BACKGROUND:The diagnosis of inclusion body myositis (IBM) can be delayed because of its heterogeneous clinical presentation and the lack of specific biomarkers. Muscle imaging has gained increasing relevance over the past decade and is now included among the supportive criteria in the international diagnostic guidelines. This study aimed to refine MRI criteria for IBM to facilitate clearer pattern recognition, increase their reproducibility and broader clinical applicability. We also aimed to provide a comprehensive evaluation of muscle wasting across the entire body, including less frequently assessed regions such as the neck, scapular girdle and trunk muscles, and to explore the presence of radiological IBM phenotypes through cluster analysis. METHODS:Sixty-eight MRI scans and clinical records from patients diagnosed with IBM between 2003 and 2024 (60% males; mean age: 66 years, range: 46-85) were retrospectively reviewed. We defined a new set of three main and three supportive MRI criteria based on muscle imaging features and assessed their sensitivity. Whole body muscle involvement was semi-quantitatively scored using standardized scales across 6006 muscles. Pairwise correlation and K-means cluster analysis were performed to evaluate clinical-radiological relationships and identify phenotypic subgroups. RESULTS:The revised MRI criteria achieved 96% sensitivity. Performance was consistent across clinical subgroups and remained robust (83%) in patients with atypical onset. Whole-body analysis highlighted mild but frequent wasting of paraspinal (90% of scans) and neck and scapular girdle muscles (87%), while intracranial muscles were consistently unaffected. Correlation analysis underlined a significant association between radiological and functional involvement in the lower (r = 0.57, p < 0.001) but not in the upper body. Cluster analysis revealed two overlapping but distinguishable imaging phenotypes, characterized by different involvement of paraspinal and distal leg muscles. Cluster 1 showed a higher proportion of male patients. CONCLUSIONS:The revised MRI criteria allow a reliable and easy recognition of the IBM pattern of muscle involvement, while whole-body imaging offers additional insights into disease heterogeneity and supports patient stratification in clinical trials. Clustering results also highlighted a possible sex-related influence on muscle vulnerability. The observed clinico-radiological correlations further support the role of muscle MRI indices as a surrogate outcome measure of muscle function.

Background and Objectives:Valosin Containing Protein-associated multisystem proteinopathy (VCP-MSP) is a progressive, autosomal dominant disorder caused by pathogenic variants in the VCP gene, resulting in a heterogeneous clinical presentation. Muscle biopsy findings are characteristic but not pathognomonic. This study aimed to comprehensively analyse VCP-related myopathology and explore correlations with clinical phenotypes, genetic variants, and disease progression. Methods:Muscle biopsy images and data were collected retrospectively from adults (≥18 years) with pathogenic or likely pathogenic VCP variants enrolled in the VCP Multicentre International Study. Biopsy data were standardized using the "Common Data Elements for Muscle Biopsy Reporting." Variations in biopsy findings were analysed by biopsy site, time from disease onset, the four most common VCP variants, and clinical phenotypes. Result:A total of 112 muscle biopsies were included. Most individuals were male (66.0%). The mean age at biopsy was 53.3 years (SD 10.0), with a mean disease duration of 6.5 years (SD 4.5). The most frequent VCP variant was c.464G>A (p.Arg155His) (18.8%). The top clinical phenotypes were isolated myopathy (37.5%), myopathy with Paget disease of bone (17.9%), and myopathy with motor neuron involvement (13.4%). The vastus lateralis was the most common biopsy site (34.8%), and 91% were open biopsies. Histopathologic findings included atrophic fibres (87.5%), rimmed vacuoles (72.3%), endomysial fibrosis (58.0%), and protein aggregates (51.8%), primarily p62 (60.3%) and VCP (36.2%). Degeneration niches with fibrofatty replacement and atrophic fibres were seen in 33.3% of biopsies without frequency differences by clinical phenotypes. There were no differences in biopsy findings among the 4 most common VCP gene variants, except for the absence of degeneration niches in muscle biopsies of 12 patients with c.277C>T (p.Arg93Cys). MRI data from 30 patients showed fat pockets corresponding to these niches and STIR hyperintensity correlated with inflammatory infiltrates in 42.9%. Concordance between clinical phenotype, biopsy, and neurophysiology was observed in only 49.4% of cases, indicating significant heterogeneity. Discussion:VCP-MSP muscle biopsies consistently show myopathic or mixed patterns with rimmed vacuoles and p62/VCP-positive inclusions, regardless of clinical phenotype, age, or progression. Some lack vacuoles, challenging diagnosis. Discrepancies between clinical, neurophysiology, and biopsy findings should prompt consideration of VCP-MSP to improve detection and management.

ABSTRACT Background and Aims In 2019, we conducted a cross‐sectional study, collecting information on 50 patients with CMT4B, an ultrarare CMT subtype, to better define the clinical phenotype. We now aimed at investigating disease progression in 26 patients with CMT4B1/CMT4B2, recruited from the previous study and among the Inherited Neuropathy Consortium. Materials and Methods We retrospectively analysed disease progression in patients with CMT4B1/CMT4B2, collecting MRC scores from nine muscle pairs, Charcot‐Marie‐Tooth Examination Score (CMTES), and a minimal dataset of clinical information (walking difficulties, aids dependency, upper limb impairment, cranial nerves involvement) at baseline and follow‐up visits. Thirteen centres from four continents were involved. Results Thirteen CMT4B1 and 13 CMT4B2 patients were followed up for 7.1 ± 4.9 and 7.9 ± 4.5 years, respectively. During follow‐up, walking aid dependency increased: two CMT4B1 patients adopted AFOs (overall 11/12 at follow‐up), and one started using wheelchair (6/12 at follow‐up) at the age of 19; among CMT4B2 patients, two more required unilateral support in walking (4/11 at follow‐up) by the age of 33 and 49 years, respectively. We found that disease progression, as measured by CMTES, was faster in CMT4B1 as compared to CMT4B2 patients (ΔCMTES/year 0.7 vs. 0.3, p = 0.037) but tended to slow down over time as burden of disease increased. At the end of follow‐up, CMT4B1 was associated to higher disability. Conclusions This international collective effort enabled collection of relevant data for characterizing natural history and estimating disease progression of CMT4B1/CMT4B2 ultrarare diseases, aiming at improving their management and paving the way for designing future clinical trials.

BACKGROUND:There is evidence that some Hereditary Spastic Paraplegia (HSP) genes are linked to Amyotrophic Lateral Sclerosis (ALS). In particular, KIF5A and SPG11 genes, which cause two different forms of HSP, are also associated with adult-onset and Juvenile ALS, respectively. OBJECTIVES:To study the frequencies of pathogenetic and likely pathogenetic variants in HSP genes in ALS patients and to determine whether they act as predisposing factors. METHODS:We analysed 72 HSP-associated genes in 1024 ALS and 44 Primary Lateral Sclerosis patients and applied customized ACMG criteria to identify pathogenic and likely pathogenic variants. Based on the frequency of identified variants, six genes, including SPG7, SPG11 and the four genes encoding the subunits of the AP4 adaptor protein, were selected for analysis in an additional cohort of 481 ALS patients. Overall results on 1549 patients were compared with 1138 controls. RESULTS:The frequency of variants in SPG7 gene was 0.45% (7/1549) in patients vs 0.18% (2/1138) in controls (p = 0.19), in SPG11 was 0.77% (12/1549) in cases and 0.26% (3/1138) in controls (p = 0.06), in AP4 genes was 0.64% (10/1549) in patients and 0.26% (3/1138) in controls (p = 0.13). The total number of variants detected across SPG7, SPG11 and AP4 genes was statistically different between patients and controls (1.87% vs 0.7%; p = 0.006). CONCLUSIONS:We found a significant enrichment of variants in a set of HSP genes, including SPG7, SPG11 and AP4 genes, in a large cohort of ALS patients, suggesting that they may act as predisposing factors for ALS.

Amyotrophic Lateral Sclerosis (ALS) is an incurable neurodegenerative disease, causing degeneration of motor neurons, paralysis, and death. About 5–10% of cases are associated with gene mutations inherited from a family member (fALS). Among them, mutations in the transactive-response (TAR)-DNA-binding protein (TARDBP), which encodes for the TAR DNA binding protein 43 (TDP-43) are responsible for 4–5% of fALS but the molecular mechanisms that initiate and sustain the neurodegenerative process are largely unknown. Metabolic impairments might be involved in the pathogenesis of ALS and are currently under investigation. In order to correlate biochemical and metabolic alterations with disease progression, here, we established the metabolic fingerprint of dermal fibroblasts derived from symptomatic and asymptomatic members of a family with fALS cases carrying to the p.G376D mutation in TDP-43. We found that increased proliferation, unbalanced oxidative homeostasis and higher ATP production rate coupled with enhanced metabolic activity are underlying traits of this family. Fibroblasts from carrier individuals deploy several mechanisms to increase mitochondrial respiration to meet increasing energy demands. This is accompanied by an upregulation of glycolysis corresponding to a metabolic reprograming towards a glycolytic phenotype for ATP production during ALS progression, particularly in late disease stages. In summary, we uncover alterations in energy metabolism in TDP43G376D patient-derived primary fibroblasts that may be used as risk biomarkers and/or to monitor ALS progression.

INTRODUCTION/AIMS:Nusinersen intrathecal administration can be challenging in spinal muscular atrophy (SMA) adults. We aimed to determine if the ultrasound (US)-assistance reduces the number of needle attempts and needle redirections needed for intrathecal drug administration and its impact on the procedure time, the incidence of adverse events (AEs), and patient satisfaction in these patients. METHODS:Fifty-eight patients aged 18 years and older scheduled for intrathecal nusinersen injection were enrolled and randomized (1:1 ratio) into Group 1 (nusinersen infusion with US-assisted technique) or Group 2 (nusinersen infusion with landmark-based technique). The number of attempts, number of redirections, periprocedural time, AEs and patient satisfaction were reported. Continuous variables were compared with the Student t-test or Wilcoxon rank sum test. Categorical variables were evaluated with the Chi-square test or Fisher's exact test in case of expected frequencies <5. The p-values <.05 were considered statistically significant. RESULTS:There were no statistical differences in the number of attempts, AEs, or patient satisfaction between the two groups. The number of needle redirections was significantly lower in the ultrasound group versus landmark-based group (p < .05) in both the overall group of patients and in the subgroup with difficult spines. The periprocedural time was about 40 seconds longer in US-group versus landmark-based group (p < .05). DISCUSSION:In SMA adults, US assistance reduces the number of needle redirections needed for intrathecal drug administration. These results suggest that the US assistance may be advantageous for nusinersen therapy to reduce the therapeutic burden of intrathecal infusion.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease due to gradual motoneurons (MN) degeneration. Among the processes associated to ALS pathogenesis, there is the formation of cytoplasmic inclusions produced by aggregation of mutant proteins, among which the RNA binding protein FUS. Here we show that, in neuronal cells and in iPSC-derived MN expressing mutant FUS, such inclusions are significantly reduced in number and dissolve faster when the RNA m6A content is diminished. Interestingly, stress granules formed in ALS conditions showed a distinctive transcriptome with respect to control cells, which reverted to similar to control after m6A downregulation. Notably, cells expressing mutant FUS were characterized by higher m6A levels suggesting a possible link between m6A homeostasis and pathological aggregates. Finally, we show that FUS inclusions are reduced also in patient-derived fibroblasts treated with STM-2457, an inhibitor of METTL3 activity, paving the way for its possible use for counteracting aggregate formation in ALS.

Introduction/Purpose:Nusinersen, the first treatment approved for all spinal muscular atrophy (SMA) types, is administered intrathecally through lumbar puncture. We used ultrasound assistance or a landmark-based technique to access the lumbar intrathecal space in adult SMA patients. This study aimed to evaluate the technical success and adverse events (AEs) in such patients using either technique over a long observation period. Methods:Fifty-one adult patients received 507 consecutive interlaminar nusinersen administrations. Patients presented with both 'uncomplicated spines' or 'complicated spines'; two patients had previous back surgery. Technical success and AEs were recorded using either technique. A generalised linear mixed model was applied to evaluate predictors of technical success and complications. Results:An overall success rate of 99.6%, with only two procedures failing to reach the intrathecal space, and an overall optimal procedure rate of 90.3% have been reported. A total of 455 procedures (89.7%) were uneventfully performed. One (0.2%) case of severe AE (puncture of a bulky abdominal annexal cyst) was recorded. Twenty-seven episodes (5.3%) of post-dural puncture headache (PDPH) and 24 episodes (4.7%) of radicular or back pain, both successfully treated with medical therapy, have also been reported. Technical success was significantly associated with 'complicated spines' (P = 0.022) and the use of ultrasound assistance (P = 0.01), and the use of ultrasound was the only independent predictor of uncomplicated procedures (P = 0.007). Discussion:In adult patients with SMA both landmark-based and ultrasound-assisted techniques are safe and effective even in the long term. The use of assistance is associated with technical success and can predict uncomplicated procedures. Conclusion:Our results support the use of ultrasonography in order to improve the success and reduce the burden of nusinersen intrathecal administration.

Genetic expansions of the hexanucleotide repeats (GGGGCC) in the C9orf72 gene appear in approximately 40% of patients with familial ALS and 7% of patients with sporadic ALS in the European population, making this mutation one of the most prevalent genetic mutations in ALS. Here, we generated a human induced pluripotent stem cell (hiPSC) line from the dermal fibroblasts of a patient carrying a 56-repeat expansion in an ALS disease-causing allele of C9orf72. These iPSCs showed stable amplification in vitro with normal karyotype and high expression of pluripotent markers and differentiated spontaneously in vivo into three germ layers.

Objectives: Variants in Cyclin F (CCNF) have been associated to amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD) in a group of cases. The objectives of this study were to determine the contribution of CCNF in a large cohort of Italian ALS patients, to look for genotype-phenotype correlation of the mutations and to evaluate the CCNF-associated clinical features. Methods: We applied next-generation sequencing technologies on 971 unrelated Italian ALS patients and we filtered results to look for variants in CCNF gene. Results: We identified 13 rare missense variants in 16 index cases (2 familial and 14 sporadic), with a cumulative mutational frequency of 1.6%. The most prevalent variant was p.Phe197Leu, found in three patients. The clinical presentation was heterogeneous, with a classic phenotype in eight patients, upper motor neuron dominant (UMN-D) phenotype in four patients, and flail arm in four patients. Clinical evaluation for cognitive impairment was performed in 13 patients using the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) test, demonstrating that almost half of the patients (n = 6) had variable degrees of frontal dysfunction. Discussion: In our cohort, we observed CCNF variants in 1.6% of patients (16/971), a percentage similar to that found in other series. Clinical presentation is heterogeneous, but CCNF variants are significantly associated to cognitive impairment. Conclusions: Our study expands the CCNF genetic variant spectrum in a large cohort of Italian ALS patients. Further studies are needed to assess genotype-phenotype associations of CCNF variants and to specify the role of each variant, which are quite common, especially in sALS patients.

BACKGROUND AND OBJECTIVES:Spinal and bulbar muscular atrophy (SBMA) is a rare, slowly progressive, and debilitating disease without effective treatments available. Lack of reliable biomarkers and sensitive outcome measures makes clinical research conduct challenging. The primary objective of this study was to identify clinically meaningful and statistically sensitive outcome measures enabling the evaluation of therapeutic interventions in late-stage clinical trials. METHODS:This study was a meta-analysis of SBMA patient-level data from 6 observational studies conducted in Italy, South Korea, Denmark, United Kingdom, Japan, and United States. Patients with confirmed SBMA genetic diagnosis and differing severity were enrolled following individual site protocols. Routine assessments were performed longitudinally for approximately 3 years, including one or more clinical outcomes, such as SBMA functional rating scale (SBMAFRS), 6-minute walk test (6MWT), quantitative muscle testing (QMT), and Adult Myopathy Assessment Tool (AMAT). A modified scale, m-SBMAFRS, was derived by including only lower limb and trunk subscales having lower variability and larger effect size compared with the others. Changes from baseline at follow-up time points were calculated for all measures, and percent changes using random slope models were calculated to compare clinical measure performances. A survey conducted on 196 patients by the Coordination of Rare Diseases at Sanford (CoRDS), elucidating the impact of specific disease aspects on patients' lives, was also evaluated to corroborate these research outcomes. RESULTS:This global SBMA dataset analyzed data from 278 men (mean age = 59.7 ± 10.8 years, mean disease duration = 17.7 ± 11.9 years). Patients progressed on SBMAFRS (-4.7 ± 6.2 points after 38 months with 1-year standard response mean [SRM] = 0.6) and 6MWT (distance walked decreased by -53.2 ± 87.0 meters after 26 months with 1-year SRM = 0.5). These measures showed lower variability and larger effect size than AMAT and QMT (1-year SRM = 0.1 and -0.2, respectively) and confirmed SBMA linear progression across a range of disease stages. The m-SBMAFRS also showed a significant yearly decline of 0.9 ± 1.5 points (SRM = 0.6) and more consistent performance with less variability across clinical sites. The CoRDS survey confirmed the relevance of lower limb strength and mobility, which correlated with higher quality-of-life metrics and were reported by patients as predominant disease issues. DISCUSSION:We generated a comprehensive global SBMA dataset, enabling the identification of sensitive functional end points for clinical trials. Possible limitations relate to data collection nuances across sites that a single study protocol could override.

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.

BACKGROUND AND PURPOSE:Myopathies are associated with classic signs and symptoms, but also with possible life-threatening complications that may require assistance in an emergency setting. This phenomenon is understudied in the literature. We aimed to assess the presentation, management, and outcomes of clinical manifestations potentially related to a muscle disorder requiring referral to the adult emergency department (ED) and hospitalization. METHODS:Anonymized patient data retrieved using the International Classification of Diseases, Ninth Revision codes related to muscle disorders over 4 years were retrospectively analyzed. Medical reports were evaluated to extract demographic and clinical variables, along with outcomes. Two groups were defined based on the presence (known diagnosis [KD] group) or absence (unknown diagnosis [UD] group) of a diagnosed muscle disorder at arrival. RESULTS:A total of 244 patients were included, 51% of whom were affected by a known myopathy, predominantly limb-girdle muscular dystrophies and myotonic dystrophies. The main reasons for ED visits in the KD group were respiratory issues, worsening of muscle weakness, and gastrointestinal problems. Heart complications were less prevalent. In the UD group, 27 patients received a new diagnosis of a specific primary muscle disorder after the ED access, mostly an inflammatory myopathy. Death during hospitalization was recorded in 26 patients, with a higher rate in the KD group and in patients affected by mitochondrial and inflammatory myopathies. Sepsis and dyspnea were associated with increased death risk. CONCLUSIONS:Respiratory complications are the most common reason for myopathic patients accessing the ED, followed by gastrointestinal issues. Infections are severe threats and, once hospitalized, these patients have relatively high mortality.

One of the genetic mutations most associated with the onset of amyotrophic lateral sclerosis, both in sporadic and familial cases, is the expansion of the C9orf72 gene. The presence of more than 30 repeats (GGGGCC) correlates with uncertain ALS symptomatology. Here we collected a dermal biopsy from a subject carrying 36 hexanucleotide repeats and reprogrammed it into an induced pluripotent stem cell line. Despite the number of repeat elements, the subject had no symptoms at the age of the biopsy (76 years), thus resulting in a healthy carrier of the mutation.

In Amyotrophic Lateral Sclerosis (ALS) patients with SOD1 mutation the intrathecal administration of tofersen slowed down the progression of disease in a controlled clinical study, but results were not statistically significant. In this multicentre, observational study, we evaluated a cohort of 27 ALS-SOD1 patients who were treated with tofersen, focussing on 17 patients who were followed for at least 48 weeks (median period of 84 weeks, range 48–108). We compared the clinical slopes, as measured by ALSFRS-R, MRC scale and Forced Vital Capacity, during tofersen treatment with retrospective data at 1 year prior to therapy. Cerebrospinal fluid (CSF) and serum neurofilament light chains (NFL) were measured in all patients. Cumulative evaluation of the ALSFRS-R and MRC progression rates showed a statistically significant change during treatment with respect to the period prior to therapy (p = 0.023 and p = 0.007, respectively). The analysis of individual patients showed that nine of the seventeen patients substantially stabilized or slightly improved. Four patients deteriorated during treatment, while in the remaining patients the very slow course did not allow to identify significant changes. CSF and serum NFL concentration markedly decreased in the near totality of patients. Increased levels of white blood cells and proteins in the CSF were found in 60

BACKGROUND:Hereditary transthyretin (ATTRv) amyloidosis is a heterogeneous, progressive, multisystemic disease with a life-threatening course if left untreated. Given the current availability of effective therapies, close follow-up of presymptomatic TTR mutation carriers is essential to recognize disease onset at the earliest sign. In addition to routine techniques, in recent years several novel tools have been proposed, although a consensus on their use has not been reached yet. In this paper, we aimed to evaluate possible markers of neuropathic disease onset intended to discriminate clinically asymptomatic carriers from early symptomatic patients, thus allowing timely treatment initiation.METHODS:Thirty-eight presymptomatic carriers were enrolled. Clinical and electrophysiological findings at first evaluation and follow-up were collected. All carriers underwent an extensive clinical and instrumental evaluation according to the standard clinical practice. One or more non-routine investigations, whose use in this field is not yet validated (henceforth "unconventional"), were additionally assessed in a subgroup of individuals.RESULTS:Based on the exclusive use of routine investigations, it was possible to define disease onset in 4/38 carriers during the follow-up. Employing additionally one or more "unconventional" tests, abnormal findings, indicative of a possible "conversion" to symptomatic disease, were detected in further 12 cases. More than half of our study cohort showed findings suggestive of small nerve fiber (SF) involvement at either invasive or non-invasive tests.CONCLUSIONS:A close, multidisciplinary monitoring of presymptomatic TTR mutation carriers is fundamental, and diagnostic workup should include both routine and "unconventional" tests. Assessment of SF involvement is important also in non-endemic countries.

The Popeye domain containing (POPDC) genes encode sarcolemma-localized cAMP effector proteins. Mutations in blood vessel epicardial substance (BVES) also known as POPDC1 and POPDC2 have been associated with limb-girdle muscular dystrophy and cardiac arrhythmia. Muscle biopsies of affected patients display impaired membrane trafficking of both POPDC isoforms. Biopsy material of patients carrying mutations in BVES were immunostained with POPDC antibodies. The interaction of POPDC proteins was investigated by co-precipitation, proximity ligation, bioluminescence resonance energy transfer and bimolecular fluorescence complementation. Site-directed mutagenesis was utilised to map the domains involved in protein–protein interaction. Patients carrying a novel homozygous variant, BVES (c.547G > T, p.V183F) displayed only a skeletal muscle pathology and a mild impairment of membrane trafficking of both POPDC isoforms. In contrast, variants such as BVES p.Q153X or POPDC2 p.W188X were associated with a greater impairment of membrane trafficking. Co-transfection analysis in HEK293 cells revealed that POPDC proteins interact with each other through a helix-helix interface located at the C-terminus of the Popeye domain. Site-directed mutagenesis of an array of ultra-conserved hydrophobic residues demonstrated that some of them are required for membrane trafficking of the POPDC1–POPDC2 complex. Mutations in POPDC proteins that cause an impairment in membrane localization affect POPDC complex formation while mutations which leave protein–protein interaction intact likely affect some other essential function of POPDC proteins.

Researchers studying Amyotrophic Lateral Sclerosis (ALS) have made significant efforts to find a unique mechanism to explain the etiopathology of the different forms of the disease. However, despite several mutations associated with ALS having been discovered in recent years, the link between the mutated genes and its onset has not yet been fully elucidated. Among the genes associated with ALS, superoxide dismutase 1 (SOD1) was the first to be identified, but its role in the etiopathogenesis of the disease is still unclear. In recent years, research has been focused on the non-coding part of the genome to fully understand the mechanisms underlying gene regulation. Non-coding RNAs are conserved molecules and are not usually translated in protein. A total of 98% of the human genome is composed of non-protein coding sequences with roles in the transcriptional and post-transcriptional regulation of gene expression. In this study, we characterized a divergent nuclear lncRNA (SOD1-DT) transcribed in the antisense direction from the 5′ region of the SOD1 coding gene in both the SH-SY5Y cell line and fibroblasts derived from ALS patients. Interestingly, this lncRNA seems to regulate gene expression, since its inhibition leads to the upregulation of surrounding genes including SOD1. SOD1-DT represents a very complex molecule, displaying allelic and transcriptional variability concerning transposable elements (TEs) included in its sequence, widening the scenario of gene expression regulation in ALS disease.