoras obtidas com o tratamento foi relacionada ao grau de evolução da SCA e à continuidade da prática de exercícios. Porém, novos estudos com maior rigor científico são necessários para eleger as abordagens mais adequadas para o tratamento de portadores de SCA...

The spinocerebellar ataxia (SCA) is an inherited disorder that leads to progressive degeneration of the cerebellum and its pathways with impairments of balance and other functions. Physical therapy studies for SCA treatment and their methodological quality were examined. We also investigated if the benefits achieved with treatment can be retained. The interventions identified included balance, gait and coordination training; strengthening; weights around the limbs during exercise and transcranial magnetic stimulation. The long-term improvements were related to the degree of SCA evolution and the continuity of exercise practice. Nevertheless, further studies with higher scientific accuracy are necessary to elect the best physical therapy approaches for SCA patients...

La ataxia espinocerebelosa (SCA) es una afección hereditaria que cursa con la degeneración progresiva del cerebelo y de sus vías, lo que causa alteraciones del equilibrio y de otras funciones. El resultado de los abordajes de la fisioterapia en el tratamiento de la SCA y la cualidad metodológica de estos estudios fueron analizados. Se investigó si los beneficios alcanzados con el tratamiento fueron retenidos. Las intervenciones encontradas incluyen entrenamiento del equilibrio, marcha y coordinación; fortalecimiento; canilleras en los miembros durante ejercicios y aplicación de la estimulación magnética transcraneana. La retención de las mejorías obtenidas con el tratamiento fue relacionada al grado de evolución de la SCA y a la continuidad de la práctica de ejercicios. Aunque nuevos estudios con mayor carácter científico son necesarios para elegir los abordajes más adecuados para el tratamiento de los portadores de la SCA...

Spinocerebellar ataxia type 2: clinical presentation, molecular mechanisms, and therapeutic perspectives.

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant genetic disease characterized by cerebellar dysfunction associated with slow saccades, early hyporeflexia, severe tremor of postural or action type, peripheral neuropathy, cognitive disorders, and other multisystemic features. SCA2, one of the most common ataxias worldwide, is caused by the expansion of a CAG triplet repeat located in the N-terminal coding region of the ATXN2 gene, which results in the incorporation of a segment of polyglutamines in the mutant protein, being longer expansions associated with earlier onset and more sever disease in subsequent generations. In this review, we offer a detailed description of the clinical manifestations of SCA2 and compile the experimental evidence showing the participation of ataxin-2 in crucial cellular processes, including messenger RNA maturation and translation, and endocytosis. In addition, we discuss in the light of present data the potential molecular mechanisms underlying SCA2 pathogenesis. The mutant protein exhibits a toxic gain of function that is mainly attributed to the generation of neuronal inclusions of phosphorylated and/or proteolytic cleaved mutant ataxin-2, which might alter normal ataxin-2 function, leading to cell dysfunction and death of target cells. In the final part of this review, we discuss the perspectives of development of therapeutic strategies for SCA2. Based on previous experience with other polyglutamine disorders and considering the molecular basis of SCA2 pathogenesis, a nuclei-acid-based strategy focused on the specific silencing of the dominant disease allele that preserves the expression of the wild-type allele is highly desirable and might prevent toxic neurodegenerative sequelae.

Epigenetics DNA methylation in the core ataxin-2 gene promoter: novel physiological and pathological implications.

Pathogenic CAG (cytosine-adenine-guanine) expansions beyond certain thresholds in the ataxin-2 (ATXN2) gene cause spinocerebellar ataxia type 2 (SCA2) and were shown to contribute to Parkinson disease, amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Regulation of ATXN2 gene expression and the function of the protein product are not known. SCA2 exhibits an inverse correlation between the size of the CAG repeat and the age at disease onset. However, a wide range of age at onset are typically observed, with CAG repeat number alone explaining only partly this variability. In this study, we explored the hypothesis that ATXN2 levels could be controlled by DNA methylation and that the derangement of this control may lead to escalation of disease severity and influencing the age at onset. We found that CpG methylation in human ATXN2 gene promoter is associated with pathogenic CAG expansions in SCA2 patients. Different levels of methylation in a SCA2 pedigree without an intergenerational CAG repeat instability caused the disease anticipation in a SCA2 family. DNA methylation also influenced the disease onset in SCA2 homozygotes and SCA3 patients. In conclusion, our study points to a novel regulatory mechanism of ATXN2 expression involving an epigenetic event resulting in differential disease course in SCA2 patients.

Saccadic latency is prolonged in Spinocerebellar Ataxia type 2 and correlates with the frontal-executive dysfunctions.

Data on saccadic latency in patients with Spinocerebellar Ataxia 2 (SCA2) are sparse and contradictory. In order to determine whether saccadic latency is definitely prolonged, identify its possible determinants and evaluate it as disease biomarker we assessed the saccadic latency by electronystagmography in 110 SCA2 patients and their paired controls. Mean saccadic latencies were significantly longer in patients when compared to controls for all tested target displacements. Forty-six percent of SCA2 patients had saccadic latencies above the normal range. Reciprobit plots of saccadic latency demonstrated a skewed distribution in the direction of longer latencies for the patients compared to controls. As saccadic latency increased, the velocity and amplitude of saccades significantly decreased in SCA2 subjects but not in controls. Saccadic latency was not influenced by any demographical, clinical or molecular SCA2 variables, but it showed a significant correlation with the performance of the Stroop test, the verbal fluency test and the Wisconsin Card Sorting Test in SCA2 patients. This paper demonstrated that saccadic latency is prolonged in SCA2 patients and it significantly correlates with the performance of frontal-executive functions, thus this parameter could be a useful biomarker to evaluate the efficiency of future therapeutical options on these dysfunctions.