Robotic and clinical evaluation of upper limb motor performance in patients with Friedreich's Ataxia: an observational study

Background: Friedreich’s ataxia (FRDA) is the most common hereditary autosomal recessive form of ataxia. In this disease there is early manifestation of gait ataxia, and dysmetria of the arms and legs which causes impairment in daily activities that require fine manual dexterity. To date there is no cure for this disease. Some novel therapeutic approaches are ongoing in different steps of clinical trial. Development of sensitive outcome measures is crucial to prove therapeutic effectiveness. The aim of the study was to assess the reliability and sensitivity of quantitative and objective assessment of upper limb performance computed by means of the robotic device and to evaluate the correlation with clinical and functional markers of the disease severity. Methods: Here we assess upper limb performances by means of the InMotion Arm Robot, a robot designed for clinical neurological applications, in a cohort of 14 children and young adults affected by FRDA, matched for age and gender with 18 healthy subjects. We focused on the analysis of kinematics, accuracy, smoothness, and submovements of the upper limb while reaching movements were performed. The robotic evaluation of upper limb performance consisted of planar reaching movements performed with the robotic system. The motors of the robot were turned off, so that the device worked as a measurement tool. The status of the disease was scored using the Scale for the Assessment and Rating of Ataxia (SARA). Relationships between robotic indices and a range of clinical and disease characteristics were examined. Results: All our robotic indices were significantly different between the two cohorts except for two, and were highly and reliably discriminative between healthy and subjects with FRDA. In particular, subjects with FRDA exhibited slower movements as well as loss of accuracy and smoothness, which are typical of the disease. Duration of Movement, Normalized Jerk, and Number of Submovements were the best discriminative indices, as they were directly and easily measurable and correlated with the status of the disease, as measured by SARA. Conclusions: Our results suggest that outcome measures obtained by means of robotic devices can improve the sensitivity of clinical evaluations of patients’ dexterity and can accurately and efficiently quantify changes over time in clinical trials, particularly when functional scales appear to be no longer sensitive

Non-invasive Focal Mechanical Vibrations Delivered by Wearable Devices: An Open-Label Pilot Study in Childhood Ataxia

Non-invasive focal mechanical vibrations (NIFMV) now represent a strategy of increasing interest to improve motor control in different neurological diseases. Nanotechnology allowed the creation of wearable devices transforming thermal variations into mechanical energy with focal vibrations. This kind of wearable stimulators (WS) has produced encouraging preliminary results when used in the treatment of movement disorders and ataxia in adults. In this open label pilot study we first evaluated the feasibility, safety and effectiveness of NIFMV by WS in a cohort of 10 patients with childhood ataxia, a phenomenological category including different conditions still lacking of effective symptomatic therapies. Through the assessment of both clinical rating scales and spatio-temporal gait parameters via standardized gait analysis, we observed that a 4 weeks long treatment with WS Equistasi® was safe and provided significantly different effects in stride features of patients with slow/non-progressive cerebellar ataxia and Friedreich's Ataxia. Although limited by the sample size, the absence of a placebo-controlled group, the poor compliance of enrolled population to the original experimental design and the partial accuracy of outcome measures in pediatric subjects, we suggest that NIFMV by WS could support locomotion of patients with childhood slow/non-progressive cerebellar ataxia with preserved sensory system and no signs of peripheral neuropathy. Future studies are definitely necessary to confirm these preliminary results and define criteria for successful NIFMV-based treatmen

Artificial Intelligence for Dysarthria Assessment in Children With Ataxia: A Hierarchical Approach

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Case Series and DARS2 Variant Analysis in Early Severe Forms With Unexpected Presentations

Objective: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is regarded a relatively mild leukodystrophy, diagnosed by characteristic long tract abnormalities on MRI and biallelic variants in DARS2, encoding mitochondrial aspartyl-tRNA synthetase (mtAspRS). DARS2 variants in LBSL are almost invariably compound heterozygous; in 95% of cases, 1 is a leaky splice site variant in intron 2. A few severely affected patients, still fulfilling the MRI criteria, have been described. We noticed highly unusual MRI presentations in 15 cases diagnosed by WES. We examined these cases to determine whether they represent consistent novel LBSL phenotypes. Methods: We reviewed clinical features, MRI abnormalities, and gene variants and investigated the variants' impact on mtAspRS structure and mitochondrial function. Results: We found 2 MRI phenotypes: early severe cerebral hypoplasia/atrophy (9 patients, group 1) and white matter abnormalities without long tract involvement (6 patients, group 2). With antenatal onset, microcephaly, and arrested development, group 1 patients were most severely affected. DARS2 variants were severer than for classic LBSL and severer for group 1 than group 2. All missense variants hit mtAspRS regions involved in tRNAAsp binding, aspartyl-adenosine-5'-monophosphate binding, and/or homodimerization. Missense variants expressed in the yeast DARS2 ortholog showed severely affected mitochondrial function. Conclusions: DARS2 variants are associated with highly heterogeneous phenotypes. New MRI presentations are profound cerebral hypoplasia/atrophy and white matter abnormalities without long tract involvement. Our findings have implications for diagnosis and understanding disease mechanisms, pointing at dominant neuronal/axonal involvement in severe cases. In line with this conclusion, activation of biallelic DARS2 null alleles in conditional transgenic mice leads to massive neuronal apoptosis

Clinico-Genetic, Imaging and Molecular Delineation of COQ8A-Ataxia: A Multicenter Study of 59 Patients.

OBJECTIVE: To foster trial-readiness of coenzyme Q8A (COQ8A)-ataxia, we map the clinicogenetic, molecular, and neuroimaging spectrum of COQ8A-ataxia in a large worldwide cohort, and provide first progression data, including treatment response to coenzyme Q10 (CoQ10). METHODS: Cross-modal analysis of a multicenter cohort of 59 COQ8A patients, including genotype-phenotype correlations, 3D-protein modeling, in vitro mutation analyses, magnetic resonance imaging (MRI) markers, disease progression, and CoQ10 response data. RESULTS: Fifty-nine patients (39 novel) with 44 pathogenic COQ8A variants (18 novel) were identified. Missense variants demonstrated a pleiotropic range of detrimental effects upon protein modeling and in vitro analysis of purified variants. COQ8A-ataxia presented as variable multisystemic, early-onset cerebellar ataxia, with complicating features ranging from epilepsy (32%) and cognitive impairment (49%) to exercise intolerance (25%) and hyperkinetic movement disorders (41%), including dystonia and myoclonus as presenting symptoms. Multisystemic involvement was more prevalent in missense than biallelic loss-of-function variants (82-93% vs 53%; p = 0.029). Cerebellar atrophy was universal on MRI (100%), with cerebral atrophy or dentate and pontine T2 hyperintensities observed in 28%. Cross-sectional (n = 34) and longitudinal (n = 7) assessments consistently indicated mild-to-moderate progression of ataxia (SARA: 0.45/year). CoQ10 treatment led to improvement by clinical report in 14 of 30 patients, and by quantitative longitudinal assessments in 8 of 11 patients (SARA: -0.81/year). Explorative sample size calculations indicate that ≥48 patients per arm may suffice to demonstrate efficacy for interventions that reduce progression by 50%. INTERPRETATION: This study provides a deeper understanding of the disease, and paves the way toward large-scale natural history studies and treatment trials in COQ8A-ataxia. ANN NEUROL 2020;88:251-263

Clinical variability at the mild end of BRAT1‐related spectrum: Evidence from two families with genotype–phenotype discordance

Biallelic mutations in the BRAT1 gene, encoding BRCA1-associated ATM activator 1, result in variable phenotypes, from rigidity and multifocal seizure syndrome, lethal neonatal to neurodevelopmental disorder, and cerebellar atrophy with or without seizures, without obvious genotype-phenotype associations. We describe two families at the mildest end of the spectrum, differing in clinical presentation despite a common genotype at the BRAT1 locus. Two siblings displayed nonprogressive congenital ataxia and shrunken cerebellum on magnetic resonance imaging. A third unrelated patient showed normal neurodevelopment, adolescence-onset seizures, and ataxia, shrunken cerebellum, and ultrastructural abnormalities on skin biopsy, representing the mildest form of NEDCAS hitherto described. Exome sequencing identified the c.638dup and the novel c.1395G>A BRAT1 variants, the latter causing exon 10 skippings. The p53-MCL test revealed normal ATM kinase activity. Our findings broaden the allelic and clinical spectrum of BRAT1-related disease, which should be suspected in presence of nonprogressive cerebellar signs, even without a neurodevelopmental disorder

Time to boundary function to assess upright stance in blind children

The goal of this preliminary study was to assess the difference in postural stability between blind and sighted children using the Time to Boundary function (TtB)