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Guillain–Barré syndrome (GBS) is an acute, immune-mediated polyradiculoneuropathy, usually triggered by an infectious episode, mostly of viral origin. Varicella zoster virus (VZV) is a rare cause of GBS, mainly in the case of latent infection reactivation. We report on three adult patients who developed GBS following chickenpox, after a short period of latency. They were promptly treated with intravenous immunoglobulin, and the first one with plasma exchange additionally. All the patients experienced almost complete clinical recovery. Our experience suggests that primary VZV infection constitutes a GBS triggering event. [ABSTRACT FROM PUBLISHER]

Magnetization transfer imaging (MTI) evaluates the exchange of magnetization between protons in free water molecules and protons bound to macromolecules, including lipids. Widely used in the study of central nervous system diseases, its application in the neuromuscular field has been previously explored only in a Spanish cohort of patients with late-onset Pompe disease (LOPD). To investigate the potential role of MTR as an early biomarker of muscle involvement, we here evaluate magnetization transfer ratio (MTR) and fat fraction (FF) in patients with LOPD in various stages of disease compared to healthy controls (HCs). Quantitative muscle MRI (qMRI) was performed on 31 LOPD patients (21 with mild and 10 with moderate/severe clinical involvement) and 31 matched HCs using 3T MRI. FF and MTR were measured in 11 thigh muscles. Correlations between FF and MTR were assessed. Additionally, FF and MTR were compared between groups of HCs vs. early vs. moderate/severe LOPD. We also explored whether MTR can detect muscle involvement in not yet fat-infiltrated muscles (FF ≤ 10%) in early LOPD. MTR of thigh muscles with FF ≤ 10% was significantly lower in LOPD compared to HCs. Changes in MTR could be detected even in mildly symptomatic patients, particularly in the medial and posterior compartments (Mann-Whitney U: p < 0.05). MTR and FF were inversely correlated in all subjects groups. We found significant differences in MTR and FF changes at the group level between mild and moderate/severe vs HCs. We conclude that MTI has potentially high sensitivity to detect mild muscle fiber damage, even before fat replacement has occurred, making it a useful biomarker to monitor early signs of disease, disease progression, and the efficacy of treatment approaches (Sanofi company provided support for this study, but had no role in study design, data collection and analysis, decision to publish, or preparation of the abstract). (The first and second authors contributed equally to this work) [ABSTRACT FROM AUTHOR]

Nesprins are a family of spectrin-repeat proteins located at the nuclear envelope which play an important role in nuclear morphology and mechano-transduction. Nesprin-1 and Nesprin-2, encoded by the synaptic nuclear envelope SYNE1 and SYNE2 , are highly expressed in cardiac and skeletal muscle. Mutations in SYNE1 have been associated with the autosomal dominant Emery‐Dreifuss Muscular Dystrophy (EDMD) type 4, Congenital Muscular Dystrophy, and Arthrogryposis Multiplex Congenita while mutations in SYNE2 only with Emery‐Dreifuss muscular dystrophy type 5. In this study, we aimed at defining the clinical characteristics, histopathological features and molecular profile of 54 patients carrying single nucleotide variants in SYNE1 and SYNE2 genes. Multiple algorithms were used to predict the deleteriousness of the variants and only variants with Combined Annotation Dependent Depletion (CADD) scores ≥20 were selected. In our cohort 56% of patients were women; 60% of patients had late onset myopathy and 23% of patients presented with EDMD-like phenotype. In 80% of patients muscle biopsy showed myopathic signs, with dystrophic changes in the 28% of cases. The subcellular localization of Nesprin-1 and -2 and their co-localization with Emerin, an inner nuclear membrane protein, were evaluated by immunofluorescence in muscle tissue from 21 patients and neither reduced nuclear staining nor mislocalization of both nesprins were detected. Our data provide a further insight into the clinical phenotypes and muscle pathology associated with SYNE1 or SYNE2 mutations and suggest that immunohistochemistry does not represent a useful diagnostic tool. [ABSTRACT FROM AUTHOR]

Inclusion body myositis (IBM) is among the most frequent acquired muscle diseases in the adult and elderly population, with onset typically > 45 years old. IBM is characterized by initially selective weakness of the quadriceps and deep finger flexors muscles, with a slow generalization and progression of weakness over the patient's lifespan. Disease monitoring may be assessed through the validated "Inclusion body myositis functional rating scale" (IBM-FRS), assessing symptoms and functional limitations in a given moment. However, poor data have been reported on IBM-FRS and its correlation with clinical features in large cohorts of IBM patients. In this cross-sectional study, we investigated the correlation of IBM-FRS specific functional domains with demographic and clinical variables in a large group of IBM patients. The following domains were considered: 1. dysphagia (item 1); 2. arm function (items 2-4); 3. independence (items 5-7); 4. leg function (items 8-10). Overall, 123 patients were included, 41 females (33%), with median age at onset of 64 (range 28 – 83), with onset in 6 patients younger than 45 years old. Walking ability was lost in 13 (10.5%), non-invasive ventilation (NIV) was needed in 13 (10.5%) and percutaneous gastrostomy (PEG) in 7 (5.6%). At IBM-FRS scoring, median age was 74 (range 44-90) and median disease duration was 8 years (range 1-42). Median IBM-FRS total score was 25 (range 3-40). When analyzing specific domains, longer disease duration significantly correlated with domains 2 (p=0.038), 3 (p=0.031) and 4 (p<0.001); age at baseline correlated with groups 2 (p=0.029), 3 (p=0.05) and 4 (p=0.008). Domain 1 correlated with female gender (p=0.001), onset with dysphagia (p=0.025) and PEG (p<0.001). Loss of walking ability correlated with domains 2, 3 and 4 (all p<0.001). No correlation was found between specific domains and age at onset or NIV. Preliminary analysis identified correlations between specific domains of IBM-FRS and clinical variables with implications for patients' stratification. Further studies are needed to investigate longitudinal changes of IBM-FRS and its domains over time. [ABSTRACT FROM AUTHOR]

Introduction/aims: Fatigue (subjective perception) and fatigability (objective motor performance worsening) are relevant aspects of disability in individuals with spinal muscular atrophy (SMA). The effect of nusinersen on fatigability in SMA patients has been investigated with conflicting results. We aimed to evaluate this in adult with SMA3., Methods: We conducted a multicenter retrospective cohort study, including adult ambulant patients with SMA3, data available on 6-minute walk test (6MWT) and Hammersmith Functional Motor Scale-Expanded (HFMSE) at baseline and at least at 6 months of treatment with nusinersen. We investigated fatigability, estimated as 10% or higher decrease in walked distance between the first and sixth minute of the 6MWT, at baseline and over the 14-month follow-up., Results: Forty-eight patients (56% females) were included. The 6MWT improved after 6, 10, and 14 months of treatment (p < 0.05). Of the 27 patients who completed the entire follow-up, 37% improved (6MWT distance increase ≥30 m), 48.2% remained stable, and 14.8% worsened (6MWT distance decline ≥30 m). Fatigability was found at baseline in 26/38 (68%) patients and confirmed at subsequent time points (p < 0.05) without any significant change over the treatment period. There was no correlation between fatigability and SMN2 copy number, sex, age at disease onset, age at baseline, nor with 6MWT total distance and baseline HFMSE score., Discussion: Fatigability was detected at baseline in approximately 2/3 of SMA3 walker patients, without any correlation with clinical features, included motor performance. No effect on fatigability was observed during the 14-month treatment period with nusinersen., (© 2024 The Author(s). Muscle & Nerve published by Wiley Periodicals LLC.)

Abstract: The leukemic stem cell (LSC) score LSC-17 based on a stemness-related gene expression signature is an indicator of poor disease outcome in acute myeloid leukemia (AML). However, it is not known whether "niche anchoring" of LSC affects disease evolution. To address this issue, we conditionally inactivated the adhesion molecule JAM-C (Junctional Adhesion Molecule-C) expressed by hematopoietic stem cells (HSCs) and LSCs in an inducible mixed-lineage leukemia (iMLL)-AF9-driven AML mouse model. Deletion of Jam3 (encoding JAM-C) before induction of the leukemia-initiating iMLL-AF9 fusion resulted in a shift from long-term to short-term HSC expansion, without affecting disease initiation and progression. In vitro experiments showed that JAM-C controlled leukemic cell nesting irrespective of the bone marrow stromal cells used. RNA sequencing performed on leukemic HSCs isolated from diseased mice revealed that genes upregulated in Jam3-deficient animals belonged to activation protein-1 (AP-1) and tumor necrosis factor α (TNF-α)/NF-κB pathways. Human orthologs of dysregulated genes allowed to identify a score that was distinct from, and complementary to, the LSC-17 score. Substratification of patients with AML using LSC-17 and AP-1/TNF-α genes signature defined 4 groups with median survival ranging from <1 year to a median of "not reached" after 8 years. Finally, coculture experiments showed that AP-1 activation in leukemic cells was dependent on the nature of stromal cells. Altogether, our results identify the AP-1/TNF-α gene signature as a proxy of LSC anchoring in bone marrow niches, which improves the prognostic value of the LSC-17 score. This trial was registered at www.ClinicalTrials.gov as #NCT02320656., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background and Aims: Since 2016, biallelic mutations in the membrane metalloendopeptidase (MME) gene have been associated with late-onset recessive CMT2 (CMT2T). More recently, heterozygous mutations have also been identified in familial and sporadic patients with late-onset axonal neuropathy, ranging from subclinical to severe. This indicates that the heterozygous MME variants may not be fully penetrant, or alternatively, that they may be a potential risk factor for neuropathy. Here, we describe the clinical, neurophysiological, and genetic findings of 32 CM2T Italian patients., Methods: The patients were recruited from four different Italian referral centers. Following a comprehensive battery of neurological, electrophysiological, and laboratory examinations, the patients' DNA was subjected to sequencing in order to identify any variants in the gene. Bioinformatic and modeling analyses were performed to evaluate the identified variants' effects., Results: We observe a relatively mild axonal sensory-motor neuropathy with a greater impairment of the lower extremities. Biallelic and monoallelic patients exhibit comparable disease severity, with an earlier onset observed in those with biallelic variants. When considering a subgroup with more than 10 years of disease, it becomes evident that biallelic patients exhibit a more severe form of neuropathy. This suggests that they are more prone to quick progression., Interpretation: CM2T has been definitively defined as a late-onset neuropathy, with a typical onset in the fifth to sixth decades of life and a more rapidly progressing worsening for biallelic patients. CMT2T can be included in the neuropathies of the elderly, particularly if MME variants heterozygous patients are included., (© 2024 The Author(s). Journal of the Peripheral Nervous System published by Wiley Periodicals LLC on behalf of Peripheral Nerve Society.)

Background: Hereditary transthyretin (ATTRv, v for variant) amyloidosis with polyneuropathy is a rare disease caused by mutations in the transthyretin gene. In ATTRv amyloidosis, multisystem extracellular deposits of amyloid cause tissue and organ dysfunction. Patisiran is a small interfering RNA molecule drug that reduces circulating levels of mutant and wild-type TTR proteins. Prior to its regulatory approval, patisiran was available in Italy through a compassionate use programme (CUP). The aim of this study was to analyse the long-term outcomes of patients who entered into the CUP., Methods: This was a multicentre, observational, retrospective study of patients with ATTRv amyloidosis treated with patisiran. The analysis included change from baseline to 12, 24, 36 and 48 months in familial amyloid polyneuropathy (FAP) stage, polyneuropathy disability (PND) class, neuropathy impairment score (NIS), modified body mass index (mBMI), Compound Autonomic Dysfunction Test (CADT), Karnofsky Performance Status (KPS) scale and Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) questionnaire. Safety data were also analysed., Results: Forty patients from 11 Italian centres were enrolled: 23 in FAP 1 (6 in PND 1 and 17 in PND 2) and 17 in FAP 2 (8 in PND 3a and 9 in PND 3b) stage. In this population, the mean NIS at baseline was 71.4 (± 27.8); mBMI, 917.1 (± 207) kg/m 2 ; KPS, 67.1 (± 14.0); Norfolk QoL-DN, 62.2 (± 25.2); and CADT, 13.2 (± 3.3). Statistical analysis showed few significant differences from baseline denoting disease stability. No new safety signals emerged., Conclusions: Patisiran largely stabilised disease in patients with ATTRv amyloidosis., (© 2024. The Author(s).)

Background: The application of massive parallel sequencing technologies in the molecular analysis of Charcot-Marie-Tooth (CMT) has enabled the rapid and cost-effective identification of numerous potentially significant variants for diagnostic purposes. The objective is to reduce the number of variants, focusing only on those with pathogenic significance. The 2015 American College of Medical Genetics and Genomics (ACMG) guidelines aid in achieving this goal, but it is now evident that a pathology or gene-specific review of these rules is essential to avoid misinterpretations that may result from blindly applying the criteria. This study demonstrates how revised ACMG criteria, combined with CMT-specific literature data and expertise, can alter the final classification of a variant., Methods: We reviewed ACMG criteria based on current knowledge of CMT and provided suggestions for adapting them to the specificities of CMT., Results: Of the 226 index patients analysed, a diagnostic yield of 20% was obtained. It is worth noting that the 9% of cases had their final diagnosis changed with the application of the revised criteria, often resulting in the loss of the pathogenic classification of a variant., Conclusions: The widespread availability of high-throughput sequencing technologies has enabled genetic testing even for laboratories without specific disease expertise. Disease-specific ACMG criteria can be a valuable tool to prevent the proliferation of variants of uncertain significance and the misinterpretation of variants., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: The diagnostic process for myofibrillar myopathies (MFM) and distal myopathies (DM) is particularly complex because of the large number of causative genes, the existence of still molecularly undefined disease entities, and the overlapping features between the 2 categories. This study aimed to characterize a large cohort of patients affected by MFM and DM and identify the most important diagnostic and prognostic aspects of these diseases., Methods: Patients with either a myopathological diagnosis of MFM or a clinical diagnosis of DM were included in this retrospective multicentric national study. Demographic, genetic, clinical, and histopathologic data of anonymized patients were collected from the neuromuscular centers of the Italian Association of Myology network., Results: Data regarding 132 patients with MFM (mean age 57.0 ± 15.8 years, 49% female) and 298 patients with DM (mean age 50.7 ± 15.9 years, 40% female) were gathered from 20 neuromuscular centers. 69 patients fulfilled the criteria for both groups (distal myopathies with myofibrillar pathology, DM-MP). Molecular confirmation was achieved in 63% of the patients. Fifty-two percent of the patients with MFM carried pathogenic variants in either DES (n = 30), MYOT (n = 20), or DNAJB6 (n = 18), which were also the most frequent disease-causing genes in DM-MP, while GNE (n = 44) and MYH7 (n = 23) were the genes most commonly carrying pathogenic variants in DM. The mean age at onset varied from <25 years in patients with causative variants in MYH7 and DYSF to 59 years in patients with myotilinopathies. Cardiac involvement was reported in 29% of patients with MFM and 16% of patients with DM, with DES and MYH7 variants significantly associated with the development of cardiomyopathy. Respiratory impairment was more prevalent in patients with TTN and DES variants and rare in other disorders such as GNE myopathy and dysferlinopathies, which were instead associated, together with DNAJB6 -related and PLIN4 -related myopathies, with the risk of losing ambulation during the disease course., Discussion: The Italian cohort of patients with MFM and DM recapitulates the phenotypic heterogeneity and the partial overlap between the 2 groups. However, in relative contrast to the encountered phenotypic variability, only 5 genes accounted for most of the molecular diagnoses. Specific genetic entities are associated with significantly increased risk of developing cardiorespiratory complications or loss of ambulation, which has relevant prognostic implications.

Background: We aimed to investigate the clinical features of a large cohort of patients with myelin protein zero ( MPZ )-related neuropathy, focusing on the five main mutation clusters across Italy., Methods: We retrospectively gathered a minimal data set of clinical information in a series of patients with these frequent mutations recruited among Italian Charcot-Marie-Tooth (CMT) registry centres, including disease onset/severity (CMTES-CMT Examination Score), motor/sensory symptoms and use of orthotics/aids., Results: We collected data from 186 patients: 60 had the p.Ser78Leu variant ('classical' CMT1B; from Eastern Sicily), 42 the p.Pro70Ser (CMT2I; mainly from Lombardy), 38 the p.Thr124Met (CMT2J; from Veneto), 25 the p.Ser44Phe (CMT2I; from Sardinia) and 21 the p.Asp104ThrfsX13 (mild CMT1B; from Apulia) mutation. Disease severity (CMTES) was higher (p<0.001) in late-onset axonal forms (p.Thr124Met=9.2±6.6; p.Ser44Phe=7.8±5.7; p.Pro70Ser=7.6±4.8) compared with p.Ser78Leu (6.1±3.5) patients. Disease progression (ΔCMTES/year) was faster in the p.Pro70Ser cohort (0.8±1.0), followed by p.Ser44Phe (0.7±0.4), p.Thr124Met (0.4±0.5) and p.Ser78Leu (0.2±0.4) patients. Disease severity (CMTES=1.2±1.5), progression (ΔCMTES/year=0.1±0.4) and motor involvement were almost negligible in p.Asp104ThrfsX13 patients, who, however, frequently (78%, p<0.001) complained of neuropathic pain. In the other four clusters, walking difficulties were reported by 69-85% of patients, while orthotic and walking aids use ranged between 40-62% and 16-28%, respectively., Conclusions: This is the largest MPZ (and late-onset CMT2) cohort ever collected, reporting clinical features and disease progression of 186 patients from five different clusters across Italy. Our findings corroborate the importance of differentiating between 'classical' childhood-onset demyelinating, late-onset axonal and mild MPZ -related neuropathy, characterised by different pathomechanisms, in view of different therapeutic targets., Competing Interests: Competing interests: GMF acknowledges donations from Pfizer to support research activities of his Research Unit, financial support from Akcea, Kedrion, Pfizer for participation in national and international meetings and from Akcea, Alnylam and Pharnext for participation in Advisory Boards; MG acknowledges donations from Sanofi Genzyme to support research activities of her Research Unit, financial support from Alnylam and Sanofi Genzyme for participation in national and international Meetings, participation in Advisory Board of Pfizer, speaker honorarium from Sanofi Genzyme; AM acknowledges financial support from Pfizer, Alnylam and Akcea for participation in national and international meetings, participation in Advisory Board of Pfizer, Alnylam and Akcea; DP acknowledges participation in Advisory Board of Inflectis, Alnylam, Akcea, Arvinas, Augustine Tx, DTx; ST is supported by the Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006) - A multiscale integrated approach to the study of the nervous system in health and disease (DN. 1553 11.10.2022). AB, LG, TC, PS, MR, SM, YMF, EM, FT, AG, GO, MF, EC, LC, PM, FB, SM, FT, SCP, AS, FM, CP report no disclosure., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of inherited peripheral neuropathies. Although the typical disease onset is reported in the second decade, earlier onsets are not uncommon. To date, few studies on pediatric populations have been conducted and the achievement of molecular diagnosis remains challenging., Methods: During the last 24 years we recruited 223 patients with early-onset hereditary peripheral neuropathies (EOHPN), negative for PMP22 duplication, 72 of them referred by a specialized pediatric hospital. Genetic testing for CMT-associated genes has been carried out with a range of different techniques., Results: Of the 223 EOHPN cases, 43% were classified as CMT1 (demyelinating), 49% as CMT2 (axonal), and 8% as CMTi (intermediate). Genetic diagnosis was reached in 51% of patients, but the diagnostic yield increased to 67% when focusing only on cases from the specialized pediatric neuromuscular centers. Excluding PMP22 rearrangements, no significant difference in diagnostic rate between demyelinating and axonal forms was identified. De novo mutations account for 38% of cases., Conclusions: This study describes an exhaustive picture of EOHPN in an Italian referral genetic center and analyzes the molecular diagnostic rate of a heterogeneous cohort compared with one referred by a specialized pediatric center. Our data identify MPZ, MFN2, GDAP1, and SH3TC2 genes as the most frequent players in EOHPN. Our study underlines the relevance of a specific neurological pediatric expertise to address the genetic testing and highlights its importance to clarify possible unexpected results when neuropathy is only a secondary clinical sign of a more complex phenotype., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Erythropoiesis is a complex developmental process in which a hematopoietic stem cell undergoes serial divisions and differentiates through well-defined stages to give rise to red blood cells. Over the last decades, several protocols have been developed to perform ex vivo erythroid differentiation, allowing investigation into erythropoiesis and red cell production in health and disease., Results: In the current study, we compared the two commonly used protocols by assessing the differentiation kinetics, synchronisation, and cellular yield, using molecular and cellular approaches. Peripheral blood CD34 + cells were cultured in a two-phase (2P) or a four-phase (4P) liquid culture (LC) and monitored for 20 days. Both protocols could recapitulate all stages of erythropoiesis and generate reticulocytes, although to different extents. Higher proliferation and viability rates were achieved in the 4P-LC, with a higher degree of terminal differentiation and enucleation, associated with higher levels of the erythroid-specific transcription factors GATA-1, KLF-1, and TAL-1. Although the 2P-LC protocol was less efficient regarding terminal erythroid differentiation and maturation, it showed a higher yield of erythroid progenitors in the erythropoietin (EPO)-free expansion phase., Conclusions: We provide data supporting the use of one protocol or the other to study the biological processes occurring in the early or late stages of erythroid differentiation, depending on the physiological process or pathological defect under investigation in a given study., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Shoe inserts, orthopaedic shoes, ankle-foot orthoses (AFOs) are important devices in Charcot-Marie-Tooth disease (CMT) management, but data about use, benefits and tolerance are scanty., Methods: We administered to Italian CMT Registry patients an online ad hoc questionnaire investigating use, complications and perceived benefit/tolerability/emotional distress of shoe inserts, orthopaedic shoes, AFOs and other orthoses/aids. Patients were also asked to fill in the Quebec User Evaluation of Satisfaction with assistive Technology questionnaire, rating satisfaction with currently used AFO and related services., Results: We analysed answers from 266 CMT patients. Seventy per cent of subjects were prescribed lower limb orthoses, but 19% did not used them. Overall, 39% of subjects wore shoe inserts, 18% orthopaedic shoes and 23% AFOs. Frequency of abandonment was high: 24% for shoe inserts, 28% for orthopaedic shoes and 31% for AFOs. Complications were reported by 59% of patients and were more frequently related to AFOs (69%). AFO users experienced greater emotional distress and reduced tolerability as compared with shoe inserts (p<0.001) and orthopaedic shoes (p=0.003 and p=0.045, respectively). Disease severity, degree of foot weakness, customisation and timing for customisation were determinant factors in AFOs' tolerability. Quality of professional and follow-up services were perceived issues., Conclusions: The majority of CMT patients is prescribed shoe inserts, orthopaedic shoes and/or AFOs. Although perceived benefits and tolerability are rather good, there is a high rate of complications, potentially inappropriate prescriptions and considerable emotional distress, which reduce the use of AFOs. A rational, patient-oriented and multidisciplinary approach to orthoses prescription must be encouraged., Competing Interests: Competing interests: GMF acknowledges donations from Pfizer to support research activities of his Research Unit, financial support from Akcea, Kedrion, Pfizer for participation in national and international meetings and from Akcea, Alnylam and Pharnext for participation in Advisory Boards; MG acknowledges donations from Sanofi Genzyme to support research activities of her Research Unit, financial support from Alnylam and Sanofi Genzyme for participation in national and international Meetings, participation in Advisory Board of Pfizer, speaker honorarium from Sanofi Genzyme; AM acknowledges financial support from Pfizer, Alnylam and Akcea for participation in national and international meetings, participation in Advisory Board of Pfizer, Alnylam and Akcea; GV acknowledges donations from Pfizer and PTC to support research activities and participation in Advisory Board of Pfizer, Alnylam, Akcea and Pharnext; DP acknowledges participation in Advisory Board of Inflectis, Alnylam, Akcea, Arvinas, Augustine Tx, DTx. AB, IT, GMF, AS, LS, TC, MT, SCP, MS, IA, LP, CP. DC, PS, AQ, PV, ST, LG, MR, AM, SP, GDD, CP report no disclosure., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

DAG1 encodes for dystroglycan, a key component of the dystrophin-glycoprotein complex (DGC) with a pivotal role in skeletal muscle function and maintenance. Biallelic loss-of-function DAG1 variants cause severe muscular dystrophy and muscle-eye-brain disease. A possible contribution of DAG1 deficiency to milder muscular phenotypes has been suggested. We investigated the genetic background of twelve subjects with persistent mild-to-severe hyperCKemia to dissect the role of DAG1 in this condition. Genetic testing was performed through exome sequencing (ES) or custom NGS panels including various genes involved in a spectrum of muscular disorders. Histopathological and Western blot analyses were performed on muscle biopsy samples obtained from three patients. We identified seven novel heterozygous truncating variants in DAG1 segregating with isolated or pauci-symptomatic hyperCKemia in all families. The variants were rare and predicted to lead to nonsense-mediated mRNA decay or the formation of a truncated transcript. In four cases, DAG1 variants were inherited from similarly affected parents. Histopathological analysis revealed a decreased expression of dystroglycan subunits and Western blot confirmed a significantly reduced expression of beta-dystroglycan in muscle samples. This study supports the pathogenic role of DAG1 haploinsufficiency in isolated or pauci-symptomatic hyperCKemia, with implications for clinical management and genetic counseling., (© 2023. The Author(s), under exclusive licence to European Society of Human Genetics.)

Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPN) characterized by clonal erythrocytosis and thrombocytosis, respectively. The main goal of therapy in PV and ET is to prevent thrombohemorrhagic complications. Despite a debated notion that red blood cells (RBCs) play a passive and minor role in thrombosis, there has been increasing evidence over the past decades that RBCs may play a biological and clinical role in PV and ET pathophysiology. This review summarizes the main mechanisms that suggest the involvement of PV and ET RBCs in thrombosis, including quantitative and qualitative RBC abnormalities reported in these pathologies. Among these abnormalities, we discuss increased RBC counts and hematocrit, that modulate blood rheology by increasing viscosity, as well as qualitative changes, such as deformability, aggregation, expression of adhesion proteins and phosphatidylserine and release of extracellular microvesicles. While the direct relationship between a high red cell count and thrombosis is well-known, the intrinsic defects of RBCs from PV and ET patients are new contributors that need to be investigated in depth in order to elucidate their role and pave the way for new therapeutical strategies.

Sleep-disordered breathing has been reported in Charcot-Marie-Tooth disease (CMT) type 1A in association with diaphragmatic weakness and sleep apnea syndrome, mainly of the obstructive type (OSA). Improvement has been observed not only in sleep quality but also in neuropathy symptoms in CMT1A patients with OSA following the initiation of continuous positive airway pressure. We report the cases of two siblings affected by CMT1A associated with hemidiaphragm relaxatio necessitating nocturnal non-invasive ventilation (NIV). Two twins, now 42 years old, with a family history of CMT1A, received a genetic diagnosis of CMT1A at the age of 16. Over the years, they developed a slowly worsening gait disorder and a decline in fine motor hand movements, currently presenting with moderate disability (CMTES:13). At the age of 40, they both started complaining of daytime sleepiness, orthopnea, and exertional dyspnea. They received a diagnosis of relaxatio of the right hemidiaphragm associated with impairment of nocturnal ventilation and they both have benefited from nocturnal NIV. Disorders of breathing during sleep may be underestimated in CMT1A since routine investigations of sleep quality are rarely performed. Our two clinical cases and a literature review suggest the importance of inquiring about symptoms of excessive daytime sleepiness and respiratory disturbances in individuals with CMT1A, even in the absence of severe neuropathy. In the presence of compatible symptoms, a pneumological assessment, along with an overnight polysomnogram and lung function tests, should be performed. Recognizing sleep-related symptoms is essential for providing accurate treatment and improving the quality of life for patients with CMT1A., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Massucco, Schenone, Faedo, Gemelli, Bellone, Marinelli, Pareyson, Pisciotta, Mongini, Schenone and Grandis.)

Biallelic mutations in the sorbitol dehydrogenase ( SORD ) gene have been identified as a genetic cause of autosomal recessive axonal Charcot-Marie-Tooth disease 2 (CMT2) and distal hereditary motor neuropathy (dHMN). We herein review the main phenotypes associated with SORD mutations and report the case of a 16-year-old man who was referred to our outpatient clinic for a slowly worsening gait disorder with wasting and weakness of distal lower limbs musculature. Since creatine phosphokinase (CPK) values were persistently raised (1.5fold increased) and a Next-Generation Sequencing CMT-associated panel failed in identifying pathogenic variants, a muscle biopsy was performed with evidence of alterations suggestive of a protein surplus distal myopathy. Finally, Whole-Exome Sequencing (WES) identified two pathogenic SORD variants in the heterozygous state: c.458C > A (p.Ala153Asp) and c.757delG (p.Ala253Glnfs*27). This is an isolated report of compound heterozygosity for two SORD mutations associated with clinical and histological signs of skeletal muscle involvement, expanding the phenotypic expression of SORD mutations., Competing Interests: The Authors declare no conflict of interest., (©2023 Gaetano Conte Academy - Mediterranean Society of Myology, Naples, Italy.)

Background: Sleep abnormalities have been reported in Charcot-Marie-Tooth disease (CMT), but data are scanty. We investigated their presence and correlation in a large CMT patients' series., Methods: Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI) were administered to CMT patients of the Italian registry and controls. ESS score > 10 indicated abnormal daytime somnolence, PSQI score > 5 bad sleep quality. We analyzed correlation with disease severity and characteristics, Hospital Anxiety and Depression Scale (HADS), Modified Fatigue Impact Scale (MFIS), Body Mass Index, drug use., Results: ESS and PSQI questionnaires were filled by 257 and 253 CMT patients, respectively, and 58 controls. Median PSQI score was higher in CMT patients than controls (6 vs 4, p = 0.006), with no difference for ESS score. Abnormal somnolence and poor sleep quality occurred in 23% and 56% of patients; such patients had more frequently anxiety/depression, abnormal fatigue, and positive sensory symptoms than those with normal ESS/PSQI. Moreover, patients with PSQI score > 5 had more severe disease (median CMT Examination Score, CMTES, 8 vs 6, p = 0.006) and more frequent use of anxiolytic/antidepressant drugs (29% vs 7%, p < 0.001)., Conclusions: Bad sleep quality and daytime sleepiness are frequent in CMT and correlated with anxiety, depression and fatigue, confirming that different components affect sleep. Sleep disorders, such as sleep apnea and restless leg syndrome, not specifically investigated here, are other factors known to impact on sleep quality and somnolence. CMT patients' management must include sleep behavior assessment and evaluation of its correlated factors, including general distress and fatigue., (© 2023. The Author(s).)