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Background. The so-called “vaccine hesitancy” still represents a common phenomenon that undermines the effectiveness of vaccination campaigns. In 2020, the Italian Medicines Agency recommended to bring forward the flu vaccination campaign, whose importance was also emphasized for patients with Multiple Sclerosis (MS). We aimed to assess vaccination behavior in patients with MS to prepare for the upcoming SARS-CoV-2 vaccination challenge. Methods. This is an observational study carried out in one MS clinical Centre that enrolled all MS patients who were eligible for any of the flu vaccines recommended by the Italian medicines Agency. Results. 194 patients were enrolled. Patients’ mean age was 43.9 years and 66% were female. Comorbidities, mainly represented by non-autoimmune diseases, were identified in 52% of patients. Almost all patients were receiving a DMT during the study period, mainly dimethyl fumarate, natalizumab, teriflunomide, and interferon. Out of 194 patients, 58.2% accepted to be vaccinated. No statistically significant differences were found, except for the use of natalizumab, which was higher among vaccinated patients. Conclusion. The results of our study emphasize the importance of education and communication campaigns addressed both to healthcare providers and patients with MS, especially considering that MS patients are currently receiving COVID-19 vaccinations.

We report the first Italian family affected by hereditary gelsolin amyloidosis (HGA), a rare autosomal dominant disease characterized by adult-onset slowly progressive cranial neuropathy, lattice corneal dystrophy, and cutis laxa. The index case was a 39-year-old male with a 9-year history of progressive bilateral facial nerve palsy. His mother had two episodes of acute facial palsy, and his maternal aunt and grandfather were also affected. Electrophysiological studies confirmed bilateral facial nerve involvement, without signs of peripheral polyneuropathy, and ophthalmological examination showed bilateral lattice corneal dystrophy, in both the index case and his mother. Gelsolin-gene sequencing revealed the heterozygous c.640G>A mutation (p.Asp187Asn) in the proband, his mother and aunt and also in three apparently asymptomatic relatives. The majority of HGA patients come from Finland, although several cases have been reported from other countries. HGA should be considered in the differential diagnosis of progressive or recurrent bilateral facial neuropathy.

Background and purpose: Tauroursodeoxycholic acid (TUDCA) is a hydrophilic bile acid that is produced in the liver and used for treatment of chronic cholestatic liver diseases. Experimental studies suggest that TUDCA may have cytoprotective and anti-apoptotic action, with potential neuroprotective activity. A proof of principle approach was adopted to provide preliminary data regarding the efficacy and tolerability of TUDCA in a series of patients with amyotrophic lateral sclerosis (ALS). Methods: As a proof of principle, using a double-blind placebo controlled design, 34 ALS patients under treatment with riluzole who were randomized to placebo or TUDCA (1 g twice daily for 54 weeks) were evaluated after a lead-in period of 3 months. The patients were examined every 6 weeks. The primary outcome was the proportion of responders [those subjects with improvement of at least 15% in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) slope during the treatment period compared to the lead-in phase]. Secondary outcomes included between-treatment comparison of ALSFRS-R at study end, comparison of the linear regression slopes for ALSFFRS-R mean scores and the occurrence of adverse events. Results: Tauroursodeoxycholic acid was well tolerated; there were no between-group differences for adverse events. The proportion of responders was higher under TUDCA (87%) than under placebo (P = 0.021; 43%). At study end baseline-adjusted ALSFRS-R was significantly higher (P = 0.007) in TUDCA than in placebo groups. Comparison of the slopes of regression analysis showed slower progression in the TUDCA than in the placebo group (P < 0.01). Conclusions: This pilot study provides preliminary clinical data indicating that TUDCA is safe and may be effective in ALS.

Introduction Mutations in the small heat shock protein 22 gene (HSPB8) have been associated with Charcot-Marie-Tooth type 2L, distal hereditary motor neuropathy (dHMN) type IIa and, more recently, distal myopathy/myofibrillar myopathy (MFM) with protein aggregates and TDP-43 inclusions. Objective To report a novel family with HSPB8 K141E-related dHMN/MFM and to investigate, in a patient muscle biopsy, whether the presence of protein aggregates was paralleled by altered TDP-43 function. Methods We reviewed clinical and genetic data. We assessed TDP-43 expression by qPCR and alternative splicing of four previously validated direct TDP-43 target exons in four genes by RT-PCR. Results The triplets and their mother presented in the II-III decade of life with progressive weakness affecting distal and proximal lower limb and truncal muscles. Nerve conduction study showed a motor axonal neuropathy. The clinical features, the moderately raised CK levels, the selective pattern of muscle involvement at MRI and the pathological changes on muscle biopsy, including the presence of protein aggregates, supported the diagnosis of a contemporary primary muscle involvement. In affected muscle tissue we observed a consistent alteration of TDP-43-dependent splicing in 3 out of 4 TDP-43-target transcripts (POLDIP3, FNIP1 and BRD8), as well as a significant decrease of TDP-43 mRNA levels. Discussion Our study confirms the role of mutated HSPB8 as a cause of a combined neuromuscular disorder encompassing dHMN and MFM with protein aggregates. We identified impaired RNA metabolism, secondary to TDP-43 loss of function, as a possible pathologic mechanism of HSPB8 K141E toxicity, leading to muscle and nerve degeneration. This article is protected by copyright. All rights reserved.

X-linked Charcot-Marie-Tooth type 1 (CMTX1) is the second most common type of CMT and is caused by mutations in the Gap-Junction Beta-1 gene (GJB1), encoding connexin 32 which is expressed in Schwann cells as well as in oligodendrocytes. More than 400 GJB1 mutations have been described to date. Many mutation-carrier males have subclinical central nervous system (CNS) involvement, a few show mild CNS clinical signs, whereas only rarely overt though transient CNS dysfunction occurs. We report a 29-year-old man with CMTX1 who, at 16 years, showed short-lived CNS symptoms with transitory white matter abnormalities on cerebral magnetic resonance imaging (MRI) as first clinical presentation of a novel GJB1 mutation (p.Gln99_His100insGln). He had three consecutive episodes of right hemiparesis, together with sensory loss in the paretic limbs and expressive aphasia, all lasting a few hours, over a 2-day period, with concurrent white matter hyperintensity on MRI. These "stroke-like" episodes occurred just after arriving at sea level, after travelling from home at 700 m of altitude. Only a few years later did symptoms of peripheral neuropathy appear. In conclusion, CMTX1 should be included in the differential diagnosis of diseases characterized by transient CNS symptoms and white matter abnormalities on MRI.

Background. Physical activity and occupational exposures appeared to play a relevant role in pathogenesis of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease of unknown origin. Materials and methods. We aimed to make an overview of the clinical characteristics and life - style (occupation and sport) of a population of 395 patients with ALS from campania, in southern Italy. Results. ALS onset resulted anticipated of about 11 years in industry workers, whilst the more frequent site of onset among farmers was upper limbs. compared to non-athletes, athletes, particu- larly soccer players, showed a 7 years anticipation of ALS onset, with higher mortality after 5 years. Discussion and conclusions. We suggest that subjects genetically prone to abnormal response to hy - poxia during strenuous physical activity or exposed to neurotoxic agents, such as athletes, farmers or industry workers, might present increased risk to develop ALS. Future case-control and follow-up studies on our population should be implemented to deepen the present results. Riassunto (Caratteristiche cliniche e stile di vita di pazienti con sclerosi laterale amiotrofica in Campania: breve panoramica di un database italiano). Introduzione. Attivita fisica ed esposizione professionale a sostanze tossiche sembrano svolgere un ruolo rilevante nella patogenesi della sclerosi laterale amiotrofica (SLA), una malattia neurodegenerativa di origine sconosciuta. Materiali e metodi. ci siamo proposti di effettuare una panoramica delle caratteristiche cliniche e dello stile di vita (attivita lavorativa e sport) di una popolazione di 395 pazienti affetti da SLA provenienti dalla regione campania, in Italia meridionale. Risultati. L'insorgenza della SLA e risultata anticipata di circa 11 anni nei lavoratori dell'industria, mentre il sito piu frequente di insorgenza tra i contadini era caratterizzato dagli arti superiori. Rispetto ai non- sportivi, gli sportivi, soprattutto i calciatori, hanno mostrato un'anticipazione di 7 anni nell'insorgenza della SLA, con maggiore mortalita a 5 anni. Discussione e conclusioni. Abbiamo ipotizzato che i soggetti geneticamente predisposti a risposte anomale all'ipossia durante l'attivita fisica intensa o esposti ad agenti neurotossici, come gli sportivi, gli agricoltori o i lavoratori dell'industria, possano presentare un aumen - tato rischio di sviluppare la SLA. Futuri studi caso-controllo e di follow-up sulla nostra popolazione dovrebbero essere effettuati per approfondire i risultati attuali.

Pathomechanisms of spinal and bulbar muscular atrophy (SBMA) have been extensively investigated and are partially understood, but no effective treatment is currently available for this disabling disorder. Its rarity, the slow disease progression, and lack of sensitive-to-change outcome measures render design and conduction of clinical trials a challenging task. Therefore, it is fundamental to strengthen the network of clinical centers interested in SBMA for clinical trial readiness. We propose to create and maintain an International SBMA Registry where as many well-characterized patients as possible can be included, with the following aims: facilitate planning of clinical trials and recruitment of patients, define natural history of the disease, characterize epidemiology, develop standards of care, and inform the community of patients about research progresses and ongoing trials. We also aim at developing harmonized and coordinated biorepositories. The experience obtained during the last years in the field of other neuromuscular disorders and of Huntington disease offers valuable precedents.

Spinal and Bulbar Muscular Atrophy (SBMA), also known as Kennedy's disease, is a rare adult-onset lower motor neuron disorder with a classic X-linked inheritance pattern. It is caused by the abnormal expansion of the CAG-repeat tract in the androgen receptor gene. Despite important progress in the understanding of the molecular pathogenesis and the availability of a broad set of model organisms, successful translation of these insights into clinical interventions remains elusive. Here we review the available information on clinical trials in SBMA and discuss the challenges and pitfalls that impede therapy development. Two important factors are the variability of the complex neuro-endocrinological phenotype and the comparatively low incidence of the disease that renders recruitment for clinical trials demanding. We propose that these challenges can be and need to be overcome by fostering closer collaborations between clinical research centers, the patient communities and the industry and non-industry sponsors of clinical trials.

Spinal and bulbar muscular atrophy is an X-linked neuromuscular disease caused by a trinucleotide CAG repeat expansion in the androgen receptor gene; it is clinically characterized by adult-onset, slowly progressive weakness and atrophy mainly affecting proximal limb and bulbar muscles. Charcot-Marie-Tooth disease type 1A is an autosomal dominant polyneuropathy due to peripheral myelin protein 22 gene duplication and characterized by slowly progressive distal limb muscle weakness, atrophy and sensory loss with foot deformities. Here we report the co-occurrence of both neuromuscular genetic diseases in the same male patient. Difficulties in climbing stairs and jaw weakness were presenting symptoms consistent with SBMA. However, predominant distal weakness and bilateral pes cavus were rather suggestive of a hereditary polyneuropathy. The combination of two diseases, even if extremely rare, should be considered in the presence of atypical symptoms; in the case of genetic diseases this event may have important implications on family members' counseling.

Peripheral nerves have peculiar energetic requirements because of considerable length of axons and therefore correct mitochondria functioning and distribution along nerves is fundamental. Mitochondrial dynamics refers to the continuous change in size, shape, and position of mitochondria within cells. Abnormalities of mitochondrial dynamics produced by mutations in proteins involved in mitochondrial fusion (mitofusin-2, MFN2), fission (ganglioside-induced differentiation-associated protein-1, GDAP1), and mitochondrial axonal transport usually present with a Charcot-Marie-Tooth disease (CMT) phenotype. MFN2 mutations cause CMT type 2A by altering mitochondrial fusion and trafficking along the axonal microtubule system. CMT2A is an axonal autosomal dominant CMT type which in most cases is characterized by early onset and rather severe course. GDAP1 mutations also alter fission, fusion and transport of mitochondria and are associated either with recessive demyelinating (CMT4A) and axonal CMT (AR-CMT2K) and, less commonly, with dominant, milder, axonal CMT (CMT2K). OPA1 (Optic Atrophy-1) is involved in fusion of mitochondrial inner membrane, and its heterozygous mutations lead to early-onset and progressive dominant optic atrophy which may be complicated by other neurological symptoms including peripheral neuropathy. Mutations in several proteins fundamental for the axonal transport or forming the axonal cytoskeleton result in peripheral neuropathy, i.e., CMT, distal hereditary motor neuropathy (dHMN) or hereditary sensory and autonomic neuropathy (HSAN), as well as in hereditary spastic paraplegia. Indeed, mitochondrial transport involves directly or indirectly components of the kinesin superfamily (KIF5A, KIF1A, KIF1B), responsible of anterograde transport, and of the dynein complex and related proteins (DYNC1H1, dynactin, dynamin-2), implicated in retrograde flow. Microtubules, neurofilaments, and chaperones such as heat shock proteins (HSPs) also have a fundamental role in mitochondrial transport and mutations in some of related encoding genes cause peripheral neuropathy (TUBB3, NEFL, HSPB1, HSPB8, HSPB3, DNAJB2). In this review, we address the abnormalities in mitochondrial dynamics and their role in determining CMT disease and related neuropathies.

Spinal and bulbar muscular atrophy (SBMA) or Kennedy's disease is an X-linked CAG/polyglutamine expansion motoneuron disease, in which an elongated polyglutamine tract (polyQ) in the N-terminal androgen receptor (ARpolyQ) confers toxicity to this protein. Typical markers of SBMA disease are ARpolyQ intranuclear inclusions. These are generated after the ARpolyQ binds to its endogenous ligands, which promotes AR release from chaperones, activation and nuclear translocation, but also cell toxicity. The SBMA mouse models developed so far, and used in preclinical studies, all contain an expanded CAG repeat significantly longer than that of SBMA patients. Here, we propose the use of SBMA patients adipose-derived mesenchymal stem cells (MSCs) as a new human in vitro model to study ARpolyQ toxicity. These cells have the advantage to express only ARpolyQ, and not the wild type AR allele. Therefore, we isolated and characterized adipose-derived MSCs from three SBMA patients (ADSC from Kennedy's patients, ADSCK) and three control volunteers (ADSCs). We found that both ADSCs and ADSCKs express mesenchymal antigens, even if only ADSCs can differentiate into the three typical cell lineages (adipocytes, chondrocytes and osteocytes), whereas ADSCKs, from SBMA patients, showed a lower growth potential and differentiated only into adipocyte. Moreover, analysing AR expression on our mesenchymal cultures we found lower levels in all ADSCKs than ADSCs, possibly related to negative pressures exerted by toxic ARpolyQ in ADSCKs. In addition, with proteasome inhibition the ARpolyQ levels increased specifically in ADSCKs, inducing the formation of HSP70 and ubiquitin positive nuclear ARpolyQ inclusions. Considering all of this evidence, SBMA patients adipose-derived MSCs cultures should be considered an innovative in vitro human model to understand the molecular mechanisms of ARpolyQ toxicity and to test novel therapeutic approaches in SBMA.

Mutations in the CLCN2 gene encoding ClC-2, a chloride channel implicated in brain ion and water homeostasis, have been recently associated with a rare autosomal recessive leukoencephalopathy, characterized by specific MRI findings caused by chronic white matter edema.1 Acknowledgment: The authors thank Mario Savoiardo, an Italian pioneer in neuroradiology, who died during the revision process of this article, for his help, insightful comments, and diagnoses. The authors and his friends around the world will miss him.

X-linked Charcot-Marie-Tooth type 1 (CMTX1) is the second most common type of CMT and is caused by mutations in the Gap-Junction Beta-1 gene (GJB1), encoding connexin 32 which is expressed in Schwann cells as well as in oligodendrocytes. More than 400 GJB1 mutations have been described to date. Many mutation-carrier males have subclinical central nervous system (CNS) involvement, a few show mild CNS clinical signs, whereas only rarely overt though transient CNS dysfunction occurs. We report a 29-year-old man with CMTX1 who, at 16 years, showed short-lived CNS symptoms with transitory white matter abnormalities on cerebral magnetic resonance imaging (MRI) as first clinical presentation of a novel GJB1 mutation (p.Gln99_His100insGln). He had three consecutive episodes of right hemiparesis, together with sensory loss in the paretic limbs and expressive aphasia, all lasting a few hours, over a 2-day period, with concurrent white matter hyperintensity on MRI. These "stroke-like" episodes occurred just after arriving at sea level, after travelling from home at 700 m of altitude. Only a few years later did symptoms of peripheral neuropathy appear. In conclusion, CMTX1 should be included in the differential diagnosis of diseases characterized by transient CNS symptoms and white matter abnormalities on MRI.

Adult polyglucosan body disease is a rare autosomal recessive disease, caused by glycogen branching enzyme gene mutations, characterised by urinary dysfunction, spastic paraplegia with vibration sense loss, peripheral neuropathy, and cognitive impairment. Fabry's disease is an X-linked lysosomal storage disorder caused by α-galactosidase A gene mutations; neurological manifestations include cerebrovascular accidents, small-fibre neuropathy and autonomic dysfunction. Here, we report the case of a 44-year-old Sicilian male with stroke-like episodes, hypohidrosis and mild proteinuria, which led to the diagnosis of Fabry's disease after a hemizygous mutation (p.Ala143Thr) in α-galactosidase A gene was detected. Subsequently, he developed progressive walking difficulties and dementia, which were considered atypical for Fabry's disease. Therefore, we performed additional investigations that eventually led to the diagnosis of adult polyglucosan body disease caused by two novel missense mutations (p.Asp413His and p.Gly534Val) in the glycogen branching enzyme gene. Recently, the pathogenic role of the p.Ala143Thr mutation in causing Fabry's disease has been questioned. This case underlines the importance of performing further investigations when facing with atypical features even in the presence of a genetic diagnosis of a rare disease.

In this review, progress in hereditary neuropathy research published in the Journal of Neurology over the last 18 months is summarised.

The concurrence of amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) is extremely rare. We reported the case of a 33-year-old woman with a past history of paresthesias at the right hand, who developed progressive quadriparesis with muscular atrophy of limbs and, finally, bulbar signs and dyspnea. Clinical and neurophysiologic investigations revealed upper and lower motor neuron signs in the bulbar region and extremities, suggesting the diagnosis of ALS. Moreover, magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) analysis demonstrated 3 periventricular and juxtacortical lesions, hyperintense in T2 and FLAIR sequences, and 3 liquoral immunoglobulin G (IgG) oligoclonal bands, consistent with diagnosis of primary progressive MS (PPMS). This unusual overlap of ALS and MS leads to the discussion of a hypothetical common pathological process of immunological dysfunction in these two disorders, although the role of immune response in ALS remains ambivalent and unclear. © 2012 Francesca Trojsi et al.

BACKGROUND AND PURPOSE: The extensive application of advanced MR imaging techniques to the study of ALS has undoubtedly improved our knowledge of disease pathophysiology, even if the actual spread of the neurodegenerative process throughout the central nervous system is not fully understood. The present study aimed to detect WM patterns of microstructural abnormalities to better investigate the pathologic process in ALS, within but also beyond CSTs, in a whole-brain analysis. MATERIALS AND METHODS: DTI was performed in 19 patients with ALS and 20 matched healthy controls, by using whole-brain TBSS and VOI analyses. RESULTS: We observed a significant decrease of FA in the body of CC of the ALS group (P < .05). At the VOI level, both FA decrease and RD increase in the body of CC significantly correlated with the UMN score (P = .003 and P = .02). Additionally, significant voxelwise positive correlations between FA and the ALSFRS-R were detected in the WM tracts underneath the left premotor cortex (P < .05). CONCLUSIONS: The correlations between reduction of FA and increase of RD in the body of CC with the UMN score indicate that the WM degeneration in the CC is strictly related to the ALS pyramidal impairment, while the correlation between FA and ALSFRS-R in the associative tracts underneath the left premotor cortex might reflect the progressive spread of the disease from the motor toward the extramotor areas.

We assessed the spontaneous blood-oxygen-level-dependent signal fluctuations in the resting-state brain networks of amyotrophic lateral sclerosis patients and their relation to physiologically sensitive and disease modified functional magnetic resonance imaging parameters. Resting-state functional magnetic resonance imaging was performed at 3 Tesla on 20 amyotrophic lateral sclerosis patients with minimal frontal cognitive dysfunction and 20 age- and sex-matched healthy volunteers. Resting-state network maps were extracted with independent component analysis and group-level statistical analyses were performed to detect disease and disease-by-age interaction effects. Whole-brain global and regional atrophy measures were obtained from same-session structural scans. The sensori-motor network showed significant disease effects, with signals suppressed in patients bilaterally in the primary motor cortex. The default-mode network showed a significant disease-by-age interaction in the posterior cingulate cortex, where signals correlated with age positively in patients and negatively in controls. Both disease and disease-by-age interaction effects were detected in the right fronto-parietal network. Although global atrophy did not show significant differences, regions of reduced gray matter volume were detected in patients compared with controls adjacent to regions of reduced functional connectivity. Our results confirm that resting-state functional magnetic resonance imaging signals in the sensori-motor network are suppressed in amyotrophic lateral sclerosis. A similar suppression is evident in the right fronto-parietal network, possibly reflecting the patients' frontal dysfunction and right-lateralized patterns of regional atrophy. The interaction between disease and aging in the default-mode network unravels a possible mechanism of compensation between motor and extramotor systems emerging as a supplementary functional push to help motor disturbances.