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Background and purpose Charcot−Marie−Tooth ( CMT) disease is the most common inherited neuropathy, but therapeutic options have been limited to symptom management. Past pharmacological trials have failed, possibly due to insensitive outcome measures ( OMs). The aim of the current study was to evaluate the validity and reliability of the 6-min walk test (6 MWT) and StepWatch™ Activity Monitoring ( SAM) with other previously validated OMs in CMT disease. Methods A prospective multicenter study was performed, consecutively enrolling 168 CMT patients (104 with CMT1A, 27 with CMT1B, 37 with X-linked CMT) from Italian centers specializing in CMT care. Results Statistical analysis showed that the 6 MWT was highly related with all previously used OMs. Some, but not all, SAM parameters were related to commonly used OMs but may provide more information about quality of life. Conclusions The current study demonstrated the validity and reliability of the 6 MWT and SAM as OMs for CMT. Moreover, SAM provides data that correlate better with quality of life measures, making it useful in future rehabilitation trials. [ABSTRACT FROM AUTHOR]

Background: The cardiomyopathic and neuropathic phenotype of hereditary transthyretin amyloidosis are well recognized. Cardiovascular autonomic dysfunction is less systematically and objectively assessed., Methods: Autonomic and clinical features, quantitative cardiovascular autonomic function, and potential autonomic prognostic markers of disease progression were recorded in a cohort of individuals with hereditary transthyretin amyloidosis and in asymptomatic carriers of TTR variants at disease onset (T0) and at the time of the first quantitative autonomic assessment (T1). The severity of peripheral neuropathy and its progression was stratified with the polyneuropathy disability score., Results: A total of 124 individuals were included (111 with a confirmed diagnosis of hereditary transthyretin amyloidosis, and 13 asymptomatic carriers of TTR variants). Symptoms of autonomic dysfunction were reported by 27% individuals at T0. Disease duration was 4.5 ± 4.0 years [mean ± standard deviation (SD)] at autonomic testing (T1). Symptoms of autonomic dysfunction were reported by 78% individuals at T1. Cardiovascular autonomic failure was detected by functional testing in 75% individuals and in 64% of TTR carriers. Progression rate from polyneuropathy disability stages I/II to III/IV seemed to be shorter for individuals with autonomic symptoms at onset [2.33 ± 0.56 versus 4.00 ± 0.69 years (mean ± SD)]., Conclusions: Cardiovascular autonomic dysfunction occurs early and frequently in individuals with hereditary transthyretin amyloidosis within 4.5 years from disease onset. Cardiovascular autonomic failure can be subclinical in individuals and asymptomatic carriers, and only detected with autonomic function testing, which should be considered a potential biomarker for early diagnosis and disease progression., (© 2024. Springer-Verlag GmbH Germany.)

Background: Paraneoplastic neurological syndromes (PNSs) are nonmetastatic complications of malignancy, defined by the presence of onconeural antibodies (ONAs). ONAs may be found in 60% of patients with central nervous system (CNS) involvement, and they are directed against intraneuronal antigens or channels, receptors or associated proteins located at the synaptic or extra-synaptic neuronal cell membrane. Given its rare incidence, there are few epidemiological case series on CNS-PNS. We aim to discuss the variability of CNS-PNSs etiology, clinical features, management and outcome, highlighting the importance of early recognition and appropriate treatment, leading to significant reduction of mortality and morbidity., Methods: We retrospectively reviewed our 7-years single-center experience, and specifically discussed the underlying etiology, parenchymal CNS involvement, and the acute treatment response. Only cases fulfilling PNS Euronetwork criteria for definitive PNS were included., Results: A total of 26 probable PNSs cases involving CNS were identified. We reported medical records of eleven (42.3%) illustrative cases, meeting the criteria of definite PNS and presenting variable clinical spectrum and different radiological appearances. Our series has a relative paucity of the most common syndromes and larger portion of clinical diagnosis with ONAs. Well-characterized ONAs had been detected in CSF of six patients., Conclusions: Our case series supports the utmost importance of early recognition of CNS-PNSs. Screening for occult malignancies should not be limited to patients with classical CNS syndrome. Empiric immunomodulatory therapy may be considered before the diagnostic evaluation is completed, in order to prevent unfavorable outcome. Late presentations should not discourage initiation of treatment., (© 2023. The Author(s) under exclusive licence to Belgian Neurological Society.)

The present study aims to investigate the benefits induced by physical activity/practiced sport in Charcot-Marie-Tooth 1A (CMT1A). Patients were divided into sport and no-sport groups according to their sports performance habit. Thirty-one patients were enrolled, of which 14 practiced sports and 17 did not. Clinical assessments were administered to evaluate disability, self-esteem, depression, quality of life, and pain. Statistical analysis revealed significant differences in terms of gender in the no-sport group compared to the sport group ( p = 0.04). Regarding the quality of life, physical function ( p = 0.001), general health ( p = 0.03), social function ( p = 0.04), and mental health ( p = 0.006) showed better patterns in the sport group than no-sport group. Moreover, neuropathic pain was reduced in the sport group according to the Neuropathic Pain Symptom Inventory ( p = 0.001) and ID-PAIN ( p = 0.03). The other administered questionnaires showed no significant differences. Our study confirms that CMT1A patients, who practice sports, with a similar severity of disability, may have a better physical quality of life while suffering less neuropathic pain than their peers who do not practice sports. Results recommend the prescription of sport in CMT1A patients.

Patient report outcome measures in Spinal Muscular Atrophy (SMA) represent a potential complement to observer rated scales which can be used to better understand treatment response. We developed, translated and validated an Italian version of the Spinal Muscular Atrophy Health Index (SMAHI), a disease-specific, patient reported outcome measure questionnaire, designed to estimate the patients' perception of disease burden. Test-retest reliability was assessed in 37 patients (16 children aged 12-17 and 21 adults) and was excellent in both cohorts. Internal consistency in an additional 98 patients (24 children, 74 adults) was also excellent (Cronbach's alpha = 0.93 and 0.91 respectively). In children the highest level of disease burden was generated from lower limb dysfunction and fatigue as well as their perception of decreased performance in social situations. Most patients in the adult cohort were sitters and complained of problems with upper limb functions as well as of fatigue. The SMAHI-IT was also able to differentiate between SMA types according to diseases severity. The results of our study demonstrate that the SMAHI can be considered a marker of disease-specific burden in patients with SMA with a high test-retest reliability and internal validity in Italian patients aged 12 and older., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The personal relationships listed below have not in any way influenced the work reported in this paper. Valeria A Sansone provides intellectual and teaching activities for Biogen, Avexis, Roche, Santhera, Sarepta, PTC, Dyne. Alice Pirola has nothing to declare. Andrea Lizio has nothing to declare. Lucia C Greco has nothing to declare. Giorgia Coratti reports consultancy activity for Biogen, Avexis, Roche, Genesis Pharma, Biologix. Jacopo Casiraghi has nothing to declare. Marika Pane provides intellectual, advisory board and teaching activities for Biogen, Avexis, Roche. Maria Carmela Pera reports consultancy activity for Roche. Italiano Cristina has nothing to declare. Sonia Messina has nothing to declare. Susanna Pozzi has nothing to declare. Maria Sframeli has nothing to declare. Adele D'Amico has nothing to declare. Enrico Bertini has nothing to declare. Claudio Bruno provides consultation in scientific Advisory Boards for Avexis, Bioegn, Roche, Sarepta, PTC. Luca Mauro has nothing to declare. Francesca Salmin has nothing to declare. Claudia Stancanelli has nothing to declare. Marina Pedemonte has nothing to declare. Emilio Albamonte has nothing to declare. Christine Izzi has provided consulting to Recursion Pharmaceuticals. Chad Heatwole receives royalties for the use of multiple disease specific instruments. He has provided consultation to Biogen Idec, Ionis Pharmaceuticals, aTyr Pharma, AMO Pharma, Acceleron Pharma, Cytokinetics, Expansion Therapeutics, Harmony Biosciences, Regeneron Pharmaceuticals, Astellas Pharmaceuticals, AveXis, Recursion Pharmaceuticals, IRIS Medicine, Inc., Scholar Rock, and the Marigold Foundation. He receives grant support from Duchenne UK, Parent Project Muscular Dystrophy, Recursion Pharmaceuticals, the National Institute of Neurological Disorders and Stroke, the Muscular Dystrophy Association, the Friedreich's Ataxia Research Alliance, Cure Spinal Muscular Atrophy, and the Amyotrophic Lateral Sclerosis Association. Eugenio Mercuri provides intellectual, advisory board and teaching activities for Biogen, Avexis, Roche., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: ATTRv amyloidosis is worldwide spread with endemic foci in Portugal and Sweden, Japan, Brazil, Maiorca, and Cyprus. A national Registry was developed to characterise the epidemiology and genotype-phenotype correlation of ATTRv amyloidosis in Italy and to allow a better planning of diagnostic and therapeutic services., Methods: Fifteen Italian referral centres for amyloidosis spread all over the country have contributed to the Registry., Results: Four-hundred-forty-seven subjects were enrolled, 187 asymptomatic carriers and 260 affected patients. Thirty-one different mutations were recorded. The seven most represented genetic variants were significantly different in terms of age at onset, clinical features and geographical distribution. National prevalence is 4.33/million with higher values in Southern Italy. Overall symptoms of polyneuropathy were present at disease onset in about half of the patients, symptoms of cardiomyopathy in a quarter of patients, the rest referring carpal tunnel syndrome, dysautonomia or lumbar spinal stenosis. 52.6% of patients were in FAP stage 1, 20.4% in stage 2 and 13.5% in stage 3, while 13.5% patients had no neuropathy, presenting only cardiological symptoms., Conclusions: We presented an epidemiological study based on collaboration among referral centres for ATTRv amyloidosis spread in all the Italian territory, using web-based Registry. It provided a detailed map of the regional distribution of the disease. The increased awareness of the disease among general practitioners and medical specialists has contributed to reduce the diagnostic delay and the rate of misdiagnosis. The Registry will allow to collect also future information about clinical and instrumental follow-up.

Previous studies demonstrated the benefits of motor exercise and physical activity in neuromuscular disorders. However, very few papers assessed the effects of sport practise. The aim of this multicentre study was to assess the impact of sport activity on self-esteem and emotional regulation in a cohort of athletes with neuromuscular disorders. The 38 patients with Duchenne, Becker or other types of muscular dystrophy or spinal muscular atrophy practising sport (aged 13-49 years) and 39 age-, gender-, disability- and disease-matched patients not practising sport were enrolled. Testing procedures to assess self-esteem, anxiety and depression disorder, personality trait and quality of life (QoL) were used. Patients practising sport had a significantly higher self-esteem, lower level of depression, greater social own identity and adherence and QoL. Frequency of sport activity may represent a complementary therapy in neuromuscular disorders to improve mental and social well-being.

Objective: To assess the prevalence and isotypes of anti-nodal/paranodal antibodies to nodal/paranodal proteins in a large chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) cohort, compare clinical features in seronegative vs seropositive patients, and gather evidence of their isotype-specific pathogenic role., Methods: Antibodies to neurofascin-155 (Nfasc155), neurofascin-140/186 (Nfasc140/186), contactin-1 (CNTN1), and contactin-associated protein 1 (Caspr1) were detected with ELISA and/or cell-based assay. Antibody pathogenicity was tested by immunohistochemistry on skin biopsy, intraneural injection, and cell aggregation assay., Results: Of 342 patients with CIDP, 19 (5.5%) had antibodies against Nfasc155 (n = 9), Nfasc140/186 and Nfasc155 (n = 1), CNTN1 (n = 3), and Caspr1 (n = 6). Antibodies were absent from healthy and disease controls, including neuropathies of different causes, and were mostly detected in patients with European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) definite CIDP (n = 18). Predominant antibody isotypes were immunoglobulin G (IgG)4 (n = 13), IgG3 (n = 2), IgG1 (n = 2), or undetectable (n = 2). IgG4 antibody-associated phenotypes included onset before 30 years, severe neuropathy, subacute onset, tremor, sensory ataxia, and poor response to intravenous immunoglobulin (IVIG). Immunosuppressive treatments, including rituximab, cyclophosphamide, and methotrexate, proved effective if started early in IVIG-resistant IgG4-seropositive cases. Five patients with an IgG1, IgG3, or undetectable isotype showed clinical features indistinguishable from seronegative patients, including good response to IVIG. IgG4 autoantibodies were associated with morphological changes at paranodes in patients' skin biopsies. We also provided preliminary evidence from a single patient about the pathogenicity of anti-Caspr1 IgG4, showing their ability to penetrate paranodal regions and disrupt the integrity of the Nfasc155/CNTN1/Caspr1 complex., Conclusions: Our findings confirm previous data on the tight clinico-serological correlation between antibodies to nodal/paranodal proteins and CIDP. Despite the low prevalence, testing for their presence and isotype could ultimately be part of the diagnostic workup in suspected inflammatory demyelinating neuropathy to improve diagnostic accuracy and guide treatment., Classification of Evidence: This study provides Class III evidence that antibodies to nodal/paranodal proteins identify patients with CIDP (sensitivity 6%, specificity 100%)., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Recent advances in pathophysiological and genetic mechanisms of some neuromuscular diseases and a rapid progress in new pharmacological technologies led to an accelerated development of innovative treatments, generating an unexpected therapeutic revolution. In part 1, we report already commercially available drugs, just approved drugs and new therapeutic promises in the treatment of peripheral neuropathies. Hereditary transthyretin amyloidosis (hATTR) is a devastating disease due to amyloid accumulation in peripheral nerves, heart and autonomic system. The first specific drug approved for hATTR was tafamidis, a TTR tetramer stabilizer. In 2018, the positive results of two phase 3 trials have been reported leading to start of regulatory approval route for inotersen, an antisense oligonucleotide and patisiran, the first-ever RNA interference (RNAi) therapeutic. System biology targeting approach has indicated baclofen, naltrexone and sorbitol in combination (PXT3003) as candidate drugs for Charcot-Marie-Tooth disease type 1A. This hypothesis was confirmed in experimental models and in phase 2 and 3 clinical trials. Givosiran, another RNAi therapeutic, targeting 5-aminolevulinic acid synthase, has been positively tested in acute intermittent porphyria in phase 1/2 and ongoing phase 3 trials. Although allogenic hematopoietic stem cell transplantation resulted recently a long-term therapy in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), a new strategy is liver transplantation which is able to revert the severe biochemical and clinical imbalance of the disease. Recently, a gene therapy has been tested in a MNGIE murine model, indicating that it may become a new therapeutic option.

Hereditary transthyretin amyloidosis (hATTR) is a life-threatening multisystemic disease with sensory-motor peripheral neuropathy, cardiomyopathy and dysautonomia. Although the six-minute walk test (6MWT) is one of the most popular clinical tests to assess functional exercise capacity in cardiopulmonary and neuromuscular diseases, little is known about 6MWT in evaluating hATTR patients. A prospective single-center pilot study was performed in twenty hATTR patients, comparing 6MWT with widely used outcome measures. After 18 months, fourteen patients were re-evaluated. 6MWT performance was highly related with familial amyloidotic polyneuropathy stage and polyneuropathy disability score, and with CMT examination score, neuropathy impairment score-lower limbs and Kumamoto score. There was no correlation with compound autonomic dysfunction test, modified body mass index and numerous indices of heart dysfunction. After 18 months, familial amyloidotic polyneuropathy stage and polyneuropathy disability score systems were not able to reveal any significant change, whereas all other outcome measures significantly worsened. Among the outcome measures monitoring the neuropathic disturbances, neuropathy impairment score-lower limbs showed the highest responsiveness to change (adjusted effect size: 0.79), followed by CMT examination score (0.67), Kumamoto scale (0.65), 6MWT (0.62). 10MWT showed a very small value (0.21). Compound autonomic dysfunction test had a large value (0.91) whereas modified body mass index a small/moderate value (0.49). 6MWT is a simple and sensitive tool to monitor neuropathic involvement but not cardiac dysfunction in hATTR course., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Coding mutations in TTR gene cause a rare hereditary form of systemic amyloidosis, which has a complex genotype-phenotype correlation. We investigated the role of non-coding variants in regulating TTR gene expression and consequently amyloidosis symptoms. We evaluated the genotype-phenotype correlation considering the clinical information of 129 Italian patients with TTR amyloidosis. Then, we conducted a re-sequencing of TTR gene to investigate how non-coding variants affect TTR expression and, consequently, phenotypic presentation in carriers of amyloidogenic mutations. Polygenic scores for genetically determined TTR expression were constructed using data from our re-sequencing analysis and the GTEx (Genotype-Tissue Expression) project. We confirmed a strong phenotypic heterogeneity across coding mutations causing TTR amyloidosis. Considering the effects of non-coding variants on TTR expression, we identified three patient clusters with specific expression patterns associated with certain phenotypic presentations, including late onset, autonomic neurological involvement, and gastrointestinal symptoms. This study provides novel data regarding the role of non-coding variation and the gene expression profiles in patients affected by TTR amyloidosis, also putting forth an approach that could be used to investigate the mechanisms at the basis of the genotype-phenotype correlation of the disease.

Transthyretin familial amyloid polyneuropathy (TTR-FAP) is an inherited amyloidosis, leading to death in about ten years in most cases due to cardiac failure or wasting syndrome. Previous studies showed that modified body mass index was related to time before death, duration of gastrointestinal disturbances, malabsorption and functional capacity. We report two patients in whom nutritional status worsened despite diet modification, hypercaloric supplement and two relevant therapeutic approaches such as liver transplant and tafamidis meglumine, respectively. The first patient, a 52-year-old lady carrying Thr49Ala mutation, had a disease duration of twelve years and had lost weight up to 35 kg because of daily diarrhea. The second patient, a 63-year-old man with Glu89Gln mutation and a disease duration of fifteen years, was in the New York Heart Association (NYHA) Functional Classification class III and his weight was 39 kg. In both cases, a peripherally inserted central catheter was placed for parenteral nutrition. It allowed to improve their nutritional status and clinical conditions, with body weight gains of 11 and 8 kg in a one year follow-up, respectively. Moreover, reduction of autonomic symptoms including postural hypotension, nausea and diarrhoea was recorded with ameliorated quality of life. Our experience suggests that parenteral nutrition may be useful in reducing complications and disabilities in TTR-FAP patients, even when all dietary adjustments have been ineffective. Reasonably, the improvement in nutritional status may prolong survival in TTR-FAP patients., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Familial amyloid polyneuropathy related to transthyretin gene (TTR-FAP) is a life-threatening disease transmitted as an autosomal dominant trait. Val30Met mutation accounts for the majority of the patients with large endemic foci especially in Portugal, Sweden and Japan. However, more than one hundred other mutations have been described worldwide. A great phenotypic variability among patients with late- and early-onset has been reported., Objective: To present a detailed report of TTR-FAP patients diagnosed in our tertiary neuromuscular center, in a 20-year period., Methods: Clinical informations were gathered through the database of our center., Results: The study involved 76 individuals carrying a TTR-FAP mutation. Three phenotypes were identified, each corresponding to a different TTR variant, homogeneous within and heterogeneous between each other: i) Glu89Gln mutation, characterised by 5th - 6th decade onset, neuropathy as presenting symptoms, early heart dysfunction, cardiomyopathy as major cause of mortality followed by dysautonomia and cachexia; ii) Phe64Leu mutation, marked by familiarity reported in one-half of cases, late onset, severe peripheral neuropathy, moderate dysautonomia and mild cardiomyopathy, death for wasting syndrome; iii) Thr49Ala mutation, distinguished by onset in the 5th decade, autonomic disturbances as inaugural symptoms which may remain isolated for many years, moderate polyneuropathy, cachexia as major cause of mortality followed by cardiomyopathy., Conclusions: This survey highlighted a prevalence of 8.8/1,000,000 in Sicily Island. Good knowledge of the natural history of the disease according to different TTR mutations allow clinicians to optimise multiprofessional care for patients and to offer carriers a personalized follow-up to reveal first signs of the disease.