SCA2 Mutation Research Articles

Quantitative Evaluation of Stance as a Sensitive Biomarker of Postural Ataxia Development in Preclinical SCA1 Mutation Carriers.

The aim of this study was to determine the time between the first detection of postural control impairments and the evident manifestation of ataxia in preclinical SCA1 individuals. Twenty five preclinical SCA1 mutation carriers: 13 with estimated disease onset ≤ 6years (SCA1 +) aged 27.8 ± 8.1years; 12 with expected disease onset > 6years (SCA1-) aged 26.6 ± 3.1years and 26 age and sex matched healthy controls (HCs) underwent static posturography during 5years of observation. The movements of the centre of feet pressure (COP) during quiet standing with eyes open (EO) and closed (EC) were quantified by calculating the mean radius (R), developed surface area (A) and mean COP movement velocity (V). Ataxia was evaluated by use of the Scale for Assessment and Rating of Ataxia (SARA).SCA1 + exhibited significantly worse quality of stance with EC vs. SCA1- (p < 0.05 for V) and HCs (p < 0.001) even 5 to 6years before estimated disease onset. There were no statistically significant differences between SCA1- and HCs. A slow increase in Cohen's d effect size was observed for VEO up to the clinical manifestation of ataxia. VEO and AEC recorded in preclinical SCA1 individuals correlated slightly but statistically significantly with SARA (r = 0.47).The study confirms that static posturography detects COP sway changes in SCA1 preclinical gene carriers even 5 to 6years before estimated disease onset. The quantitative evaluation of stance in preclinical SCA is a sensitive biomarker for the monitoring of the disease progression and may be useful in clinical trials.

Incidence of different pressure patterns of spinal cerebellar ataxia and analysis of imaging and genetic diagnosis.

Neurologists have a difficult time identifying sporadic cerebellar ataxia. Multiple system atrophy of the cerebellar type (MSA-C), spontaneous late cortical cerebellar atrophy, and prolonged alcohol use are a few possible causes. In a group of people with sporadic cerebellar ataxia that was not MSA-C, an autosomal-dominant spinocerebellar ataxia (SCA) mutation was recently discovered. Chinese single-hospital cohort will be used in this study to genetic screen for SCA-related genes. One hundred forty individuals with CA were monitored over 8 years. Thirty-one individuals had familial CA, 109 patients had sporadic CA, 73 had MSA-C, and 36 had non-MSA-C sporadic CA. In 28 of the 31 non-MSA-C sporadic patients who requested the test, we carried out gene analysis, including SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17, SCA31, and dentatorubro-pallidoluysian atrophy (DRPLA). The control group consisted of family members of the patients. In 57% of the instances with spontaneous CA that were not MSA-C, gene abnormalities were discovered. The most frequent exception among individuals with sporadic CA was SCA6 (36%), followed by monsters in SCA1, 2, 3, 8, and DRPLA. In contrast, 75% of the patients with familial CA had gene abnormalities, the most frequent of which was SCA6 abnormality. The age of 69 vs 59 was higher, and the CAG repeat length was a minor age of 23 vs 25 in the former instances compared to the last one among individuals with SCA6 anomalies that were sporadic as opposed to familial cases. In sporadic CA, autosomal-dominant mutations in SCA genes, notably in SCA6, are common. Although the cause of the increased incidence of SCA6 mutations is unknown, it may be related to a greater age of onset and varied penetrance of SCA6 mutations.

Evolution of disability in spinocerebellar ataxias type 1, 2, 3, and 6.

ObjectiveThe aim was to study the evolution of disability in spinocerebellar ataxias (SCAs) type 1, 2, 3, and 6 (SCA1, 2, 3, 6).MethodsWe analyzed data of two longitudinal cohorts (RISCA, EUROSCA) which recruited ataxic and non‐ataxic SCA1, SCA2, SCA3, and SCA6 mutation carriers. To study disability, we used a five‐stage system for ataxia defined by walking ability (stages 0–3) and death (stage 4). Transitions were analyzed using a multi‐state model with proportional transition hazards. Based on the hazard estimates, transition probabilities and the expected lengths of stay in each stage were calculated. We further studied the effect of sex and CAG repeat length on progression.ResultsData of 3138 visits in 677 participants were analyzed. Median SARA scores for SCA1, SCA2, SCA3, and SCA6 ranged from 1.5 (interquartile range [IQR] = 0.0–3.5) to 3.5 (IQR = 1.4–6.1) in stage 0, 11.5 (IQR = 9.6–14.0) to 13.8 (IQR = 11.0–16.0) in stage 1, 19.0 (IQR = 17.0–21.0) to 23.8 (IQR = 19.5–27.0) in stage 2, and 28.5 (IQR = 26.0–32.5) to 34.0 (IQR = 32.6–37.1) in stage 3. Modeling allowed to calculate the subtype‐specific probability to be in a certain stage at a given age and duration of each stage. CAG repeat length was associated with faster progression in SCA1 (HR, 95% CI: 1.1, 1.1–1.2), SCA2 (1.2, 1.1–1.3), and SCA3 (1.1, 1.0–1.2). In SCA6, female sex was associated with faster progression (1.7, 1.1–2.6).InterpretationOur data are important for counselling of patients, assessment of the relevance of outcome markers, and design of clinical trials.

Распространённость спиноцеребеллярной атаксии 1 типа в Якутии: современное состояние

Республика Саха (Якутия) является одним из крупнейших очагов накопления спиноцеребеллярной атаксии 1 типа в мире. В 1997 году показатель распространённости СЦА1 среди якутов составлял 35 случаев на 100000 населения, а в настоящее время данный показатель возрос до 77,6 случаев. Значительный прирост показателей распространённости СЦА1 может быть объяснён внедрением системы учёта семейных случаев и современных молекулярно-генетических методов диагностики мутации. С другой стороны, результаты мониторинга свидетельствуют о продолжающемся накоплении мутации в якутской популяции. Кроме того, установлено расширение границ известных географических очагов накопления мутации и сделано предположение о популяционной неоднородности носителей мутации по числу CAG повторов. The Republic of Sakha (Yakutia) is one of the largest centers of accumulation of type 1 spinocerebellar ataxia in the world. In 1997, the prevalence of the SCA1 mutation among Yakuts was 35 cases per 100,000 population, and now this indicator has increased to 77.6 cases. A significant increase in the prevalence rates of SCA1 can be explained by the introduction of a family case accounting system and modern molecular genetic methods for the diagnosis of mutations. On the other hand, the monitoring results indicate the ongoing accumulation of mutations in the Yakut population. In addition, it was found that the boundaries of the known geographical centers of mutation accumulation were expanded and an assumption was made about the population heterogeneity of mutation carriers by the number of CAG repeats.

Heterogeneous nonataxic phenotypes of spinocerebellar ataxia in a Taiwanese population.

BackgroundSpinocerebellar ataxia (SCA) presents with variable clinical presentations in addition to ataxia. The aim of this study was to reappraise the diverse nonataxic clinical characteristics of the five most common SCA subtypes in the Asian population.MethodsThe clinical presentations of 90 patients with genetically confirmed SCA1, SCA2, SCA3, SCA6, or SCA17 were assessed retrospectively between November 2008 and September 2018 at a tertiary referral center in Taiwan.ResultsParkinsonism was the most common nonataxic phenotype (21.1%), with a greater prevalence than Caucasian and other Asian SCA carriers. Patients with parkinsonism feature had fewer CAG repeats in SCA2 (31.0 ± 4.5 vs. 36.9 ± 6.0, p = .03) and SCA3 (65.6 ± 7.9 vs. 70.0 ± 4.2, p = .02) compared to those with pure ataxia presentation. The average age of symptom onset was significantly higher in the parkinsonism group of SCA2 (51.5 ± 8.9 vs. 35.3 ± 12.6 years, p = .007) than those with pure ataxia. Focal or segmental dystonia was identified in 4.4% of SCA patients (n = 2 each SCA2 and SCA3). Nonmotor symptoms, including impaired cognition (6.1% of SCA2 and 8.3% of SCA3 patients) and depression (9.1% of SCA2 and 8.3% of SCA3 patients), were also common nonataxic features in our SCA patients.ConclusionsParkinsonism, dystonia, and cognitive‐psychiatric symptoms are common features in patients with SCA mutations in our population. Our study identifies a different clinical spectrum of SCA1, SCA2, SCA3, SCA6, and SCA17 compared to Caucasians.

Abnormal eyeblink conditioning is an early marker of cerebellar dysfunction in preclinical SCA3 mutation carriers

BackgroundSpinocerebellar ataxias (SCAs) are a group of autosomal dominantly inherited degenerative diseases. As the pathological process probably commences years before the first appearance of clinical symptoms, preclinical carriers of a SCA mutation offer the opportunity to study the earliest stages of cerebellar dysfunction and degeneration. Eyeblink classical conditioning (EBCC) is a motor learning paradigm, crucially dependent on the integrity of the olivocerebellar circuit, and has been shown to be able to detect subtle alterations of cerebellar function, which might already be present in preclinical carriers.MethodsIn order to acquire conditioned responses, we performed EBCC, delay paradigm, in 18 preclinical carriers of a SCA3 mutation and 16 healthy, age-matched controls by presenting repeated pairings of an auditory tone with a supraorbital nerve stimulus with a delay interval of 400 ms.ResultsPreclinical carriers acquired significantly less conditioned eyeblink responses than controls and learning rates were significantly reduced. This motor learning defect was, however, not associated with the predicted time to onset.ConclusionsEBCC is impaired in preclinical carriers of a SCA3 mutation, as a result of impaired motor learning capacities of the cerebellum and is thus suggestive of cerebellar dysfunction. EBCC can be used to detect but probably not monitor preclinical cerebellar dysfunction in genetic ataxias, such as SCA3.

A study of Huntington disease-like syndromes in black South African patients reveals a single SCA2 mutation and a unique distribution of normal alleles across five repeat loci

Huntington disease (HD) is a progressive neurodegenerative disease, characterised by a triad of movement disorder, emotional and behavioural disturbances and cognitive impairment. The underlying cause is an expanded CAG repeat in the huntingtin gene. For a small proportion of patients presenting with HD-like symptoms, the mutation in this gene is not identified and they are said to have a HD “phenocopy”.South Africa has the highest number of recorded cases of an African-specific phenocopy, Huntington disease-like 2 (HDL2), caused by a repeat expansion in the junctophilin-3 gene. However, a significant proportion of black patients with clinical symptoms suggestive of HD still test negative for HD and HDL2. This study thus aimed to investigate five other loci associated with HD phenocopy syndromes - ATN1, ATXN2, ATXN7, TBP and C9orf72.In a sample of patients in whom HD and HDL2 had been excluded, a single expansion was identified in the ATXN2 gene, confirming a diagnosis of Spinocerebellar ataxia 2. The results indicate that common repeat expansion disorders do not contribute significantly to the HD-like phenotype in black South African patients. Importantly, allele sizing reveals unique distributions of normal repeat lengths across the associated loci in the African population studied.

Brain atrophy measures in preclinical and manifest spinocerebellar ataxia type 2.

ObjectiveSpinocerebellar ataxia type 2 (SCA2) is an autosomal dominantly inherited neurodegenerative disease mainly affecting the cerebellum and brainstem. In this Cuban‐German research collaboration, we aimed to characterize atrophy patterns and associations with clinical measures in preclinical and manifest SCA2.MethodsIn this study, 16 nonmanifest SCA2 mutation carriers, 26 manifest patients with SCA2, and 18 healthy control subjects underwent magnetic resonance imaging, as well as genetic and clinical characterization including assessment of ataxia (Scale for the Assessment and Rating of Ataxia) and saccade velocity in Cuba were enrolled. Semiautomated quantitative volumetry of the cerebellum and brainstem, subdivided into the medulla oblongata, the pontine brainstem, and mesencephalon was performed. Additionally, the anteroposterior diameter of the pontine brainstem was measured.ResultsAnalysis of volumetric data revealed degeneration of the cerebellum and brainstem, in particular of pontine volumes and the anteroposterior diameter of the pons, in both manifest SCA2 patients and individuals at risk for SCA2 compared to controls. Comparing patients with nonataxic preclinical SCA2 mutation carriers, we found more pronounced reductions of the pontine brainstem and cerebellum in manifest SCA2. Volumetric data further showed associations with CAG repeat length and predicted age of onset in preclinical SCA2 individuals, and by trend with ataxia signs in patients. Although saccade velocity was associated with reduction in the pontine brainstem in preclinical and manifest SCA2, reduced ability to suppress interfering stimuli measured by the Stroop task was related to cerebellar volume loss in patients.InterpretationPreclinical SCA2 mutation carriers exhibit brain abnormalities, which could be targeted as surrogate parameters for disease progression and in future preventive trials.

Genetic Screening for Spinocerebellar Ataxia Genes in a Japanese Single-Hospital Cohort.

Objective Diagnosis of sporadic cerebellar ataxia is a challenge for neurologists. A wide range of potential causes exist, including chronic alcohol use, multiple system atrophy of cerebellar type (MSA-C), and sporadic late cortical cerebellar atrophy. Recently, an autosomal-dominant spinocerebellar ataxia (SCA) mutation was identified in a cohort of patients with non-MSA-C sporadic cerebellar ataxia. The aim of this study is to genetically screen genes involved in SCA in a Japanese single-hospital cohort. Methods Over an 8-year period, 140 patients with cerebellar ataxia were observed. There were 109 patients with sporadic cerebellar ataxia (no family history for at least four generations, 73 patients with MSA-C, and 36 patients with non-MSA-C sporadic cerebellar ataxia) and 31 patients with familial cerebellar ataxia. We performed gene analysis comprising SCA1, 2, 3, 6, 7, 8, 12, 17, 31, and dentatorubro-pallidoluysian atrophy (DRPLA) in 28 of 31 non-MSA-C sporadic patients who requested the test. Familial patients served as a control.Results Gene abnormalities were found in 57% of non-MSA-C sporadic cerebellar ataxia cases. Among patients with sporadic cerebellar ataxia, abnormalities in SCA6 were the most common (36%), followed by abnormalities in SCA1 (7.1%), SCA2 (3.6%), SCA3 (3.6%), SCA8 (3.6%), and DRPLA (3.6%). In contrast, gene abnormalities were found in 75% of familial cerebellar ataxia cases, with abnormalities in SCA6 being the most common (29%). For sporadic versus familial cases for those with SCA6 abnormalities, the age of onset was older (69 years vs. 59 years, respectively), and CAG repeat length was shorter (23 vs. 25, respectively) in the former than in the latter (not statistically significant).Conclusion Autosomal-dominant mutations in SCA genes, particularly in SCA6, are not rare in sporadic cerebellar ataxia. The reason for the frequency of mutations in SCA6 remains unclear; however, the reason may reflect a higher age at onset and variable penetrance of SCA6 mutations.

Comment: CAG repeats in idiopathic Parkinson disease-To screen or not to screen.

In this large study within the Genetic Epidemiology of Parkinson's Disease Consortium, Wang et al.1 examined the relationship between idiopathic Parkinson disease (PD) and CAG repeat expansions in ataxia genes. They examined, on a larger scale, an issue that has been examined by several authors. The rationale for the study is that parkinsonian phenotypes, and even l-dopa–responsive PD, occur in carriers of SCA mutations, mainly in Asians, and that intermediate poly-Q expansions are predisposing factors for dominant PD.2,3 The authors studied 12,346 patients with PD from Caucasian and Asian populations and 8,164 controls, seeking CAG expansions in SCA2, SCA3, SCA6, and SCA17 genes. The study is “negative” since they did not identify causative mutations or increased risk of PD attributable to long normal repeat alleles.

Bolivian kindred with combined spinocerebellar ataxia types 2 and 10.

Spinocerebellar ataxias (SCA) are a group of rare hereditary neurodegenerative disorders. Rare cases of two SCA mutations in the same individual have been reported in the literature, however, family descriptions are lacking. To characterize a family with combined SCA2 and SCA10 mutations. Analysis of the clinical features and genetic findings of a Bolivian family expressing both SCA2 and SCA10 mutations. The index case and his mother had both SCA2 and SCA10 mutations with a combined clinical phenotype of both disorders, including slow saccades (SCA2) and seizures (SCA10). The uncle of the index case had only an SCA10 mutation. Although the presence of two SCA mutations in the same individuals may be coincidental, the low probability of having both mutations suggests that these mutations might be particularly prevalent in Bolivian population. This is the first description of a family with two SCA mutations with affected subjects having a combined SCA2 and SCA10 phenotype.

Prediction of the age at onset in spinocerebellar ataxia type 1, 2, 3 and 6

BackgroundThe most common spinocerebellar ataxias (SCA)—SCA1, SCA2, SCA3, and SCA6—are caused by (CAG)n repeat expansion. While the number of repeats of the coding (CAG)n expansions is correlated with the age...

Lessons from preclinical disease

Identifying individuals at risk of developing neurodegenerative conditions prior to clinical manifestation of disease, has become a popular subject for recent neurological research. It is well established that by the time patients present with these disorders, a significant degree of irreversible neuronal loss has already occurred. Understanding the evolution of preclinical disease may, therefore, highlight methods by which the pathological processes can be slowed or curtailed; either through modifying environmental factors or by the use of novel disease modifying agents. Encouragingly this approach already has a number of successful precedents and is widely employed in the prevention of heart disease and indeed in many other branches of medicine. An important first step in this process will be the ability to screen individuals at risk for predictive biomarkers of disease, but identifying the population at risk for sporadic neurodegenerative conditions has proved problematic. However, the study of fully penetrant autosomal dominant disorders, in which a reliable genetic test is currently available, offers an opportunity to identify specific predefined cohorts. These very specific cohorts can then be assessed in detail, if necessary over prolonged time periods, for a large range of potential clinical, biological and radiological biomarkers. Although the numbers of individuals at risk of these relatively rare genetic disorders are commonly limited, the hope is that studies of this important group of individuals may offer important insights into more common sporadic conditions. In this month’s journal club, we examine three articles; each one addressing these issues in seperate neurodegenerative disorders, all of which are autosomal dominant and fully penetrant conditions and in which the age at onset can be predicted with varying degrees of accuracy: Huntington’s disease (HD), autosomal dominant cerebellar ataxias (SCA) and presenilin 1 autosomal dominant Alzheimer’s disease. In the first paper Tabrizi et al., examine premanifest carriers of HD and early HD patients in a 36-month longitudinal study. The second paper by Jacobi et al., examines carriers of the SCA1, SCA2, SCA3 and SCA6 mutations prior to disease onset. The final paper describes a cross sectional analysis of a Colombian cohort of Presenilin 1 mutation carriers. All three studies have employed different methodologies in search of a common goal; to identify informative clinical, biological or radiological biomarkers for these diseases.

Biological and clinical characteristics of individuals at risk for spinocerebellar ataxia types 1, 2, 3, and 6 in the longitudinal RISCA study: analysis of baseline data

Spinocerebellar ataxias (SCAs) are autosomal, dominantly inherited, fully penetrant neurodegenerative diseases. Our aim was to study the preclinical stage of the most common SCAs: SCA1, SCA2, SCA3, and SCA6. Between Sept 13, 2008, and Dec 1, 2011, offspring or siblings of patients with SCA1, SCA2, SCA3, or SCA6 were enrolled into a prospective, longitudinal observational study at 14 European centres. To be eligible for inclusion in our study, individuals had to have no ataxia and be aged 18-50 years if directly related to individuals with SCA1, SCA2, or SCA3, or 35-70 years if directly related to individuals with SCA6. We did anonymous genetic testing to identify mutation carriers. We assessed participants with clinical scales, questionnaires, and performance-based coordination tests. In eight of the 14 centres, participants underwent MRI. We analysed relations between outcome variables and time from onset (defined as the difference between present age and estimated age at ataxia onset). This study is registered with ClinicalTrials.gov, number NCT01037777. 276 participants met inclusion criteria and agreed to participate, of whom 12 (4%) were excluded from final analysis because DNA samples were missing or genotyping failed. Estimated time from onset was -9 years (IQR -13 to -6) in 50 carriers of the SCA1 mutation, -12 years (-15 to -9) in 31 SCA2 mutation carriers, -8 years (-11 to -6) in 26 SCA3 mutation carriers, and -18 years (-22 to -16) in 16 SCA6 mutation carriers. Compared with non-carriers of each mutation, SCA1 mutation carriers had higher median scores on the scale for the assessment and rating of ataxia (SARA; 0·5 [IQR 0-1·0] vs 0 [0-0]; p=0·0052), as did SCA2 mutation carriers (0·5 [0-2·0] vs 0 [0-0·5]; p=0·0037). SCA2 mutation carriers had lower SCA functional index scores than did non-carriers (-0·43 [-0·91 to -0·07] vs 0·09 [-0·30 to 0·56]; p=0·0007). SCA2 mutation carriers had worse composite cerebellar functional scores than did their non-carrier counterparts (0·915 [0·861-0·959] vs 0·849 [0·764-0·886]; p=0·0039). All other differences between carriers and non-carriers were non-significant. In SCA1 and SCA2 mutation carriers, SARA scores were increased in participants who were closer to the estimated age at onset (SCA1: r=0·36, p=0·0112; SCA2: r=0·50, p=0·0038). 83 individuals (30%) underwent MRI. Voxel-based morphometry showed grey-matter loss in the brainstem and cerebellum in SCA1 and SCA2 mutation carriers, and normalised brainstem volume was lower in SCA2 mutation carriers (median 0·015, range 0·012-0·016) than in non-carriers (0·019, 0·017-0·021; p=0·0107). Preclinical SCA1 and SCA2 mutation carriers seem to have mild coordination deficits and abnormalities in the brain that are more common in carriers who are closer to the estimated onset of ataxia. Individuals in this early disease stage could be targeted in future preventive trials. ERA-Net E-Rare and Polish Ministry of Science and Higher Education.

Investigation of SCA10 in the Cypriot population: Further exclusion of SCA dynamic repeat mutations

Autosomal dominant cerebellar ataxias (ADCAs) encompass a heterogeneous group of rare diseases that affect the cerebellum and its connections. The most common forms have been associated with dynamic mutations while some rarer forms with conventional mutations. Studies in different populations revealed differences in their relative frequencies both within and between the studied populations, showing that the frequencies are depended on ethnic and geographical factors. Previous investigation of triplet repeat expansion SCAs (SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17 and DRPLA) in the Cypriot population, revealed no pathogenic expansion in the Cypriot SCA patients. We hereby present our recent investigation of the SCA10 pentanucleotide repeat expansion. Forty-two ascertained Cypriot sporadic ataxia patients, the index case from 1 ADCA and 14 ARCA families and a cohort of normal population individuals were included in the study. All our patients have normal range ATXN10 gene ATTCT repeat numbers (10–19). In the normal population group, repeat lengths ranged from 11 to 20 with the 14 repeats allele being the most frequent. Therefore, all currently established dynamic repeat SCA mutations are absent from the Cypriot population, indicating distinct genetic causes.

Preclinical and clinical neural network changes in SCA2 parkinsonism

BackgroundThe pathophysiological changes before the presentation of clinical symptoms in parkinsonism are unclear. In this study, we investigated neural network modulations in persons in the preclinical stage of familial parkinsonism, and how the network interactions change at the clinical stage. MethodsWe performed functional MRI in a family with SCA2 mutation, including 9 asymptomatic carriers and 10 mutation carriers with parkinsonian symptoms. Functional connectivity from the posterior putamen bilaterally and rostral supplementary motor area was used to explore network interactions in the subjects. ResultsBoth the asymptomatic carriers and patients had decreased connectivity within the basal ganglia-thalamus-cortical motor loop compared to controls. The asymptomatic carriers showed extensively increased connectivity compared to controls, including the cortico-cortical motor, cortico-cerebellar, cortico-brainstem, and part of the basal ganglia-thalamus-cortical motor circuits. In contrast, the connectivity of most of these networks was decreased in the patients. These abnormalities were relatively normalized after levodopa administration. ConclusionsIn the preclinical stage of SCA2 parkinsonism, the connectivity of a part of the basal ganglia motor loop is weakened as a consequence of dopaminergic deficits; meanwhile, the connectivity of other large-scale brain networks is strengthened presumably to compensate for the dysfunction of the basal ganglia to maintain brain function in the early stage of dopaminergic deficits. The simultaneous effects of progressive disruption of basal ganglia motor circuits and failure of compensatory mechanisms as dopaminergic dysfunction progresses may contribute to the onset of clinical symptoms.

Sample Size Estimation for Future Therapeutic Trials in SCAs (S12.004)

Objective: To evaluate disease progression and determine validity of clinical tools for therapeutic trials in a cohort of dominant ataxias. Background Autosomal dominant cerebellar ataxias (SCAs) are genetically heterogeneous with more than 30 loci involved. Cerebellar degeneration is accompanied by changes in the brainstem, basal ganglia, cerebral cortex, spinal cord and peripheral nervous system. Design/Methods: 162 patients with SCAs, including SCAs with polyglutamine expansions (25 SCA1, 35 SCA2, 58 SCA3, 5 SCA6, 10 SCA7) and other SCAs (1 SCA5, 1 SCA14, 2 SCA21,1 SCA25, 2 SCA28, 22 unknown genotypes) were followed prospectively for 3 years in the national French Referral Network including 7 centers. The outcome measures were the quantitative composite cerebellar functional score with writing (CCFSw) and the scale for the assessment and rating of ataxia (SARA). Results: Disease worsened in patients with SCA1, 2, 3 mutations and remained stable in patients with SCA6, SCA7 or other SCA mutations with both the CCFSw and the SARA. CCFSw progression was faster in SCA3 patients with Parkinsonism and/or dystonia at baseline (p=.003) while SARA progression in SCA2 patients depend of the gender, the age at onset and at inclusion, the number of repeats of the normal SCA2 allele, and the posterior column dysfunction. A two-arm trial with SARA as the outcome measure would require 57 SCA2, 70 SCA1 and 75 SCA3 patients per group to detect a 50% reduction in disease progression (power 80%, alpha 0.05). Conclusions: Disease progressed faster in SCAs with polyglutamine expansions in SCA1, 2 and 3 than the other groups. Both outcome measures are suitable for therapeutic trials; SARA requires fewer patients to attain the same power, but CCFSw needs less stratification. We demonstrate that the choice of clinical outcome measure is critical for reliable evaluation of progression in neurodegenerative diseases. Disclosure: Dr. Tezenas Du Montcel has nothing to disclose. Dr. Charles Ignatiew has nothing to disclose. Dr. Goizet has received research support from Genzyme Corporation. Dr. Marelli has nothing to disclose. Dr. Anheim has nothing to disclose. Dr. Guyant-Marchal has nothing to disclose. Dr. Le Bayon has nothing to disclose. Dr. Vandenberghe has nothing to disclose. Dr. Tchikviladze has nothing to disclose. Dr. Devos has received personal compensation for activities with Novartis and Aguettant. Dr. Le Ber has nothing to disclose. Dr. N9Guyen has nothing to disclose. Dr. Cazeneuve has nothing to disclose. Dr. Tallaksen has nothing to disclose. Dr. Brice has nothing to disclose. Dr. Durr has nothing to disclose.

Factors Influencing Disease Progression in Autosomal Dominant Cerebellar Ataxia and Spastic Paraplegia

To evaluate disease progression and determine validity of clinical tools for therapeutic trials. Prospective cohort study (36 months). Referral center. One hundred sixty-two patients with autosomal dominant cerebellar ataxia and 64 with hereditary spastic paraplegia. The quantitative Composite Cerebellar Functional Severity Score with the writing test (CCFSw) and Scale for the Assessment and Rating of Ataxia (SARA) score. Disease worsened in patients with SCA1, SCA2, and SCA3 mutations (mean [SE] increase in CCFSw, +0.014 [0.005] to +0.025 [0.004] per year), improved in patients with SPG4 mutations (mean [SE] increase in CCFSw, -0.012 [0.003] per year; P = .02), and remained stable in patients with SCA6, SCA7, or other SCA mutations (mean [SE] increase in CCFSw, -0.015 [0.011] to +0.009 [0.013] per year) or hereditary spastic paraplegia with other SPG mutations (mean [SE] increase in CCFSw, -0.005 [0.005] per year). Progression was faster in patients with SCA2 mutations and normal alleles with 22 or fewer repeats (P = .02) and in patients with SCA3 mutations with parkinsonism and/or dystonia at baseline (P = .003). Whereas CCFSw distinguished between patients with ataxia and spasticity, SARA scores increased in both groups. A 2-arm trial with SARA score as the outcome measure would require 57 patients with SCA2 mutations, 70 with SCA1 mutations, and 75 with SCA3 mutations per group to detect a 50% reduction in disease progression (power, 80%; α = .05). Disease progressed faster in SCA s with polyglutamine expansions in SCA1, 2, and 3 than the other groups. Both outcome measures are suitable for therapeutic trials; SARA requires fewer patients to attain the same power, but CCFSw needs less stratification. We demonstrate that the choice of clinical outcome measure is critical for reliable evaluation of progression in neurodegenerative diseases.

Spinocerebellar Ataxia: A Rational Approach to Aetiological Diagnosis

The objective of this study was to determine the main causal diagnosis for spinocerebellar ataxia (SCA) in a geographically defined population of ataxia patients and to suggest a rational basis for choosing appropriate clinical and paraclinical assessments. Given the many aetiologies responsible for SCA, the diagnosis requires the performance of a wide range of paraclinical analyses. At present, there is no consensus on the diagnostic value of these examinations. Furthermore, most of the currently available data gathered by reference centres suffer from selection bias. We performed a prospective study of consecutive cerebellar ataxia patients referred by their family doctors to a university hospital in northern France. Multiple system atrophy and obvious secondary causes (e.g. alcoholism) were excluded by our screening process. The patient's family members were also assessed. Of the 204 patients examined, 47% presented autosomal dominant ataxia and 33% presented sporadic ataxia. Autosomal recessive ataxia was rare (8%) and age at onset was significantly earlier for this condition than for other forms. An aetiological diagnosis was established in 44% of patients, a plausible hypothesis could be formed in 13% of cases, and no diagnosis was made in the remaining 44%. Established diagnoses included SCA1, SCA2, SCA3 and SCA6 mutations, Friedreich's ataxia, and one rare case of ataxia associated with anti-glutamic acid decarboxylase antibodies. Two families presented ataxia associated with autosomal, dominant, optic atrophy with an OPA1 mutation. Mitochondrial diseases were suspected in about 10% of patients. In SCA, reliable determination of the transmission mode always requires the assessment of family members. Mitochondrial disease may be an emerging cause of ataxia. Metabolite assays appeared to be of little value when systematically performed and so should be prescribed only by metabolic disorder specialists in selected cases of sporadic and recessive ataxia. Ophthalmological examination was the most helpful physiological assessment.

Genotyping and prenatal diagnosis of a large spinocerebellar ataxia pedigree in northeastern China

The spinocerebellar ataxias (SCAs) are a group of serious debilitating disorders characterized by gait and limb ataxia, disturbances of speech and oculomotor control, and other variable clinical features, usually with onset in adulthood (Harding 1983). Since the identification of the first gene is responsible for spinocerebellar ataxia type 1 (SCA1) (Orr et al. 1993), an increasing number of genes and chromosomal loci have been characterized, which demonstrates the wide genetic heterogeneity in these hereditary disorders (Schols et al. 2004; Taroni and Di Donato 2004; Duenas et al. 2006). To date, at least 28 different SCA subtypes have been described (SCA 1–8, 10–29) (Duenas et al. 2006; Dudding et al. 2004). SCA3/MJD mutations have a prevalence of 20–25% for all the SCA, with regional variations worldwide, (Silveira et al. 2002; Van de Warrenburg et al. 2002). The mutation incidence of SCA1, SCA2, SCA6 and SCA7, on average, displayed a prevalence of approximately 2–5% (Schols et al. 2004). However, the SCA1 mutations are most frequently identified in Africa (Bryer et al. 2003), while SCA2 mutations account for most of the cases in India, Cuba and Italy (Saleem et al. 2000; Brusco et al. 2004). The remaining SCA types are considered as rare mutations, identified in singular families or specific populations. In 2009, we ascertained a large SCA pedigree from northeastern China with a slowly progressive, isolated form of ataxia. In this paper, we describe our initial experience with genotyping, carrier testing, and prenatal diagnosis.