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The spectrum of coenzyme Q 10 (CoQ 10 ) deficiency syndromes comprises a variety of disorders, including a form of autosomal recessive cerebellar ataxia (ARCA2) caused by mutations in the AarF domain-containing kinase 3 gene (ADCK3). Due to the potential response to CoQ 10 supplementation, a timely diagnosis is crucial. Herein, we describe two siblings with a novel homozygous ADCK3 variant and an unusual presentation consisting of isolated writer's cramp with adult-onset. Cerebellar ataxia developed later in the disease course and remained stable during the follow-up. This report highlights that ARCA2 should be considered in the differential diagnosis of familial writer's cramp.

Friedreich's ataxia (FRDA) is a rare genetic disorder leading to degenerative processes. So far, no effective treatment has been found. Therefore, it is important to assist the development of medication with imaging biomarkers reflecting disease status and progress. Ten FRDA patients (mean age 37 ± 14 years; four female) and 10 age- and sex-matched controls were included. Acquisition of magnetic resonance imaging (MRI) data for quantitative susceptibility mapping, R 1 , R 2 relaxometry and diffusion imaging was performed at 7 Tesla. Results of volume of interest (VOI)-based analyses of the quantitative data were compared with a voxel-based morphometry (VBM) evaluation. Differences between patients and controls were assessed using the analysis of covariance (ANCOVA; p < 0.01) with age and sex as covariates, effect size of group differences, and correlations with disease characteristics with Spearman correlation coefficient. For the VBM analysis, a statistical threshold of 0.001 for uncorrected and 0.05 for corrected p-values was used. Statistically significant differences between FRDA patients and controls were found in five out of twelve investigated structures, and statistically significant correlations with disease characteristics were revealed. Moreover, VBM revealed significant white matter atrophy within regions of the brainstem, and the cerebellum. These regions overlapped partially with brain regions for which significant differences between healthy controls and patients were found in the VOI-based quantitative MRI evaluation. It was shown that two independent analyses provided overlapping results. Moreover, positive results on correlations with disease characteristics were found, indicating that these quantitative MRI parameters could provide more detailed information and assist the search for effective treatments., (© 2020 The Authors. Journal of Neuroscience Research published by Wiley Periodicals LLC.)

Background: In rare disorders diagnosis may be delayed due to limited awareness and unspecific presenting symptoms. Herein, we address the issue of diagnostic delay in Friedreich's Ataxia (FRDA), a genetic disorder usually caused by homozygous GAA-repeat expansions., Methods: Six hundred eleven genetically confirmed FRDA patients were recruited within a multicentric natural history study conducted by the EFACTS (European FRDA Consortium for Translational Studies, ClinicalTrials.gov -Identifier NCT02069509). Age at first symptoms as well as age at first suspicion of FRDA by a physician were collected retrospectively at the baseline visit., Results: In 554 of cases (90.7%), disease presented with gait or coordination disturbances. In the others (n = 57, 9.3%), non-neurological features such as scoliosis or cardiomyopathy predated ataxia. Before the discovery of the causal mutation in 1996, median time to diagnosis was 4(IQR = 2-9) years and it improved significantly after the introduction of genetic testing (2(IQR = 1-5) years, p < 0.001). Still, after 1996, time to diagnosis was longer in patients with a) non-neurological presentation (mean 6.7, 95%CI [5.5,7.9] vs 4.5, [4.2,5] years in those with neurological presentation, p = 0.001) as well as in b) patients with late-onset (3(IQR = 1-7) vs 2(IQR = 1-5) years compared to typical onset < 25 years of age, p = 0.03). Age at onset significantly correlated with the length of the shorter GAA repeat (GAA1) in case of neurological onset (r = - 0,6; p < 0,0001), but not in patients with non-neurological presentation (r = - 0,1; p = 0,4). Across 54 siblings' pairs, differences in age at onset did not correlate with differences in GAA-repeat length (r = - 0,14, p = 0,3)., Conclusions: In the genetic era, presentation with non-neurological features or in the adulthood still leads to a significant diagnostic delay in FRDA. Well-known correlations between GAA1 repeat length and disease milestones are not valid in case of atypical presentations or positive family history.

Background: Cerebellar ataxias are a heterogeneous group of disorders of both genetic and non-genetic origin. In sporadic cases, two entities are recognized: multiple system atrophy of cerebellar type (MSA-C) and SAOA (sporadic adult-onset ataxia). The presence of severe cardiovascular autonomic failure reliably distinguishes MSA-C from other ataxias, but it may appear only late in the disease course., Objective: To evaluate the diagnostic yield of cardiovascular autonomic function tests in the work-up of cerebellar ataxia., Methods: We applied a cardiovascular autonomic tests battery in consecutive patients with neurodegenerative cerebellar ataxia and matched healthy controls. We recorded the presence of both orthostatic hypotension (OH) and blood pressure falls non-fulfilling the criteria of OH (non-OH BP). Sporadic cases were followed-up for an eventual conversion to MSA-C., Results: Forty-two patients were recruited, 19 of whom with sporadic disease (2 probable MSA-C, 6 possible MSA-C, 11 SAOA). Sporadic and hereditary cases showed no difference concerning ataxia severity at baseline. At head-up tilt, non-OH BP falls were detected in nine patients, but not in controls. This finding was significantly more frequent in sporadic cases (p = 0.006) and was detected in five out of seven patients that during follow-up converted to possible/probable MSA-C. Findings at standing test were normal in four out of nine cases with non-OH BP falls at head-up tilt., Conclusions: A complete cardiovascular autonomic battery with head-up tilt can detect early signs of BP dysregulation which may be missed at bed-side tests, thus warranting its application in the first line work-up of cerebellar ataxias.

Introduction: SYNE1 encodes nesprin-1, a scaffold protein which is involved in the binding between cytoskeleton, nuclear envelope and other subcellular compartments. In 2007, recessive truncating SYNE1 mutations have been linked to a genetic form of pure cerebellar ataxia with adult onset and mild phenotype. Subsequent reports described a number of patients with SYNE1-ataxia and widespread neurological involvement including features of motor neuron disease. Recently, heterozygote missense SYNE1 mutations have been associated with muscular disorders, such as Emery-Dreifuss muscular dystrophy, arthrogryposis multiplex congenita and dilated cardiomyopathy., Methods: Herein we describe novel genotypic and phenotypic findings in an independent cohort of 5 patients with SYNE1-ataxia referring to the Department of Neurology of the Innsbruck Medical University and performed a review of the related literature., Results: We report 3 novel mutations and describe for the first time myocardial involvement in a patient with a complicated spastic-ataxic phenotype and C-terminal mutation. In the literature, mutations associated with additional motor neuron signs spanned over the entire gene, but patients with a particularly severe phenotype and premature death bore C-terminal mutations., Conclusion: Our findings support a genotype-phenotype correlation in SYNE1-ataxia and suggest the need for a systematic cardiologic evaluation in the setting of complicated spastic-ataxia phenotypes., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Friedreich ataxia (FRDA) is a rare neurological disorder due to deficiency of the mitochondrial protein frataxin. Frataxin deficiency results in impaired mitochondrial function and iron deposition in affected tissues. Erythropoietin (EPO) is a cytokine which was mostly known as a key regulator of erythropoiesis until cumulative evidence showed additional neurotrophic and neuroprotective properties. These features offered the rationale for advancement of EPO in clinical trials in different neurological disorders in the past years, including FRDA. Several mechanisms of action of EPO may be beneficial in FRDA. First of all, EPO exposure results in frataxin upregulation in vitro and in vivo . By promoting erythropoiesis, EPO influences iron metabolism and induces shifts in iron pool which may ameliorate conditions of free iron excess and iron accumulation. Furthermore, EPO signaling is crucial for mitochondrial gene activation and mitochondrial biogenesis. Up to date nine clinical trials investigated the effects of EPO and derivatives in FRDA. The majority of these studies had a proof-of-concept design. Considering the natural history of FRDA, all of them were too short in duration and not powered for clinical changes. However, these studies addressed significant issues in the treatment with EPO, such as (1) the challenge of the dose finding, (2) stability of frataxin up-regulation, (3) continuous versus intermittent stimulation with EPO/regimen, or (4) tissue changes after EPO exposure in humans in vivo (muscle biopsy, brain imaging). Despite several clinical trials in the past, no treatment is available for the treatment of FRDA. Current lines of research focus on gene therapy, frataxin replacement strategies and on regulation of key metabolic checkpoints such as NrF2. Due to potential crosstalk with all these mechanisms, interventions on the EPO pathway still represent a valuable research field. The recent development of small EPO mimetics which maintain cytoprotective properties without erythropoietic action may open a new era in EPO research for the treatment of FRDA.

Friedreich's Ataxia (FRDA) is caused by a homozygous intronic GAA expansion in the FXN gene. FRDA affects primarily the peripheral nervous system (PNS) with cumulative evidence from postmortem studies and in vitro models suggesting a developmental component of its pathology. In the present study, we aimed at gaining further insight in the PNS involvement in FRDA by investigating small nerve fibers in vivo. For this purpose, we evaluated the intraepidermal nerve fiber (IENF) density in skin-biopsies of the lower leg and applied clinical assessments of small fiber function (painDETECT, quantitative sensory testing) in 17 FRDAs. Mean IENF density was significantly lower in FRDAs compared to controls (5.77 ± 4.68 vs 9.33 ± 1.41, p = 0.013). Clinically, cold detection threshold was decreased in FRDAs (FRDA = -3.47(-6.64; -3.14), controls = -1.71 (-3.43; -1.23), p = 0.001) while other measures of small fiber function such as warm and pain sensation thresholds did not differ from controls. Five patients had sensory complaints, but none was diagnosed with neuropathic pain at painDETECT. The degree of small fiber loss was markedly variable in our cohort and showed an inverse correlation with the GAA repeat length (R2 = 0.573, p = 0.001). Our findings support a genetically determined small fiber loss in FRDA.

Background: Friedreich ataxia (FRDA) is an inherited movement disorder which manifests with progressive gait instability, sensory loss and cardiomyopathy. Peripheral neuropathy is an established feature of FRDA. At neuropathological examination, a depletion of large, myelinated axons is evident, but also unmyelinated fibers are affected which may result in a variety of sensory and autonomic signs and symptoms. Impaired temperature perception, vasomotor disturbances of lower extremities and a high prevalence of urinary symptoms have been documented in FRDA, but data from autonomic function testing in genetically confirmed cases are lacking., Methods: Genetically confirmed FRDAs were recruited in an outpatient setting. In a screening visit, general and neurological examination, laboratory testing, ECG and echocardiography were performed. Autonomic functions were evaluated by means of systematic questionnaires (SCOPA-Aut, OHQ), skin sympathetic reflex and cardiovascular autonomic function testing (CAFT). For the latter, a comparison with matched healthy controls was performed., Results: 20 patients were recruited and 13 underwent CAFT. Symptoms referred to multiple autonomic domains, particularly bladder function, thermoregulation and sweating were reported. SCOPA-Aut scores were significantly predicted by disease severity. At CAFT, FRDAs did not differ from controls except for increased heart rate at rest and during orthostatic challenge. Two patients had non-neurogenic orthostatic hypotension (14%). Skin sympathetic responses were pathologic in 3 out of 10 patients (of whom 2 aged > 50)., Conclusions: FRDA patients may experience several autonomic symptoms and overall their burden correlates with disease severity. Nonetheless, clinical testing shows no major involvement of sudomotor and cardiovascular autonomic function.

Purpose: To assess whether autonomic failure belongs to the clinical spectrum of spinocerebellar ataxia type 2 (SCA2), an autosomal dominant genetic disorder showing progressive cerebellar and brainstem dysfunction., Methods: We evaluated cardiovascular autonomic function in 8 patients with SCA2 and 16 age- and gender-matched healthy controls. Other autonomic domains were examined through standardized questionnaires and by testing the skin sympathetic reflex., Results: Patients with SCA2 showed normal responses to cardiovascular autonomic function tests, with the exception of lower baroreflex sensitivity upon standing compared to controls. In questionnaires, 7 out of 8 patients reported bladder disturbances, while 3 out of 6 tested patients had no skin sympathetic reflex., Conclusions: We did not observe clinically overt cardiovascular autonomic failure in patients with SCA2. Other autonomic domains (i.e., bladder and sudomotor function) may be affected in the disease.

Background Familial hemiplegic migraine (FHM) is a rare, genetic form of migraine with aura. The severity of the aura imposes an effective prophylaxis that is currently based on standard anti-migraine drugs. To this concern, only short-term reports are currently available. Methods Eight patients from a multigenerational FHM type 1 family harbouring a T666M mutation in the CACNA1A gene were referred to our ataxia outpatient clinic. Medical history, general and neurological examination as well as therapeutic approaches were recorded regularly on a routine basis for an average period of 13 years (range 9-15 years). Brain imaging studies and EEG data were also collected. Results Our long-term follow-up revealed that ictal manifestations, which usually improve after the adolescence, may reoccur later in the adulthood. Permanent neurological signs as assessed by means of clinical evaluation as well as follow-up MRIs, EEGs and neuropsychological testing remained stable. Interval therapy with non-selective calcium antagonists reduced the burden of migraine attacks and was well tolerated in the long term.

Cerebral autoregulation is a complex homeostatic process which ensures constant brain blood supply, despite continuous blood pressure fluctuations. Recent evidence suggests that in Parkinson's disease (PD) and multiple system atrophy (MSA) this process is maintained in a broadened range of blood pressure values, consistent with an adaptive mechanism to increase tolerance to orthostatic hypotension. In PD and MSA orthostatic hypotension may be accompanied by supine hypertension which has been recently linked with cerebral white matter lesions in these conditions. We hypothesize that cerebral autoregulation adaptation to chronic orthostatic hypotension may be directly related with an increase susceptibility to hypertensive peaks. Evaluation of cerebral autoregulatory behavior may thus represent a novel approach to simultaneously target orthostatic symptoms and silent end-organ damage in alpha-synucleinopathies, with a beneficial impact on cerebrovascular and cognitive outcome., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The aim of this study was to analyse the transfer of steam through different types of textile layers as a function of sample parameters such as thickness and permeability. In order to simulate the human body, a cylinder releasing defined amounts of moisture was also used. The influence of sweating on heat and mass transfer was assessed. The results show that in general impermeable materials offer better protection against hot steam than semi-permeable ones. The transfer of steam depended on the water vapour permeability of the samples, but also on their thermal insulation and their thickness. Increasing the thickness of the samples with a spacer gave a larger increase in protection with the impermeable samples compared to semi-permeable materials. Measurements with pre-wetted samples showed a reduction in steam protection in any case. On the other hand, the measurements with a sweating cylinder showed a beneficial effect of sweating.