Integrative miRNA-mRNA profiling of human epidermis: unique signature of SCN9A painful neuropathy.

Personalized management of neuropathic pain is an unmet clinical need due to heterogeneity of the underlying aetiologies, incompletely understood pathophysiological mechanisms and limited efficacy of existing treatments. Recent studies on microRNA in pain preclinical models have begun to yield insights into pain-related mechanisms, identifying nociception-related species differences and pinpointing potential drug candidates. With the aim of bridging the translational gap towards the clinic, we generated a human pain-related integrative miRNA and mRNA molecular profile of the epidermis, the tissue hosting small nerve fibres, in a deeply phenotyped cohort of patients with sodium channel-related painful neuropathy not responding to currently available therapies. We identified four miRNAs strongly discriminating patients from healthy individuals, confirming their effect on differentially expressed gene targets driving peripheral sensory transduction, transmission, modulation and post-transcriptional modifications, with strong effects on gene targets including NEDD4. We identified a complex epidermal miRNA-mRNA network based on tissue-specific experimental data suggesting a cross-talk between epidermal cells and axons in neuropathy pain. Using immunofluorescence assay and confocal microscopy, we observed that Nav1.7 signal intensity in keratinocytes strongly inversely correlated with NEDD4 expression that was downregulated by miR-30 family, suggesting post-transcriptional fine tuning of pain-related protein expression. Our targeted molecular profiling advances the understanding of specific neuropathic pain fine signatures and may accelerate process towards personalized medicine in patients with neuropathic pain.

Development, validation and feasibility of a Patient Satisfaction Questionnaire for evaluating the quality performance of a diagnostic small fibre neuropathy service: A qualitative study.

INTRODUCTION AND AIM: Small fibre neuropathy (SFN) is a peripheral neuropathy, leading to neuropathic pain and autonomic dysfunction. An evidence-based standardized patient diagnostic SFN service has been implemented in the Netherlands for improving patient-centred SFN care. However, the quality of care of this diagnostic SFN service has never been assessed from a patient perspective. The aim of this study was to develop and validate an SFN-Patient Satisfaction Questionnaire (SFN-PSQ) to measure the quality performance of a standardized diagnostic SFN service. METHODS: A descriptive qualitative study to create the SFN-PSQ was performed using the (COREQ (Consolidated Criteria for Reporting Qualitative Research) checklist. For item generation and content development, domains and/or items from validated PSQs were selected. The content development and content validity were performed using a Delphi method with SFN expert caregivers with different backgrounds. By using the three-step-test method in individual cognitive interviews, the content validity by patients was finalized. RESULTS: In one online Delphi panel round, the content of the first concept of the SFN-PSQ was validated, which resulted in the second concept of the SFN-PSQ. From July 2019 till March 2020, nine patients consented to participate in the individual cognitive interviews. The most significant changes of the new questionnaire were adding domains and items concerning the waiting list, the diagnostic services and consultation by the hospital psychiatrist. Also, a differentiation was made for both an inpatient and outpatient diagnostic SFN service. Furthermore, the clarity and intelligibility of the domains/items were improved, resulting in an increased comprehension of the SFN-PSQ. Ultimately, the new developed SFN-PSQ consisted of 10 domains and 51 items, suitable for measuring patient satisfaction of the neurological analysis in patients with SFN. CONCLUSION: Through item generation, expert opinions and interviews with patients, the SFN-PSQ was developed and validated, and feasibility was confirmed. The structure of the questionnaire, based on the logistic and diagnostic SFN pathway, could be used as a model in other hospitals to improve the quality, continuity and access of SFN care and other chronic diseases taking into account potential cross-cultural differences. PATIENT OR PUBLIC CONTRIBUTION: Caregivers were involved in the item generation and content development of the questionnaire. Patients were directly involved in testing the content validity and feasibility of the SFN-PSQ. CLINICAL TRIAL REGISTRATION: Not applicable.

Myotonic dystrophy type 1: A comparison between the adult- and late-onset subtype.

INTRODUCTION/AIMS: Although the extent of muscle weakness and organ complications has not been well studied in patients with late-onset myotonic dystrophy type 1 (DM1), adult-onset DM1 is associated with severe muscle involvement and possible life-threatening cardiac and respiratory complications. In this study we aimed to compare the clinical phenotype of adult-onset vs late-onset DM1, focusing on the prevalence of cardiac, respiratory, and muscular involvement. METHODS: Data were prospectively collected in the Dutch DM1 registry. RESULTS: Two hundred seventy-five adult-onset and 66 late-onset DM1 patients were included. Conduction delay on electrocardiogram was present in 123 of 275 (45%) adult-onset patients, compared with 24 of 66 (36%) late-onset patients (P = .218). DM1 subtype did not predict presence of conduction delay (odds ratio [OR] 0.706; confidence interval [CI] 0.405 to 1.230, P = .219). Subtype did predict indication for noninvasive ventilation (NIV) (late onset vs adult onset: OR, 0.254; CI, 0.104 to 0.617; P = .002) and 17% of late-onset patients required NIV compared with 40% of adult-onset patients. Muscular Impairment Rating Scale (MIRS) scores were significantly different between subtypes (MIRS 1 to 3 in 66% of adult onset vs 100% of late onset [P < .001]), as were DM1-activC scores (67 ± 21 in adult onset vs 87 ± 15 in late onset; P < .001). DISCUSSION: Although muscular phenotype was milder in late-onset compared with adult-onset DM1, the prevalence of conduction delay was comparable. Moreover, subtype was unable to predict the presence of cardiac conduction delay. Although adult-onset patients had an increased risk of having an NIV indication, 17% of late-onset patients required NIV. Despite different muscular phenotypes, screening for multiorgan involvement should be equally thorough in late-onset as in adult-onset DM1.

An evaluation of 24 h Holter monitoring in patients with myotonic dystrophy type 1.

AIMS: To evaluate the clinical effectiveness of routine 24 h Holter monitoring to screen for conduction disturbances and arrhythmias in patients with myotonic dystrophy type 1 (DM1). METHODS AND RESULTS: A retrospective two-centre study was conducted including DM1-affected individuals undergoing routine cardiac screening with at least one 24 h Holter monitoring between January 2010 and December 2020. For each individual, the following data were collected: Holter results, results of electrocardiograms (ECGs) performed at the same year as Holter monitoring, presence of cardiac complaints, and neuromuscular status. Holter findings were compared with the results of cardiac screening (ECG + history taking) performed at the same year. Cardiac conduction abnormalities and/or arrhythmias that would have remained undiagnosed based on history taking and ECG alone were considered de novo findings. A total 235 genetically confirmed DM1 patients were included. Abnormal Holter results were discovered in 126 (54%) patients after a mean follow-up of 64 ± 28 months in which an average of 3 ± 1 Holter recordings per patient was performed. Abnormalities upon Holter mainly consisted of conduction disorders (70%) such as atrioventricular (AV) block. Out of 126 patients with abnormal Holter findings, 74 (59%) patients had de novo Holter findings including second-degree AV block, atrial fibrillation/flutter and non-sustained ventricular tachycardia. Patient characteristics were unable to predict the occurrence of de novo Holter findings. In 39 out of 133 (29%) patients with normal ECGs upon yearly cardiac screening, abnormalities were found on Holter monitoring during follow-up. CONCLUSION: Twenty-four hour Holter monitoring is of added value to routine cardiac screening for all DM1 patients.

IgM anti-MAG± peripheral neuropathy (IMAGiNe) study protocol: An international, observational, prospective registry of patients with IgM M-protein peripheral neuropathies.

BACKGROUND: International consensus on IgM ± anti-MAG ± PNP (IgM PNP) is lacking. Despite increasing interest in clinical trials, validated disease-specific measures are needed to adequately capture limitations and changes over time. The IMAGiNe (IgM ± anti-myelin associated glycoprotein [MAG] peripheral neuropathy) study surges as an international collaboration to create a standardized registry of patients with IgM ± anti-MAG PNP. The consortium, which currently consists of 11 institutions from 7 countries, presents here the IMAGiNe study design and protocol. AIMS: Functional outcome measures will be constructed at the level of impairment, as well as activity and participation. We aim to describe the natural history of the cohort, the role of anti-MAG antibodies, the presence of clinical subtypes, and potential biomarkers. METHODS: The IMAGiNe study is a prospective, observational cohort study with a 3-year follow-up. At each assessment, researchers collect clinical data and subjects complete a list of preselected outcome measures. Among these, the "Pre-Rasch-built Overall Disability Scale (Pre-RODS)" questionnaire will be submitted to Rasch analysis to assess classic and modern clinimetric requirements. RESULTS: The final measures will include the IgM-PNP-specific RODS and Ataxia Rating Scale (IgM-PNP-ARS). Descriptions of the disease course, clinical heterogeneity, treatment regimes, variations in laboratory values, and antibody titers will help reach consensus on diagnosis and follow-up strategies. CONCLUSION: The constructed interval scales will be cross-culturally valid and suitable for use in future clinical trials and daily practice. The ultimate goals are to improve functional individualized assessment, reach international consensus, and lay the foundations for successful designs in future studies.

Withdrawal of intravenous immunoglobulin in chronic inflammatory demyelinating polyradiculoneuropathy.

Intravenous immunoglobulins are an efficacious treatment for chronic inflammatory demyelinating polyradiculoneuropathy. Biomarkers for disease activity are lacking, making the need for ongoing treatment difficult to assess, leading to potential overtreatment and high health-care costs. Our objective was to determine whether intravenous immunoglobulin withdrawal is non-inferior to continuing intravenous immunoglobulin treatment and to determine how often patients are overtreated. We performed a randomized, double-blind, intravenous immunoglobulin-controlled non-inferiority trial in seven centres in the Netherlands (Trial registration: ISRCTN 13637698; www.isrctn.com/ISRCTN13637698). Adults with clinically stable chronic inflammatory demyelinating polyradiculoneuropathy using intravenous immunoglobulin maintenance treatment for at least 6 months were included. Patients received either intravenous immunoglobulin withdrawal (placebo) as investigational treatment or continuation of intravenous immunoglobulin treatment (control). The primary outcome was the mean change in logit scores from baseline to 24-week follow-up on the patient-reported Inflammatory Rasch-Overall Disability Scale. The non-inferiority margin was predefined as between-group difference in mean change scores of -0.65. Patients who deteriorated could reach a relapse end point according to predefined criteria. Patients with a relapse end point after intravenous immunoglobulin withdrawal entered a restabilization phase. All patients from the withdrawal group who remained stable were included in an open-label extension phase of 52 weeks. We included 60 patients, of whom 29 were randomized to intravenous immunoglobulin withdrawal and 31 to continuation of treatment. The mean age was 58 years (SD 14.7) and 67% was male. The between-group difference in mean change Inflammatory Rasch-Overall Disability Scale scores was -0.47 (95% CI -1.24 to 0.31), indicating that non-inferiority of intravenous immunoglobulin withdrawal could not be established. In the intravenous immunoglobulin withdrawal group, 41% remained stable for 24 weeks, compared to 58% in the intravenous immunoglobulin continuation group (-17%; 95% CI -39 to 8). Of the intravenous immunoglobulin withdrawal group, 28% remained stable at the end of the extension phase. Of the patients in the restabilization phase, 94% restabilized within 12 weeks. In conclusion, it remains inconclusive whether intravenous immunoglobulin withdrawal is non-inferior compared to continuing treatment, partly due to larger than expected confidence intervals leading to an underpowered study. Despite these limitations, a considerable proportion of patients could stop treatment and almost all patients who relapsed were restabilized quickly. Unexpectedly, a high proportion of intravenous immunoglobulin-treated patients experienced a relapse end point, emphasizing the need for more objective measures for disease activity in future trials, as the patient-reported outcome measures might not have been able to identify true relapses reliably. Overall, this study suggests that withdrawal attempts are safe and should be performed regularly in clinically stable patients.

Use of the experience sampling method in adolescents with Duchenne muscular dystrophy: a feasibility study.

Experience sampling methods (ESM) using mobile health (mHealth) technology with a smartphone application are increasingly used in clinical practice and research. Still, recommendations are limited in young people, and adaptations may be necessary. Patients with Duchenne muscular dystrophy (DMD) are chronically treated with steroids from a young age. However, the impact of intermittent treatment schedules on fluctuations in somatic, cognitive and behavioural symptoms is poorly investigated. Existing studies are often cross-sectional and occur in controlled clinical settings, which do not provide sufficiently detailed insights into possible correlations. ESM might alleviate these problems. ESM innovates data collection with a smartphone application, which repeatedly assesses specific symptoms and contextual factors at random moments in daily life. We aimed to evaluate its feasibility in adolescents with DMD. In three (without/with/without steroids) 4-day periods of ESM, that were nested in 10/10 or 11/9 day on/off-medication periods, we evaluated its user-friendliness and compliance, and explored its ability to objectify fluctuations in somatic, cognitive and behavioural symptom severity and their relationship with contextual factors in seven DMD patients (age range 12-18 years) using intermittent corticosteroid treatment (dosage range 0.3-0.6 mg/kg/day). Patients reported that ESM was convenient and user-friendly. We were able to capture extensive intra-individual symptom fluctuations during intermittent corticosteroid treatment that were not revealed by routine clinical assessment. Implementing ESM to evaluate symptom fluctuation patterns in relation to treatment effects shows promise in adolescents with DMD. Optimization in further research is needed.

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.

Small fiber neuropathies: expanding their etiologies.

PURPOSE OF REVIEW: Several conditions have been associated with the development of small fiber neuropathy (SFN). The list of metabolic, immune-mediated, infectious, toxic, drugs-related, and hereditary conditions is still growing and various hypotheses are made about the underlying pathophysiological mechanisms. Understanding these processes is important to provide new targets for treatment. In addition, the specific SFN phenotype can provide direction for the underlying etiology. This review discusses the latest developments concerning the expanding etiologies in SFN. RECENT FINDINGS: In the past 18 months, special attention has been paid to immunological etiologies, partly due to the coronavirus disease 2019 pandemic, but also new auto-antibodies in SFN have been demonstrated. Identifying patients with immune-mediated SFN can be challenging, since contrary to the classical distal sensory phenotype, a nonlength-dependent pattern is more common.Besides the etiologies of classical SFN, small fiber pathology is increasingly described in diseases without the typical neuropathic pain features of SFN, sometimes called syndromic SFN. However, the clinical relevance is not yet fully understood. SUMMARY: The expansion of the etiologies of SFN continues and brings more insight in possible targets for treatment. The clinical presentation may vary as a result of the underlying condition.

Corneal nerve loss is related to the severity of painful diabetic neuropathy.

BACKGROUND AND PURPOSE: Previously it has been shown that patients with painful diabetic neuropathy (PDN) have greater corneal nerve loss compared to patients with painless diabetic neuropathy. This study investigated if the severity of corneal nerve loss was related to the severity of PDN. METHODS: Participants with diabetic neuropathy (n = 118) and healthy controls (n = 38) underwent clinical and neurological evaluation, quantitative sensory testing, nerve conduction testing and corneal confocal microscopy and were categorized into those with no (n = 43), mild (n = 34) and moderate-to-severe (n = 41) neuropathic pain. RESULTS: Corneal nerve fibre density (p = 0.003), corneal nerve fibre length (p < 0.0001) and cold perception threshold (p < 0.0001) were lower and warm perception threshold was higher (p = 0.002) in patients with more severe pain, but there was no significant difference in the neuropathy disability score (p = 0.5), vibration perception threshold (p = 0.5), sural nerve conduction velocity (p = 0.3) and amplitude (p = 0.7), corneal nerve branch density (p = 0.06) and deep breathing heart rate variability (p = 0.08) between patients with differing severity of PDN. The visual analogue scale correlated significantly with corneal nerve fibre density (r = -0.3, p = 0.0002), corneal nerve branch density (r = -0.3, p = 0.001) and corneal nerve fibre length (r = -0.4, p < 0.0001). Receiver operating curve analysis showed that corneal nerve fibre density had an area under the curve of 0.78 with a sensitivity of 0.73 and specificity of 0.72 for the diagnosis of PDN. CONCLUSIONS: Corneal confocal microscopy reveals increasing corneal nerve fibre loss with increasing severity of neuropathic pain and a good diagnostic outcome for identifying patients with PDN.

Anxiety and depression in small fiber neuropathy.

Psychiatric comorbidity is common in patients with chronic pain. In peripheral neuropathic pain, particularly anxiety and mood disorders are frequently present and associated with a high level of catastrophizing. Small fiber neuropathy (SFN) is a peripheral neuropathy dominated by pain. This study aimed to investigate the prevalence of and factors associated with anxiety and depressive symptoms in SFN. All consecutive patients diagnosed with SFN at Maastricht University Medical Center+, between September 2016 and October 2021, were included (n = 1310). Data on demographics, medical history, diagnostic tests, and questionnaires about pain, SFN-specific symptoms, and mental health were collected once. The Hospital Anxiety and Depression Scale (HADS) was used to measure anxiety and depression and the Pain Catastrophizing Scale (PCS) to measure the degree of catastrophizing. One-third of the patients had an abnormal HADS score (≥11) on the subscales anxiety and/or depression (26.5% anxiety and 23.0% depression) indicating clinical relevance. Regression analysis showed that higher pain intensity, catastrophizing, and more SFN-related complaints were significantly associated with an abnormal HADS-score. In conclusion, the prevalence of reported anxiety or depressive symptoms in SFN is 36.3%. A multidisciplinary approach, not only focusing on pain relief, is therefore essential for the treatment of SFN.

Peripheral Ion Channel Gene Screening in Painful- and Painless-Diabetic Neuropathy.

Neuropathic pain is common in diabetic peripheral neuropathy (DN), probably caused by pathogenic ion channel gene variants. Therefore, we performed molecular inversion probes-next generation sequencing of 5 transient receptor potential cation channels, 8 potassium channels and 2 calcium-activated chloride channel genes in 222 painful- and 304 painless-DN patients. Twelve painful-DN (5.4%) patients showed potentially pathogenic variants (five nonsense/frameshift, seven missense, one out-of-frame deletion) in ANO3 (n = 3), HCN1 (n = 1), KCNK18 (n = 2), TRPA1 (n = 3), TRPM8 (n = 3) and TRPV4 (n = 1) and fourteen painless-DN patients (4.6%-three nonsense/frameshift, nine missense, one out-of-frame deletion) in ANO1 (n = 1), KCNK18 (n = 3), KCNQ3 (n = 1), TRPA1 (n = 2), TRPM8 (n = 1), TRPV1 (n = 3) and TRPV4 (n = 3). Missense variants were present in both conditions, presumably with loss- or gain-of-functions. KCNK18 nonsense/frameshift variants were found in painless/painful-DN, making a causal role in pain less likely. Surprisingly, premature stop-codons with likely nonsense-mediated RNA-decay were more frequent in painful-DN. Although limited in number, painful-DN patients with ion channel gene variants reported higher maximal pain during the night and day. Moreover, painful-DN patients with TRP variants had abnormal thermal thresholds and more severe pain during the night and day. Our results suggest a role of ion channel gene variants in neuropathic pain, but functional validation is required.

Peripheral Ion Channel Genes Screening in Painful Small Fiber Neuropathy.

Neuropathic pain is a characteristic feature of small fiber neuropathy (SFN), which in 18% of the cases is caused by genetic variants in voltage-gated sodium ion channels. In this study, we assessed the role of fifteen other ion channels in neuropathic pain. Patients with SFN (n = 414) were analyzed for ANO1, ANO3, HCN1, KCNA2, KCNA4, KCNK18, KCNN1, KCNQ3, KCNQ5, KCNS1, TRPA1, TRPM8, TRPV1, TRPV3 and TRPV4 variants by single-molecule molecular inversion probes-next-generation sequencing. These patients did not have genetic variants in SCN3A, SCN7A-SCN11A and SCN1B-SCN4B. In twenty patients (20/414, 4.8%), a potentially pathogenic heterozygous variant was identified in an ion-channel gene (ICG). Variants were present in seven genes, for two patients (0.5%) in ANO3, one (0.2%) in KCNK18, two (0.5%) in KCNQ3, seven (1.7%) in TRPA1, three (0.7%) in TRPM8, three (0.7%) in TRPV1 and two (0.5%) in TRPV3. Variants in the TRP genes were the most frequent (n = 15, 3.6%), partly in patients with high mean maximal pain scores VAS = 9.65 ± 0.7 (n = 4). Patients with ICG variants reported more severe pain compared to patients without such variants (VAS = 9.36 ± 0.72 vs. VAS = 7.47 ± 2.37). This cohort study identified ICG variants in neuropathic pain in SFN, complementing previous findings of ICG variants in diabetic neuropathy. These data show that ICG variants are central in neuropathic pain of different etiologies and provides promising gene candidates for future research.

Hydropathicity-based prediction of pain-causing NaV1.7 variants.

BACKGROUND: Mutation-induced variations in the functional architecture of the NaV1.7 channel protein are causally related to a broad spectrum of human pain disorders. Predicting in silico the phenotype of NaV1.7 variant is of major clinical importance; it can aid in reducing costs of in vitro pathophysiological characterization of NaV1.7 variants, as well as, in the design of drug agents for counteracting pain-disease symptoms. RESULTS: In this work, we utilize spatial complexity of hydropathic effects toward predicting which NaV1.7 variants cause pain (and which are neutral) based on the location of corresponding mutation sites within the NaV1.7 structure. For that, we analyze topological and scaling hydropathic characteristics of the atomic environment around NaV1.7's pore and probe their spatial correlation with mutation sites. We show that pain-related mutation sites occupy structural locations in proximity to a hydrophobic patch lining the pore while clustering at a critical hydropathic-interactions distance from the selectivity filter (SF). Taken together, these observations can differentiate pain-related NaV1.7 variants from neutral ones, i.e., NaV1.7 variants not causing pain disease, with 80.5[Formula: see text] sensitivity and 93.7[Formula: see text] specificity [area under the receiver operating characteristics curve = 0.872]. CONCLUSIONS: Our findings suggest that maintaining hydrophobic NaV1.7 interior intact, as well as, a finely-tuned (dictated by hydropathic interactions) distance from the SF might be necessary molecular conditions for physiological NaV1.7 functioning. The main advantage for using the presented predictive scheme is its negligible computational cost, as well as, hydropathicity-based biophysical rationalization.

A novel gain-of-function sodium channel ß2 subunit mutation in idiopathic small fiber neuropathy.

Small fiber neuropathy (SFN) is a common condition affecting thinly myelinated Aδ and unmyelinated C fibers, often resulting in excruciating pain and dysautonomia. SFN has been associated with several conditions, but a significant number of cases have no discernible cause. Recent genetic studies have identified potentially pathogenic gain-of-function mutations in several pore-forming voltage-gated sodium channel α subunits (NaV) in a subset of patients with SFN, but the auxiliary sodium channel ß subunits have been less implicated in the development of the disease. ß subunits modulate NaV trafficking and gating, and several mutations have been linked to epilepsy and cardiac dysfunction. Recently, we provided the first evidence for the contribution of a mutation in the ß2 subunit to pain in human painful diabetic neuropathy. Here, we provide the first evidence for the involvement of a sodium channel ß subunit mutation in the pathogenesis of SFN with no other known causes. We show, through current-clamp analysis, that the newly identified Y69H variant of the ß2 subunit induces neuronal hyperexcitability in dorsal root ganglion neurons, lowering the threshold for action potential firing and allowing for increased repetitive action potential spiking. Underlying the hyperexcitability induced by the ß2-Y69H variant, we demonstrate an upregulation in tetrodotoxin-sensitive, but not tetrodotoxin-resistant sodium currents. This provides the first evidence for the involvement of ß2 subunits in SFN and strengthens the link between sodium channel ß subunits and the development of neuropathic pain in humans.NEW & NOTEWORTHY Small fiber neuropathy (SFN) often has no discernible cause, although mutations in the voltage-gated sodium channel α subunits have been implicated in some cases. We identify a patient suffering from SFN with a mutation in the auxiliary ß2 subunit and no other discernible causes for SFN. Functional assessment confirms this mutation renders dorsal root ganglion neurons hyperexcitable and upregulates tetrodotoxin-sensitive sodium currents. This study strengthens a newly emerging link between sodium channel ß2 subunit mutations and human pain disorders.

Clinical, genetic, and histological features of centronuclear myopathy in the Netherlands.

Centronuclear myopathy (CNM) is a genetically heterogeneous congenital myopathy characterized by muscle weakness, atrophy, and variable degrees of cardiorespiratory involvement. The clinical severity is largely explained by genotype (DNM2, MTM1, RYR1, BIN1, TTN, and other rarer genetic backgrounds), specific mutation(s), and age of the patient. The histopathological hallmark of CNM is the presence of internal centralized nuclei on muscle biopsy. Information on the phenotypical spectrum, subtype prevalence, and phenotype-genotype correlations is limited. To characterize CNM more comprehensively, we retrospectively assessed a national cohort of 48 CNM patients (mean age = 32 ± 24 years, range 0-80, 54% males) from the Netherlands clinically, histologically, and genetically. All information was extracted from entries in the patient's medical records, between 2000 and 2020. Frequent clinical features in addition to muscle weakness and hypotonia were fatigue and exercise intolerance in more mildly affected cases. Genetic analysis showed variants in four genes (18 DNM2, 14 MTM1, 9 RYR1, and 7 BIN1), including 16 novel variants. In addition to central nuclei, histologic examination revealed a large variability of myopathic features in the different genotypes. The identification and characterization of these patients contribute to trial readiness.

The facioscapulohumeral muscular dystrophy Rasch-built overall disability scale (FSHD-RODS).

BACKGROUND AND OBJECTIVES: Facioscapulohumeral muscular dystrophy (FHSD) is a debilitating inherited muscle disease for which various therapeutic strategies are being investigated. Thus far, little attention has been given in FSHD to the development of scientifically sound outcome measures fulfilling regulatory authority requirements. The aim of this study was to design a patient-reported Rasch-built interval scale on activity and participation for FSHD. METHODS: A pre-phase FSHD-Rasch-built overall disability scale (pre-FSHD-RODS; consisting of 159 activity/participation items), based on the World Health Organization international classification of disease-related functional consequences was completed by 762 FSHD patients (Netherlands: n = 171; UK: n = 287; United States: n = 221; France: n = 52; Australia: n = 32). A proportion of the patient cohort completed it twice (n = 230; interval 2-4 weeks; reliability studies). The pre-FSHD-RODS was subjected to Rasch analyses to create a model fulfilling its requirements. Validity studies were performed through correlation with the motor function measure. RESULTS: The pre-FSHD-RODS did not meet the Rasch model expectations. Based on determinants such as misfit statistics and misfit residuals, differential item functioning, and local dependency, we systematically removed items until a final 38-inquiry (originating from 32 items; six items split) FSHD-RODS was constructed achieving Rasch model expectations. Adequate test-retest reliability and (cross-cultural and external) validity scores were obtained. CONCLUSIONS: The FSHD-RODS is a disease-specific interval measure suitable for detecting activity and participation restrictions in patients with FSHD with good item/person reliability and validity scores. The use of this scale is recommended in the near future, to determine the functional deterioration slope in FSHD per year as a preparation for the upcoming clinical intervention trials in FSHD.

Electrocardiographic predictors of infrahissian conduction disturbances in myotonic dystrophy type 1.

AIMS: The aim of this study was to determine electrocardiographic (ECG) criteria predicting abnormal infrahissian conduction in patients with myotonic dystrophy type 1 (DM1), as these criteria could be used to identify the need for an electrophysiological study (EPS). METHODS AND RESULTS: A retrospective multicentre study was conducted including DM1-affected individuals who underwent EPS between 2007 and 2018. For each individual, EPS indication, His-ventricle (HV) interval, resting ECG parameters prior to EPS, left ventricular ejection fraction (LVEF), neurological status, and DM1 DNA analysis results were collected. Electrocardiographic parameters of patients with a normal HV interval were compared with ECG parameters of patients with a prolonged HV interval. Logistic regression was performed to determine predictors for a prolonged HV interval of ≥70 ms on EPS and diagnostic accuracy of ECG parameters was ascertained. Among 100 DM1-affected individuals undergoing EPS, 47 had a prolonged HV interval. The sole presence of a PR interval >200 ms [odds ratio (OR) 8.45, confidence interval (CI) 2.64-27.04] or a QRS complex >120 ms (OR 9.91, CI 3.53-27.80) on ECG were independent predictors of a prolonged HV interval. The combination of both parameters had a positive predictive value of 78% for delayed infrahissian conduction on EPS. His-ventricle interval was independent of DM1 genetic mutation size, neuromuscular status, and LVEF. CONCLUSION: The combination of a prolonged PR interval and widened QRS complex on ECG accurately predicts abnormal infrahissian conduction on EPS in patients with DM1. These ECG parameters could be used as a screening tool to determine the need for referral to a specialized multidisciplinary neuromuscular team with EPS capacity.

Differential effect of lacosamide on Nav1.7 variants from responsive and non-responsive patients with small fibre neuropathy.

Small fibre neuropathy is a common pain disorder, which in many cases fails to respond to treatment with existing medications. Gain-of-function mutations of voltage-gated sodium channel Nav1.7 underlie dorsal root ganglion neuronal hyperexcitability and pain in a subset of patients with small fibre neuropathy. Recent clinical studies have demonstrated that lacosamide, which blocks sodium channels in a use-dependent manner, attenuates pain in some patients with Nav1.7 mutations; however, only a subgroup of these patients responded to the drug. Here, we used voltage-clamp recordings to evaluate the effects of lacosamide on five Nav1.7 variants from patients who were responsive or non-responsive to treatment. We show that, at the clinically achievable concentration of 30 µM, lacosamide acts as a potent sodium channel inhibitor of Nav1.7 variants carried by responsive patients, via a hyperpolarizing shift of voltage-dependence of both fast and slow inactivation and enhancement of use-dependent inhibition. By contrast, the effects of lacosamide on slow inactivation and use-dependence in Nav1.7 variants from non-responsive patients were less robust. Importantly, we found that lacosamide selectively enhances fast inactivation only in variants from responders. Taken together, these findings begin to unravel biophysical underpinnings that contribute to responsiveness to lacosamide in patients with small fibre neuropathy carrying select Nav1.7 variants.

Non-extensitivity and criticality of atomic hydropathicity around a voltage-gated sodium channel's pore: a modeling study.

Voltage-gated sodium channels (NavChs) are pore-forming membrane proteins that regulate the transport of sodium ions through the cell membrane. Understanding the structure and function of NavChs is of major biophysical, as well as clinical, importance given their key role in cellular pathophysiology. In this work, we provide a computational framework for modeling system-size-dependent, i.e., cumulative, atomic properties around a NavCh's pore. We illustrate our methodologies on the bacterial NavAb channel captured in a closed-pore state where we demonstrate that the atomic environment around its pore exhibits a bi-phasic spatial organization dictated by the structural separation of the pore domains (PDs) from the voltage-sensing domains (VSDs). Accordingly, a mathematical model describing packing of atoms around NavAb's pore is constructed that allows-under certain conservation conditions-for a power-law approximation of the cumulative hydropathic dipole field effect acting along NavAb's pore. This verified the non-extensitivity hypothesis for the closed-pore NavAb channel and revealed a long-range hydropathic interactions law regulating atom-packing around the NavAb's selectivity filter. Our model predicts a PDs-VSDs coupling energy of [Formula: see text] kcal/mol corresponding to a global maximum of the atom-packing energy profile. Crucially, we demonstrate for the first time how critical phenomena can emerge in a single-channel structure as a consequence of the non-extensive character of its atomic porous environment.