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Background: The use of standardized tools and objective measurements is essential to test the effectiveness of new drugs or rehabilitative protocols. Friedreich's ataxia (FRDA) patients with severe disease are often unable to perform the quantitative measurement tests currently used.Aim: The purpose of our study was to develop an easy-to-use application, for touchscreen devices, able to quantify the degree of upper limb movement impairment in patients with severe Friedreich's ataxia. The APP, which we named "Twelve-Red-Squares App-Coo-Test" (12-RSACT), assesses the upper limb ataxia by measuring the test execution time.Methods: All patients were clinically evaluated using the Composite Cerebellar Functional Severity (CCFS) and the Scale for the Assessment and Rating of Ataxia (SARA). We recruited 92 healthy subjects and 36 FRDA patients with a SARA mean value of 28.8.1 ± 8.2. All participants in our study underwent upper limb movement assessment using the new 12-RSACT, the Click Test, and a well-established system, i.e., the Nine-Hole Peg Test (9HPT).Results: We observed a strong linear correlation between the measurements obtained with the 12-RSACT and those obtained with 9HPT, Click Test, CCFS, and SARA. The 12-RSACT was characterized by excellent internal consistency and intra-rater and test-retest reliability. The minimal detectable change (MDC%) was excellent too. Additionally, the 12-RSACT turned out to be faster and easier to perform compared with the 9HPT.Conclusion: The 12-RSACT is an inexpensive test and is easy to use, which can be administered quickly. Therefore, 12-RSACT is a promising tool to assess the upper limb ataxia in FRDA patients and even those with severe diseases. [ABSTRACT FROM AUTHOR]

Background: Cerebellar ataxia is characterized by difficulty in the planning of movement and lack of anticipatory postural adjustments, which can result in deficits of balance. Being able to have quantitative measurements in clinical practice, to detect any improvements on balance resulting from new rehabilitation treatments or experimental drugs is very important. Aim: The purpose of this study was to develop an application (APP) able to assess static and dynamic balance in patients with cerebellar ataxias (CA). The APP that works by a wearable device (smartphone) placed at the breastbone level and immobilized by an elastic band, measures the body sway by means of a triaxial accelerometer. Methods: We investigated 40 CA patients and 80 healthy subjects. All patients were clinically evaluated using the "Berg Balance Scale" (BBS) and the "Scale for the Assessment and Rating of Ataxia" (SARA). Balance impairment was quantitatively assessed using a validated static balance evaluating systems, i.e., Techno-body Pro-Kin footboard. All participants underwent static and dynamic balance assessments using the new APP. Results: We observed a strong correlation between the APP measurements and the score obtained with the BBS, SARA, and Pro-Kin footboard. The intra-rater reliability and the test–retest reliability of the APP measurements, estimated by intraclass correlation coefficient, were excellent. The standard error of measurement and the minimal detectable change were small. No learning effect was observed. Conclusions: We can state that the APP is an easy, reliable, and valid evaluating system to quantify the trunk sway in a static position and during the gait. [ABSTRACT FROM AUTHOR]

Background: The use of objective measurements is essential to assess disease progression and to evaluate the effectiveness of rehabilitation protocols and clinical treatments. Aim: The purpose of this study was to develop a touch-screen application, that we named 15-White Dots APP-Coo-Test (15-WDACT), able to carry out quantitative and objective measurements of the rapid and coordinated upper limb movements, typically impaired in patients with cerebellar ataxias (CA). Methods: A total of 87 CA patients and 170 healthy subjects participated in this study. The subject was asked to touch with their index finger a white dot, appearing consecutively and randomly on the screen at different positions, for a total of 15 dots per session. The score is the execution time of a single session. Results: 15-WDACT measurements have highly correlated with the scores obtained with the Scale for the Assessment and Rating of Ataxia (SARA), with the Composite Cerebellar Functional Severity (CCFS) and with the measurements obtained using two validated evaluating systems, i.e., the Nine Hole Pegboard test (9HPT) and the Click Test. We also observed high internal consistency and an excellent intra-rater and test–retest reliability. We found a small Standard Error of Measurement (SEM) and an excellent Minimal Detectable Change (MDC), indicating that even small variations in the 15-WDACT measurements are to be associated with real changes in performance. Conclusions: We have concluded that 15-WDACT is an easy, fast and reliable tool to assess the severity of the upper limb ataxia in patients with CA. [ABSTRACT FROM AUTHOR]

Friedreich's ataxia is an autosomal recessive progressive degenerative disorder caused by deficiency of the protein frataxin. The most common genetic cause is a homozygotic expansion of GAA triplets within intron 1 of the frataxin gene leading to impaired transcription. Preclinical in vivo and in vitro studies have shown that interferon gamma (IFNγ) is able to up-regulate the expression of frataxin gene in multiple cell types. We designed a phase IIa clinical trial, the first in Italy, aimed at assessing both safety and tolerability of IFNγ in Friedreich's patients and ability to increase frataxin levels in peripheral blood mononuclear cells. Nine patients (6 female and 3 males aged 21-38 years) with genetically confirmed disease were given 3 subcutaneous escalating doses (100, 150 and 200 μg) of IFNγ (human recombinant interferon 1 b gamma, trade name IMUKIN(®)), over 4 weeks. The primary end-point was the assessment of the safety and tolerability of IFNγ by means of standard clinical and hematological criteria. The secondary end-point was the detection of changes of frataxin levels in peripheral blood mononuclear cells after each single escalating dose of the drug. IFNγ was generally well tolerated, the main adverse event was hyperthermia/fever. Although, increases in frataxin levels could be detected in a minority of patients, these changes were not significant. A large phase III multicenter, randomized clinical trial with IFNγ in Friedreich's ataxia patients is currently ongoing. This study is expected to conclusively address the clinical efficacy of IFNγ therapy in patients with Friedreich's ataxia. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disorder manifested by ataxia with a variable presentation of epileptic seizures, which is caused by a large expansion of an intronic ATTCT pentanucleotide repeat in ATXN10 on 22q13.3. Herein, we report the first description of SCA10 in a Peruvian family, supporting the Amerindian origin of SCA10 and the Panamerican geographical distribution of the disease in North, Central and South America. Moreover, the presence of an interruption motif in the SCA10 expansion along with epileptic seizures in this family supports the correlation between the two, as seen in other families. Finally, this is the first SCA10 patient ever observed outside of America, specifically in Italy. Since this patient is a Peruvian immigrant of Amerindian ancestry, our case report highlights the growing need for awareness amongst clinicians of seemingly geographically restricted rare diseases. [ABSTRACT FROM AUTHOR]

Pathogenic mutations in CYP7B1 account for SPG5, an autosomal recessive hereditary spastic paraplegia characterized by a complex phenotype including visual problems and cerebellar dysfunction. Sensory ataxia is not usually regarded as a typical clinical feature of SPG5. The purpose of this study was to describe six patients showing features of sensory ataxia as the prominent and/or initial symptoms of SPG5. Six patients from three distinct pedigrees (three women, three men; age 49.5 ± 18.2 years), all presenting gait unsteadiness and frequent falls since childhood, underwent clinical and molecular investigations. All showed marked sensory ataxic gait with positive Romberg's sign, as well as severely impaired position and vibration sense. Comparatively minor signs of pyramidal involvement were also detected. In four of the patients, brain MRI showed white matter hyperintensities on T2-weighted images. An already reported homozygous c.889A>G (p.T297A) mutation in SPG5/CYP7B1 was found in five patients from two families, whereas the remaining case harbored the novel c.250_251delC/p.L84Ffs*6 and c.266A>C/p.Y89S variants. Marked and enduring sensory ataxia can be a pivotal sign in SPG5, and expands the phenotypic spectrum associated with mutations in CYP7B1. [ABSTRACT FROM AUTHOR]

Mutations in the mitofusin 2 ( MFN2) gene cause CMT2A the most common form of autosomal dominant axonal Charcot-Marie-Tooth (CMT). In addition, mutations in MFN2 have been shown to be responsible for Hereditary Motor Sensory Neuropathy type VI (HSMN VI), a rare early-onset axonal CMT associated with optic neuropathy. Most reports of HMSN VI presented with a sub-acute form of optic neuropathy. Herein, we report a CMT2A patient, who developed very rapidly progressing severe optic neuropathy. A 40-year-old Caucasian man was evaluated for gait disturbance and lower limbs weakness, slowly progressed over the last 2 years. Due to clinical data and family history, a diagnosis of CMT2 was made. The novel heterozygous c.775C > T (p.Arg259Cys) mutation in MFN2 was detected in the patient and his clinical affected mother. Interestingly, the patient developed a severe sudden bilateral visual deterioration few years early, with clinical and instrumental picture suggestive of acute bilateral optic neuropathy. Our report expands the spectrum of MFN2-related manifestation because it indicates that visual symptoms of HMSN VI may enter in the differential with acquired or hereditary acute optic neuropathies, and that severe optic neuropathy is not invariably an early manifestation of the disease but may occur as disease progressed. This report could have an impact on clinicians who evaluate patients with otherwise unexplainable bilateral acute-onset optic neuropathy, especially if associated with a motor and sensory axonal neuropathy. [ABSTRACT FROM AUTHOR]

The article focuses on a case of SPG7-Paraplegin mutation in a 43 year old patient, who first experienced severe visual problems since his childhood. Topics discussed include the medical history of the patient including identification of moderate spastic paraparesis at age 43, as well as identification of the same mutation on his father. Also mentioned is the association of optic neuropathy and SPG7 mutations.

The aim of this pilot study is to test the feasibility and effectiveness of a wearable proprioceptive stabilizer that emits focal mechanical vibrations in patients affected by hereditary cerebellar ataxias. Eleven adult patients with a confirmed genetic diagnosis of autosomal dominant spinocerebellar ataxia or Friedreich's ataxia were asked to wear an active device for 3 weeks. Assessments were performed at baseline, after the device use (T1), and 3 weeks after (T2). SARA, 9-HPT, PATA, 6MWT, and spatial and temporal gait parameters, measured with a BTS-G-Walk inertial sensor, were used as study endpoints. As expected, no adverse effects were reported. Statistically significant improvements in SARA, 9HPT dominant hand, PATA test, 6MWT, cadence, length cycle, support right/cycle, support left/cycle, flight right/cycle, flight left/cycle, double support right/cycle, double support left/cycle, single support right/cycle, and single support left/cycle were observed between T0 and T1. All parameters improved at T1 did not show statistically significant differences a T2, with the exception of length of cycle. This small open-labeled study shows preliminary evidence that focal mechanical vibration exerted by a wearable proprioceptive stabilizer might improve limb and gait ataxia in patients affected by hereditary cerebellar ataxias. [ABSTRACT FROM AUTHOR]

Friedreich's ataxia (FRDA) is a rare autosomal recessive neurodegenerative disorder due to the homozygous pathological expansion of guanine-adenine-adenine (GAA) triplet repeats in the first intron of the FXN gene, which encodes for the mitochondrial protein frataxin. In the visual system, the typical manifestations are ocular motility abnormality, optic neuropathy, and retinopathy. Despite the evidence of ophthalmological impairment in FRDA patients, there is a lack of information about the morpho-functional condition of the retina and of the optic pathways in healthy heterozygous carriers of Friedreich's ataxia (C-FRDA). Ten C-FRDA subjects (providing 20 eyes) and thirty-five Controls (providing 70 eyes) underwent a complete neurological and ophthalmological examination comprehensive of functional (full-field Electroretinogram (ffERG), multifocal Electroretinogram (mfERG), Visual Evoked Potential (VEP), and Pattern Reversal Electroretinogram (PERG)) and morphological assessments (Optical Coherence Tomography, OCT) of the retina, macula, retinal ganglion cells, and visual pathways. The groups' data were compared using a two-sample t-test. Pearson's test was used to investigate the morpho-functional correlations. Statistically significant differences (p < 0.01) between C-FRDA and Control eyes for the values of the following parameters were found: ffERG b-wave amplitude, mfERG Response Amplitude Densities, PERG P50 implicit time and P50-N95 amplitude, VEP P100 implicit time, Retinal Nerve Fiber Layer (RNFL) Overall, and Nasal thickness. The values of the OCT macular volume were not statistically different (p > 0.01) between the two Groups. Therefore, our data suggest that, in C-FRDA, a dysfunction of retinal elements without morphological macular impairment may occur. In addition, a morphological impairment of RNFL associated with an abnormal neural conduction along the visual pathways can be also detected. [ABSTRACT FROM AUTHOR]

Background: Our previous study in patients with cerebellar ataxias of different causes showed significant benefit of riluzole after 8 weeks. We aimed to confirm these results in patients with spinocerebellar ataxia or Friedreich's ataxia in a 1-year trial.Methods: Patients with spinocerebellar ataxia or Friedreich's ataxia (2:1 ratio) from three Italian neurogenetic units were enrolled in this multicentre, double-blind, placebo-controlled trial, and randomly assigned to riluzole (50 mg orally, twice daily) or placebo for 12 months. The randomisation list was computer-generated and a centralised randomisation system was implemented. Participants and assessing neurologists were masked to treatment allocation. The primary endpoint was the proportion of patients with improved Scale for the Assessment and Rating of Ataxia (SARA) score (a drop of at least one point) at 12 months. An intention-to-treat analysis was done. This trial is registered at ClinicalTrials.gov, number NCT01104649.Findings: Between May 22, 2010, and Feb 25, 2013, 60 patients were enrolled. Two patients in the riluzole group and three in the placebo group withdrew their consent before receiving treatment, so the intention-to-treat analysis was done on 55 patients (19 with spinocerebellar ataxia and nine with Friedreich's ataxia in the riluzole group, and 19 with spinocerebellar ataxia and eight with Friedreich's ataxia in the placebo group). The proportion with decreased SARA score was 14 (50%) of 28 patients in the riluzole group versus three (11%) of 27 in the placebo group (OR 8·00, 95% CI 1·95-32·83; p=0·002). No severe adverse events were recorded. In the riluzole group, two patients had an increase in liver enzymes (less than two times above normal limits). In two participants in the riluzole group and two participants in the placebo group, sporadic mild adverse events were reported.Interpretation: Our findings lend support to the idea that riluzole could be a treatment for cerebellar ataxia. Longer studies and disease-specific trials are needed to confirm whether these findings can be applied in clinical practice.Funding: Agenzia Italiana del Farmaco. [ABSTRACT FROM AUTHOR]

SPG56 is an autosomal recessive form of hereditary spastic paraplegia (HSP) associated with mutations in CYP2U1. There is no clear documentation of visual impairment in the few reported cases of SPG56, although this form is complex on clinical ground and visual deficit are extremely frequent in complicated HSP. We report three patients in a consanguineous family harboring the novel homozygous c.1168C>T (p.R390*) in SPG56/ CYP2U1, and showing a pigmentary degenerative maculopathy associated with progressive spastic paraplegia. Furthermore, we characterized precisely the ophthalmologic phenotype through indirect ophthalmoscopy, retinal optical coherence tomography and visual evoked potentials. This is the first formal report of pigmentary degenerative maculopathy associated with a CYP2U1 homozygous mutation. [ABSTRACT FROM AUTHOR]

Background: Patients with degenerative neurological diseases such as cerebellar ataxia, spastic paraplegia, and Parkinson's disease often display progressive gait function decline that inexorably impacts their autonomy and quality of life. Therefore, considering the related social and economic costs, one of the most important areas of intervention in neurorehabilitation should be the treatment of gait abnormalities. This study aims to determine whether an entire dataset of gait parameters recorded in patients with degenerative neurological diseases can be clustered into homogeneous groups distinct from each other and from healthy subjects. Patients affected by three different types of primary degenerative neurological diseases were studied. These diseases were: i) cerebellar ataxia (28 patients), ii) hereditary spastic paraplegia (31 patients), and iii) Parkinson's disease (70 patients). Sixty-five gender-age-matched healthy subjects were enrolled as a control group. An optoelectronic motion analysis system was used to measure time-distance parameters and lower limb joint kinematics during gait in both patients and healthy controls. When clustering single parameters, step width and ankle joint range of motion (RoM) in the sagittal plane differentiated cerebellar ataxia group from the other groups. When clustering sets of two, three, or four parameters, several pairs, triples, and quadruples of clusters differentiated the cerebellar ataxia group from the other groups. Interestingly, the ankle joint RoM parameter was present in 100% of the clusters and the step width in approximately 50% of clusters. In addition, in almost all clusters, patients with cerebellar ataxia showed the lowest ankle joint RoM and the largest step width values compared to healthy controls, patients with hereditary spastic paraplegia, and Parkinson's disease subjects. This study identified several clusters reflecting specific gait patterns in patients with degenerative neurological diseases. In particular, the specific gait pattern formed by the increased step width, reduced ankle joint RoM, and increased gait variability, can differentiate patients with cerebellar ataxia from healthy subjects and patients with spastic paraplegia or Parkinson's disease. These abnormal parameters may be adopted as sensitive tools for evaluating the effect of pharmacological and rehabilitative treatments. [ABSTRACT FROM AUTHOR]

In the present study, the progression of gait impairment in a group of patients with primary degenerative cerebellar ataxias was observed over a period of 4 years. A total of 30 patients underwent an initial gait analysis study, and thereafter only 12 were evaluated because they completed the 2- and 4-year follow-up evaluations. Time-distance parameters, trunk and joint range of motion (RoM), and variability parameters (e.g., coefficients of variation) were measured at the baseline and at each follow-up evaluation. The scale for the assessment and rating of ataxia (SARA) was used to evaluate disease severity. We found a significant increase in the SARA score at both the 2- and 4-year follow-up evaluations. Almost all the gait variables changed significantly only at the 4-year follow-up. Particularly, we found a significant decrease in the step length and in the hip, knee, and ankle joint RoM values and noted a significant increase in the trunk rotation RoM and stride-to-stride and step length variability. Furthermore, a significant difference in ankle joint RoM was found between spinocerebellar ataxia and sporadic adult-onset ataxia patients, with the value being lower in the former group of patients. Our findings suggest that patients with degenerative cerebellar ataxias exhibit gait decline after 4 years from the baseline. Moreover, patients try to maintain an effective gait by adopting different compensatory mechanisms during the course of the disease in spite of disease progression. [ABSTRACT FROM AUTHOR]

Background: Friedreich ataxia is an autosomal recessive disease with no available therapy. Clinical trials with erythropoietin in Friedreich ataxia patients have yielded conflicting results, and the long-term effect of the drug remains unknown.Methods: We designed a double-blind, placebo-controlled, multicenter trial to test the efficacy of epoetin alfa on 56 patients with Friedreich ataxia. The primary endpoint of the study was the effect of epoetin alfa on peak oxygen uptake (VO2 max) at the cardiopulmonary exercise test. Secondary endpoints were frataxin levels in peripheral blood mononuclear cells, improvement in echocardiography findings, vascular reactivity, neurological progression, upper limb dexterity, safety, and quality of life. Epoetin alfa or placebo (1:1 ratio) was administered subcutaneously at a dose of 1200 IU/Kg of body weight every 12 weeks for 48 weeks.Results: A total of 56 patients were randomized; 27 completed the study in the active treatment group, and 26 completed the study in the placebo group[KG1]. VO2 max was not modified after treatment (0.01 [-0.04 to 0.05]; P = .749), as well as most of the secondary endpoint measures, including frataxin. The 9-hole peg test showed a significant amelioration in the treatment group (-17.24 sec. [-31.5 to -3.0]; P = .018). The treatment was safe and well tolerated.Conclusions: Although results are not in favor of an effect of epoetin alfa in Friedreich ataxia, this is the largest trial testing its effect. It is still possible that epoetin alfa may show some symptomatic effect on upper-limb performance. This study provides class I evidence that erythropoietin does not ameliorate VO2 max in patients with Friedreich ataxia. © 2016 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Objective: Resting state electroencephalographic (EEG) rhythms are abnormal in multiple sclerosis (MS) patients, but it is unclear if they can reflect different neurophysiologic abnormalities in MS sub-types (phenotypes) such as relapsing-remitting (RR) and secondary progressive (SP). Methods: We tested whether cortical sources of resting state EEG rhythms are abnormal in MS patients and differ between MS phenotypes. Resting state eyes-closed EEG activity was recorded in 36 RR, 23 SP, and 41 matched healthy subjects. EEG bands of interest were individually identified based on Transition frequency (TF), Individual alpha frequency (IAF), and Individual beta frequency (IBF). LORETA freeware estimated cortical EEG sources. Results: Widespread TF -4 Hz (delta) and IAF (alpha) cortical sources were abnormal in the MS sub-groups compared to the control group. Furthermore, TF 4 Hz sources in central, parietal, and limbic regions were higher in amplitude in the SP compared to the RR sub-group. Conclusion: Cortical sources of resting state EEG rhythms are abnormal in MS patients at group level and differ between RR and SP sub-groups. Significance: Future studies should test the utility of these EEG markers in the diagnosis and management of MS clinical phenotypes and in the therapy evaluation. [ABSTRACT FROM AUTHOR]

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare neurodegenerative disorder characterized by ataxia, spastic paraparesis, polyneuropathy, and evidence of superior cerebellar vermis atrophy at magnetic resonance imaging (MRI). Reports of atypical presentations and additional clinical or MRI findings have been recently published, but psychiatric disturbances have never been associated with ARSACS. We describe four ARSACS patients manifesting severe psychiatric symptoms including psychosis, panic disorder, and depression during the course of the disease. Our case reports further expand the ARSACS phenotype and add clinical data in favor of the hypothesized relationship between cerebellar dysfunction and psychiatric disorders. [ABSTRACT FROM AUTHOR]