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Background The ongoing SARS-CoV-2 pandemic, which is dramatically spreading worldwide, is well known for its respiratory sequelae. Besides cases of Guillain-Barre Syndrome, encephalitis, hyposmia, the whole range of neurological complications due to SARSCoV-2 is still not well known. Methods and findings Herein, we report a new case of COVID-19, associated with mononeuropathy with reversible conduction block (CB). After SARS-CoV-2 infection, the patient developed acute weakness of left peroneal muscles. He underwent an endovenous immunoglobulin treatment, and symptoms improved. Two electroneurographic exam (before and after treatment), showed a reversible CB on left peroneal nerve. Dosage of serum antiganglioside antibodies showed anti-GM1 IgM positivity. Conclusions The present case gives new informations about reversible CB neuropathy as an acute presentation of SARS-CoV-2. Besides, antiganglioside antibodies evaluation could be useful to understand etiology of the increasing number of neurological manifestations related to SARS-CoV-2.

Aims To explore the feasibility of upper limbs cardiopulmonary exercise test (CPET) in Friedreich ataxia (FRDA) patients and to compare the results with sex, age, and body mass index (BMI) matched cohort of healthy controls (HC). Methods and results Cardiopulmonary exercise test was performed using an upper limbs cycle ergometer on fasting subjects. Peak oxygen uptake (peak VO2) was recorded as the mean value of VO2 during a 20 s period at the maximal effort of the test at an appropriate respiratory exchange rate. The ventilatory anaerobic threshold (AT) was detected by the use of the V-slope method. We performed echocardiography with an ultrasound system equipped with a 2.5 MHz multifrequency transducer for complete M-mode, two-dimensional, Doppler, and Tissue Doppler Imaging analyses. We studied 55 FRDA and 54 healthy matched controls (HC). Peak VO2 showed a significant 31% reduction in FRDA patients compared to HC (15.2 ± 5.7 vs. 22.0 ± 6.1 mL/kg/min; P Conclusions Upper limb CPET is useful in the assessment of exercise tolerance and a possible tool to determine the functional severity of the mitochondrial oxidative defect in patients with FRDA. The cardiopulmonary exercise test is an ideal functional endpoint for Phases II and III trials through a simple, non-invasive, and safe exercise test.

Background and Objectives: Hereditary spastic paraplegias (HSPs) are a group of inherited rare neurologic disorders characterized by length-dependent degeneration of the corticospinal tracts and dorsal columns, whose prominent clinical feature is represented by spastic gait. Spastic paraplegia type 4 (SPG4, SPAST-HSP) is the most common form. We present both clinical and molecular findings of a large cohort of patients, with the aim of (1) defining the clinical spectrum of SPAST-HSP in Italy; (2) describing their molecular features; and (3) assessing genotype-phenotype correlations to identify features associated with worse disability.MethodsA cross-sectional retrospective study with molecular and clinical data collected in an anonymized database was performed.ResultsA total of 723 Italian patients with SPAST-HSP (58% men) from 316 families, with a median age at onset of 35 years, were included. Penetrance was 97.8%, with men showing higher Spastic Paraplegia Rating Scale (SPRS) scores (19.67 ± 12.58 vs 16.15 ± 12.61, p = 0.009). In 26.6% of patients with SPAST-HSP, we observed a complicated phenotype, mainly including intellectual disability (8%), polyneuropathy (6.7%), and cognitive decline (6.5%). Late-onset cases seemed to progress more rapidly, and patients with a longer disease course displayed a more severe neurologic disability, with higher SPATAX (3.61 ± 1.46 vs 2.71 ± 1.20, p < 0.001) and SPRS scores (22.63 ± 11.81 vs 12.40 ± 8.83, p < 0.001). Overall, 186 different variants in the SPAST gene were recorded, of which 48 were novel. Patients with SPAST-HSP harboring missense variants displayed intellectual disability (14.5% vs 4.4%, p < 0.001) more frequently, whereas patients with truncating variants presented more commonly cognitive decline (9.7% vs 2.6%, p = 0.001), cerebral atrophy (11.2% vs 3.4%, p = 0.003), lower limb spasticity (61.5% vs 44.5%), urinary symptoms (50.0% vs 31.3%, p < 0.001), and sensorimotor polyneuropathy (11.1% vs 1.1%, p < 0.001). Increasing disease duration (DD) and abnormal motor evoked potentials (MEPs) were also associated with increased likelihood of worse disability (SPATAX score>3).DiscussionThe SPAST-HSP phenotypic spectrum in Italian patients confirms a predominantly pure form of HSP with mild-to-moderate disability in 75% of cases, and slight prevalence of men, who appeared more severely affected. Early-onset cases with intellectual disability were more frequent among patients carrying missense SPAST variants, whereas patients with truncating variants showed a more complicated disease. Both longer DD and altered MEPs are associated with worse disability. Methods: A cross-sectional retrospective study with molecular and clinical data collected in an anonymized database was performed. Results: A total of 723 Italian patients with SPAST-HSP (58%men) from 316 families, with a median age at onset of 35 years, were included. Penetrance was 97.8%, withmen showing higher Spastic Paraplegia Rating Scale (SPRS) scores (19.67 ± 12.58 vs 16.15 ± 12.61, p = 0.009). In 26.6% of patients with SPAST-HSP, we observed a complicated phenotype, mainly including intellectual disability (8%), polyneuropathy (6.7%), and cognitive decline (6.5%). Late-onset cases seemed to progress more rapidly, and patients with a longer disease course displayed a more severe neurologic disability, with higher SPATAX (3.61 ± 1.46 vs 2.71 ± 1.20, p < 0.001) and SPRS scores (22.63 ± 11.81 vs 12.40 ± 8.83, p < 0.001). Overall, 186 different variants in the SPAST gene were recorded, of which 48 were novel. Patients with SPAST-HSP harboring missense variants displayed intellectual disability (14.5% vs 4.4%, p < 0.001) more frequently,whereas patients with truncating variants presentedmore commonly cognitive decline (9.7%vs 2.6%, p = 0.001), cerebral atrophy (11.2% vs 3.4%, p = 0.003), lower limb spasticity (61.5% vs 44.5%), urinary symptoms (50.0% vs 31.3%, p < 0.001), and sensorimotor polyneuropathy (11.1% vs 1.1%, p < 0.001). Increasing disease duration (DD) and abnormalmotor evoked potentials (MEPs) were also associated with increased likelihood of worse disability (SPATAX score>3). Discussion The SPAST-HSP phenotypic spectrum in Italian patients confirms a predominantly pure form of HSP with mild-to-moderate disability in 75% of cases, and slight prevalence of men, who appeared more severely affected. Early-onset cases with intellectual disability were more frequent among patients carrying missense SPAST variants, whereas patients with truncating variants showed a more complicated disease. Both longer DD and altered MEPs are associated with worse disability.

Frataxin (FXN) deficiency is responsible for Friedreich’s ataxia (FRDA) in which, besides the characteristic features of spinocerebellar ataxia, two thirds of patients develop hypertrophic cardiomyopathy that often progresses to heart failure and premature death. Different mechanisms might underlie FRDA pathogenesis. Among them, the role of miRNAs deserves investigations. We carried out an miRNA PCR-array analysis of plasma samples of early-, intermediate- and late-onset FRDA groups, defining a set of 30 differentially expressed miRNAs. Hsa-miR223-3p is the only miRNA shared between the three patient groups and appears upregulated in all of them. The up-regulation of hsa-miR223-3p was further validated in all enrolled patients (n = 37, Fc = +2.3; P

Introduction Spinocerebellar ataxia type 14 (SCA14) is a dominantly inherited neurological disorder characterized by slowly progressive cerebellar ataxia. SCA14 is caused by mutations in PRKCG, a gene encoding protein kinase C gamma (PKCγ), a master regulator of Purkinje cells development. Methods We performed next-generation sequencing targeted resequencing panel encompassing 273 ataxia genes in 358 patients with genetically undiagnosed ataxia. Results We identified fourteen patients in ten families harboring nine pathogenic heterozygous variants in PRKCG, seven of which were novel. We encountered four patients with not previously described phenotypes: one with episodic ataxia, one with a spastic paraparesis dominating her clinical manifestations, and two children with an unusually severe phenotype. Conclusions Our study broadens the genetic and clinical spectrum of SCA14.

Hereditary transthyretin amyloidosis (ATTRv, v for variant) prevalence in Italy, a non-endemic region, has been established by ATTRv amyloidosis Italian Registry. However, values of prevalence were extremely heterogeneous, considering different regions. To properly establish the prevalence of the disease in the Lazio region, a survey was sent to university regional hospitals and to main regional hospitals, in order to collect all affected patients regularly followed. We identified 100 ATTRv patients and, considering a Lazio population of 5.8/million, we estimated a ATTRv prevalence of 17.2/million. The ATTRv amyloidosis Italian Registry reported a prevalence of 8.0/million in Lazio, while our survey showed a value of double this. Our survey documented a high-prevalence for a non-endemic country. The increased awareness of the disease among general practitioners and medical specialists is a fundamental step to reduce the diagnostic delay and start an effective treatment of this disease.

BACKGROUND AND PURPOSE Spinocerebellar ataxia 21 (SCA21) is a rare autosomal dominant neurodegenerative disorder caused by TMEM240 gene mutations. To date, SCA21 has been reported only in a limited number of families worldwide. Here, we describe clinical and molecular findings in five additional SCA21 patients from four unrelated families, diagnosed through a multicentre next generation sequencing-based molecular screening project on a large cohort of patients with degenerative and congenital ataxias. METHODS A cohort of 393 patients with ataxia of unknown aetiology was selected. Following the identification of heterozygous pathogenic TMEM240 variants using a target resequencing panel, we carried out an in-depth phenotyping of the novel SCA21 patients. RESULTS Five patients from four unrelated families, three of Italian and one of Libyan origin, were identified. These patients were carriers of previously reported TMEM240 mutations. Clinically, our SCA21 cohort includes both adult onset, slowly progressive cerebellar ataxias associated with cognitive impairment resembling cerebellar cognitive affective syndrome and early onset forms associated with cognitive delay, neuropsychiatric features, or evidence of hypomyelination on brain magnetic resonance imaging. None of our patients exhibited signs of extrapyramidal involvement. The so-called "recurrent" c.509C>T (p.Pro170Leu) mutation was detected in two of four families, corroborating its role as a hot spot. CONCLUSIONS Our results confirm that SCA21 is present also in Italy, suggesting that it might not be as rare as previously thought. The phenotype of these novel SCA21 patients indicates that slowly progressive cerebellar ataxia, and cognitive and psychiatric symptoms are the most typical clinical features associated with mutations in the TMEM240 gene.

Korrektur zu 10.1038/s41436-020-0899-x

The term hereditary ataxia (HA) refers to a heterogeneous group of neurological disorders with multiple genetic etiologies and a wide spectrum of ataxia-dominated phenotypes. Massive gene analysis in next-generation sequencing has entered the HA scenario, broadening our genetic and clinical knowledge of these conditions. In this study, we employed a targeted resequencing panel (TRP) in a large and highly heterogeneous cohort of 377 patients with a clinical diagnosis of HA, but no molecular diagnosis on routine genetic tests. We obtained a positive result (genetic diagnosis) in 33.2% of the patients, a rate significantly higher than those reported in similar studies employing TRP (average 19.4%), and in line with those performed using exome sequencing (ES, average 34.6%). Moreover, 15.6% of the patients had an uncertain molecular diagnosis. STUB1, PRKCG, and SPG7 were the most common causative genes. A comparison with published literature data showed that our panel would have identified 97% of the positive cases reported in previous TRP-based studies and 92% of those diagnosed by ES. Proper use of multigene panels, when combined with detailed phenotypic data, seems to be even more efficient than ES in clinical practice.

Purpose Pseudoxanthoma elasticum (PXE) is a recessive disorder involving skin, eyes and arteries, mainly caused by ABCC6 pathogenic variants. However, almost one fifth of patients remain genetically unsolved despite extensive genetic screening of ABCC6, as illustrated in a large French PXE series of 220 cases. We searched for new PXE gene(s) to solve the ABCC6-negative patients. Methods First, family-based exome sequencing was performed, in one ABCC6-negative PXE patient with additional neurological features, and her relatives. CYP2U1, involved in hereditary spastic paraplegia type 56 (SPG56), was selected based on this complex phenotype, and the presence of two candidate variants. Second, CYP2U1 sequencing was performed in a retrospective series of 46 additional ABCC6-negative PXE probands. Third, six additional SPG56 patients were evaluated for PXE skin and eye phenotype. Additionally, plasma pyrophosphate dosage and functional analyses were performed in some of these patients. Results 6.4% of ABCC6-negative PXE patients (n=3) harbored biallelic pathogenic variants in CYP2U1. PXE skin lesions with histological confirmation, eye lesions including maculopathy or angioid streaks, and various neurological symptoms were present. CYP2U1 missense variants were confirmed to impair protein function. Plasma pyrophosphate levels were normal. Two SPG56 patients (33%) presented some phenotypic overlap with PXE. Conclusion CYP2U1 pathogenic variants are found in unsolved PXE patients with neurological findings, including spastic paraplegia, expanding the SPG56 phenotype and highlighting its overlap with PXE. The pathophysiology of ABCC6 and CYP2U1 should be explored to explain their respective role and potential interaction in ectopic mineralization.

The balance between HIPK2-mediated phosphorylation and neddylation-dependent degradation controls spastin protein levels, revealing novel therapeutic targets for hereditary spastic paraplegia., Hereditary Spastic Paraplegia (HSP) is a neurodegenerative disease most commonly caused by autosomal dominant mutations in the SPG4 gene encoding the microtubule-severing protein spastin. We hypothesise that SPG4-HSP is attributable to reduced spastin function because of haploinsufficiency; thus, therapeutic approaches which elevate levels of the wild-type spastin allele may be an effective therapy. However, until now, how spastin levels are regulated is largely unknown. Here, we show that the kinase HIPK2 regulates spastin protein levels in proliferating cells, in differentiated neurons and in vivo. Our work reveals that HIPK2-mediated phosphorylation of spastin at S268 inhibits spastin K48-poly-ubiquitination at K554 and prevents its neddylation-dependent proteasomal degradation. In a spastin RNAi neuronal cell model, overexpression of HIPK2, or inhibition of neddylation, restores spastin levels and rescues neurite defects. Notably, we demonstrate that spastin levels can be restored pharmacologically by inhibiting its neddylation-mediated degradation in neurons derived from a spastin mouse model of HSP and in patient-derived cells, thus revealing novel therapeutic targets for the treatment of SPG4-HSP.

International audience; Purpose: Pathogenic variants in STUB1 were initially described in autosomal recessive spinocerebellar ataxia type 16 and dominant cerebellar ataxia with cerebellar cognitive dysfunction (SCA48).Methods: We analyzed a large series of 440 index cerebellar ataxia cases, mostly with dominant inheritance.Results: STUB1 variants were detected in 50 patients. Age at onset and severity were remarkably variable. Cognitive impairment, predominantly frontal syndrome, was observed in 54% of STUB1 variant carriers, including five families with Huntington or frontotemporal dementia disease-like phenotypes associated with ataxia, while no STUB1 variant was found in 115 patients with frontotemporal dementia. We report neuropathological findings of a STUB1 heterozygous patient, showing massive loss of Purkinje cells in the vermis and major loss in the cerebellar hemispheres without atrophy of the pons, hippocampus, or cerebral cortex. This screening of STUB1 variants revealed new features: (1) the majority of patients were women (70%) and (2) "second hits" in AFG3L2, PRKCG, and TBP were detected in three families suggesting synergic effects.Conclusion: Our results reveal an unexpectedly frequent (7%) implication of STUB1 among dominantly inherited cerebellar ataxias, and suggest that the penetrance of STUB1 variants could be modulated by other factors, including sex and variants in other ataxia-related genes.

We collected the gait parameters and lower limb joint kinematics of patients with three different types of primary degenerative neurological diseases: (i) cerebellar ataxia (19 patients), (ii) hereditary spastic paraparesis (26 patients), and (iii) Parkinson’s disease (32 patients). Sixty-five gender-age matched healthy subjects were enrolled as 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.

BACKGROUND AND PURPOSE: Mitochondrial neurogastrointestinal encephalopathy is a rare disorder due to recessive mutations in the thymidine phosphorylase gene, encoding thymidine phosphorylase protein required for mitochondrial DNA replication. Clinical manifestations include gastrointestinal dysmotility and diffuse asymptomatic leukoencephalopathy. This study aimed to elucidate the mechanisms underlying brain leukoencephalopathy in patients with mitochondrial neurogastrointestinal encephalopathy by correlating multimodal neuroradiologic features to postmortem pathology. MATERIALS AND METHODS: Seven patients underwent brain MR imaging, including single-voxel proton MR spectroscopy and diffusion imaging. Absolute concentrations of metabolites calculated by acquiring unsuppressed water spectra at multiple TEs, along with diffusion metrics based on the tensor model, were compared with those of healthy controls using unpaired t tests in multiple white matters regions. Brain postmortem histologic, immunohistochemical, and molecular analyses were performed in 1 patient. RESULTS: All patients showed bilateral and nearly symmetric cerebral white matter hyperintensities on T2-weighted images, extending to the cerebellar white matter and brain stem in 4. White matter, N -acetylaspartate, creatine, and choline concentrations were significantly reduced compared with those in controls, with a prominent increase in the radial water diffusivity component. At postmortem examination, severe fibrosis of brain vessel smooth muscle was evident, along with mitochondrial DNA replication depletion in brain and vascular smooth-muscle and endothelial cells, without neuronal loss, myelin damage, or gliosis. Prominent periependymal cytochrome C oxidase deficiency was also observed. CONCLUSIONS: Vascular functional and histologic alterations account for leukoencephalopathy in mitochondrial neurogastrointestinal encephalopathy. Thymidine toxicity and mitochondrial DNA replication depletion may induce microangiopathy and blood-brain-barrier dysfunction, leading to increased water content in the white matter. Periependymal cytochrome C oxidase deficiency could explain prominent periventricular impairment.

Spinocerebellar ataxia type 1 (SCA-ATXN1) is an autosomal dominant, neurodegenerative disease, caused by CAG repeat expansion in the ataxin-1 gene (ATXN1). In isolated reports of patients with neurological signs [symptomatic patients (SP)], macular abnormalities have been described. However, no reports exist about macular anomalies in SCA1 subjects carrying the ATXN1 mutation without neurological signs [not symptomatic carriers (NSC)]. Therefore, the main aim of our work was to evaluate whether the macular functional and morphological abnormalities could be detectable in SP, genetically confirmed and with neurological signs, as well as in SCA-ATXN1-NSC, harboring pathogenic CAG expansion in ATXN1. In addition, we investigated whether the macular involvement could be associated or not to an impairment of RGCs and of their fibers and of the neural conduction along the visual pathways. Herein, nine SCA-ATXN1 subjects (6 SP and 3 NSC) underwent the following examinations: visual acuity and chromatic test assessments, fundus oculi (FO) examination, macular and peripapillary retinal nerve fiber layer thickness (RNFL-T) analysis by Spectral domain-Optical Coherence Tomography (Sd-OCT) acquisition, multifocal electroretinogram (mfERG), pattern reversal electroretinogram (PERG) and visual evoked potentials (VEP) recordings. In four eyes of two SP, visual acuity reduction and chromatic abnormalities were observed, in three of them FO changes associated with macular thinning and outer retinal defects were also detected. In three NSC eyes, slight FO abnormalities were associated with qualitative macular morphological changes. By contrast, abnormal mfERG responses (exclusively from foveal and parafoveal areas) were detected in all SP and NSC (18 eyes). No abnormalities of PERG values, RNFL-T, and VEP responses were found, but in one SP, presenting abnormal papillo-macular bundle neural conduction. Results from our SCA-ATXN1 cohort suggest that a macular dysfunction, detectable by mfERG recordings, may occur in the overt disorder, and unexpectedly in the stage of the disease in which there is still an absence of neurological signs. In NSC, an exclusive dysfunction of preganglionic macular elements can be observed, and this is associated with both normal RGCs function and neural conduction along the visual pathways.

Summary Background Spinocerebellar ataxias (SCAs) are autosomal dominant neurodegenerative diseases. Our aim was to study the conversion to manifest ataxia among apparently healthy carriers of mutations associated with the most common SCAs (SCA1, SCA2, SCA3, and SCA6), and the sensitivity of clinical and functional measures to detect change in these individuals. Methods In this prospective, longitudinal, observational cohort study, based at 14 referral centres in seven European countries, we enrolled children or siblings of patients with SCA1, SCA2, SCA3, or SCA6. Eligible individuals were those without ataxia, defined by a score on the Scale for the Assessment and Rating of Ataxia (SARA) of less than 3; participants had to be aged 18–50 years for children or siblings of patients with SCA1, SCA2, or SCA3, and 35–70 years for children or siblings of patients with SCA6. Study visits took place at recruitment and after 2, 4, and 6 years (plus or minus 3 months). We did genetic testing to identify mutation carriers, with results concealed to the participant and clinical investigator. We assessed patients with clinical scales, questionnaires of patient-reported outcome measures, a rating of the examiner's confidence of presence of ataxia, and performance-based coordination tests. Conversion to ataxia was defined by an SARA score of 3 or higher. We analysed the association of factors at baseline with conversion to ataxia and the evolution of outcome parameters on temporal scales (time from inclusion and time to predicted age at ataxia onset) in the context of mutation status and conversion status. This study is registered with ClinicalTrials.gov , NCT01037777 . Findings Between Sept 13, 2008, and Oct 28, 2015, 302 participants were enrolled. We analysed data for 252 participants with at least one follow-up visit. 83 (33%) participants were from families affected by SCA1, 99 (39%) by SCA2, 46 (18%) by SCA3, and 24 (10%) by SCA6. In participants who carried SCA mutations, 26 (52%) of 50 SCA1 carriers, 22 (59%) of 37 SCA2 carriers, 11 (42%) of 26 SCA3 carriers, and two (13%) of 15 SCA6 carriers converted to ataxia. One (3%) of 33 SCA1 non-carriers and one (2%) of 62 SCA2 non-carriers converted to ataxia. Owing to the small number of people who met our criteria for ataxia, subsequent analyses could not be done in carriers of the SCA6 mutation. Baseline factors associated with conversion were age (hazard ratio 1·13 [95% CI 1·03–1·24]; p=0·011), CAG repeat length (1·25 [1·11–1·41]; p=0·0002), and ataxia confidence rating (1·72 [1·23–2·41]; p=0·0015) for SCA1; age (1·08 [1·02–1·14]; p=0·0077) and CAG repeat length (1·65 [1·27–2·13]; p=0·0001) for SCA2; and age (1·27 [1·09–1·50]; p=0·0031), confidence rating (2·60 [1·23–5·47]; p=0·012), and double vision (14·83 [2·15–102·44]; p=0·0063) for SCA3. From the time of inclusion, the SARA scores of SCA1, SCA2, and SCA3 mutation carriers increased, whereas they remained stable in non-carriers. On a timescale defined by the predicted time of ataxia onset, SARA progression in SCA1, SCA2, and SCA3 mutation carriers was non-linear, with marginal progression before ataxia and increasing progression after ataxia onset. Interpretation Our study provides quantitative data on the conversion of non-ataxic SCA1, SCA2, and SCA3 mutation carriers to manifest ataxia. Our data could prove useful for the design of preventive trials aimed at delaying the onset of ataxia by aiding sample size calculations and stratification of study participants. Funding European Research Area Network for Research Programmes on Rare Diseases, Polish Ministry of Science and Higher Education, Italian Ministry of Health, European Community's Seventh Framework Programme.

Frataxin deficiency, responsible for Friedreich’s ataxia (FRDA), is crucial for cell survival since it critically affects viability of neurons, pancreatic beta cells and cardiomyocytes. In FRDA, the heart is frequently affected with typical manifestation of hypertrophic cardiomyopathy, which can progress to heart failure and cause premature death. A microarray analysis performed on FRDA patient’s lymphoblastoid cells stably reconstituted with frataxin, indicated HS-1-associated protein X-1 (HAX-1) as the most significantly upregulated transcript (FC = +2, P

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.

Background Patients with cerebellar ataxia show increased upper body movements, which have an impact on balance and walking. Aim In this study, we investigated the effect of using dynamic movement orthoses (DMO), designed as elastic suits, on trunk motion and gait parameters. Design Longitudinal uncontrolled study. Setting Outpatient rehabilitation unit. Population Eleven patients (7 men, 4 women; mean age: 49.9±9.5 years) with degenerative cerebellar ataxia were enrolled in this study. Methods Linear overground gait of patients was recorded by means of an optoelectronic gait analysis system before DMO use (DMO-) and during DMO use (DMO+). Time-distance parameters, lower limb joint kinematics, body sway, trunk oscillations, and gait variability (coefficient of variation [CV]) were recorded. Patient satisfaction with DMO device was measured using Quebec user evaluation of satisfaction with assistive technology. Results When using the DMO, patients showed a significant decrease in stance phase duration, double support phase duration, swing phase CV, pelvic range of motion (ROM), body sway, and trunk ROMs. A significant increase was observed in the swing phase duration and knee joint ROM. Out of 11 patients, 10 were either quite satisfied (8 points) or very satisfied (2 points) with the assistive device. Conclusions The DMO reduce the upper body motion and in improve balance-related gait parameters. Clinical rehabilitation impact We propose use of DMO as an assistive/rehabilitative device in the neurorehabilitation of cerebellar ataxia to improve the trunk control and gait stability. DMO may be considered a prototype that can be modified in terms of material characteristics, textile layers, elastic components, and diagonal and lateral seams.

Background Spastic gait is a key feature in patients with hereditary spastic paraparesis, but the gait characterization and the relationship between the gait impairment and clinical characteristics have not been investigated. Objectives To describe the gait patterns in hereditary spastic paraparesis and to identify subgroups of patients according to specific kinematic features of walking. Methods We evaluated fifty patients by computerized gait analysis and compared them to healthy participants. We computed time-distance parameters of walking and the range of angular motion at hip, knee, and ankle joints, and at the trunk and pelvis. Lower limb joint moments and muscle co-activation values were also evaluated. Results We identified three distinct subgroups of patients based on the range of motion values. Subgroup one was characterized by reduced hip, knee, and ankle joint range of motion. These patients were the most severely affected from a clinical standpoint, had the highest spasticity, and walked at the slowest speed. Subgroup three was characterized by an increased hip joint range of motion, but knee and ankle joint range of motion values close to control values. These patients were the most mildly affected and had the highest walking speed. Finally, subgroup two showed reduced knee and ankle joint range of motion, and hip range of motion values close to control values. Disease severity and gait speed in subgroup two were between those of subgroups one and three. Conclusions We identified three distinctive gait patterns in patients with hereditary spastic paraparesis that correlated robustly with clinical data. Distinguishing specific features in the gait patterns of these patients may help tailor pharmacological and rehabilitative treatments and may help evaluate therapeutic effects over time.

Spinocerebellar ataxia type 2 (SCA2) is a late-onset autosomal dominant cerebellar ataxia caused by triplet CAG/CTG expansion in the ATX2 gene. The initial symptoms usually appear when subjects are in their 30s. Pediatric onset is less common and usually associated with larger triplet expansions. We here report the case of a 1-year-old girl who presented with facial dysmorphism, dystonic features, developmental delay, and retinitis pigmentosa. She was diagnosed as carrying an expanded CAG/CTG tract (92 repeats) before a molecular diagnosis of SCA2 was made in her father. Facial dysmorphism associated with developmental delay and retinitis pigmentosa in early childhood should prompt a careful family investigation for ataxia and study of ATX2.

Background:It has been proposed that the patent foramen ovale (PFO) may be associated with migraine, in particular migraine with aura. However, it is not clear whether paradoxical embolism triggers crises of headache. Cerebral embolization is provoked in subjects with PFO through contrast echocardiography, a safe method to diagnose the presence of foramen ovale pervium.Methods:Twenty-four men practicing diving, an activity characterized by increased prevalence of PFO and migraine, underwent trans-thoracic echocardiography with contrast solution, composed of saline and air mixture and checked for the occurrence of migraine in the following 24 hours.Results:A PFO (five of minimal size, i.e. visible only during Valsalva, one of small and two of medium size) was detected in 8/24 divers (33%). No one reported headache over the 24 hours after the procedure.Discussion:Our preliminary data suggest that cerebral micro-embolism, provoked by contrast echocardiography, does not systematically trigger migraine crises when a minimal-to-medium sized patent foramen ovale is present.

Medication overuse headache (MOH) can be considered a clinical condition at the boundaries between drug addiction and chronic pain disorder. The common 196G > A single-nucleotide polymorphism of BDNF gene, resulting in a valine 66 to methionine (Val66Met), is related with behaviour disorders and substance abuse. With the aim of identifying a worsening factor in MOH, rather than the detection of a specific risk factor for the development of the disease, we investigated whether the presence of a functional BDNF polymorphism might determine clinical differences within a group of 90 MOH patients, particularly in monthly drug consumption, that is the hallmark of disease. Directly comparing MOH patients homozygous for G allele (G/G) with carriers of A allele (non-G/G), we have observed 47 G/G genotypes and 60 non-G/G genotypes. Non-G/G had a higher consumption of monthly drug number (Cohen’s d = 0.76) than G/G patients. At multiple regression analysis, the Val66Met BDNF polymorphism emerged as a significant independent predictor of analgesic drug consumption (Beta = 0.33, Cohen’s f2 = 0.134). These findings showed an influence of examined BDNF polymorphism in the MOH clinical features, supporting the idea that MOH is a substance abuse disorder.

A subgroup of neutral lipid storage disease has been recently associated with myopathy (NLSDM) and attributed to mutations in the gene (PNPLA2) encoding an adipose triglyceride lipase involved in the degradation of intracellular triglycerides. Five NLSDM patients have been described thus far and we reported three additional patients. A 44-year old Iranian woman and two Italian brothers, aged 40 and 35, presented with exercise intolerance and proximal limb weakness, elevated CK levels, and Jordan’s anomaly. Muscle biopsies showed marked neutral lipid accumulation in all patients. The 10 exons and the intron–exon junctions of the PNPLA2 gene were sequenced. Two novel homozygous mutations in exon 5 of PNPLA2 gene were found (c.695delT and c.542delAC). Both mutations resulted in frameshifts leading to premature stop codons (p.L255X and p.I212X, respectively). These mutations predict a truncated PNPLA2 protein lacking the C-terminal hydrophobic domain. These findings indicate that NLSDM is rare, but genetically heterogeneous.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a fatal, recessive disease caused by mutations in the gene encoding thymidine phosphorylase, leading to reduced enzymatic activity, toxic nucleoside accumulation, and secondary mitochondrial DNA damage. Thymidine phosphorylase replacement has been achieved by allogeneic hematopoietic stem cell transplantation, a procedure hampered by high mortality. Based on high thymidine phosphorylase expression in the liver, a 25-year-old severely affected patient underwent liver transplantation. Serum levels of toxic nucleosides rapidly normalized. At 400 days of follow-up, the patient's clinical conditions are stable. We propose liver transplantation as a new therapy for MNGIE. Ann Neurol 2016;80:448-455.

Mitochondrial neuro-gastro-intestinal encephalomyopathy (MNGIE) is a rare and unavoidably fatal disease due to mutations in thymidine phosphorylase (TP). Clinically it is characterized by gastrointestinal dysfunction, malnutrition/cachexia and neurological manifestations. MNGIE diagnosis remains a challenge mainly because of the complexity and rarity of the disease. Thus, our purposes were to promote a better knowledge of the disease in Emilia-Romagna region (ERR) by creating an accurate and dedicated network; to establish the minimal prevalence of MNGIE in Italy starting from ERR. Blood TP activity level was used as screening test to direct candidates to complete diagnostic work-up. During the study period of 1 year, only 10/71 units of ERR recruited 14 candidates. Their screening did not show TP activity changes. An Italian patient not resident in ERR was actually proved to have MNGIE. At the end of study in Italy there were nine cases of MNGIE; thus, the Italian prevalence of the disease is ~0.15/1,000,000 as a gross estimation. Our study confirms that MNGIE diagnosis is a difficult process which reflects the rarity of the disease and, as a result, a low level of awareness among specialists and physicians. Having available novel therapeutic options (e.g., allogenic hematopoietic stem cell transplantation and, more recently, liver transplantation) and an easy screening test, an early diagnosis should be sought before tissue damage occurs irreversibly.

Background Neurodegenerative cerebellar ataxias represent a group of disabling disorders for which we currently lack effective therapies. Cerebellar transcranial direct current stimulation (tDCS) is a non-invasive technique, which has been demonstrated to modulate cerebellar excitability and improve symptoms in patients with cerebellar ataxias. Objective The present study investigated whether a two-weeks’ treatment with cerebellar anodal tDCS could improve symptoms in patients with neurodegenerative cerebellar ataxia and could modulate cerebello-motor connectivity, at short and long term. Methods We performed a double-blind, randomized, sham controlled trial with cerebellar tDCS (5 days/week for 2 weeks) in twenty patients with ataxia. Each patient underwent a clinical evaluation pre- and post-anodal tDCS or sham stimulation. A follow-up evaluation was performed at one and three months. Cerebello-motor connectivity was evaluated using transcranial magnetic stimulation (TMS) at baseline and at follow-up. Results Patients who underwent anodal tDCS showed a significant improvement in all performance scores (scale for the assessment and rating of ataxia, international cooperative ataxia rating scale, 9-hole peg test, 8-m walking time) and in cerebellar brain inhibition compared to patients who underwent sham stimulation. Conclusions A two-weeks’ treatment with anodal cerebellar tDCS improves symptoms in patients with ataxia and restores physiological cerebellar brain inhibition pathways. Cerebellar tDCS might represent a promising future therapeutic and rehabilitative approach in patients with neurodegenerative ataxia.

The most common autosomal recessive spastic paraplegia is caused by mutations in SPG11. Denora et al. report the first postmortem neuropathological analysis of two unrelated patients with SPG11, and demonstrate clinical and pathological overlap between this disease and ALS. Abnormal neuronal lipid accumulation is identified as a hallmark of SPG11., The most common form of autosomal recessive hereditary spastic paraplegia is caused by mutations in the SPG11/KIAA1840 gene on chromosome 15q. The nature of the vast majority of SPG11 mutations found to date suggests a loss-of-function mechanism of the encoded protein, spatacsin. The SPG11 phenotype is, in most cases, characterized by a progressive spasticity with neuropathy, cognitive impairment and a thin corpus callosum on brain MRI. Full neuropathological characterization has not been reported to date despite the description of >100 SPG11 mutations. We describe here the clinical and pathological features observed in two unrelated females, members of genetically ascertained SPG11 families originating from Belgium and Italy, respectively. We confirm the presence of lesions of motor tracts in medulla oblongata and spinal cord associated with other lesions of the central nervous system. Interestingly, we report for the first time pathological hallmarks of SPG11 in neurons that include intracytoplasmic granular lysosome-like structures mainly in supratentorial areas, and others in subtentorial areas that are partially reminiscent of those observed in amyotrophic lateral sclerosis, such as ubiquitin and p62 aggregates, except that they are never labelled with anti-TDP-43 or anti-cystatin C. The neuropathological overlap with amyotrophic lateral sclerosis, associated with some shared clinical manifestations, opens up new fields of investigation in the physiopathological continuum of motor neuron degeneration.

A compact description of coordinated muscle activity is provided by the factorization of electromyographic (EMG) signals. With the use of this approach, it has consistently been shown that multimuscle activity during human locomotion can be accounted for by four to five modules, each one comprised of a basic pattern timed at a different phase of gait cycle and the weighting coefficients of synergistic muscle activations. These modules are flexible, in so far as the timing of patterns and the amplitude of weightings can change as a function of gait speed and mode. Here we consider the adjustments of the locomotor modules related to unstable walking conditions. We compared three different conditions, i.e., locomotion of healthy subjects on slippery ground (SL) and on narrow beam (NB) and of cerebellar ataxic (CA) patients on normal ground. Motor modules were computed from the EMG signals of 12 muscles of the right lower limb using non-negative matrix factorization. The unstable gait of SL, NB, and CA showed significant changes compared with controls in the stride length, stride width, range of angular motion, and trunk oscillations. In most subjects of all three unstable conditions, >70% of the overall variation of EMG waveforms was accounted for by four modules that were characterized by a widening of muscle activity patterns. This suggests that the nervous system adopts the strategy of prolonging the duration of basic muscle activity patterns to cope with unstable conditions resulting from either slippery ground, reduced support surface, or pathology.

We described a family with a molecularly confirmed form of CFEOM1 and a late-onset cerebellar syndrome. Brain MRI showed vermis atrophy in two older family members, who also manifested gait impairment, whereas both neurological examination and neuroimaging findings were normal in a younger relative who harbored the same mutation.

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.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset familial disease with prominent myelinated fibers in the optic fundus. ARSACS is frequent in the Charlevoix-Saguenay region of Quebec but rare elsewhere. Mutations in SACS, encoding sacsin, a protein of unknown function, are associated with ARSACS. The authors identified three new SACS mutations in two Italian patients whose phenotype closely matches that of Quebec cases, but without retinal striation.

A novel 4949-base pair mitochondrial DNA (mtDNA) deletion was detected in various tissues in a postmortem study of a patient with Kearns-Sayre syndrome (KSS). Deleted mtDNA levels were higher in skeletal muscle and brain and lower in kidney, working myocardium, and endocrine tissues (thyroid, parathyroids, pancreas, and adrenal glands). The distribution of the deletion in skeletal muscle and conducting myocardium was analyzed by means of laser capture microdissection (LCM). In skeletal muscle, the abundance of deleted mtDNA was slightly higher in cytochrome c oxidase (COX)-negative fibers (70%) than in COX-positive fibers (64%), whereas in the conducting myocardium it was lower in the atrioventricular node (9%) than in the sinus node and bundle of His (30% and 32%, respectively). In this study, LCM proved to be a reliable technique for a more accurate assessment of genotype/phenotype correlation when investigating mtDNA-related disorders.

ObjectivesThe purpose of this study was to understand the clinical and molecular features of familial hypertrophic cardiomyopathy (HCM) in which a mitochondrial abnormality was strongly suspected.BackgroundDefects of the mitochondrial genome are responsible for a heterogeneous group of clinical disorders, including cardiomyopathy. The majority of pathogenic mutations are heteroplasmic, with mutated and wild-type mitochondrial deoxyribonucleic acid (mtDNA) coexisting within the same cell. Homoplasmic mutations (present in every copy of the genome within the cell) present a difficult challenge in terms of diagnosis and assigning pathogenicity, as human mtDNA is highly polymorphic.MethodsA detailed clinical, histochemical, biochemical, and molecular genetic analysis was performed on two families with HCM to investigate the underlying mitochondrial defect.ResultsCardiac tissue from an affected child in the presenting family exhibited severe deficiencies of mitochondrial respiratory chain enzymes, whereas histochemical and biochemical studies of the skeletal muscle were normal. Mitochondrial DNA sequencing revealed an A4300G transition in the mitochondrial transfer ribonucleic acid (tRNA)Ilegene, which was shown to be homoplasmic by polymerase chain reaction/restriction fragment length polymorphism analysis in all samples from affected individuals and other maternal relatives. In a second family, previously reported as heteroplasmic for this base substitution, the mutation has subsequently been shown to be homoplasmic. The pathogenic role for this mutation was confirmed by high-resolution Northern blot analysis of heart tissue from both families, revealing very low steady-state levels of the mature mitochondrial tRNAIle.ConclusionsThis report documents, for the first time, that a homoplasmic mitochondrial tRNA mutation may cause maternally inherited HCM. It highlights the significant contribution that homoplasmic mitochondrial tRNA substitutions may play in the development of cardiac disease. A restriction of the biochemical defect to the affected tissue has important implications for the screening of patients with cardiomyopathy for mitochondrial disease.

PURPOSE: To investigate whether specific patterns of brain gray matter (GM) regional volumes and white matter (WM) microstructural abnormalities and spinal cord atrophy occur in patients with pure and complicated hereditary spastic paraplegias (HSPs). Relationships between clinical and cognitive features of patients with HSP who had brain and cervical cord damage were also investigated.MATERIALS AND METHODS: This study was approved by the local ethical committees on human studies, and written informed consent from all subjects was obtained prior to enrollment. Forty-four patients with HSP (20 genetically defined cases and 24 without genetic diagnosis) and 19 healthy control subjects underwent clinical, neuropsychological, and advanced magnetic resonance (MR) imaging evaluations. Patterns of GM atrophy and WM microstructural damage obtained by using structural and diffusion-tensor MR imaging were compared between groups. Cervical cord atrophy was also assessed by using an active surface method. Correlations between clinical, cognitive, and diffusion-tensor MR imaging measures were evaluated.RESULTS: Clinical data showed that spastic paraplegia is accompanied by a number of other features, including sensory disturbances, and verbal and spatial memory deficits, not only in complicated HSP but also in pure HSP. MR imaging demonstrated a similar involvement of motor, association, and cerebellar WM pathways (P < .05, family-wise error corrected for multiple comparisons) and cervical cord (P < .001) in patients with HSP relative to healthy control subjects, regardless of their clinical picture. The severity of WM damage correlated with the degree of spasticity (P < .05, family-wise error corrected) and cognitive impairment (r values, -0.39 to 0.51; P values, .001-.05) in both pure and complicated HSP.CONCLUSION: The detection of a distributed pattern of central nervous system damage in patients with pure and complicated HSP suggests that the "primary" corticospinal tract involvement known to occur in these patients may be associated with a neurodegenerative process, which spreads out to extramotor regions, likely via anatomic connections. This observation is in line with emerging pieces of evidence that, independent of the clinical phenotype, there is a common neurodegenerative cascade shared by different neurologic disorders.

We studied nine Italian families with a pure form of autosomal dominant spastic paraplegia (ADHSP) to assess the frequency of mutations in the SPG4 gene. We observed marked intrafamilial variability in both age-at-onset and clinical severity, ranging from severe congenital presentation to mild involvement after age 55 years to healthy carriers of the mutation after age 70. Four of nine probands harboured SPG4 mutations, We identified three new SPG4 mutations, all predicting a loss-of-func-tion with apparently important consequences for spastin function. RT-PCR studies predict loss-of-function as a possible mechanism leading to spastin-related HSP. The current study expands the spectrum of allelic variants in SPG4, confirming their pathological significance in pure AD-HSP and suggesting implications for the presumed function of spastin.