Speech and Language Disorders in Friedreich Ataxia: Highlights on Phenomenology, Assessment, and Therapy.

Speech and language disorders are prominent signs in Friedreich ataxia (FRDA), which significantly impact on patients' quality of life. Despite such relevance, several issues regarding phenomenology, assessment, and treatment are still unmet. In this short review, we thus analyzed the existing literature to summarize what is known about the features of speech and language disorders in FRDA, which methods are used for evaluation and rating, and what are the available therapeutic strategies and future direction of scientific research in this field, in order to highlight critical aspects for a better clinical approach to the problem. FRDA patients often present dysarthria, resulting from central and peripheral causes and additional primary language disorders. Speech disturbances have peculiar characteristics, although variable among patients, and progress along the disease course. Assessment relies on multiple but not specific clinical scales, some of which can also reflect the general severity of ataxia; classical instrumental investigations and novel technologies allow more accurate measurements of several speech parameters, which could found application as potential disease's biomarkers. No successful treatments exist for communication disorders of FRDA patients; however, the tailored speech training or the non-invasive neuromodulation appear as the most reliable therapeutic options to be validate in future trials.

Intensive Postural and Motor Activity Program Reduces Scoliosis Progression in People with Rett Syndrome.

BACKGROUND: A scoliosis prevalence of 94% was reported in the population with Rett syndrome (RTT), with an annual progression rate of 14 to 21° Cobb which may result in pain, loss of sitting balance, deterioration of motor skills, and lung disfunction. This paper describes the efficacy of an intensive conservative individualized physical and postural activity program in preventing scoliosis curvature progression in patients with RTT. METHODS: Twenty subjects diagnosed with RTT and scoliosis were recruited, and an individualized intensive daily physical activity program was developed for each participant. Each program was conducted for six months by participants' primary caregivers in their daily living environment. Fortnightly remote supervision of the program implementation was provided by an expert therapist. Pre- and post-intervention radiographs and motor functioning were analyzed. RESULTS: An averaged progression of +1.7° ± 8.7° Cobb, over one year (12.3 ± 3.5 months) was observed in our group, together with motor function improvements. A relation between curve progression and motor skill improvement was observed. CONCLUSIONS: The intervention prevented scoliosis progression in our group. The achievement of functional motor improvements could enable better body segment control and muscle balancing, with a protective effect on scoliosis progression. The intervention was effective for individuals with RTT across various ages and severity levels. Individual characteristics of each participant and the details of their activity program are described.

Friedreich ataxia in COVID-19 time: current impact and future possibilities.

COVID-19 outbreak profoundly impacted on daily-life of patients with neurodegenerative diseases, including those with ataxia. Effects on interventional trials have been recently described. Conversely, changes in physical activity programs, which are crucial in care of ataxic patients, have not been assessed yet.Here we used a structured electronic survey to interview twenty patients with Friedreich ataxia (FA) on changes in physical activity during the lockdown in Italy.Regular physiotherapy was interrupted for most patients and up to 60% of them referred a substantial worsening of self-perceived global health. However, FA patients (especially those mildly affected) adopted voluntarily home-based training strategies and, in 30% of cases, used technology-based tools (TBTs) for exercise.COVID-19 crisis thus disclosed the urgent need to support ataxic patients improving systems for remote physical activity and technology-based assistance.

Expanding the Clinical and Mutational Spectrum of the PLP1-Related Hypomyelination of Early Myelinated Structures (HEMS).

The PLP1 gene, located on chromosome Xq22, encodes the proteolipid protein 1 and its isoform DM20. Mutations in PLP1 cause a spectrum of white matter disorders of variable severity. Here we report on four additional HEMS patients from three families harboring three novel PLP1 mutations in exon 3B detected by targeted next-generation sequencing. Patients experienced psychomotor delay or nystagmus in the first year of age and then developed ataxic-spastic or ataxic syndrome, compatible with a phenotype of intermediate severity in the spectrum of PLP1-related disorders. Regression occurred at the beginning of the third decade of the eldest patient. Extrapyramidal involvement was rarely observed. Brain MRI confirmed the involvement of structures that physiologically myelinate early, although the pattern of abnormalities may differ depending on the age at which the study is performed. These new cases contribute to expanding the phenotypic and genotypic spectrum of HEMS. Additional studies, especially enriched by systematic functional evaluations and long-term follow-up, are welcome to better delineate the natural history of this rare hypomyelinating leukodystrophy.

Movement disorders in ADAR1 disease: Insights from a comprehensive cohort.

ADAR1 variants are associated to rare and heterogenous neurological conditions, including Aicardi-Goutières syndrome type 6, bilateral striatal necrosis, and dyschromatosis symmetrica hereditaria. Movement disorders (MDs) commonly occur in ADAR1-related diseases although a complete overview on the phenomenology has not been provided yet. Here, a cohort of 57 patients with ADAR1-related diseases, including 3 unpublished patients and 54 previously reported cases, was reviewed. Data on demographics, clinical features of MDs, genetics and biomarkers were collected and descriptive statistics, group analysis for genotype and logistic regression were run. Manifestations of MD characterized the onset of ADAR1-related disease in 60% of patients. Specifically, dystonia occurred in 39% of cases, even as severe status dystonicus, while prevalence of other MDs was lower. Patients often presented brain lesions (>90%) and progressive disease course (43%), fatal in some cases. Clinical presentation and outcome differed among patients with distinct genotype. This review shows that phenomenology of MDs in ADAR1-related diseases is wide and heterogeneous, although a severe motor syndrome (often characterized by dystonia) secondary to brain lesions represents the most common manifestation. Waiting for future development of disease-modifying treatments, an appropriate symptomatic intervention is crucial for ADAR1 patients. Accordingly, a deeper knowledge of phenomenology is fundamental.

A wearable video-oculography based evaluation of saccades and respective clinical correlates in patients with early onset ataxia.

BACKGROUND: Friedreich Ataxia (FRDA) and other inherited chronic ataxias (CAs) are common causes of early onset ataxias (EOA), a group of conditions still lacking effective therapies and biomarkers. Ocular saccades are considered a reliable paradigm of motor control, useful to track the functioning of underlying neural networks and serving as potential markers for neurological diseases. NEW METHOD: A non-invasive video-oculography device (EyeSeeCam) was used to test saccadic parameters (latency, amplitude, duration, velocity) and peak velocity/amplitude ratio ("main sequence") in pediatric patients with FRDA, CAs and healthy controls, providing correlations with standard clinical scores. RESULTS: Pattern of saccadic features differed between CA and FRDA. The main sequence analysis was impaired respectively in vertical saccades in CA, and in horizontal saccades in FRDA. In CA, the amplitude of vertical saccades was reduced, and the size inversely correlated with the Scale for the assessment and rating of ataxia (SARA) score. In FRDA the amplitude of horizontal saccades directly correlated with SARA score. COMPARISON WITH EXISTING METHOD: EyeSeeCam allowed testing saccades easily and quickly even in pediatric patients with EOA. CONCLUSIONS: The pattern of saccadic impairment differed between FRDA and CAs, resulting a prominent involvement of vertical saccades in CA and of horizontal ones in FRDA, which respectively correlated with SARA score. Since such differences may reflect distinct pathophysiological substrates, saccades emerged as a potential source of biomarkers in EOAs. Availability of handy tools, such as EyeSeeCam, may facilitate future research in this field.

Practice-dependent motor cortex plasticity is reduced in non-disabled multiple sclerosis patients.

OBJECTIVES: Skill acquisition after motor training involves synaptic long-term potentiation (LTP) in primary motor cortex (M1). In multiple sclerosis (MS), LTP failure ensuing from neuroinflammation could contribute to worsen clinical recovery. We therefore addressed whether practice-dependent plasticity is altered in MS. METHODS: Eighteen relapsing-remitting (RR)-MS patients and eighteen healthy controls performed 600 fast abductions of index finger in 30 blocks of 20 movements. Before and after practice, transcranial magnetic stimulation (TMS) was delivered over the hot spot of the trained first dorsal interosseous muscle. Movements kinematics, measures of cortical excitability, and the input/output curves of motor evoked potentials (MEPs) were assessed. RESULTS: Kinematic variables of movement improved with practice in patients and controls to a similar extent, although patients showed lower MEPs amplitude increase after practice. Practice did not change the difference in resting motor threshold values observed between patients and controls, nor did modulate short-interval intracortical inhibition. Clinical/radiological characteristics were not associated to practice-dependent effects. CONCLUSIONS: Practice-induced reorganization of M1 is altered in non-disabled RR-MS patients, as shown by impaired MEPs modulation after motor learning. SIGNIFICANCE: These findings suggest that in RR-MS physiological mechanisms of practice-dependent plasticity are altered.

One-year outcome of coenzyme Q10 supplementation in ADCK3 ataxia (ARCA2).

BACKGROUND: The recessive ataxia ARCA2 is a rare disorder characterized by Coenzyme Q10 (CoQ10) deficiency due to biallelic mutations in ADCK3 gene. Despite the pathophysiological role, available data are not univocal on clinical efficacy of CoQ10 supplementation in ARCA2. Here we described the long-term motor outcome of 4 untreated ARCA2 patients prospectively followed-up for one year after starting CoQ10 oral supplementation (15 mg/kg/day). METHODS: Clinical rating scales (SARA; 9 holes peg test; 6 min walking test; Timed 25-Foot Walk) and videoelectronic gait analysis were performed at baseline and every 6 months (T0, T1, T2) to evaluate the motor performances. Since two patients discontinued the treatment at the 7th month, we could provide comparative analysis between longer and shorter supplementation. RESULTS: At T2, the gait speed (Timed 25-Foot Walk test) significantly differed between patients with long and short treatment; overall, the clinical condition tended to be better in patients continuing CoQ10. CONCLUSIONS: Although preliminarily, this observation suggests that only prolonged and continuous CoQ10 supplementation may induce mild clinical effects on general motor features of ARCA2. Dedicated trials are now necessary to extend and validate such observation.

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 treatment.

Longitudinal gait assessment in a stiff person syndrome.

Stiff person syndrome (SPS) is an autoimmune disorder with multiple clinical presentations, all characterized by generalized or focal muscular stiffness leading to abnormal postures and movements. To date, no standardized treatments are available; also, the outcome measures are mainly clinical based and unstandardized, limiting the reliability of clinical trials. In this case study, we used the eight-camera motion capture system for gait analysis (GA) to outline the gait features and track the clinical evolution of a young patient with SPS receiving a personalized multimodal therapy. GA was accurate in reflecting clinical changes over a 7-week-long period, thus representing a potential source for objective biomarkers in SPS. Therefore, future studies focusing on either the natural history or the treatment of SPS could adopt GA for reliable outocome measures, confirming this preliminary observation.

Cannabinoids in Parkinson's Disease.

The endocannabinoid system plays a regulatory role in a number of physiological processes and has been found altered in different pathological conditions, including movement disorders. The interactions between cannabinoids and dopamine in the basal ganglia are remarkably complex and involve both the modulation of other neurotransmitters (γ-aminobutyric acid, glutamate, opioids, peptides) and the activation of different receptors subtypes (cannabinoid receptor type 1 and 2). In the last years, experimental studies contributed to enrich this scenario reporting interactions between cannabinoids and other receptor systems (transient receptor potential vanilloid type 1 cation channel, adenosine receptors, 5-hydroxytryptamine receptors). The improved knowledge, adding new interpretation on the biochemical interaction between cannabinoids and other signaling pathways, may contribute to develop new pharmacological strategies. A number of preclinical studies in different experimental Parkinson's disease (PD) models demonstrated that modulating the cannabinoid system may be useful to treat some motor symptoms. Despite new cannabinoid-based medicines have been proposed for motor and nonmotor symptoms of PD, so far, results from clinical studies are controversial and inconclusive. Further clinical studies involving larger samples of patients, appropriate molecular targets, and specific clinical outcome measures are needed to clarify the effectiveness of cannabinoid-based therapies.

Neurophysiology of synaptic functioning in multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory immune-mediate disorder of the central nervous system (CNS), primarily affecting the myelin sheath and followed by neurodegeneration. Synaptic alterations are emerging as critical determinants of early neurodegeneration in MS. Inflammation-induced alterations of synaptic transmission and plasticity have been investigated in vitro and also in human MS using transcranial magnetic stimulation (TMS) techniques. Specific inflammatory cytokines alter glutamatergic and GABAergic transmission, resulting in synaptic hyperexcitability. In both experimental autoimmune encephalomyelitis (EAE) and MS, excitotoxic damage and neurodegeneration are found even in the early phases of disease, conversely inflammation persists in the progressive phases. Inflammatory cytokines also affect synaptic plasticity, as both long-term potentiation (LTP) and long-term depression (LTD) are altered in EAE and in MS patients. In particular, inflammation profoundly subverts plasticity and influence both clinical recovery after a relapse and disease course. Regulation of neuronal activity by cytokines plays important roles in the neuro-immune crosstalk involved in inflammation-associated excitotoxic neuronal damage, and in the chance of developing compensatory plasticity. Innate and adaptive immunity interact with the CNS in MS, in line with the concept that cytokines and chemokines, in concert with neurotransmitters and neuropeptides, represent a major communication system in the CNS.

Transcranial magnetic stimulation primes the effects of exercise therapy in multiple sclerosis.

Exercise therapy (ET) can be beneficial in disabled multiple sclerosis (MS) patients. Intermittent transcranial magnetic theta burst stimulation (iTBS) induces long-term excitability changes of the cerebral cortex and may ameliorate spasticity in MS. We investigated whether the combination of iTBS and a program of ET can improve motor disability in MS patients. In a double-blind, sham-controlled trial, 30 participants were randomized to three different interventions: iTBS plus ET, sham stimulation plus ET, and iTBS alone. Before and after 2 weeks of treatment, measures of spasticity through the modified Ashworth scale (MAS) and the 88 items Multiple Sclerosis Spasticity Score questionnaire (MSSS-88), fatigue through the Fatigue Severity Scale (FSS), daily living activities (ADL) through the Barthel index and health-related quality of life (HRQoL) through the 54 items Multiple Sclerosis Quality of life inventory (MSQoL-54) were collected. iTBS plus ET reduced MAS, MSSS-88, FSS scores, while in the Barthel index and MSQoL-54, physical composite scores were increased. iTBS alone caused a reduction of the MAS score, while none of the measured scales showed significant changes after sham iTBS plus ET. iTBS associated with ET is a promising tool for motor rehabilitation of MS patients.