Safety, tolerability, and efficacy of subcutaneous efgartigimod in patients with chronic inflammatory demyelinating polyradiculoneuropathy (ADHERE): a multicentre, randomised-withdrawal, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disease of the peripheral nervous system that can lead to severe disability from muscle weakness and sensory disturbances. Around a third of patients do not respond to currently available treatments, and many patients with a partial response have residual neurological impairment, highlighting the need for effective alternatives. Efgartigimod alfa, a human IgG1 antibody Fc fragment, has demonstrated efficacy and safety in patients with generalised myasthenia gravis. We evaluated the safety, tolerability, and efficacy of subcutaneous efgartigimod PH20 in adults with CIDP. METHODS: ADHERE, a multistage, double-blind, placebo-controlled trial, enrolled participants with CIDP from 146 clinical sites from Asia-Pacific, Europe, and North America. Participants with evidence of clinically meaningful deterioration entered an open-label phase of weekly 1000 mg subcutaneous efgartigimod PH20 for no longer than 12 weeks (stage A). Those with confirmed evidence of clinical improvement (ECI; treatment responders) entered a randomised-withdrawal phase of 1000 mg subcutaneous efgartigimod PH20 weekly treatment versus placebo for a maximum of 48 weeks (stage B). Participants were randomised (1:1) through interactive response technology and stratified by their adjusted Inflammatory Neuropathy Cause and Treatment (aINCAT) score change during stage A and their most recent CIDP medication within 6 months before screening. Investigators, the clinical research organisation, and participants were masked to the treatment. The primary endpoint in stage A, evaluated in the stage A safety population, was confirmed ECI (≥1 points aINCAT decrease, ≥4 points [centile metric] Inflammatory Rasch-built Overall Disability Scale increase, or ≥8 kPa grip strength increase after four injections and two consecutive visits). The primary endpoint in stage B, evaluated in the modified intention-to-treat population, was the risk of relapse (time to first aINCAT increase of ≥1 points). ADHERE is registered with ClinicalTrials.gov (NCT04281472) and EudraCT (2019-003076-39) and is completed. FINDINGS: Between April 15, 2020, and May 11, 2023, 629 participants were screened; 322 (114 female, 208 male) entered stage A, of whom 214 (66%, 95% CI 61·0-71·6) had confirmed ECI. In stage B, 221 participants were randomised (79 female, 142 male; 111 to subcutaneous efgartigimod PH20, 110 to placebo). Subcutaneous efgartigimod PH20 significantly reduced the risk of relapse versus placebo (hazard ratio 0·39 [95% CI 0·25-0·61]; p<0·0001). 31 (27·9% [19·6-36·3]) participants given subcutaneous efgartigimod PH20 had a relapse versus 59 (53·6% [44·3-63·0]) given placebo. In stage A, treatment-emergent adverse events (TEAEs) occurred in 204 (63%) participants and serious TEAEs in 21 (7%). In stage B, TEAEs occurred in 71 (64%) participants on subcutaneous efgartigimod PH20 and 62 (56%) participants on placebo, and serious TEAEs in six (5%) on subcutaneous efgartigimod PH20 and six (5%) on placebo. Three deaths occurred: two in stage A (one non-related and one unlikely related to treatment) and one in stage B (placebo group). INTERPRETATION: ADHERE showed the efficacy of subcutaneous efgartigimod PH20 in reducing the risk of relapse versus placebo in people with CIDP who responded to treatment. Further studies are needed to provide data on the longer-term effects of efgartigimod alfa and how it compares with currently available treatment options. FUNDING: argenx.

Prevalence and motor-functional correlates of frontotemporal-spectrum disorders in a large cohort of non-demented ALS patients.

BACKGROUND: This study aimed at (1) delivering generalizable estimates of the prevalence of frontotemporal-spectrum disorders (FTSDs) in non-demented ALS patients and (2) exploring their motor-functional correlates. METHODS: N = 808 ALS patients without FTD were assessed for motor-functional outcomes-i.e., disease duration, severity (ALSFRS-R), progression rate (ΔFS), and stage (King's and Milano-Torino-MiToS-systems)-cognition-via the cognitive section of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS)-and behaviour-via the ECAS-Carer Interview. Neuropsychological phenotypes were retrieved via Strong's revised criteria-i.e., ALS cognitively and behaviourally normal (ALScbn) or cognitively and/or behaviourally impaired (ALSci/bi/cbi). RESULTS: Defective ECAS-Total performances were detected in ~ 29% of patients, with the ECAS-Executive being failed by the highest number of patients (~ 30%), followed by the ECAS-Language, -Fluency, and -Memory (~ 15-17%) and -Visuospatial (~ %8). Apathy was the most frequent behavioural change (~ 28%), followed by loss of sympathy/empathy (~ 13%); remaining symptoms were reported in < 4% of patients. The distribution of Strong's classifications was as follows: ALScbn: 46.7%; ALSci/bi/cbi: 22.9%/20.0%/10.4%. Multinomial regressions on Strong's classifications revealed that lower ALSFRS-R scores were associated with a higher probability of ALSbi and ALScbi classifications (p ≤ .008). Higher King's and MiToS stages were associated with a higher probability of ALSbi classification (p ≤ .031). CONCLUSIONS: FTSDs affect ~ 50% of non-demented ALS patients, with cognitive deficits being as frequent as behavioural changes. A higher degree of motor-functional involvement is associated with worse behavioural outcomes-with this link being weaker for cognitive deficits.

Characteristics, Outcome and Prognostic Factors of Patients with Emergency Department Cardiac Arrest: A 14-Year Retrospective Study.

Introduction: Cardiac arrests are traditionally classified according to the setting in which they occur, including out-of-hospital cardiac arrest (OHCA) and in-hospital cardiac arrest (IHCA). However, cardiac arrests that occur in the emergency department (EDCA) could constitute a third category, due to the peculiar characteristics of the emergency department (ED). In recent years, the need to study EDCAs separately from other intra-hospital events has emerged. The aim of this study was to describe the characteristics and outcomes of a cohort of patients experiencing EDCA in an Italian hospital over a 14-year period. Methods: This was a single-centre retrospective observational study conducted in the ED of the Santa Croce e Carle Hospital in Cuneo, Italy. All adult patients who experienced EDCA between 1 January 2010 and 30 June 2023 were included. OHCA patients, those arriving in the ED with on-going resuscitation measures, patients with EDCA not undergoing resuscitation, and patients with post-traumatic cardiac arrest were excluded from the study. The main outcome of the study was survival at hospital discharge with a favourable neurological outcome. Results: 350 cases of EDCA were included. The median age was 78 (63-85) years, and the median Charlson Comorbidity Index score was 5 (3-6). A total of 35 patients (10%) survived to hospital discharge with a cerebral performance category (CPC) Score of 1-2; survival in the ED was 28.3%. The causes of cardiac arrests were identified in 212 cases (60.6%) and included coronary thrombosis (35%), hypoxia (22%), hypovolemia (17%), pulmonary embolism (11%), metabolic (8%), cardiac tamponade (4%), toxins (2%) and hypothermia (1%). Variables associated with survival with a favourable neurological outcome were young age, a lower Charlson Comorbidity Index, coronary thrombosis as the primary EDCA cause, and shockable presenting rhythm; however, only the latter was associated with the outcome in a multivariate age-weighted model. Conclusions: In a cohort of patients with EDCA over a period of more than a decade, the most frequent cause identified was coronary thrombosis; 10% of patients survived with a good neurological status, and the only factor associated with the best prognosis was presenting a shockable rhythm. EDCA should be considered an independent category in order to fully understand its characteristics and outcomes.

Emotional awareness in patients with amyotrophic lateral sclerosis.

INTRODUCTION: It has been recently acknowledged that deficits in experiencing and processing one's own emotions, also termed alexithymia, may possibly feature the frontotemporal-spectrum disorders. This study aims to determine whether alexithymia could be included within the frontotemporal syndromes of amyotrophic lateral sclerosis (ALS). METHODS: Alexithymic traits were estimated in a cohort of 68 non-demented ALS patients with the 20-item Toronto Alexithymia Scale (TAS-20). Patients were assessed for the identification of motor-phenotypes and frontotemporal syndromes based on current classification criteria. Spearman's coefficients explored the correlates of TAS-20 measures with motor-functional profiles, global cognitive, social-cognitive (emotion recognition and empathy) and behavioral status. RESULTS: Abnormal TAS-20 scores were found in 13% of patients, and their distribution did not vary within motor and frontotemporal phenotypes. Significant associations were detected between TAS-20 and executive (p ≤ .011), memory (p = .006), state-anxiety (p ≤ .013) and depression measures (p ≤ .010). By contrast, TAS-20 scores were unrelated to social-cognitive performances, dysexecutive and apathetic profiles. Disease duration was the only motor-functional feature being related to the TAS-20 (p ≤ .008). CONCLUSIONS: Alexithymia of potential clinical relevance occur in a minority of ALS patients, and its neuropsychological correlates mostly resemble those featuring the general population. Hence, it is unlikely that alexithymia is a specific feature of frontotemporal-spectrum characterizing ALS, rather it could be an expression of psychogenic factors as a reaction to the disease.

YAP Ultralate Laser-Evoked Responses in Fibromyalgia: A Pilot Study in Patients with Small Fiber Pathology.

Background: The investigation of C-fiber-evoked ultralow-level responses (ULEPs) at somatic sites is difficult in clinical practice but may be useful in patients with small fiber neuropathy. Aim: The aim of the study was to investigate changes in LEPs and ULEPs in patients with fibromyalgia affected or not by abnormal intraepidermal innervation. Methods: We recorded LEPs and ULEPs of the hand, thigh and foot in 13 FM patients with a normal skin biopsy (NFM), 13 patients with a reduced intraepidermal nerve fiber density (IENFD) (AFM) and 13 age-matched controls. We used a YAP laser, changing the energy and spot size at the pain threshold for LEPs and at the heat threshold for ULEPs. Results: ULEPs occurred at a small number of sites in both the NFM and AFM groups compared to control subjects. The absence of ULEPs during foot stimulation was characteristic of AFM patients. The amplitude of LEPs and ULEPs was reduced in patients with AFM at the three stimulation sites, and a slight reduction was also observed in the NFM group. Conclusions: The present preliminary results confirmed the reliability of LEPs in detecting small fiber impairments. The complete absence of ULEPs in the upper and lower limbs, including the distal areas, could confirm the results of LEPs in patients with small fiber impairments. Further prospective studies in larger case series could confirm the present findings on the sensitivity of LEP amplitude and ULEP imaging in detecting small fiber impairments and the development of IENFD in FM patients.

New clinical insight in amyotrophic lateral sclerosis and innovative clinical development from the non-profit repurposing trial of the old drug guanabenz.

Drug repurposing is considered a valid approach to accelerate therapeutic solutions for rare diseases. However, it is not as widely applied as it could be, due to several barriers that discourage both industry and academic institutions from pursuing this path. Herein we present the case of an academic multicentre study that considered the repurposing of the old drug guanabenz as a therapeutic strategy in amyotrophic lateral sclerosis. The difficulties encountered are discussed as an example of the barriers that academics involved in this type of study may face. Although further development of the drug for this target population was hampered for several reasons, the study was successful in many ways. Firstly, because the hypothesis tested was confirmed in a sub-population, leading to alternative innovative solutions that are now under clinical investigation. In addition, the study was informative and provided new insights into the disease, which are now giving new impetus to laboratory research. The message from this example is that even a repurposing study with an old product has the potential to generate innovation and interest from industry partners, provided it is based on a sound rationale, the study design is adequate to ensure meaningful results, and the investigators keep the full clinical development picture in mind.

The COL6A5-p.Glu2272* mutation induces chronic itch in mice.

Pruritus is a common irritating sensation that provokes the desire to scratch. Environmental and genetic factors contribute to the onset of pruritus. Moreover, itch can become a major burden when it becomes chronic. Interestingly, the rare Collagen VI alpha 5 (COL6A5) gene variant p.Glu2272* has been identified in two families and an independent patient with chronic neuropathic itch. These patients showed reduced COL6A5 expression in skin and normal skin morphology. However, little progress has been made until now toward understanding the relationships between this mutation and chronic itch. Therefore, we developed the first mouse model that recapitulates COL6A5-p.Glu2272* mutation using the CRISPR-Cas technology and characterized this new mouse model. The mutant mRNA, measured by RT-ddPCR, was expressed at normal levels in dorsal root ganglia and was decreased in skin. The functional exploration showed effects of the mutation with some sex dysmorphology. Mutant mice had increased skin permeability. Elevated spontaneous scratching and grooming was detected in male and female mutants, with increased anxiety-like behavior in female mutants. These results suggest that the COL6A5-p.Glu2272* mutation found in patients contributes to chronic itch and induces in mice additional behavioral changes. The COL6A5-p.Glu2272* mouse model could elucidate the pathophysiological mechanisms underlying COL6A5 role in itch and help identify potential new therapeutic targets.

FM19G11-loaded nanoparticles modulate energetic status and production of reactive oxygen species in myoblasts from ALS mice.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. Considerable evidence indicates that early skeletal muscle atrophy plays a crucial role in the disease pathogenesis, leading to an altered muscle-motor neuron crosstalk that, in turn, may contribute to motor neuron degeneration. Currently, there is no effective treatment for ALS, highlighting the need to dig deeper into the pathological mechanisms for developing innovative therapeutic strategies. FM19G11 is a novel drug able to modulate the global cellular metabolism, but its effects on ALS skeletal muscle atrophy and mitochondrial metabolism have never been evaluated, yet. This study investigated whether FM19G11-loaded nanoparticles (NPs) may affect the bioenergetic status in myoblasts isolated from G93A-SOD1 mice at different disease stages. We found that FM19G1-loaded NP treatment was able to increase transcriptional levels of Akt1, Akt3, Mef2a, Mef2c and Ucp2, which are key genes associated with cell proliferation (Akt1, Akt3), muscle differentiation (Mef2c), and mitochondrial activity (Ucp2), in G93A-SOD1 myoblasts. These cells also showed a significant reduction of mitochondrial area and networks, in addition to decreased ROS production after treatment with FM19G11-loaded NPs, suggesting a ROS clearance upon the amelioration of mitochondrial dynamics. Our overall findings demonstrate a significant impact of FM19G11-loaded NPs on muscle cell function and bioenergetic status in G93A-SOD1 myoblasts, thus promising to open new avenues towards possible adoption of FM19G11-based nanotherapies to slow muscle degeneration in the frame of ALS and muscle disorders.

Loneliness as neurobehavioral issue in amyotrophic lateral sclerosis.

OBJECTIVE: In elderly people loneliness represents a risk factor for dementia and may negatively impact on mental and physical health. The specific contribute of loneliness to cognitive and behavioral functioning have not yet been determined in amyotrophic lateral sclerosis (ALS). Our hypothesis was that loneliness may be related to motor dysfunction with a negative impact on cognitive and behavioral decline, possibly related to specific cortical involvement. METHODS: In 200 ALS patients (ALSpts) and 50 healthy controls (HCs) we measured loneliness, mood, and quality of life (QoL). ALSpts underwent comprehensive clinical, genetic, and neuropsychological assessment to define phenotypes. Seventy-seven ALSpts performed 3T MRI scans to measure cortical thickness. Between-group, partial correlation and regression analyses were used to examined clinical, neuropsychological, and cortical signatures of loneliness. RESULTS: Feelings of loneliness were documented in 38% of ALSpts (ALS/L+pts) and in 47% of HCs. In both groups loneliness was associated with anxiety (P < 0.001), depression (P ≤ 0.005), and poor QoL (P < 0.001). ALS/L+pts had similar motor dysfunctions and cognitive abilities than non-lonely ALSpts, but distinct behavioral profiles (P ≤ 0.005) and frontoparietal involvement (P < 0.05). Loneliness in ALS is related to behavioral changes, apathy, and emotional dysregulation (P < 0.001). INTERPRETATION: Our cross-sectional study indicates that, in ALS, the satisfaction of social environment is associated with a sense of life well-being that is not limited to the motor status, proving instead that loneliness can impact on disease-related neurobehavioral changes with a possible flashback on brain architecture. This suggests that sociality could promote personal resilience against behavioral and affective decline in ALS.

A multicomponent physical activity home-based intervention for fibromyalgia patients: effects on clinical and skin biopsy features.

OBJECTIVES: Adapted physical activity (APA) has been recommended for fibromyalgia (FM) treatment as an essential component of a biopsychosocial therapeutic approach for patients. Previous studies report that aerobic and resistance training are the most effective programs in improving the quality of life and psycho-physical well-being. Patients with FM are frequently affected by an impairment of small fibers innervation, which is evident in the proximal somatic districts. Therefore, this pilot randomised controlled not pharmacological trial aimed to investigate if a 12-week home-based multicomponent (aerobic and resistance training and mobility) physical activity (PA) intervention was effective in improving pain perception, FM-related disability, and IntraEpidermal Nerve Fibers Density (IENFD) in adult FM patients. METHODS: Thirty-four female subjects with a fibromyalgia diagnosis (51.5±11.88 years) were randomly assigned to an experimental group (n=17) that received a supervised home-based multicomponent PA intervention twice a week and a control group (n=17) that received a generic program of aerobic exercise. Skin biopsy was performed before the physical program and after 18 months with constant execution of the supervised PA intervention or generic aerobic exercise. Both groups assumed pharmacological treatment with duloxetine and/or pregabalin. RESULTS: We found that the group performing physical activity in a supervised and regular way showed a significant improvement in the Fibromyalgia-linked invalidity questionnaire (FIQ) as well as epidermal fibers density at proximal and distal sites. CONCLUSIONS: Physical activity could improve FM outcomes, with a possible beneficial impact on peripheral factors contributing to pain-related disability.

Archival skin biopsy specimens as a tool for miRNA-based diagnosis: Technical and post-analytical considerations.

Archived specimens, taken by standardized procedures in clinical practice, represent a valuable resource in translational medicine. Their use in retrospective molecular-based studies could provide disease and therapy predictors. Microfluidic array is a user-friendly and cost-effective method allowing profiling of hundreds of microRNAs (miRNAs) from a low amount of RNA. However, even though tissue miRNAs may include potentially robust biomarkers, non-uniformed post-analytical pipelines could hinder translation into clinics. In this study, epidermal RNA from archival skin biopsy specimens was isolated from patients with peripheral neuropathy and healthy individuals. Unbiased miRNA profiling was performed using RT-qPCR-based microfluidic array. We demonstrated that RNA obtained from archival tissue is appropriate for miRNA profiling, providing evidence that different practices in threshold selection could significantly influence the final results. We showed the utility of software-based quality control for amplification curves. We revealed that selection of the most stable reference and the calculation of geometric mean are suitable when utilizing microfluidic arrays without known references. By applying appropriate post-analytical settings, we obtained miRNA profile of human epidermis associated with biological processes and a list of suitable references. Our results, which outline technical and post-analytical considerations, support the broad use of archived specimens for miRNA analysis to unravel disease-specific molecular signatures.

Clinical Presentation and Emergency Department Management Checkpoints of Acute Aortic Syndromes during the First Two Waves of the COVID-19 Pandemic.

The COVID-19 pandemic has deeply affected the activity and patient flows of Emergency Departments (EDs), and concern for the worsening outcome of cardiovascular emergencies has been raised. However, the impact of COVID-19 on all subtypes of acute aortic syndromes (AASs) has not been evaluated so far. Cases of AASs managed in the ED of three hub hospitals in a large area of Northern Italy were retrospectively analyzed, comparing those registered during the pandemic (March 2020 to May 2021) with corresponding pre-COVID-19 periods. A total of 124 patients with AAS were managed during the COVID-19 period vs. 118 pre-COVID-19 (p = 0.70), despite a -34.6% change in ED visits. Posterior chest pain at presentation was the only clinical variable with a different prevalence (46.0% vs. 32.2%, p = 0.03). Surgery and endovascular treatment rates were unchanged. Time intervals influenced by patient transfer to the hub center were longer during the COVID-19 period and longest during high viral circulation periods. Ninety-day mortality was unchanged, with a higher mortality trend during the pandemic surges. In conclusion, ED presentation and care of AASs were marginally affected by COVID-19, but efforts are needed to preserve efficient patient transfer to specialized centers and prevent mortality, especially during pandemic peaks.

Advent of severe mitral regurgitation in surgical ventricular restoration and ventricular septal rupture repair.

BACKGROUND: Per-procedural severe mitral regurgitation is a rare complication in concomitant surgical ventricular restoration and postinfarction ventricular septal rupture repair. It is challenging to discover the underlying etiology and adopt an appropriate strategy, in particular, in a high-risk patient. CASE PRESENTATION: Semi-emergent surgical ventricular restoration combined with ventricular septal rupture closure and coronary artery bypassing was performed in a 67-year-old male patient. Severe mitral regurgitation was detected after the weaning of cardiopulmonary bypass. Two key questions arose in the management of this condition: did the regurgitation exist previously and was dissimulated by significant left-to-right shunt, or it occurred secondarily to the Dor procedure? Which was the better management strategy, chordal-sparing mitral valve replacement or mitral plasty? We believed that severe mitral regurgitation was under-estimated pre-operatively and we performed an downsizing annuloplasty to treat mitral regurgitation. The outcomes were promising and the patient did well in follow-up. CONCLUSIONS: Our case brought out an open discussion on the etiology and therapeutic strategies of this complicated condition.

Randomized, double-blind, placebo-controlled trial of rapamycin in amyotrophic lateral sclerosis.

In preclinical studies rapamycin was found to target neuroinflammation, by expanding regulatory T cells, and affecting autophagy, two pillars of amyotrophic lateral sclerosis (ALS) pathogenesis. Herein we report a multicenter, randomized, double-blind trial, in 63 ALS patients who were randomly assigned in a 1:1:1 ratio to receive rapamycin 2 mg/m2/day,1 mg/m2/day or placebo (EUDRACT 2016-002399-28; NCT03359538). The primary outcome, the number of patients exhibiting an increase >30% in regulatory T cells from baseline to treatment end, was not attained. Secondary outcomes were changes from baseline of T, B, NK cell subpopulations, inflammasome mRNA expression and activation status, S6-ribosomal protein phosphorylation, neurofilaments; clinical outcome measures of disease progression; survival; safety and quality of life. Of the secondary outcomes, rapamycin decreased mRNA relative expression of the pro-inflammatory cytokine IL-18, reduced plasmatic IL-18 protein, and increased the percentage of classical monocytes and memory switched B cells, although no corrections were applied for multiple tests. In conclusion, we show that rapamycin treatment is well tolerated and provides reassuring safety findings in ALS patients, but further trials are necessary to understand the biological and clinical effects of this drug in ALS.

[Diagnostic atypique d'une myiase]. / Atypical diagnosis of myiasis.

Muscoid larvae were observed on self-medicated dressing material loaded with purulent material taken from a 91-year-old hospital patient. These larvae were identified as Lucilia sericata. However, no larvae were found in the patient's tissues. The observation of larvae on dressings should not automatically lead to a diagnosis of cutaneous myiasis.

Genetic Profiling of Sodium Channels in Diabetic Painful and Painless and Idiopathic Painful and Painless Neuropathies.

Neuropathic pain is a frequent feature of diabetic peripheral neuropathy (DPN) and small fiber neuropathy (SFN). Resolving the genetic architecture of these painful neuropathies will lead to better disease management strategies, counselling and intervention. Our aims were to profile ten sodium channel genes (SCG) expressed in a nociceptive pathway in painful and painless DPN and painful and painless SFN patients, and to provide a perspective for clinicians who assess patients with painful peripheral neuropathy. Between June 2014 and September 2016, 1125 patients with painful-DPN (n = 237), painless-DPN (n = 309), painful-SFN (n = 547) and painless-SFN (n = 32), recruited in four different centers, were analyzed for SCN3A, SCN7A-SCN11A and SCN1B-SCN4B variants by single molecule Molecular inversion probes-Next Generation Sequence. Patients were grouped based on phenotype and the presence of SCG variants. Screening of SCN3A, SCN7A-SCN11A, and SCN1B-SCN4B revealed 125 different (potential) pathogenic variants in 194 patients (17.2%, n = 194/1125). A potential pathogenic variant was present in 18.1% (n = 142/784) of painful neuropathy patients vs. 15.2% (n = 52/341) of painless neuropathy patients (17.3% (n = 41/237) for painful-DPN patients, 14.9% (n = 46/309) for painless-DPN patients, 18.5% (n = 101/547) for painful-SFN patients, and 18.8% (n = 6/32) for painless-SFN patients). Of the variants detected, 70% were in SCN7A, SCN9A, SCN10A and SCN11A. The frequency of SCN9A and SCN11A variants was the highest in painful-SFN patients, SCN7A variants in painful-DPN patients, and SCN10A variants in painless-DPN patients. Our findings suggest that rare SCG genetic variants may contribute to the development of painful neuropathy. Genetic profiling and SCG variant identification should aid in a better understanding of the genetic variability in patients with painful and painless neuropathy, and may lead to better risk stratification and the development of more targeted and personalized pain treatments.