Degenerative Ataxia Research Articles

Degenerative ataxias, from genes to therapies: The 2015 Cotzias Lecture.

To review progress in spinocerebellar ataxias (SCAs) and novel approaches to treatment. Autosomal dominant ataxias are now referred to as SCAs, with polyglutamine expansion mutations constituting the most common cause of SCAs. Phenotypic variation in patients with SCA is remarkable even in patients with identical mutations. In patients with SCA2, cerebellar ataxia is typically associated with slowed saccadic eye movements. In addition to classic cerebellar and brainstem signs, however, SCA2 can also present as a parkinsonian syndrome or as amyotrophic lateral sclerosis. After identifying the SCA2 gene (gene symbol ATXN2) in 1996, we generated several mouse models that recapitulated salient features of the human disease. In these models, behavioral and physiologic changes preceded cell death. Modified antisense oligonucleotides (ASOs) provide a unique tool to target mRNA transcripts in vivo with extended stability of ASOs and better activation of RNAse H. We generated methoxyethyl group-gapmer ASOs that reduced ATXN2 expression >80% in vitro and then progressed the lead ASO to in vivo testing in an SCA2 mouse model. Compared to intraventricular injection of saline, treatment with ASO resulted in significant knockdown of endogenous mouse and human transgenic ATXN2. In addition, progression of the motor phenotype was slowed and Purkinje cell firing in the acute cerebellar slice normalized. ASO-based therapies are underway in humans providing hope that this approach will also be applicable to patients with cerebellar degenerations.

Cellular and circuit mechanisms underlying spinocerebellar ataxias.

Degenerative ataxias are a common form of neurodegenerative disease that affect about 20 individuals per 100,000. The autosomal dominant spinocerebellar ataxias (SCAs) are caused by a variety of protein coding mutations (single nucleotide changes, deletions and expansions) in single genes. Affected genes encode plasma membrane and intracellular ion channels, membrane receptors, protein kinases, protein phosphatases and proteins of unknown function. Although SCA-linked genes are quite diverse they share two key features: first, they are highly, although not exclusively, expressed in cerebellar Purkinje neurons (PNs), and second, when mutated they lead ultimately to the degeneration of PNs. In this review we summarize ataxia-related changes in PN neurophysiology that have been observed in various mouse knockout lines and in transgenic models of human SCA. We also highlight emerging evidence that altered metabotropic glutamate receptor signalling and disrupted calcium homeostasis in PNs form a common, early pathophysiological mechanism in SCAs. Together these findings indicate that aberrant calcium signalling and profound changes in PN neurophysiology precede PN cell loss and are likely to lead to cerebellar circuit dysfunction that explains behavioural signs of ataxia characteristic of the disease.

The effect of a task-specific locomotor training strategy on gait stability in patients with cerebellar disease: a feasibility study

Purpose: There is a lack of evidence-based recommendations for the physiotherapeutic intervention specifically for locomotor training in patients with cerebellar ataxia. The purpose of this study is to determine the feasibility and effect of a more specific rehabilitation strategy that aims to improve gait quality in patients with cerebellar ataxia.Methods: Nineteen patients with degenerative cerebellar ataxia were recruited to participate in the study. The patients participated in a 12-week locomotor training program, two times per week for 1.5 h per session (a total of 24 training sessions). The treatment approach emphasized the relearning of proper gait movement strategies through intensive practice that enhances the patient's perception and control of the essential components of normal gait movement.Results: A quantitative analysis of step-by-step gait performance indicated that postural sway during locomotion was reduced, and the gait movement pattern became more consistent after the 12-week locomotor training program. These improvements in gait stability persisted over the 3-month period following intervention.Conclusion: This study provides preliminary evidence that learning-based rehabilitation strategies targeting disease-specific locomotion symptoms may be helpful for reducing ataxic gait and improving motor control during walking in patients with cerebellar dysfunction.Implications for rehabilitationPhysiotherapeutic interventions that aim to promote gait stability in cerebellar patients need to create a specific learning context that improve disease-related gait deficits.It is desirable to use explicit instructions to facilitate the conscious awareness and control of body center and posture.As patients reacquire the fundamental gait ability, providing training experience with various locomotor tasks that facilitate the transfer of learning may be helpful to increase generalizability of locomotor intervention.

Ambulatory Activity Components Deteriorate Differently across Neurodegenerative Diseases: A Cross-Sectional Sensor-Based Study

Background and Purpose: Reduced ambulatory activity is a major burden in neurodegenerative disease (NDD), leading to severe restrictions in social participation and further deterioration of motor capacities. However, objective evidence on walking behavior patterns and components underlying this impairment and its decline with disease progression is scarce for many NDDs. We aimed to unravel the detailed metrics underlying the reduced ambulatory activity in selected NDDs, and their relation to disease duration. We hypothesized that progressively reduced ambulatory activity is a feature shared across different NDDs, characterized by changes in both common and distinct components. Methods: Sixty-five subjects with NDD (n = 34 degenerative ataxia; n = 15 progressive supranuclear palsy, and n = 16 Parkinson's disease) and 38 healthy older adults (total n = 103) wore a three-axial accelerometer (activPAL3™) for 7 consecutive days. Detailed metrics of ambulatory activity were calculated. Results: The average daily walking duration was significantly decreased in all three NDDs, yet characterized by a differential pattern of changes in number and length of walking bouts and sit-to-stand transfers. Decline in walking duration progressed with increased disease duration in all three NDDs, yet at a differing rate. This decline was associated with progressive reductions in walking bout length and walking behavior pattern diversity in all three NDDs. Conclusions: These findings provide objective evidence that reduced ambulatory activity is a shared feature across different NDDs. Moreover, they reveal that several underlying walking behavior components change with increasing disease duration, yet at a differing rate in different NDDs. This indicates that metric analysis of ambulatory activity might provide ecologically relevant and disease-specific progression and outcome markers in several NDDs.

Local Stability of the Trunk in Patients with Degenerative Cerebellar Ataxia During Walking.

This study aims to evaluate trunk local stability in a group of patients with degenerative primary cerebellar ataxia and to correlate it with spatio-temporal parameters, clinical variables, and history of falls. Sixteen patients affected by degenerative cerebellar ataxia and 16 gender- and age-matched healthy adults were studied by means of an inertial sensor to measure trunk kinematics and spatio-temporal parameters during over-ground walking. Trunk local dynamic stability was quantified by the maximum Lyapunov exponent with short data series of the acceleration data. According to this index, low values indicate more stable trunk dynamics, while high values denote less stable trunk dynamics. Disease severity was assessed by means of International Cooperative Ataxia Rating Scale (ICARS) according to which higher values correspond to more severe disease, while lower values correspond to less severe disease.Patients displayed a higher short-term maximum Lyapunov exponent than controls in all three spatial planes, which was correlated with the age, onset of the disease, and history of falls. Furthermore, the maximum Lyapunov exponent was negatively correlated with ICARS balance, ICARS posture, and ICARS total scores.These findings indicate that trunk local stability during gait is lower in patients with cerebellar degenerative ataxia than that in healthy controls and that this may increase the risk of falls. Local dynamic stability of the trunk seems to be an important aspect in patients with ataxia and could be a useful tool in the evaluation of rehabilitative and pharmacological treatment outcomes.

Chapter 23 - Cerebellar disorders: clinical/radiologic findings and modern imaging tools

Cerebellar disorders, also called cerebellar ataxias, comprise a large group of sporadic and genetic diseases. Their core clinical features include impaired control of coordination and gait, as well as cognitive/behavioral deficits usually not detectable by a standard neurologic examination and therefore often overlooked. Two forms of cognitive/behavioral syndromes are now well identified: (1) the cerebellar cognitive affective syndrome, which combines an impairment of executive functions, including planning and working memory, deficits in visuospatial skills, linguistic deficiencies such as agrammatism, and inappropriate behavior; and (2) the posterior fossa syndrome, a very acute form of cerebellar cognitive affective syndrome occurring essentially in children. Sporadic ataxias include stroke, toxic causes, immune ataxias, infectious/parainfectious ataxias, traumatic causes, neoplasias and paraneoplastic syndromes, endocrine disorders affecting the cerebellum, and the so-called "degenerative ataxias" (multiple system atrophy, and sporadic adult-onset ataxias). Genetic ataxias include mainly four groups of disorders: autosomal-recessive cerebellar ataxias, autosomal-dominant ataxias (spinocerebellar ataxias and episodic ataxias), mitochondrial disorders, and X-linked ataxias. In addition to biochemical studies and genetic tests, brain imaging techniques are a cornerstone for the diagnosis, clinicoanatomic correlations, and follow-up of cerebellar ataxias. Modern radiologic tools to assess cerebellar ataxias include: functional imaging studies, magnetic resonance spectroscopy, volumetric studies, and tractography. These complementary methods provide a multimodal appreciation of the whole long-range cerebellar network functioning, and allow the extraction of potential biomarkers for prognosis and rating level of recovery after treatment.

Structural and Functional Magnetic Resonance Imaging of the Cerebellum: Considerations for Assessing Cerebellar Ataxias.

Magnetic resonance imaging (MRI) of the brain is of high interest for diagnosing and understanding degenerative ataxias. Here, we present state-of-the-art MRI methods to characterize structural alterations of the cerebellum and introduce initial experiments to show abnormalities in the cerebellar nuclei. Clinically, T1-weighted MR images are used to assess atrophy of the cerebellar cortex, the brainstem, and the spinal cord, whereas T2-weighted and PD-weighted images are typically employed to depict potential white matter lesions that may be associated with certain types of ataxias. More recently, attention has also focused on the characterization of the cerebellar nuclei, which are discernible on spatially highly resolved iron-sensitive MR images due to their relatively high iron content, including T2 (*)-weighted images, susceptibility-weighted images (SWI), effective transverse relaxation rate (R2 (*)) maps, and quantitative susceptibility maps (QSM). Among these iron-sensitive techniques, QSM reveals the best contrast between cerebellar nuclei and their surroundings. In particular, the gyrification of the dentate nuclei is prominently depicted, even at the clinically widely available field strength of 3T. The linear relationship between magnetic susceptibility and local iron content allows for determination of iron deposition in cerebellar nuclei non-invasively. The increased signal-to-noise ratio of ultrahigh-field MRI (B0 ≥ 7T) and advances in spatial normalization methods enable functional MRI (fMRI) at the level of the cerebellar cortex and cerebellar nuclei. Data from initial fMRI studies are presented in three common forms of hereditary ataxias (Friedreich's ataxia, spinocerebellar ataxia type 3, and spinocerebellar ataxia type 6). Characteristic changes in the fMRI signal are discussed in the light of histopathological data and current knowledge of the underlying physiology of the fMRI signal in the cerebellum.

Neuronal Atrophy Early in Degenerative Ataxia Is a Compensatory Mechanism to Regulate Membrane Excitability.

In neurodegenerative disease, neuronal atrophy has long been assumed to be an early nonspecific event preceding neuronal loss. However, in a mouse model of spinocerebellar ataxia type 1 (SCA1), we identify a previously unappreciated compensatory role for neuronal shrinkage. Purkinje neuron firing in these mice is initially normal, but is followed by abnormal membrane depolarization resulting from a reduction in potassium channels. Subsequently, these electrophysiological effects are counteracted by cell atrophy, which by restoring normal potassium channel membrane density, re-establishes pacemaker firing. Reversing the initial membrane depolarization improved motor function and Purkinje neuron morphology in the SCA1 mice. These results suggest that Purkinje neuron remodeling in ataxia is an active compensatory response that serves to normalize intrinsic membrane excitability.

Primary and secondary ataxias.

This article discusses recent advances in the understanding of clinical and genetic aspects of primary ataxias, including congenital, autosomal recessive, autosomal dominant, episodic, X-linked, and mitochondrial ataxias, as well as idiopathic degenerative and secondary ataxias. Many important observations have been published in recent years in connection with primary ataxias, particularly new loci and genes. The most commonly inherited ataxias may present with typical and atypical phenotypes. In the group of idiopathic degenerative ataxias, genes have been found in patients with multiple system atrophy type C. Secondary ataxias represent an important group of sporadic, cerebellar, and afferent/sensory ataxias. Knowledge of primary ataxias has been growing rapidly in recent years. Here we review different forms of primary ataxia, including inherited forms, which are subdivided into congenital, autosomal recessive cerebellar ataxias, autosomal dominant cerebellar ataxias, episodic ataxias, X-linked ataxias, and mitochondrial ataxias, as well as sporadic ataxias and idiopathic degenerative ataxias. Secondary or acquired ataxias are also reviewed and the most common causes are discussed.

Genetic analysis of ten common degenerative hereditary ataxia loci in patients with essential tremor.

To investigate the association of repeat expansion size in 10 common degenerative hereditary ataxia genes with essential tremor. These genes were spinocerebellar ataxia (SCA)-1 (ATXN1), SCA-2 (ATXN2), SCA-3 (ATXN3), SCA-6 (CACNA1A), SCA-7 (ATXN7), SCA-8 (ATXN8OS), SCA-10 (ATXN10), SCA-12 (PPP2R2B), SCA-17 (TBP) and dentatorubral-pallidolysian atrophy (DRPLA) (ATN1). Genetic analysis of repeat size in 10 degenerative hereditary ataxia loci was performed in 323 essential tremor patients and 299 controls enrolled at Columbia University. To test for differences in the allele distribution between patients and controls, a CLUMP analysis was performed. None of the essential tremor patients had a repeat expansion in the intermediate or pathogenic range. Significant differences in the distribution of repeats in the 'normal' range for SCA2 and SCA8 (both p≤0.02) were observed between essential tremor patients and controls. Our study suggests that pathogenic repeat expansions in SCA loci are not associated with essential tremor.

Src inhibitors modulate frataxin protein levels.

Defective expression of frataxin is responsible for the inherited, progressive degenerative disease Friedreich's Ataxia (FRDA). There is currently no effective approved treatment for FRDA and patients die prematurely. Defective frataxin expression causes critical metabolic changes, including redox imbalance and ATP deficiency. As these alterations are known to regulate the tyrosine kinase Src, we investigated whether Src might in turn affect frataxin expression. We found that frataxin can be phosphorylated by Src. Phosphorylation occurs primarily on Y118 and promotes frataxin ubiquitination, a signal for degradation. Accordingly, Src inhibitors induce accumulation of frataxin but are ineffective on a non-phosphorylatable frataxin-Y118F mutant. Importantly, all the Src inhibitors tested, some of them already in the clinic, increase frataxin expression and rescue the aconitase defect in frataxin-deficient cells derived from FRDA patients. Thus, Src inhibitors emerge as a new class of drugs able to promote frataxin accumulation, suggesting their possible use as therapeutics in FRDA.

Treatment for speech disorder in Friedreich ataxia and other hereditary ataxia syndromes.

Treatment for speech disorder in Friedreich ataxia and other hereditary ataxia syndromes.

Upper body kinematics in patients with cerebellar ataxia.

Although abnormal oscillations of the trunk are a common clinical feature in patients with cerebellar ataxia, the kinematic behaviour of the upper body in ataxic patients has yet to be investigated in quantitative studies. In this study, an optoelectronic motion analysis system was used to measure the ranges of motion (ROMs) of the head and trunk segments in the sagittal, frontal and yaw planes in 16 patients with degenerative cerebellar ataxia during gait at self-selected speed. The data obtained were compared with those collected in a gender-, age- and gait speed-matched sample of healthy subjects and correlated with gait variables (time-distance means and coefficients of variation) and clinical variables (disease onset, duration and severity). The results showed significantly larger head and/or trunk ROMs in ataxic patients compared with controls in all three spatial planes, and significant correlations between trunk ROMs and disease duration and severity (in sagittal and frontal planes) and time-distance parameters (in the yaw plane), and between both head and trunk ROMs and swing phase duration variability (in the sagittal plane). Furthermore, the ataxic patients showed a flexed posture of both the head and the trunk during walking. In conclusion, our study revealed abnormal motor behaviour of the upper body in ataxic patients, mainly resulting in a flexed posture and larger oscillations of the head and trunk. The results of the correlation analyses suggest that the longer and more severe the disease, the larger the upper body oscillations and that large trunk oscillations may explain some aspects of gait variability. These results suggest the need of specific rehabilitation treatments or the use of elastic orthoses that may be particularly useful to reduce trunk oscillations and improve dynamic stability.

Treatment Options in Degenerative Cerebellar Ataxia: A Systematic Review.

The etiology of cerebellar ataxia (CA) is heterogeneous and includes easily identified and often reversible causes (i.e., drug toxicity and vitamin B12 deficiency) as well as irreversible degenerative conditions. It is the latter that poses a significant therapeutic challenge for practitioners treating this population of patients. To date, there are no U.S. Food and Drug Administration-approved medications for the treatment of CA. The literature, consisting mostly of case reports, case series, and small clinical trials, is sparse and scattered. These studies are difficult to translate clinically because they often describe diverse study populations with various identified and unidentified genetic etiologies. In addition, the reported treatment duration is often brief, and it is uncertain whether any of these options provide substantially lasting benefits. In this article, we review published reports and studies to aid the practitioner counseling patients with degenerative ataxias.

Gait adaptability training improves obstacle avoidance and dynamic stability in patients with cerebellar degeneration

Balance and gait problems in patients with cerebellar degeneration lead to reduced mobility, loss of independence, and frequent falls. It is currently unclear, however, whether balance and gait capacities can be improved by training in this group of patients. Therefore, the aim of this study was to examine the effects of gait adaptability training on obstacle avoidance and dynamic stability during adaptive gait. Ten patients with degenerative cerebellar ataxia received 10 protocolized gait adaptability training sessions of 1h each during 5 weeks. Training was performed on a treadmill with visual stepping targets and obstacles projected on the belt’s surface. As the primary outcome, we used an obstacle avoidance task while walking on a treadmill. We determined avoidance success rates, as well as dynamic stability during the avoidance manoeuvre. Clinical ratings included the scale for the assessment of ataxia (SARA), 10m walking test, timed up-and-go test, berg balance scale, and the obstacle subtask of the emory functional ambulation profile (EFAP). Following the intervention, success rates on the obstacle avoidance task had significantly improved compared to pre-intervention. For successful avoidance, participants allowed themselves smaller stability margins in the sagittal plane in the (shortened) pre-crossing step. However, in the subsequent steps they returned to baseline stability values more effectively than before training. SARA scores and the EFAP obstacle subtask improved significantly as well. This pilot study provides preliminary evidence of a beneficial effect of gait adaptability training on obstacle avoidance capacity and dynamic stability in patients with cerebellar degeneration.

The assessment and treatment of postural disorders in cerebellar ataxia: A systematic review

Gait and balance disorders are often major causes of handicap in patients with cerebellar ataxia. Although it was thought that postural and balance disorders in cerebellar ataxia were not treatable, recent studies have demonstrated the beneficial effects of rehabilitation programs. This article is the first systematic review on the treatment of postural disorders in cerebellar ataxia. Nineteen articles were selected, of which three were randomized, controlled trials. Various aetiologies of cerebellar ataxia were studied: five studies assessed patients with multiple sclerosis, four assessed patients with degenerative ataxia, two assessed stroke patients and eight assessed patients with various aetiologies. Accurate assessment of postural disorders in cerebellar ataxia is very important in both clinical trials and clinical practice. The Scale for the Assessment and Rating of Ataxia (SARA) is a simple, validated measurement tool, for which 18 of the 40 points are related to postural disorders. This scale is useful for monitoring ataxic patients with postural disorders. There is now moderate level evidence that rehabilitation is efficient to improve postural capacities of patients with cerebellar ataxia – particularly in patients with degenerative ataxia or multiple sclerosis. Intensive rehabilitation programs with balance and coordination exercises are necessary. Although techniques such as virtual reality, biofeedback, treadmill exercises with supported bodyweight and torso weighting appear to be of value, their specific efficacy has to be further investigated. Drugs have only been studied in degenerative ataxia, and the level of evidence is low. There is now a need for large, randomized, controlled trials testing rehabilitation programs suited to postural and gait disorders of patients with cerebellar ataxia.

Motor training in degenerative spinocerebellar disease: ataxia-specific improvements by intensive physiotherapy and exergames.

The cerebellum is essentially involved in movement control and plays a critical role in motor learning. It has remained controversial whether patients with degenerative cerebellar disease benefit from high-intensity coordinative training. Moreover, it remains unclear by which training methods and mechanisms these patients might improve their motor performance. Here, we review evidence from different high-intensity training studies in patients with degenerative spinocerebellar disease. These studies demonstrate that high-intensity coordinative training might lead to a significant benefit in patients with degenerative ataxia. This training might be based either on physiotherapy or on whole-body controlled videogames (“exergames”). The benefit shown in these studies is equal to regaining one or more years of natural disease progression. In addition, first case studies indicate that even subjects with advanced neurodegeneration might benefit from such training programs. For both types of training, the observed clinical improvements are paralleled by recoveries in ataxia-specific dysfunctions (e.g., multijoint coordination and dynamic stability). Importantly, for both types of training, the retention of the effects seems to depend on the frequency and continuity of training. Based on these studies, we here present preliminary recommendations for clinical practice, and articulate open questions that might guide future studies on neurorehabilitation in degenerative spinocerebellar disease.

Phenotype and frequency of STUB1 mutations: next-generation screenings in Caucasian ataxia and spastic paraplegia cohorts.

BackgroundMutations in the gene STUB1, encoding the protein CHIP (C-terminus of HSC70-interacting protein), have recently been suggested as a cause of recessive ataxia based on the findings in few Chinese families. Here we aimed to investigate the phenotypic and genotypic spectrum of STUB1 mutations, and to assess their frequency in different Caucasian disease cohorts.Methods300 subjects with degenerative ataxia (n = 167) or spastic paraplegia (n = 133) were screened for STUB1 variants by whole-exome-sequencing (n = 204) or shotgun-fragment-library-sequencing (n = 96). To control for the specificity of STUB1 variants, we screened an additional 1707 exomes from 891 index families with other neurological diseases.ResultsWe identified 3 ataxia patients (3/167 = 1.8%) with 4 novel missense mutations in STUB1, including 3 mutations in its tetratricopeptide-repeat domain. All patients showed evidence of pyramidal tract damage. Cognitive impairment was present only in one and hypogonadism in none of them. Ataxia did not start before age 48 years in one subject. No recessive STUB1 variants were identified in families with other neurological diseases, demonstrating that STUB1 variants are not simply rare polymorphisms ubiquitous in neurodegenerative disease.ConclusionsSTUB1-disease occurs also in Caucasian ataxia populations (1.8%). Our results expand the genotypic spectrum of STUB1-disease, showing that pathogenic mutations affect also the tetratricopeptide-repeat domain, thus providing clinical evidence for the functional importance of this domain. Moreover, they further delineate the phenotypic core features of STUB1-ataxia. Pyramidal tract damage is a common accompanying feature and can include lower limb spasticity, thus adding STUB1-ataxia to the differential diagnosis of “spastic ataxias”. However, STUB1 is rare in subjects with predominant spastic paraplegia (0/133). In contrast to previous reports, STUB1-ataxia can start even above age 40 years, and neither hypogonadism nor prominent cognitive impairment are obligatory features.

Paraneoplastic cerebellar ataxia associated with anti-Hu antibodies and benign ganglioneuroma

We describe a case of cerebellar ataxia associated with anti-Hu antibodies and benign ganglioneuroma. A 28-year-old woman developed progressive ataxia with hyporeflexia at the age of 19. Brain MRI showed progressive cerebellar atrophy. Neurophysiological studies, screening of immune-mediated ataxias, oncological markers, vitamin E and genetic tests for spinocerebellar ataxia types 1,2,3, Friedreich ataxia and POLG1 were negative. Anti-Hu antibodies were positive in Western blot and indirect immunofluorescence (1:640). Total-body computed tomography revealed a mediastinum mass; the histological diagnosis was maturing ganglioneuroma. Immunohistochemistry showed a mild reaction between the tumor and the patient's serum, and no reaction between the tumor and control serum. After surgery, serum anti-Hu titer decreased, while ataxic symptoms initially worsened and then stabilized. Ganglioneuroma is a benign tumor, usually derived from the maturation of a neuroblastoma. The benign histology and the presence of anti-Hu antibodies could be related to the positive oncological prognosis and to the slow clinical course mimicking a degenerative ataxia.

Gait impairment precedes clinical symptoms in spinocerebellar ataxia type 6

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. We studied 9 gait variables in 24 SCA6 (6 presymptomatic; 18 symptomatic) and 24 controls and correlated gait with clinical severity (presymptomatic and symptomatic). 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. 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.