BackgroundMyotonic dystrophy type 1 (DM1) is associated with reduced physical activity, overweight and cardiovascular morbidity. Nutritional management requires accurate estimation of total daily energy expenditure (TEE), based on basal metabolic rate (BMR) and physical activity level (PAL). However, DM1-related changes in body composition may reduce the accuracy of commonly used BMR equations. This study evaluated BMR equation accuracy in DM1 versus controls, and assessed PAL and substrate oxidation.MethodsIn this secondary analysis of a prospective case-control study, 15 DM1 patients were compared with 15 age-, sex-, and BMI-matched controls. Body composition was measured using dual-energy X-ray absorptiometry. Overnight metabolic rate (OMR) was assessed by room calorimetry and compared with standard predictive equations (Harris-Benedict, WHO, Mifflin-St Jeor). Additionally, OMR was compared to body composition-based equations (Wang, Nelson, Sabounchi structures 4, 5, and 11). TEE was measured over 15 days using doubly labeled water. PAL was calculated as TEE/OMR, and substrate oxidation was assessed using the respiratory exchange ratio (RER).ResultsStandard predictive equations significantly overestimated metabolic rate in DM1, with median biases of +100 to +165 kcal/day (+7% to +12%, p<0.01), with no significant bias in controls. Structure 11 performed best in DM1 (+0.0%, p=1.000). PAL was lower in DM1 than in controls (1.42 vs. 1.69, p<0.001), whereas RER did not differ.ConclusionCommon predictive equations overestimate energy requirements in DM1. Body composition-based approaches or correction factors may improve estimation, while low PAL should be considered when estimating TEE. These findings have direct implications for nutritional management in DM1.

BACKGROUND:Small fibre neuropathy (SFN) affects small myelinated Aδ- and unmyelinated C-fibres and causes neuropathic pain and autonomic symptoms. Earlier Dutch estimates, over a decade old, reported a minimum prevalence of 52.95 and an incidence of 11.75 per 100 000 adults. As recognition of SFN has likely increased, this study aimed to estimate the total SFN population in the Netherlands and to provide updated incidence and prevalence rates using a multiple system estimation (MSE) approach. METHODS:MSE was used to estimate the total adult SFN population by matching patients from three national databases: the SFN expertise centre, the national SFN registry and the Dutch Neuromuscular Disorders Association. Prevalence was calculated by using total population numbers from Statistics Netherlands, adjusting for mortality with age- and sex-specific survival rates. Annual incidence and prevalence by sex and region were calculated using stratified MSE. Missing diagnosis years in the patient association data were imputed using multiple imputations. RESULTS:The prevalence of SFN in 2024 was estimated at 69.69 and the incidence at 3.55 per 100 000 adults in the general Dutch population, with higher rates in females. Incidence increased over time, particularly among females. CONCLUSIONS:This study reveals a higher prevalence than previously reported. The lower incidence compared with previous estimates likely reflects differences in geographic coverage, while the rising trend suggests increasing awareness and recognition of SFN. These findings suggest that SFN represents a larger problem than previously recognised and the burden of SFN emphasises the urgent need for novel therapeutic strategies.

Summary Induced pluripotent stem cells (iPSCs) are widely used as patient-specific disease models, yet substantial unexplained variability in molecular and functional readouts limits their reliability. Here, we systematically investigated the sources of variation in iPSC-derived neurons for three rare genetic disorders: Myotonic Dystrophy Type 1, chromodomain-DNA-helicase-binding protein 2-related disorder and N -acetylneuraminic acid synthase deficiency. This was performed by profiling multi-omics layers: genomics, epigenomics, transcriptomics, proteomics, metabolomics and lipidomics. Our study found that clonal variability was comparable to inter-patient differences and that neuronal differentiation state and nutrient-driven metabolic activity emerged as dominant contributors to variability observed across omics layers. Clonal differences could partly be attributed to stochastic differences in DNA methylation established during reprogramming. By modeling and correcting the observed variation, we improved the detection of disease-associated molecular signatures. Our study provides guidelines for improved study design and data analysis to minimize variability, enabling robust biomarker discovery and reliable iPSC-based disease modeling.

BACKGROUND AND AIMS:Small fiber neuropathy (SFN) is a peripheral neuropathy causing neuropathic pain, reduced quality of life (QoL), and high societal costs. Previous studies assessed these societal costs before a definitive diagnosis was established, leaving it unclear whether diagnostic confirmation affects costs, pain intensity, or QoL. This study assessed changes in these outcomes before and after diagnosis. METHODS:Patients referred to the tertiary SFN expertise center in the Netherlands completed questionnaires before diagnosis (at placement on the waiting list, approximately 7 months before consultation) and at 3 and/or 6 months after confirmation. Healthcare utilization, patient and family costs, and productivity losses were assessed using the iMTA Medical Consumption and Productivity Cost Questionnaires. QoL was measured with the EQ-5D-5L and pain intensity with a numeric rating scale. Missing data were handled using multiple imputation, and changes over time were analyzed using within-subject comparisons and generalized linear mixed models. RESULTS:Eighty-four patients completed both pre- and postdiagnosis questionnaires. After follow-up, total healthcare costs, patient and family costs, productivity losses, pain intensity, and QoL remained unchanged. However, diagnostic confirmation of SFN was associated with fewer medical specialist visits, lower related costs, and improved health perception. INTERPRETATION:These findings suggest that diagnostic clarification alone is insufficient to reduce the overall burden of SFN, highlighting the need for more effective symptom management and supportive care strategies.

BACKGROUND:Myotonic Dystrophy type 1 (DM1) is a multisystemic neuromuscular disorder. Gastrointestinal (GI) symptoms significantly impact quality of life, but remain under-assessed. Currently, no DM1 specific GI questionnaire is available. The Gastrointestinal Symptoms Rating Scale (GSRS) is widely used but lacks validation with modern clinimetric methods. OBJECTIVES:To evaluate the GSRS using Rasch analysis in DM1 patients and develop a disease-specific, interval-level GI symptom measure. METHODS:Rasch analysis evaluated item fit, threshold ordering, differential item functioning (DIF), local dependency, and unidimensionality. Model fit was evaluated using chi-square statistics, item and person fit residuals, and the Person Separation Index (PSI). RESULTS:Four hundred and three DM1 patients (206 women, mean age 48.3 years) completed the GSRS questionnaire. The GSRS initial data did not meet Rasch model expectations. Three items (hard stools, heartburn, diarrhea) were removed and the item nausea was split by age category. The item constipation had misfit exceeding the Bonferroni threshold, but was retained due to its clinical relevance. The final model did not fulfill Rasch requirements (item fit residuals: -0.23, SD 1.29; person fit residuals: mean -0.27, SD 1.15; item-trait Chi-square: p-value < 0.001; degrees of freedom: 60). Acceptable person separation index (0.76) was obtained. CONCLUSION:This study highlights the challenges of measuring GI symptoms in DM1. Although this research is an important first step, more research is needed for developing a questionnaire that reflects the patient experience whilst simultaneously considering measurement accuracy.

BACKGROUND AND OBJECTIVES:Chronic idiopathic axonal polyneuropathy (CIAP) is a common type of chronic polyneuropathy that often affects health-related quality of life. Currently, no patient-reported disease-specific outcome measure is available to assess functional deficit in patients with CIAP. The aim of this study was to construct a patient-reported Rasch-built interval scale for patients with CIAP. METHODS:A historic prospective cohort study was conducted to develop a CIAP-specific Rasch-built overall disability scale (CIAP-RODS). The preliminary scale (pre-CIAP-RODS) comprised 196 items, including 146 activity and participation items selected from the World Health Organization International Classification of Functioning, Disability and Health and 50 expert-derived items formulated in collaboration with a CIAP patients advocacy group. Participants were patients with CIAP who were requested to score their perceived difficulty to perform each item as (0) unable to perform; (1) able to perform, but with difficulty; or (2) easily performed, without difficulty. For test-retest reliability studies, 150 participants completed the pre-CIAP-RODS twice with an interval of 2-4 weeks. The pre-CIAP-RODS was subjected to Rasch analyses (RUMM2030+) to develop the final CIAP-RODS, and external validity was assessed by examining associations with the European Quality of Life 5 Dimensions 3 Level Version (EQ-5D-3L). RESULTS:Of 551 eligible patients invited, 268 completed the pre-CIAP-RODS (mean age 72 years; 31% female; median disease duration 14 years). Patients with relevant comorbidities or newly identified risk factors of polyneuropathy were excluded. The pre-CIAP-RODS was subjected to Rasch analyses and did not meet the Rasch model expectations. In a systematic and stepwise manner, items were removed based on disordered thresholds, misfit statistics, local dependency, previously reported patient perceptions, and clinical applicability, resulting in a final 24-item CIAP-RODS that fulfilled Rasch model requirements. Test-retest reliability was good, internal validity was robust (person separation index 0.95), and significant associations between CIAP-RODS person location and EQ-5D-3L item scores indicated good discriminative external validity. DISCUSSION:The 24-item CIAP-RODS is a disease-specific interval measure developed for detection of activity and participation limitations in patients with CIAP. Use of the CIAP-RODS in future studies is recommended to evaluate longitudinal changes in the disease course. Further studies are needed to determine responsiveness and cross-cultural validity.

Objectives To determine the prevalence and clinical characteristics associated with polyneuropathy in kidney transplant recipients (KTRs).Design Cross-sectional study.Setting SENS study at the University Medical Center Groningen, the Netherlands, December 2021–May 2023.Participants KTR, participating in the ongoing TransplantLines Biobank and Cohort Study, ≥12 months post-transplantation.Main outcome measures Participants underwent a structured neurological assessment including history taking, neurological examination, quantitative sensory testing and nerve conduction studies. An expert panel classified participants into no/possible, probable/definite large fibre polyneuropathy or small fibre neuropathy. Large-fibre subtypes included axonal or demyelinating, pure sensory, pure motor and sensorimotor. To assess potential associations with clinical characteristics, logistic regression analysis was conducted.Results We included 160 KTRs with a mean age of 59.8±11.6 years at a median of 6.1 (95% CI 3.9 to 13.1) years post-transplantation, with 16 KTRs (10%) diagnosed with polyneuropathy before study inclusion. In total, 84 KTRs (53%) were identified with large fibre polyneuropathy and 7 KTRs (4%) with small fibre neuropathy. KTRs with large fibre polyneuropathy presented with either sensor-predominant polyneuropathy (40 KTR (48%)) or sensorimotor polyneuropathy (44 KTR (52%)). We found no neurophysiological characteristics of demyelination. Overall, 18% (95% CI 11% to 27%) of KTRs with large fibre polyneuropathy were asymptomatic. Higher age (OR=1.04 (1.01 to 1.08), p=0.01), male sex (OR=2.55 (1.19 to 5.60), p=0.02), diabetes (OR=5.58 (1.36 to 38.14), p=0.03) and elevated urea levels (OR=1.12 (1.04 to 1.23), p=0.01) were significantly associated with polyneuropathy in KTR.Conclusions In contrast with previous studies, axonal sensory or sensorimotor polyneuropathy is highly prevalent and often underdiagnosed in KTR. Next to higher age and male sex, it was independently associated with diabetes and higher urea levels. Further research is needed to reveal the aetiology and course of polyneuropathy in KTRs.Trial registration number NCT04664426.

Changes in gene function or expression caused by epigenetic modifications may play a role in painful diabetic neuropathy. Two independent cohorts of patients deeply phenotyped for painful diabetic neuropathy underwent whole genome DNA methylation data analysis. Burden of rare site events at the global, chromosomal and gene level; epigenetic homogeneity for regions enriched in epivariants (epilesions) and functional analysis of the genes with stochastic phenomena was undertaken. This revealed significant involvement of the SLIT/ROBO signaling axis-engaged in peripheral nerve regeneration after injury, among several molecular pathways, making it an attractive therapeutic target in patients with diabetic painful neuropathy.

Background and aims Cardiac involvement occurs in approximately 80% of patients with myotonic dystrophy type 1 (DM1), and annual follow-up with a routine 12‑lead ECG (rECG) is recommended. We assessed a mobile 6‑lead ECG device (mECG) as a triage tool to identify DM1 patients with suspected prolonged ECG intervals, validating the feasibility and accuracy of mECG-derived PQ and QRS intervals against rECG. Methods This supervised in-clinic proof-of-concept study included 50 patients with DM1 and 50 cardiology patients from the cardiology outpatient clinic. All underwent rECG and mECG during a single routine visit. Agreement was assessed using correlation, intra-class correlation coefficient (ICC), and Bland-Altman analyses. Results Median [IQR] age was 56 [40–66] years; 45% were women. mECG-derived PQ and QRS intervals correlated moderately to strongly with rECG (Pearson's r = 0.83 and 0.74; ICC = 0.80 and 0.74). Bland-Altman analyses showed mean differences of −2 ms (PQ) and − 14 ms (QRS). The 95%-sensitivity thresholds for detecting prolonged rECG PQ intervals was 175 ms. Consulting only DM1 patients exceeding these limits would potentially reduce hospital visits by 37%. QRS demonstrated the highest systematic bias. Conclusion mECG is feasible in patients with DM1 and provides reliable assessment of PQ intervals. Integrated into annual cardiac follow-up, it could serve as a triage tool, potentially reducing outpatient visits by 37% for DM1. This may become increasingly valuable as novel DM1 therapies expand the population requiring regular cardiac surveillance. QRS triage is unsuitable in its current form.

About one out of two diabetic patients develop diabetic neuropathy (DN), of these 20% experience neuropathic pain (NP) leading to individual, social, and health-economic burden. Risk factors for NP are largely unknown; however, premature aging was recently associated with several chronic pain disorders. DNA methylation-based biological age (DNAm) is associated with disease risk, morbidity, and mortality in different clinical settings. The purpose of this work was to study, for the first time, whether biological age is involved in pain development in a huge cohort of DN patients with neuropathy assessed by anatomopathological assay (99 painful (PDN), 132 painless (PLDN) patients, 84 controls (CTRL)). Six subsets of DNAm biomarkers were calculated to evaluate NP-associated changes in epigenetic aging, telomere shortening, blood cell count estimates, and plasma protein surrogates. We observed pain-related acceleration of epigenetic age (DNAmAgeHannum, DNAmGrimAgeBasedOnPredictedAge, DNAmAgeSkinBloodClock), pace of aging (DunedinPoAm), and shortening of telomeres between PDN and PLDN patients. PDN showed decreased predicted counts of B lymphocytes, naive and absolute CD8 T cells, and increased granulocyte counts. Several surrogates of plasma proteins were significantly different (GHR, MMP1, THBS2, PAPPA, TGF-α, GDF8, EDA, MPL, CCL21) in PDNs compared to PLDNs. These results provide the first evidence of an acceleration of biological aging in patients with painful compared to painless DN. This achievement has been possible thanks to the state of the art clinical phenotyping of the enrolled patients. Our findings indicate that the aging process may be directly involved in the PDN progression and in general health degeneration in the T2DM patients. Therefore, it is possible to hypothesize that the administration of effective antiaging drugs could slow down or even block the disease advancement.

Neuromuscular disorders are a very heterogeneous group of diseases and comprise a large number of patients. Epidemiological key figures on incidence, prevalence and mortality serve as basic information for individualised and public health care and researchers. Geographical mapping of the specific disorders is expected to provide valuable insights into clustering of the conditions, which points to possible environmental and genetical determinants. So far, mostly geographical maps of motor neuron diseases have been reported. By using record information from the Dutch nationwide Computer Registry of All Myopathies and Polyneuropathies (CRAMP) we aimed to generate geographical maps for eight disorders predominantly diagnosed in adults.We investigated the geographical distribution of newly diagnosed patients in the Netherlands from 2004-2011. The variables used were diagnosis, date of diagnosis, and the first two digits of the postal code for geographical location from CRAMP. The number of incident cases was divided by the total number of people populating the postal code area.Nationwide incidence maps were constructed for myotonic dystrophy, progressive (spinal) muscular atrophy, chronic inflammatory demyelinating polyneuropathy, facioscapulohumeral muscular dystrophy, inclusion body myositis, hereditary motor and sensory neuropathy, Pompe disease and oculopharyngeal muscular dystrophy. Considerable regional variation between disorders was observed, particularly for myotonic dystrophy and facioscapulohumeral muscular dystrophy.We provided the first neuromuscular atlas of the Netherlands with maps for eight disorders commonly seen in the neuromuscular practice. To address possible outliers due to low population numbers, Bayesian smoothing techniques should be considered in future research.

The 287th ENMC International Workshop convened experts from ten countries to address the harmonization and federated analysis of Myotonic Dystrophy Type 1 (DM1) registries. With over 10,500 patients enrolled globally, registries remain fragmented, limiting their utility in modeling disease trajectories and supporting clinical trials. As new therapies enter advanced clinical testing, registries must evolve - not only to enable trial readiness but also to support downstream functions like pharmacovigilance. The workshop focused on four objectives: re-defining a core dataset, enabling FAIRification of registries, establishing federated analysis infrastructure, and developing longitudinal modeling strategies. Key outcomes included a revised core set of clinical and patient reported outcome measures that is feasible to collect in a routine care setting, strategies for FAIR data integration, and governance models for federated analysis. Pragmatic and interpretable statistical approaches such as latent variable modeling and unsupervised clustering were discussed, with key prediction targets identified across motor, cardiac, and pulmonary domains. The workshop emphasized the need for sustainable funding, patient-centered design, and international collaboration.

BACKGROUND AND PURPOSE:Small fiber neuropathy (SFN) is a neuropathic disorder that is associated with chronic pain. While most SFN cases are idiopathic, SFN can also have hereditary causes. For example, rare SCN9A gene mutations can impair the NaV1.7 sodium channel, which leads to dorsal root ganglion neuron hyperexcitability, causing SFN. Although chronic pain may induce cerebral changes, the specific structural brain alterations in SCN9A-associated SFN (SFN-SCN9A) remain insufficiently characterized. Therefore, potential alterations in the structural brain network of idiopathic SFN and SFN-SCN9A were explored. METHODS:Ten SFN-SCN9A patients, 20 idiopathic SFN patients, and 20 controls were included. All participants underwent 3-Tesla diffusion MRI (66 gradient directions, b-value = 1200 s/mm2), and the brain network was quantified using nodal importance, which describes the influence of a group of regions on the whole network. RESULTS:The nodal importance of pain-associated regions (postcentral gyrus, insular cortex, anterior cingulate cortex, and thalamus) was increased in SFN-SCN9A patients compared to controls (β = 0.43, p = 0.02) and idiopathic SFN patients (β = 0.43, p = 0.02). Moreover, higher self-reported pain was associated with higher nodal importance of pain-associated regions in the SFN-SCN9A group (r = 0.67, p = 0.03), while this effect was not observed in the idiopathic SFN patients (r = -0.22, p = 0.34). As self-reported pain did not differ between the SFN groups, it is likely specific to the SCN9A-mutation and not to differences in pain intensity. CONCLUSION:Combined, these results suggest the potential involvement of a distinct structural pathway related to pain processing in SFN-SCN9A.

BACKGROUND:Abnormal delayed relaxation of skeletal muscles, known as myotonia, can cause disability in myotonic disorders. Sodium channel blockers, tricyclic antidepressive drugs, benzodiazepines, calcium-antagonists, taurine and prednisone may be of use in reducing myotonia. OBJECTIVES:To consider the evidence from randomised controlled trials on the efficacy and tolerability of drug treatment in patients with clinical myotonia due to a myotonic disorder. SEARCH STRATEGY:We searched the Cochrane Neuromuscular Disease Group trials register (April 2004), MEDLINE (January 1966 to December 2003) and EMBASE (January 1980 to December 2003). Grey literature was handsearched and reference lists of identified studies and reviews were examined. Authors, disease experts and manufacturers of anti-myotonic drugs were contacted. SELECTION CRITERIA:We considered all (quasi) randomised trials of participants with myotonia treated with any drug treatment versus no therapy, placebo or any other active drug treatment. The primary outcome measure was:reduced clinical myotonia using two categories: (1) no residual myotonia or improvement of myotonia or (2) No change or worsening of myotonia. Secondary outcome measures were:(1) clinical relaxation time; (2) electromyographic relaxation time; (3) stair test; (4) presence of percussion myotonia; and (5) proportion of adverse events. DATA COLLECTION AND ANALYSIS:Two authors extracted the data independently onto standardised extraction forms and disagreements were resolved by discussion. MAIN RESULTS:Nine randomised controlled trials were found comparing active drug treatment versus placebo or another active drug treatment in patients with myotonia due to a myotonic disorder. Included trials were double-blind or single-blind crossover studies involving a total of 137 patients of which 109 had myotonic dystrophy type 1 and 28 had myotonia congenita. The studies were of poor quality. Therefore, we were not able to analyse the results of all identified studies. Two small crossover studies without a washout period demonstrated a significant effect of imipramine and taurine in myotonic dystrophy. One small crossover study with a washout period demonstrated a significant effect of clomipramine in myotonic dystrophy. Meta-analysis was not possible. AUTHORS' CONCLUSIONS:Due to insufficient good quality data and lack of randomised studies, it is impossible to determine whether drug treatment is safe and effective in the treatment of myotonia. Small single studies give an indication that clomipramine and imipramine have a short-term beneficial effect and that taurine has a long-term beneficial effect on myotonia. Larger, well-designed randomised controlled trials are needed to assess the efficacy and tolerability of drug treatment for myotonia.

Neuropathic pain is commonly accompanied by hyperexcitability of nociceptive neurons, which is driven by regulation of several ion channels, including two-pore domain potassium channels (K2P) that stabilize the resting membrane potential. The TWIK-Related Spinal cord potassium channel (TRESK, K2p18.1) is predominantly expressed in sensory ganglia, where it provides major background K⁺ conductance. We describe a heterozygous c.1107del frameshift mutation in KCNK18 , encoding TRESK, found in a patient with painful small fiber neuropathy and dysautonomia. This C-terminal c.1107del mutant is predicted to generate an elongated C-terminal domain, with an altered protein sequence. Whole-cell patch calmp recordings showed that the c.1107del variant reduced K⁺ current density, while heterozygous-like expression resulted in intermediate currents, consistent with a haploinsufficiency mechanism. Confocal imaging revealed decreased plasma membrane expression, indicating a trafficking-dependent loss of function while oligomerization with TRESK (homomeric channels) or TREK1 remained intact. In silico analysis revealed an altered phosphorylation pattern and reduced C-terminal hydrophobicity in the mutant TRESK. Overall, these findings support c.1107del as a pathogenic KCNK18 variant causing TRESK haploinsufficiency, offering mechanistic insight into the pathophysiology of neuropathic pain.

Although myotonic dystrophy type 1 (DM1) is named after its characteristic muscle symptoms, it is in fact a multisystem disorder that can affect many different organs. It is therefore not surprising that this disease can manifest with a myriad of symptoms, depending on the organs involved. The age of onset and severity of symptoms vary widely. Diagnostic delays of more than ten years are common and it’s not unusual for an entire family to be diagnosed only after the birth of a child with a severe phenotype. Knowledge of the spectrum of possible symptoms in DM1 can aid clinicians to recognise this disorder, thereby preventing unnecessary diagnostic delay and facilitating early treatment of disease complications. Here, we present an overview of the potential symptoms of DM1 at different ages, with the aim of raising awareness among healthcare professionals about the recognition of this disabling disease.

BACKGROUND AND AIMS:Polyneuropathy is highly prevalent among kidney transplant recipients (KTR), underscoring the need for an accurate yet easy-to-perform diagnostic method to improve understanding and enable early identification of treatable cases. METHODS:This study included KTR at least 12 months post-transplant at the University Medical Centre Groningen, the Netherlands. An expert panel assessed polyneuropathy through a structured neurological examination, quantitative sensory testing, and nerve conduction studies. The modified Toronto Clinical Neuropathy Score (mTCNS) was obtained from all participants. Logistic regression analyses with Firth penalization validated the mTCNS components. A new model, the Kidney Transplant Neuropathy Score (KTNS), was developed through stepwise elimination. Diagnostic performance was evaluated with bootstrapped metrics and ROC curve analyses. RESULTS:Among 160 KTR, 91 (57%) were diagnosed with polyneuropathy. All 10 mTCNS components were univariably associated with polyneuropathy; numbness (OR = 4.9 [1.8-18.0]), tingling (OR = 2.5 [1.2-5.9]), impaired nociception (OR = 1.5 [1.1-2.2]), and reduced vibration perception (OR = 1.5 [1.0-2.4]) remained independently associated in multivariable analysis. The mTCNS achieved an area under the curve (AUC) in ROC analysis of 0.83 [0.76-0.89]. Two KTNS were derived: the KTNSBasic, including history of numbness, tingling in the feet, and pinprick and vibration perception testing (AUC-ROC: 0.85 [0.79-0.90]); and the KTNSAdvanced, replacing vibration perception with Achilles and patellar deep tendon reflex testing (AUC-ROC: 0.90 [0.85-0.94]). INTERPRETATION:The mTCNS is a valid diagnostic tool for polyneuropathy in KTR. The KTNS offers a simplified alternative based on key symptoms and sensory tests, with reflex testing included in the KTNSAdvanced for settings with neurological expertise. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT04664426.

BACKGROUND AND AIM:IgM monoclonal gammopathy-associated polyneuropathy with(out) anti-myelin associated glycoprotein (±anti-MAG) is a rare immune-mediated disease that may cause severe limitations in daily activities and quality of life. The absence of a systematic comparison between patients with/without anti-MAG IgM polyneuropathy, no disease-specific functional metric, and lack of international consensus regarding assessment and treatment of these patients are factors obstructing future clinical trials. Therefore, it was decided to develop an interval Rasch-built activity/participation scale specifically for IgM polyneuropathy ±anti-MAG (IgM-RODS) and examine its clinimetric properties. METHODS:A pre-phase IgM-RODS questionnaire containing 146 activity/participation items, based on the WHO International Classification of Functioning, Disability and Health, was completed by participants (≥ 18 years) of the IMAGiNe observational registry that fulfilled international criteria for IgM-polyneuropathy ±anti-MAG. Data was subjected to Rasch analyses, and reliability/validity studies were performed as well. RESULTS:The pre-RODS data of 259 subjects (originating from 8 different countries) underwent quality assessment, and 244 remaining records were submitted to the Rasch model, evidencing the model's expectations. Based on requirements like exceeding fit residuals, misfit statistics, item bias, local dependency, and less face validity, we systematically removed items until the final 36-item IgM-RODS fulfilled all Rasch requirements and showed acceptable test-retest reliability, cross-cultural, construct and discriminant validity, and unidimensionality. Compared to the Inflammatory-RODS, the IgM-RODS showed lower standard errors across the metric, indicating greater sensitivity. INTERPRETATION:The 36-item IgM-RODS is a disease-specific interval measure suitable for detecting functional deficits in patients with IgM-polyneuropathy ±anti-MAG. Future studies are needed to determine its responsiveness.

BACKGROUND:Chronic itch, or pruritus, is a common discomfort of the skin. Chronic itch has been described as a symptom of small fiber neuropathy (SFN), a disorder affecting the small myelinated Aδ- and unmyelinated C-fibers. While prior studies report itch rates in SFN ranging from 63%-68%, a distinct pattern has not been identified. AIM:This study aimed to describe the clinical characteristics of itch in a large cohort of SFN patients. METHODS:Between May 2016 and August 2022, 1415 patients filled out an exploratory questionnaire about characteristics of their itch symptoms. 83% were diagnosed with SFN based on the Besta criteria. RESULTS:Itch was reported in 66% of SFN patients, mainly experienced as tickling, prickling, and tingling sensations. Itch was most common in the evening, with 98% reporting continuous or episodic symptoms during this time. The itch was predominantly localized to the distal extremities, especially the lower legs and feet (over 50% of patients), with additional reports on the back (25%) and face (27%). Unlike the typical stocking-glove distribution seen with neuropathic pain, itch showed a slightly more proximal locus. SFN patients were more likely to report itching in the hands and feet than non-SFN patients. INTERPRETATION:This study reveals that itch in SFN is a frequent, heterogeneous symptom that may differ from neuropathic pain in its distribution. Itch, particularly in the hands and feet, may provide diagnostic guidance and suggest SFN as a potential diagnosis. This finding warrants further research on itch mechanisms and its diagnostic value in SFN.