An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14.

Adult-onset cerebellar ataxias are a group of neurodegenerative conditions that challenge both genetic discovery and molecular diagnosis. In this study, we identified an intronic (GAA) repeat expansion in fibroblast growth factor 14 (FGF14). Genetic analysis of 95 Australian individuals with adult-onset ataxia identified four (4.2%) with (GAA)>300 and a further nine individuals with (GAA)>250. PCR and long-read sequence analysis revealed these were pure (GAA) repeats. In comparison, no control subjects had (GAA)>300 and only 2/311 control individuals (0.6%) had a pure (GAA)>250. In a German validation cohort, 9/104 (8.7%) of affected individuals had (GAA)>335 and a further six had (GAA)>250, whereas 10/190 (5.3%) control subjects had (GAA)>250 but none were (GAA)>335. The combined data suggest (GAA)>335 are disease causing and fully penetrant (p = 6.0 × 10-8, OR = 72 [95% CI = 4.3-1,227]), while (GAA)>250 is likely pathogenic with reduced penetrance. Affected individuals had an adult-onset, slowly progressive cerebellar ataxia with variable features including vestibular impairment, hyper-reflexia, and autonomic dysfunction. A negative correlation between age at onset and repeat length was observed (R2 = 0.44, p = 0.00045, slope = -0.12) and identification of a shared haplotype in a minority of individuals suggests that the expansion can be inherited or generated de novo during meiotic division. This study demonstrates the power of genome sequencing and advanced bioinformatic tools to identify novel repeat expansions via model-free, genome-wide analysis and identifies SCA50/ATX-FGF14 as a frequent cause of adult-onset ataxia.

Patient-Related Outcome Measures for Oculomotor Symptoms in the Cerebellar Ataxias: Insights from Non-Cerebellar Disorders.

In patients with cerebellar ataxia (CA), symptoms related to oculomotor dysfunction significantly affect quality of life (QoL). This study aimed to analyze the literature on patient-related outcome measures (PROMs) assessing QoL impacts of vestibular and cerebellar oculomotor abnormalities in patients with CA to identify the strengths and limitations of existing scales and highlight any areas of unmet need. A systematic review was conducted (Medline, Embase) of English-language original articles reporting on QoL measures in patients with vertigo, dizziness or CA. Pre-specified parameters were retrieved, including diseases studied, scales applied and conclusions drawn. Our search yielded 3671 articles of which 467 studies (n = 111,606 participants) were deemed relevant. The most frequently studied disease entities were (a) non-specific dizziness/gait imbalance (114 studies; 54,581 participants), (b) vestibular schwannomas (66; 15,360), and (c) vestibular disorders not further specified (66; 10,259). The Dizziness Handicap Inventory (DHI) was the most frequently used PROM to assess QoL (n = 91,851), followed by the Penn Acoustic Neuroma Quality-of-Life Scale (n = 12,027) and the Activities-Specific Balance Confidence Scale (n = 2'471). QoL-scores capturing symptoms related to oculomotor abnormalities in CA were rare, focused on visual impairments (e.g., National-Eye-Institute Visual Function Questionnaire, Oscillopsia Functional Impact, oscillopsia severity score) and were unvalidated. The DHI remains the most widely used and versatile scale for evaluating dizziness. A lack of well-established PROMs for assessing the impact of oculomotor-related symptoms on QoL in CA was noted, emphasizing the need for developing and validating a new QoL-score dedicated to the oculomotor domain for individuals with CA.

Quantitative Oculomotor Assessment in Hereditary Ataxia: Discriminatory Power, Correlation with Severity Measures, and Recommended Parameters for Specific Genotypes.

Characterizing bedside oculomotor deficits is a critical factor in defining the clinical presentation of hereditary ataxias. Quantitative assessments are increasingly available and have significant advantages, including comparability over time, reduced examiner dependency, and sensitivity to subtle changes. To delineate the potential of quantitative oculomotor assessments as digital-motor outcome measures for clinical trials in ataxia, we searched MEDLINE for articles reporting on quantitative eye movement recordings in genetically confirmed or suspected hereditary ataxias, asking which paradigms are most promising for capturing disease progression and treatment response. Eighty-nine manuscripts identified reported on 1541 patients, including spinocerebellar ataxias (SCA2, n = 421), SCA3 (n = 268), SCA6 (n = 117), other SCAs (n = 97), Friedreich ataxia (FRDA, n = 178), Niemann-Pick disease type C (NPC, n = 57), and ataxia-telangiectasia (n = 85) as largest cohorts. Whereas most studies reported discriminatory power of oculomotor assessments in diagnostics, few explored their value for monitoring genotype-specific disease progression (n = 2; SCA2) or treatment response (n = 8; SCA2, FRDA, NPC, ataxia-telangiectasia, episodic-ataxia 4). Oculomotor parameters correlated with disease severity measures including clinical scores (n = 18 studies (SARA: n = 9)), chronological measures (e.g., age, disease duration, time-to-symptom onset; n = 17), genetic stratification (n = 9), and imaging measures of atrophy (n = 5). Recurrent correlations across many ataxias (SCA2/3/17, FRDA, NPC) suggest saccadic eye movements as potentially generic quantitative oculomotor outcome. Recommendation of other paradigms was limited by the scarcity of cross-validating correlations, except saccadic intrusions (FRDA), pursuit eye movements (SCA17), and quantitative head-impulse testing (SCA3/6). This work aids in understanding the current knowledge of quantitative oculomotor parameters in hereditary ataxias, and identifies gaps for validation as potential trial outcome measures in specific ataxia genotypes.

A patient with neuropathy and ataxia: what do I have to consider?

PURPOSE OF REVIEW: An increasing number of peripheral neuro(no)pathies are identified as involving other components of the neurological system, particularly those that further impair balance. Here we aim to outline an evidence-based approach to the diagnosis of patients who present with a somatosensory disorder which also involves at least one other area of neurological impairment such as the vestibular, auditory, or cerebellar systems. RECENT FINDINGS: Detailed objective investigation of patients who present with sensory impairment, particularly where the degree of imbalance is greater than would be expected, aids the accurate diagnosis of genetic, autoimmune, metabolic, and toxic neurological disease. SUMMARY: Diagnosis and management of complex somatosensory disorders benefit from investigation which extends beyond the presenting sensory impairment.

Quantitative Oculomotor Assessment in Hereditary Ataxia: Systematic Review and Consensus by the Ataxia Global Initiative Working Group on Digital-motor Biomarkers.

Oculomotor deficits are common in hereditary ataxia, but disproportionally neglected in clinical ataxia scales and as outcome measures for interventional trials. Quantitative assessment of oculomotor function has become increasingly available and thus applicable in multicenter trials and offers the opportunity to capture severity and progression of oculomotor impairment in a sensitive and reliable manner. In this consensus paper of the Ataxia Global Initiative Working Group On Digital Oculomotor Biomarkers, based on a systematic literature review, we propose harmonized methodology and measurement parameters for the quantitative assessment of oculomotor function in natural-history studies and clinical trials in hereditary ataxia. MEDLINE was searched for articles reporting on oculomotor/vestibular properties in ataxia patients and a study-tailored quality-assessment was performed. One-hundred-and-seventeen articles reporting on subjects with genetically confirmed (n=1134) or suspected hereditary ataxia (n=198), and degenerative ataxias with sporadic presentation (n=480) were included and subject to data extraction. Based on robust discrimination from controls, correlation with disease-severity, sensitivity to change, and feasibility in international multicenter settings as prerequisite for clinical trials, we prioritize a core-set of five eye-movement types: (i) pursuit eye movements, (ii) saccadic eye movements, (iii) fixation, (iv) eccentric gaze holding, and (v) rotational vestibulo-ocular reflex. We provide detailed guidelines for their acquisition, and recommendations on the quantitative parameters to extract. Limitations include low study quality, heterogeneity in patient populations, and lack of longitudinal studies. Standardization of quantitative oculomotor assessments will facilitate their implementation, interpretation, and validation in clinical trials, and ultimately advance our understanding of the evolution of oculomotor network dysfunction in hereditary ataxias.

Interrater Reliability of the Scale for the Assessment and Rating of Ataxia, Berg Balance Scale, and Functional Independence Measure Motor Domain in Individuals With Hereditary Cerebellar Ataxia.

OBJECTIVE: To determine the interrater reliability of the Scale for the Assessment and Rating of Ataxia (SARA), Berg Balance Scale (BBS), and motor domain of the FIM (m-FIM) administered by physiotherapists in individuals with a hereditary cerebellar ataxia (HCA). DESIGN: Participants were assessed by 1 of 4 physiotherapists. Assessments were video-recorded and the remaining 3 physiotherapists scored the scales for each participant. Raters were blinded to each other's scores. SETTING: Assessments were administered at 3 clinical locations in separate states in Australia. PARTICIPANTS: Twenty-one individuals (mean age=47.63 years; SD=18.42; 13 male and 8 female) living in the community with an HCA were recruited (N=21). MAIN OUTCOME MEASURES: Total and single-item scores of the SARA, BBS, and m-FIM were examined. The m-FIM was conducted by interview. RESULTS: Intraclass coefficients (2,1) for the total scores of the m-FIM (0.92; 95% confidence interval [CI], 0.85-0.96), SARA (0.92; 95% CI, 0.86-0.96), and BBS (0.99; 95% CI, 0.98-0.99) indicated excellent interrater reliability. However, there was inconsistent agreement with the individual items, with SARA item 5 (right side) and item 7 (both sides) demonstrating poor interrater reliability and items 1 and 2 demonstrating excellent reliability. CONCLUSIONS: The m-FIM (by interview), SARA, and BBS have excellent interrater reliability for use when assessing individuals with an HCA. Physiotherapists could be considered for administration of the SARA in clinical trials. However, further work is required to improve the agreement of the single-item scores and to examine the other psychometric properties of these scales.

Bioinformatics-Based Identification of Expanded Repeats: A Non-reference Intronic Pentamer Expansion in RFC1 Causes CANVAS.

Genomic technologies such as next-generation sequencing (NGS) are revolutionizing molecular diagnostics and clinical medicine. However, these approaches have proven inefficient at identifying pathogenic repeat expansions. Here, we apply a collection of bioinformatics tools that can be utilized to identify either known or novel expanded repeat sequences in NGS data. We performed genetic studies of a cohort of 35 individuals from 22 families with a clinical diagnosis of cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Analysis of whole-genome sequence (WGS) data with five independent algorithms identified a recessively inherited intronic repeat expansion [(AAGGG)exp] in the gene encoding Replication Factor C1 (RFC1). This motif, not reported in the reference sequence, localized to an Alu element and replaced the reference (AAAAG)11 short tandem repeat. Genetic analyses confirmed the pathogenic expansion in 18 of 22 CANVAS-affected families and identified a core ancestral haplotype, estimated to have arisen in Europe more than twenty-five thousand years ago. WGS of the four RFC1-negative CANVAS-affected families identified plausible variants in three, with genomic re-diagnosis of SCA3, spastic ataxia of the Charlevoix-Saguenay type, and SCA45. This study identified the genetic basis of CANVAS and demonstrated that these improved bioinformatics tools increase the diagnostic utility of WGS to determine the genetic basis of a heterogeneous group of clinically overlapping neurogenetic disorders.

Instrumented Objective Clinical Examination of Cerebellar Ataxia: the Upper and Lower Limb-a Review.

Cerebellar dysfunction results in impairments in co-ordination or 'ataxia'. Bedside examination of cerebellar function has changed little since the early nineteenth century with the exception being the oculomotor examination which has become instrumented. Otherwise, competence and confidence in performing the clinical assessment relies heavily on the skill and experience of the clinician. Potentially, instrumented objective measurement will more accurately assess the severity of ataxia and the changes brought about by advancing therapies in pharmaceutical trials and in rehabilitation intervention. This study describes instrumented versions of several bedside tests of cerebellar function, including rhythmic tapping of the hand (RTH), finger-nose test (FNT), dysdiadochokinesia (DDK), ramp tracking (RMT), ballistic tracking (BT), rhythmic tapping of the foot (RTF) and the heel shin (HST) examination which were validated against scores from Ataxia Rating Scales (ARS) such as the Scale of Assessment and Rating of Ataxia (SARA). While all of the instrumented tests accurately distinguished between ataxic subjects and controls, there was a difference in performance, with the best four performing upper limb tests being RTH, FNT, DDK and BT. A combination of BT plus RTH provided the best correlation with the SARA and outperformed a combination of all the bedside tests (Spearman 0.8; p < 0.001 compared to 0.68; p < 0.001 for the combined set) in identifying the presence and severity of ataxia. This indicates that there is redundancy in the information provided by the bedside tests and that adding other tests to BT plus RTH does not add accuracy to the assessment of ataxia. This analysis highlighted the need for metrics that could be generalised to each of the assessments of ataxia, so, in turn, domains of stability, timing, accuracy and rhythmicity (STAR domains) were developed and compared to the SARA. The STAR criteria could potentially influence the future of instrumented assessment in CA and pave the way for further research into the objective measurement of the cerebellar examination.

Developing an Instrumented Measure of Upper Limb Function in Friedreich Ataxia.

Upper limb function for people with Friedreich ataxia determines capacity to participate in daily activities. Current upper limb measures available do not fully capture impairments related to Friedreich ataxia. We have developed an objective measure, the Ataxia Instrumented Measure-Spoon (AIM-S), which consists of a spoon equipped with a BioKin wireless motion capture device, and algorithms that analyse these signals, to measure ataxia of the upper limb during the pre-oral phase of eating. The aim of this study was to evaluate the AIM-S as a sensitive and functionally relevant clinical outcome for use in clinical trials. A prospective longitudinal study evaluated the capacity of the AIM-S to detect change in upper limb function over 48 weeks. Friedreich ataxia clinical severity, performance on the Nine-Hole Peg Test and Box and Block Test and responses to a purpose-designed questionnaire regarding acceptability of AIM-S were recorded. Forty individuals with Friedreich ataxia and 20 control participants completed the baseline assessment. Thirty individuals with Friedreich ataxia completed the second assessment. The sensitivity of the AIM-S to detect deterioration in upper limb function was greater than other measures. Patient-reported outcomes indicated the AIM-S reflected a daily activity and was more enjoyable to complete than other assessments. The AIM-S is a more accurate, less variable measure of upper limb function in Friedreich ataxia than existing measures. The AIM-S is perceived by individuals with Friedreich ataxia to be related to everyday life and will permit individuals who are non-ambulant to be included in future clinical trials.

Rapid Diagnosis of Spinocerebellar Ataxia 36 in a Three-Generation Family Using Short-Read Whole-Genome Sequencing Data.

BACKGROUND: Spinocerebellar ataxias are often caused by expansions of short tandem repeats. Recent methodological advances have made repeat expansion (RE) detection with whole-genome sequencing (WGS) feasible. OBJECTIVES: The objective of this study was to determine the genetic basis of ataxia in a multigenerational Australian pedigree with autosomal-dominant inheritance. METHODS AND RESULTS: WGS was performed on 3 affected relatives. The sequence data were screened for known pathogenic REs using 2 RE detection tools: exSTRa and ExpansionHunter. This screen provided a clear and rapid diagnosis (<5 days from receiving the sequencing data) of spinocerebellar ataxia 36, a rare form of ataxia caused by an intronic GGCCTG RE in NOP56. CONCLUSIONS: The diagnosis of rare ataxias caused by REs is highly feasible and cost-effective with WGS. We propose that WGS could potentially be implemented as the frontline, cost-effective methodology for the molecular testing of individuals with a clinical diagnosis of ataxia. © 2020 International Parkinson and Movement Disorder Society.

A comprehensive scheme for the objective upper body assessments of subjects with cerebellar ataxia.

BACKGROUND: Cerebellar ataxia refers to the disturbance in movement resulting from cerebellar dysfunction. It manifests as inaccurate movements with delayed onset and overshoot, especially when movements are repetitive or rhythmic. Identification of ataxia is integral to the diagnosis and assessment of severity, and is important in monitoring progression and improvement. Ataxia is identified and assessed by clinicians observing subjects perform standardised movement tasks that emphasise ataxic movements. Our aim in this paper was to use data recorded from motion sensors worn while subjects performed these tasks, in order to make an objective assessment of ataxia that accurately modelled the clinical assessment. METHODS: Inertial measurement units and a Kinect© system were used to record motion data while control and ataxic subjects performed four instrumented version of upper extremities tests, i.e. finger chase test (FCT), finger tapping test (FTT), finger to nose test (FNT) and dysdiadochokinesia test (DDKT). Kinematic features were extracted from this data and correlated with clinical ratings of severity of ataxia using the Scale for the Assessment and Rating of Ataxia (SARA). These features were refined using Feed Backward feature Elimination (the best performing method of four). Using several different learning models, including Linear Discrimination, Quadratic Discrimination Analysis, Support Vector Machine and K-Nearest Neighbour these extracted features were used to accurately discriminate between ataxics and control subjects. Leave-One-Out cross validation estimated the generalised performance of the diagnostic model as well as the severity predicting regression model. RESULTS: The selected model accurately ([Formula: see text]) predicted the clinical scores for ataxia and correlated well with clinical scores of the severity of ataxia ([Formula: see text], [Formula: see text]). The severity estimation was also considered in a 4-level scale to provide a rating that is familiar to the current clinically-used rating of upper limb impairments. The combination of FCT and FTT performed as well as all four test combined in predicting the presence and severity of ataxia. CONCLUSION: Individual bedside tests can be emulated using features derived from sensors worn while bedside tests of cerebellar ataxia were being performed. Each test emphasises different aspects of stability, timing, accuracy and rhythmicity of movements. Using the current models it is possible to model the clinician in identifying ataxia and assessing severity but also to identify those test which provide the optimum set of data. Trial registration Human Research and Ethics Committee, Royal Victorian Eye and Ear Hospital, East Melbourne, Australia (HREC Reference Number: 11/994H/16).

Central Conditions Mimicking Benign Paroxysmal Positional Vertigo: A Case Series.

BACKGROUND AND PURPOSE: Benign paroxysmal positional vertigo (BPPV) is the most common cause of positional vertigo. The term "benign" is consistent with a peripheral vestibular disorder that does not carry the potentially sinister sequelae of a central nervous system (CNS) cause. However, in 12% to 20% of cases, positional vertigo may be attributed to CNS pathology, including tumors of the cerebellum. CASE DESCRIPTION: Here, we present a series of 3 cases in which positional vertigo and nystagmus were the only presenting features in 2 cases of cerebellar tumor and 1 case of obstructive hydrocephalus. INTERVENTION: All patients underwent surgical intervention for removal of posterior fossa tumors or posterior fossa decompression for obstructive hydrocephalus. Following surgery, all 3 patients underwent a period of vestibular rehabilitation for postoperative motion sensitivity and balance impairment. OUTCOMES: Despite the continuing presence of central positioning nystagmus, all 3 patients recovered well, putatively with the aid of vestibular rehabilitation. DISCUSSION: The presence of central positioning nystagmus may be the sole presenting feature of serious neurological conditions such as posterior fossa tumor. It is recommended that a diagnosis of BPPV can only be made if Dix-Hallpike or supine roll maneuver elicits nystagmus that is consistent with BPPV. Any features of the nystagmus, which are not consistent with BPPV, should raise suspicion of central pathology, and warrant further investigation.Video Abstract available for more insights from the authors (see Video Abstract, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A265).

Quantitative assessment of cerebellar ataxia, through automated limb functional tests.

BACKGROUND: Cerebellar damage can often result in disabilities affecting the peripheral regions of the body. These include poor and inaccurate coordination, tremors and irregular movements that often manifest as disorders associated with balance, gait and speech. The severity assessment of Cerebellar ataxia (CA) is determined by expert opinion and is likely to be subjective in nature. This paper investigates automated versions of three commonly used tests: Finger to Nose test (FNT), test for upper limb Dysdiadochokinesia Test (DDK) and Heel to Shin Test (HST), in evaluating disability due to CA. METHODS: Limb movements associated with these tests are measured using Inertial Measurement Units (IMU) to capture the disability. Kinematic parameters such as acceleration, velocity and angle are considered in both time and frequency domain in three orthogonal axes to obtain relevant disability related information. The collective dominance in the data distributions of the underlying features were observed though the Principal Component Analysis (PCA). The dominant features were combined to substantiate the correlation with the expert clinical assessments through Linear Discriminant Analysis. Here, the Pearson correlation is used to examine the relationship between the objective assessments and the expert clinical scores while the performance was also verified by means of cross validation. RESULTS: The experimental results show that acceleration is a major feature in DDK and HST, whereas rotation is the main feature responsible for classification in FNT. Combining the features enhanced the correlations in each domain. The subject data was classified based on the severity information based on expert clinical scores. CONCLUSION: For the predominantly translational movement in the upper limb FNT, the rotation captures disability and for the DDK test with predominantly rotational movements, the linear acceleration captures the disability but cannot be extended to the lower limb HST. The orthogonal direction manifestation of ataxia attributed to sensory measurements was determined for each test. TRIAL REGISTRATION: Human Research and Ethics Committee, Royal Victorian Eye and Ear Hospital, East Melbourne, Australia (HREC Reference Number: 11/994H/16).

Neurophysiological evidence for generalized sensory neuronopathy in cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome.

INTRODUCTION: Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) is a recently described multisystem ataxia defined by the presence of cerebellar ataxia, bilateral vestibulopathy, and a somatosensory deficit. The characteristic clinical sign is an abnormal visually enhanced vestibuloocular reflex. The somatosensory deficit contributes to a significant level of disability in CANVAS. METHODS: This study was a neurophysiological investigation of 14 patients with CANVAS. RESULTS: Findings revealed uniformly absent sensory nerve action potentials in all limbs, abnormal blink reflexes in 13 of 14 patients, and abnormal masseter reflexes in 6 of 11 patients. Tibial H-reflexes were absent in 11 of 14 patients. Somatosensory evoked potentials were abnormal in 10 of the 11 patients tested, and brainstem auditory evoked responses were abnormal in 3 of 8. Cutaneous silent period responses were abnormal in 7 of 14 patients. CONCLUSIONS: We suggest that a sensory neuronopathy should be sought in cerebellar and/or vestibular ataxias, particularly where the degree of ataxia is out of proportion to the clinically identified cerebellar and/or vestibular dysfunction.

Machine Learning Based Diagnosis of Vertigo using Video Head Impulse Test.

This work utilises the strength of state space based dynamic modelling and the ability of machine learning based segmentation of SRM standard descriptors to reach superior diagnostic capabilities. Dynamic modelling ensured vHIT input-output characteristics generated SRM standard descriptors, which were consequently used in formation of ML classification models.The best ML model was Linear SVM when built on left and right sided data with the SRM standard descriptors: rise time, settling time, settling minimum, settling maximum, overshoot and undershoot. The model was able to classify individuals to patient or control groups with an accuracy of 100% and a sensitivity and specificity of 1.Clinical Relevance- Dizziness is one of the most common presentations to family physicians and emergency departments. It is associated with significant medical complications such as falls as well as economic costs to both the individual and the community. Vestibular diseases comprise the bulk of dizzy disorders and are often associated with dysfunction of the vestibular or inner ear balance apparatus. This is most commonly the result of hypo-function of the semi-circular canals. Clinically, the most commonly employed objective test of semicircular function is the video Head Impulse Test (vHIT). Here we provide a machine learning approach to a more comprehensible and accurate interpretation of the results obtained by the vHIT to more robustly establish the presence and severity of VOR dysfunction, and ultimately aid in the diagnosis of vestibular disorders.

Machine Learning-Based Scoring System to Predict the Risk and Severity of Ataxic Speech Using Different Speech Tasks.

The assessment of speech in Cerebellar Ataxia (CA) is time-consuming and requires clinical interpretation. In this study, we introduce a fully automated objective algorithm that uses significant acoustic features from time, spectral, cepstral, and non-linear dynamics present in microphone data obtained from different repeated Consonant-Vowel (C-V) syllable paradigms. The algorithm builds machine-learning models to support a 3-tier diagnostic categorisation for distinguishing Ataxic Speech from healthy speech, rating the severity of Ataxic Speech, and nomogram-based supporting scoring charts for Ataxic Speech diagnosis and severity prediction. The selection of features was accomplished using a combination of mass univariate analysis and elastic net regularization for the binary outcome, while for the ordinal outcome, Spearman's rank-order correlation criterion was employed. The algorithm was developed and evaluated using recordings from 126 participants: 65 individuals with CA and 61 controls (i.e., individuals without ataxia or neurotypical). For Ataxic Speech diagnosis, the reduced feature set yielded an area under the curve (AUC) of 0.97 (95% CI 0.90-1), the sensitivity of 97.43%, specificity of 85.29%, and balanced accuracy of 91.2% in the test dataset. The mean AUC for severity estimation was 0.74 for the test set. The high C-indexes of the prediction nomograms for identifying the presence of Ataxic Speech (0.96) and estimating its severity (0.81) in the test set indicates the efficacy of this algorithm. Decision curve analysis demonstrated the value of incorporating acoustic features from two repeated C-V syllable paradigms. The strong classification ability of the specified speech features supports the framework's usefulness for identifying and monitoring Ataxic Speech.

The Electrophysiological Findings in Spinocerebellar Ataxia Type 6: Evidence From 24 Patients.

PURPOSE: Peripheral neuropathy has been reported commonly in several spinocerebellar ataxia (SCA) types. To date, there is a lack of robust evidence for neuropathy or neuronopathy in SCA type 6 (SCA6). Here, we aim to evaluate the presence of neuropathy or neuronopathy in a cohort of SCA6 patients. METHODS: Twenty-four individuals with genetically confirmed SCA6 underwent detailed neurophysiological assessment. This included nerve conduction studies, and in some, cutaneous silent periods, blink reflexes, tilt table tests, quantitative sudomotor axon reflex tests, and somatosensory (median and tibial) evoked potentials. RESULTS: Mean age was 56.1 years (range, 22-94 years) at the time of testing. Four patients were presymptomatic of SCA6 at recruitment. The mean disease duration of symptomatic patients was 11.9 years (range, 1-40 years). Most patients (79.2%, 19/24) had no neurophysiological evidence of a peripheral neuropathy. One with impaired glucose tolerance had mild, large, and small fiber sensorimotor polyneuropathy. One elderly patient had length-dependent axonal sensorimotor polyneuropathy. Two had minor sensory abnormalities (one had type II diabetes and previous chemotherapy). One other had minor small fiber abnormalities. Ten patients (41.7%) had median neuropathies at the wrist. All somatosensory evoked potential (15/15), and most autonomic function tests (13/14) were normal. CONCLUSIONS: A large proportion of subjects (79.2%) in our cohort had no evidence of large or small fiber neuropathy. This study does not support the presence of neuropathy or neuronopathy as a common finding in SCA6 and confirms the importance of considering comorbidities as the cause of neurophysiological abnormalities.

A Bayesian Network Approach for Friedreich Ataxia Severity Classification using Probability Modelling.

Friedreich ataxia (FRDA) requires an objective measure of severity to overcome the shortcoming of clinical scales when applied to trials for treatments. This is hindered due to the rarity of the disease resulting in small datasets. Further, the published quantitative measures for ataxia do not incorporate or underutilise expert knowledge. Bayesian Networks (BNs) provide a structure to adopt both subjective and objective measures to give a severity value while addressing these issues. The BN presented in this paper uses a hybrid learning approach, which utilises both subjective clinical assessments as well as instrumented measurements of disordered upper body movement of individuals with FRDA. The final model's estimates gave a 0.93 Pearson correlation with low error, 9.42 root mean square error and 7.17 mean absolute error. Predicting the clinical scales gave 94% accuracy for Upright Stability and Lower Limb Coordination and 67% accuracy for Functional Staging, Upper Limb Coordination and Activities of Daily Living.Clinical relevance- Due to the nature of rare diseases conventional machine learning is difficult. Most clinical trials only generate small datasets. This approach allows the combination of expert knowledge with instrumented measures to develop a clinical decision support system for the prediction of severity.

A Study of Upper-Limb Motion using Kinematic Measures for Clinical Assessment of Cerebellar Ataxia.

Cerebellar Ataxia (CA) is a group of diseases affecting the cerebellum, which is responsible for movement coordination. It causes uncoordinated movements and can also impact balance, speech, and eye movements. There are no approved disease-modifying medications for CA, so clinical studies to assess potential treatments are crucial. These studies require robust, objective measurements of CA severity to reflect changes in the progression of the disease due to medication. In recent years, studies have used kinematic measures to evaluate CA severity, but the current method relies on subjective clinical observations and is insufficient for telehealth. There is a need for a non-intrusive system that can monitor people with CA regularly to better understand the disease and develop an automated assessment system. In this study, we analyzed kinematic measures of upper-limb movements during a ballistic tracking test, which primarily involves movements at the shoulder joint. We aimed to understand the challenges of identifying CA and evaluating its severity when measuring such movements. Statistical features of the kinematic signals were used to develop machine learning models for classification and regression. The Gradient Boosting Classifier model had a maximum accuracy of 74%, but the models had low specificity and performed poorly in regression, suggesting that kinematic measures from shoulder-dominated movements during ballistic tracking are not as viable for CA assessment as other measures.