BACKGROUND AND AIMS:In the NEURO-TTRansform clinical trial (NCT04136184), eplontersen improved neuropathy impairment and quality of life (QoL) through Week 66 versus the NEURO-TTR historical placebo in patients with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN). This analysis assessed the impact of baseline ATTRv-PN severity on eplontersen response in patients from NEURO-TTRansform. METHODS:This post hoc analysis grouped patients into tertiles by baseline Neuropathy Impairment Score (NIS): T1 (least baseline impairment: 3.5 to < 27.5; n = 67), T2 (27.5 to < 55.0; n = 67), and T3 (55.0 to < 127.8; n = 66). Outcomes assessed were neuropathy impairment (modified NIS+7 [mNIS+7] and NIS, Neuropathy Symptom and Change, Polyneuropathy Disability), QoL (Norfolk QoL-Diabetic Neuropathy), physical functioning (36-Item Short-Form Health Survey Physical Component Summary), nutritional status (modified body mass index), and serum transthyretin levels; these were compared with NEURO-TTR historical placebo. Autonomic dysfunction (Composite Autonomic Symptom Score-31), disability (Rasch-built Overall Disability Scale), and walking speed (10-Meter Walk Test) were also assessed. Final assessments were carried out following 65/66 or 81/85 weeks of treatment. RESULTS:Mean mNIS+7 composite scores were maintained over 85 weeks with eplontersen (changes from baseline of -4.5 [T1], -1.3 [T2], and -2.6 [T3] points). Other disease parameter scores were similarly maintained or improved with eplontersen. Patients receiving placebo experienced disease worsening across outcomes. T1 mean disease scores were typically better than in T2 and T3. INTERPRETATION:Consistent, sustained benefits of eplontersen were observed regardless of baseline ATTRv-PN severity. These findings strengthen the importance of early treatment initiation for patients with ATTRv-PN across the disease spectrum.
The immunobiology of Guillain-Barré syndrome (GBS) has long been organized around a dichotomy: acute motor axonal neuropathy (AMAN) is an antibody-mediated nodal disorder, whereas acute inflammatory demyelinating polyneuropathy (AIDP) has been interpreted mainly through T-cell-mediated models of compact-myelin injury. Four successive findings challenge this separation. Intraneural injection of GBS sera produced demyelination without transfer of immune cells; pathological studies in AIDP localized complement activation to the Schwann-cell surface before macrophage-associated myelin stripping. Serum IgG from a substantial subset of patients with AIDP bound nodal or paranodal surface domains; and identification of gelsolin-3 defined an AIDP subset in which patient IgG, together with active complement, produced nodal disruption before internodal demyelination. Peripheral-myelin-reactive T cells further indicate that T-cell-mediated and antibody-mediated immunity may coexist. Within this evidence hierarchy, AMAN and a subset of AIDP have distinct initiating targets but converge on nodal dysfunction. CD55 and CD59 are membrane-bound complement regulators: CD55 limits complement amplification, whereas CD59 prevents assembly of the membrane attack complex. Both are detectable in compact myelin but not at human nodes of Ranvier, revealing a localized discontinuity in complement control. This local absence of complement regulators may influence whether antibody binding progresses to conduction failure, axonal degeneration, or internodal demyelination, but should be regarded as a permissive substrate for injury rather than as evidence of lesion localization. Observations in chronic inflammatory demyelinating polyneuropathy (CIDP) suggest that antibody-mediated functional injury may precede structural demyelination. This Review proposes complement-regulated nodal vulnerability to integrate evidence across AMAN and subsets of AIDP and CIDP while preserving differences in targets, tempo, and mechanistic strength.
BACKGROUND:Peripheral nerve injury (PNI) repair remains challenging, with metabolic regulation and neuronal senescence playing critical roles. This study explored whether intermittent hypoxia modulates injured dorsal root ganglion (DRG) neuron regeneration via lactate-mediated mechanisms. METHODS:DRG neurons were subjected to impairment via acrylamide (ACR) to develop an in vitro injury model, followed by the induction of intermittent hypoxia and lactate production inhibitors including 2-deoxy-d-glucose (2-DG) and oxamate. In vivo experiments employed a rat PNI model exposed to intermittent hypoxia. Cellular evaluations comprised the CCK-8 assay to determine cell viability, β-galactosidase staining to identify cellular senescence, and immunofluorescence for the detection of p21 and Lamin B1. The m5C-RIP-qPCR assay was used to assess m5C modification of SETD2 mRNA. The immunoprecipitation was applied to examine the lactylation of NSUN3 protein. RESULTS:Intermittent hypoxia increased lactate production, improved ACR-impaired DRG viability, reduced ROS and MDA levels, and promoted damaged neuron regeneration, effects reversed by 2-DG or oxamate. Hypoxia inhibited ACR-induced neuron senescence, which was abrogated by lactate inhibitors. Mechanistically, hypoxia-induced lactate promoted NSUN3 lactylation, further enhanced m5C modification and stability of SETD2 mRNA. NSUN3 knockdown exacerbated senescence and suppressed mitochondrial biogenesis, while SETD2 overexpression reversed these impacts. CONCLUSION:Intermittent hypoxia facilitated the regeneration of injured DRG neurons through lactate-mediated NSUN3 lactylation. This process was correlated with the stability of SETD2 mRNA via m5C modification, thereby mitigating cellular senescence and promoting mitochondrial function. These findings present novel targets for strategies aimed at nerve repair.
BACKGROUND AND AIMS:The HARS1 gene encodes cytoplasmic histidyl-tRNA synthetase, which catalyzes the ligation of histidine to tRNAHIS in the cytoplasm as an early step in protein biosynthesis and is essential for cell viability. Pathogenic variants in HARS1 have been associated with three phenotypes: autosomal dominant Charcot-Marie-Tooth (CMT) disease, a multisystem recessive syndrome with prominent ataxia, and autosomal recessive Usher syndrome. Here, we present a patient who is compound heterozygous for HARS1 variants and who has a complex recessive phenotype that includes a neuropathy with demyelinating features and active denervation. Our computational and functional analyses support the pathogenicity of these alleles, suggesting that our findings expand the allelic and clinical heterogeneity of HARS1-related disease. METHODS:The individual found to have pathogenic compound heterozygous HARS1 variants was evaluated in a neuromuscular clinic and was further investigated in research studies. Functional consequences of the HARS1 variants were tested in yeast complementation assays; the phase of these alleles was confirmed via long-range PCR and long-read sequencing on DNA isolated from the proband, the mother, and the father. RESULTS:A 25-year-old male with CMT1 and mild intellectual disability had a maternally inherited variant (p.Q410*) and a de novo variant in the HARS1 gene (p.R375C) identified via trio exome sequencing. Studies in yeast revealed ablated function for p.Q410* and reduced function for p.R375C. Of 2480 informative sequencing reads generated from the proband: (a) 1765 (71%) included only p.R375C or only p.Q410*; (b) 237 (10%) included both alleles; and (c) 478 (19%) included neither allele. INTERPRETATION:Studies in yeast revealed loss-of-function characteristics for both p.Q410* and p.R375C HARS1, consistent with these variants being pathogenic. Allele-specific sequencing analyses are consistent with the proband having a compound heterozygous genotype and with p.R375C being a de novo variant that arose on the chromosome 5 transmitted by the father. There is therefore moderate evidence that the two identified HARS1 variants are responsible for the recessive phenotype. This case report expands the allelic and phenotypic heterogeneity of biallelic HARS1 pathogenic variants.
BACKGROUND AND AIMS:Chronic idiopathic axonal polyneuropathy (CIAP) accounts for approximately 20%-30% of adult-onset axonal polyneuropathies. Pathogenic RFC1 repeat expansions have emerged as a frequent cause of idiopathic sensory neuropathy, but their recognition in routine clinical practice may be challenging, particularly in the presence of potentially confounding comorbidities. We aimed to determine the prevalence of pathogenic RFC1 repeat expansions in a well-defined CIAP cohort, characterize the associated clinical and electrophysiological phenotype, and evaluate whether coexisting well-controlled diabetes mellitus (DM) or monoclonal gammopathy of undetermined significance (MGUS) may hinder recognition of RFC1-related neuropathy. METHODS:We performed a retrospective observational study of adult patients with CIAP followed at a tertiary neuromuscular unit. All patients underwent RFC1 genetic testing. Clinical and electrophysiological features were compared between RFC1+ and RFC1- patients in the full cohort and after exclusion of patients with DM or MGUS. RESULTS:Ninety patients met CIAP criteria and were analyzed. Twenty-four (27%) carried biallelic pathogenic AAGGG repeat expansions in RFC1, of whom 6 (25%) had coexisting DM or MGUS. Compared with RFC1- patients, RFC1+ individuals more frequently exhibited dysautonomic symptoms, unsteadiness, history of falls, need for walking support, chronic cough, impaired vibration sense in the upper limbs and up to the knees in the lower limbs, brisk upper-limb reflexes, mild cerebellar signs, an abnormal head-impulse test, and a positive Romberg's test. Most of these differences persisted after exclusion of DM or MGUS. Electrophysiological studies in RFC1+ patients showed widespread sensory nerve involvement, including the upper limbs, with relative motor sparing, whereas RFC1- patients exhibited a more typical length-dependent pattern. INTERPRETATION:Biallelic AAGGG repeat expansions in RFC1 were identified in 27% of patients with CIAP. Specific clinical and electrophysiological features may help distinguish RFC1-related disease from other forms of CIAP and identify candidates for genetic testing, even in the presence of potentially confounding comorbidities such as well-controlled DM or MGUS.
BACKGROUND AND AIMS:Nonsystemic vasculitic neuropathy classically presents as a painful asymmetric axonal neuropathy, multiple mononeuropathies or radiculoplexus neuropathy. Demyelinating electrophysiologic features are rare and may lead to misdiagnosis. We describe a patient with biopsy-proven vasculitic neuropathy presenting as a severe symmetric demyelinating polyradiculoneuropathy. METHODS:Clinical, electrophysiologic, imaging, laboratory, and histopathologic findings are presented. RESULTS:A 57-year-old man developed acute ascending weakness, sensory loss, facial weakness, and areflexia following a febrile illness, with initial improvement before developing recurrent neurological decline 6 weeks after initial symptom onset despite treatment with intravenous immunoglobulin and plasma exchange. Cerebrospinal fluid protein was elevated. Nerve conduction studies demonstrated prolonged distal motor latencies, slowed conduction velocities, conduction block, and prolonged blink reflex latencies, fulfilling 2021 European Academy of Neurology/Peripheral Nerve Society electrodiagnostic criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). MRI demonstrated mild but diffuse lumbosacral plexus enlargement and T2 hyperintensity. Sural nerve biopsy ultimately demonstrated evidence of epineurial inflammation and microvasculitis with ischemic nerve injury, accompanied by both increased rates of axonal degeneration (12%) and segmental demyelination (9%) on teased fiber analysis. Treatment with corticosteroids and rituximab resulted in complete neurological recovery. INTERPRETATION:Vasculitic neuropathy may closely mimic CIDP clinically, radiologically, and electrophysiologically. Clues to the vasculitis diagnosis were prominent neuropathic pain, dense denervation on electrophysiology, and poor response to typical CIDP treatment. Peripheral nerve biopsy remains a critical tool in the evaluation of atypical or treatment-refractory inflammatory neuropathies.
BACKGROUND AND AIMS:Subcutaneous immunoglobulin (SCIg) is an alternative maintenance therapy to intravenous immunoglobulin (IVIg) in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). The CIDP guideline considers switching from IVIg to SCIg at an equivalent dosage reasonable; however, the optimal dosing strategy is unknown. This case series examines whether a 1:1 IVIg-to-SCIg switch maintains clinical stability. METHODS:IVIg-dependent, clinically stable CIDP patients who switched from IVIg to SCIg in the Erasmus Medical Center were retrospectively evaluated. Clinical deterioration was defined as a decline in grip strength or muscle strength, or an increase in disability based on minimal clinically important difference criteria within 4 months after the switch. RESULTS:A total of 10 consecutive CIDP patients on stable IVIg regimens switched to an equivalent (1:1) SCIg dose. One patient remained clinically stable, while nine patients deteriorated. Three of these became clinically stable after increasing the SCIg dose to 1:1.3 or 1:1.5, whereas three patients did not regain stability despite a dose increase to 1:1.3. Clinical stability was maintained in the patient receiving a low dose (0.4 g/kg every 3 weeks), whereas patients receiving higher doses (≥ 1 g/kg every 3 weeks) deteriorated. Five patients switched back to IVIg, while five remained on SCIg throughout follow-up. INTERPRETATION:A 1:1 IVIg-to-SCIg switch was insufficient to maintain clinical stability in most CIDP patients, including those on higher IVIg maintenance doses. Some but not all patients regained stability after increasing the SCIg dose. Optimal dose adjustment strategies, including whether temporary higher dosing is required, remain to be determined in future studies.
Charcot-Marie-Tooth disease (CMT) encompasses a heterogeneous group of inherited peripheral neuropathies. Despite being the most common genetic neurological condition, individual CMT subtypes are rare, presenting unique challenges for therapeutic development. The Together Patients Industry Clinicians versus CMT (ToPIC: CMT) Advocacy Group was formed with a diverse group of patient advocacy groups, clinician-scientists who treat patients with CMT, and pharmaceutical industry representatives to develop a common guidance on development of new treatments for CMT with clear expectations for meaningful patient outcomes and objective assessments of improvement. The ToPIC: CMT Group developed recommendations for clinical development of drugs and biological products for treating CMT, addressing trial design considerations for this rare progressive disease. Key challenges in CMT include small patient populations, variable disease progression, and the need for sensitive outcome measures. Recommendations emphasize flexible trial designs including adaptive designs, external controls, and single-participant designs when scientifically justified. Where possible, broad inclusion criteria based on clinical phenotype rather than genetic subtype alone are recommended. Disease-specific, validated outcome measures should assess function across ages and disease stages. Biomarkers reflecting peripheral nervous system health may serve as surrogate endpoints to support accelerated approval pathways. Patient and care partner perspectives are essential throughout development, particularly regarding treatment goals, risk tolerance, and meaningful endpoints. Successful therapeutic development for CMT and related neuropathies requires innovative approaches that balance rigorous scientific standards with the realities of rare disease research. Regulatory flexibility, informed by patient input and natural history data, can facilitate efficient development while maintaining assurance of safety and effectiveness.
BACKGROUND AND AIM:Neuropathic pain (NeuP) is widely underdiagnosed, and treatment-related adverse events often drive nonadherence. We investigated the probable NeuP prevalence, symptoms recognition, and treatment preferences among the general population in Malaysia. METHODS:We utilized a digital ID-Pain questionnaire across nine tertiary hospitals to screen for probable NeuP. We also designed a discrete choice experiment (DCE) to assess participants' ability to differentiate NeuP from nociceptive symptoms and to evaluate treatment preferences across five attributes (perceived pain reduction, time to effect, proven effectiveness, risk of common side effects, and cost) among the general population. RESULTS:The screening cohort included 13 592 adults (17.1% with diabetes). The overall prevalence of screen-positive for probable NeuP was 18.3% in the general population, increasing to 40.1% among people with diabetes. In the DCE cohort (n = 3999), 82.1% of participants demonstrated poor-to-moderate NeuP symptom recognition. Regarding treatment preferences, avoiding a high risk of common side effects was the primary driver of choice (coefficient -1.744, 95% CI -1.820, -1.669), followed by the desire for strong scientific evidence (coefficient 1.237, 95% CI 1.182, 1.291). Apart from clinical attributes, participants showed significant cost sensitivity (coefficient -5.565, 95% CI -6.909, -4.221). INTERPRETATION:Despite a high prevalence of probable NeuP, poor symptom recognition creates a significant diagnostic challenge. Given that aversion to side effects is prioritized over other attributes, clinicians need to focus on tolerable anti-neuropathic agents and employ proactive side-effect management to optimize NeuP treatment adherence.
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:Nitrous oxide (N2O) misuse is a growing health concern, with N2O-induced neurological disorders increasingly reported across Europe. Among these, N2O-induced polyneuropathy (PNP) can lead to permanent deficits, yet its neurophysiological characteristics remain inconsistently described. This retrospective case series aimed to characterize the electrophysiological pattern of N2O-induced polyneuropathy. METHODS:We reviewed the records of 12 patients with acute neurological symptoms and a history of N2O abuse, all of whom underwent electrophysiological testing at a German tertiary care hospital between July 2023 and December 2024. Data were analyzed descriptively. RESULTS:Conduction studies revealed evidence of PNP in eight out of 12 patients and the most common pattern was pure motor (5/8). No distinct clinical phenotype could be identified for patients with electrophysiologically confirmed PNP or Pure-Motor PNP. SSEPs were abnormal in all assessable patients, whereas signs of SCD on MRI were present in a smaller proportion. Only three of 10 tested patients had reduced vitamin B12 levels, while all showed elevated methylmalonic acid (MMA) levels. Mean MMA levels were higher in patients with PNP than in those without. INTERPRETATION:The reason why N2O leads to different patterns of PNP remains unclear and a distinct phenotype for N2O-induced PNP or Pure-Motor PNP was not found in this cohort. MMA represents a more reliable biomarker than serum vitamin B12 in the diagnostic workup of N2O-induced neurotoxicity. These findings highlight the need for further research into additional neurotoxic properties of N2O and individual predisposing factors underlying the different electrophysiological patterns of N2O-induced PNP.
ABSTRACT Background and Aims To determine the role of phrenic nerve conduction studies (NCS) in identifying subtypes of Guillain‐Barré syndrome (GBS) and to investigate the correlations between phrenic NCS and clinical and respiratory scores. Methods A clinical evaluation was conducted on 23 patients diagnosed with GBS, encompassing the Medical Research Council (MRC) sum scores, GBS disability scores, and Erasmus GBS Respiratory Insufficiency Scores (EGRIS). Electrodiagnostic studies (EDX) were conducted twice and bilateral phrenic NCSs once within the 6 weeks after symptom onset. The latency, peak‐to‐peak amplitude, and negative peak area of phrenic compound muscle action potential (CMAP) elicited using surface electrodes were measured, and the values indicating prolonged latency (≥ 110%–130% of upper limit of normal (ULN)) and/or prolonged negative peak duration (≥ 130% of ULN) were considered as demyelinating. Results Phrenic NCSs revealed 87.0% sensitivity and 89.5% specificity in the diagnosis of demyelinating subtype (cut‐off value of latency 8.6 ms). Most of the phrenic CMAP parameters revealed moderate correlations with clinical scores and with the results of median and ulnar EDX studies. Interpretation Besides its importance for having correlations with clinical and respiratory features, phrenic NCS may improve the diagnostic sensitivity in differentiating GBS subtypes.
The peripheral nervous system (PNS) is responsible for innervating all regions of the body outside of the central nervous system (CNS), the latter consisting of the brain, spinal cord, and optic nerves. While myelin is an essential component for the efficient functioning of both CNS and peripheral nerve cells, it is particularly important for PNS neurons since their cell bodies lie at considerable distances from their innervated targets. As such, regulation of myelin content and formation in the PNS is a carefully controlled process that involves many cellular and molecular players. The peripheral nerve is a multicellular environment containing several non-neuronal cell types such as fibroblasts, endothelial cells, pericytes, resident macrophages, and nonmyelinating and myelinating Schwann cells, all of which contribute to PNS homeostasis. This review focuses on the contributions of Schwann cells and macrophages and their molecular mediators in the formation, maintenance, degradation, and reformation of peripheral myelin during homeostasis of, and after damage to the PNS.
BACKGROUND AND AIMS:SCO2 encodes a mitochondrial copper chaperone required for cytochrome c oxidase (COX) assembly and is classically associated with severe multisystem mitochondrial disease. We characterize a motor-predominant axonal neuropathy presentation associated with biallelic SCO2 variants. METHODS:Clinical, genetic, and functional studies were performed in a 15-year-old female presenting with axonal neuropathy. Functional studies were conducted in patient-derived fibroblasts, including Western blot analysis and spectrophotometric cytochrome c oxidation assay. Structural modeling was performed using ChimeraX. RESULTS:The patient presented with a motor-predominant axonal neuropathy consistent with Charcot-Marie-Tooth (CMT) disease. Clinical genetic testing identified compound heterozygous SCO2 variants of uncertain significance: a missense variant (p.Arg120Trp) and a frameshift variant (p.Asp252ValfsTer24). Structural modeling predicted disruption of protein stability for both variants. Functional studies in patient-derived fibroblasts demonstrated complete absence of SCO2 protein and reduced mitochondrial complex IV activity, supporting a loss-of-function mechanism. INTERPRETATION:These findings demonstrate that SCO2-related disease can present as an isolated axonal neuropathy, a phenotype that remains rarely reported. Our study also highlights the value of integrating in silico prediction tools with functional assays to establish pathogenicity in rare sporadic cases of inherited neuropathy.
BACKGROUND AND AIMS:Hereditary neuropathies are a group of genetically and phenotypically heterogeneous neuropathies. These are classified into: hereditary sensory motor neuropathy (HSMN) aka Charcot-Marie-Tooth disease (CMT), distal motor neuropathy (dMN), hereditary sensory autonomic neuropathy (HSAN), episodic neuropathies and polyneuropathy as part of a complex clinical presentation. The aim of this study was to determine final diagnoses in patients referred from the tertiary center in Serbia under suspicion of hereditary neuropathy. METHODS AND MATERIALS:This research included 340 patients directed for genetic testing from the Neurology Clinic, University Clinical Center of Serbia during the period from 2009 to 2023, who underwent complete genetic analyses available. RESULTS:The most prominent demyelinating neuropathy was group consisted of patients with CMT1A (93 (27.3%)), followed by CMT1B (10 (2.9%)). In the group of patients with axonal form of the disease, the most prevalent was the one with pathogenic variant in HINT1 (18 (5.3%)). Nineteen (5.6%) patients have had variants in GJB1 gene. DMN group was composed of seven (2%) patients. HSAN was final diagnosis in 2 (0.6%) patients. Group of 16 (4.7%) patients have had neuropathy as part of a complex clinical presentation. In 70 (20.6%) patients no significant genetic variant was found, even though clinical presentation was highly suggestive of hereditary neuropathy. INTERPRETATION:In line with other populations, CMT1A was the most common cause of hereditary neuropathy in Serbia. The axonal cohort predominantly included patients with variants in the HINT1 gene, which represents a population-specific characteristic. These findings highlight the importance of targeted genetic analysis in diagnosing hereditary neuropathies in certain populations.
BACKGROUND:Late-onset Tay-Sachs disease (LOTS) is a rare lysosomal disorder that contrasts with the classical infantile form by presenting with milder and heterogeneous neurological manifestations, including lower motor neuron phenotypes. While muscle MRI fatty infiltration patterns have been described in selected inherited motor neuron disorders, the corresponding imaging features in LOTS remain poorly defined. CASE:We report two female patients presenting in the second decade of life with slowly progressive, lower limb-predominant flaccid weakness associated with tremor. Hip flexion and arm extension were disproportionately affected. Electromyography demonstrated a neurogenic pattern. Whole-body muscle MRI (wbMRI) revealed selective fatty infiltration on T1-weighted sequences with normal STIR imaging. At the pelvic and thigh levels, this pattern showed marked overlap with the characteristic fatty infiltration described in SMA with lower extremity predominance (SMALED), including relative sparing of the adductor longus and semimembranosus. In contrast, consistent additional involvement of the iliopsoas and triceps brachii muscles was observed. Whole-exome sequencing identified compound heterozygous pathogenic variants in the HEXA gene in each patient, confirmed to be in trans, and enzymatic testing demonstrated reduced β-hexosaminidase A activity. CONCLUSION:LOTS may reproduce key elements of the SMALED muscle MRI fatty infiltration pattern, particularly at the pelvic and thigh levels, while maintaining a distinct clinical presentation. Recognition of this partial radiological overlap, together with its discriminative features, is important to avoid diagnostic misclassification and to guide appropriate genetic testing.
BACKGROUND AND AIMS:In ADHERE, subcutaneous efgartigimod PH20 (1000 mg once weekly) was effective and well tolerated in participants with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). ADHERE+ is an open-label extension of ADHERE assessing long-term safety and efficacy. METHODS:Eligible participants from ADHERE run-in period (prior CIDP treatments discontinued), stage A (open-label efgartigimod), and stage B (stage A responders randomized to placebo or efgartigimod) could roll over to ADHERE+ and receive efgartigimod. The primary outcome was to assess long-term safety and tolerability. Efficacy outcomes evaluated adjusted Inflammatory Neuropathy Cause and Treatment (aINCAT) score, Inflammatory Rasch-built Overall Disability Scale (I-RODS) score, and mean grip strength (GS) from ADHERE run-in baseline through ADHERE+ week 36. RESULTS:At interim data cut-off (February 16, 2024), 228/229 eligible participants advanced to ADHERE+. Prolonged efgartigimod exposure did not increase the incidence (n = 171/228 [75.0%]) or severity of TEAEs (grade ≥ 3 TEAEs, n = 41/228 [18.0%]); regardless of immunoglobulin G level, there was a low incidence of infections. Stage A responders reported long-term clinically meaningful improvements in mean aINCAT (decreased by 1.2 points), I-RODS centile metric (increase of 8.8 points), and GS scores (increase of 17.5 kPa) from run-in baseline to ADHERE+ week 36, irrespective of stage B treatment. INTERPRETATION:Interim results from ADHERE+ indicate long-term efgartigimod PH20 treatment in participants with CIDP was well tolerated (maximum exposure = 187.3 weeks; mean (SD) treatment duration = 58.0 [33.8] weeks). Clinically meaningful improvements in disability and strength were observed across assessments, regardless of stage B treatment or prior treatment status, with greater improvements seen over time.
BACKGROUND AND AIMS:Amyloid-like immunoglobulin deposition neuropathy is a rare cause of polyneuropathy, characterised by unique clinical and histological features in combination with proteomics that distinguish it from both amyloidosis and anti-MAG neuropathy. While light microscopic findings resemble amyloidosis with 'amyloid-like deposits', they are negative for Congo-red stain and have granular ultrastructure appearances under electron microscopy, unlike the characteristic fibrillary appearance of amyloid. METHODS:We present five cases of polyneuropathy associated with IgM paraprotein, without anti-MAG antibodies, with a distinctive phenotype: predominant neuropathic pain, skin changes or neuropathic ulcers, and a progressive distal sensory neuropathy. RESULTS:All patients demonstrated an axonal sensorimotor neuropathy and histopathology of 'amyloid-like' (Congo-red negative) material with predominant granular deposition on electron microscopy consistent with a combination of heavy and light chain deposition. Skin involvement demonstrated similar histological features, but there was no evidence of renal or cardiac involvement. Most patients had treatment for their underlying haematological disorder and subsequently had no further progression in their neuropathy. DISCUSSION:Amyloid-like immunoglobulin deposition neuropathy is a slowly progressive painful axonal polyneuropathy associated with paraproteinaemia. Diagnosis is made with biopsy and electron microscopy. Treatment targets the source of the paraproteins and controls disease progression, leading to favourable survival compared to AL amyloidosis.
INTRODUCTION:Hereditary motor neuropathies (HMN) represent a heterogeneous group of disorders with wide clinical and genetic variability. Despite advances in molecular diagnostics, approximately 50% of cases remain genetically unresolved, particularly those where distinguishing length-dependent motor neuropathy from motor neuron disorder with disproportionate segmental involvement is a challenge. Variants in the VRK1 gene, originally described in association with pontocerebellar hypoplasia, are now known to produce a broad clinical spectrum, including amyotrophic lateral sclerosis, dHMN, and less frequently, spastic paraplegia. OBJECTIVES:This study's aim was to characterize the clinical presentation, electrophysiological findings, and muscle MRI patterns associated with VRK1-related motor neuron disease in a cohort of nine patients from five unrelated families. METHODS:Five unrelated families with inherited motor neuropathy were investigated using next-generation sequencing techniques, including targeted gene panels or whole-exome sequencing, with subsequent confirmation by Sanger sequencing. A total of nine affected individuals underwent detailed clinical evaluation, nerve conduction studies (NCS), electromyography (EMG), and whole-body muscle MRI (wbMRI). RESULTS:Nine affected individuals carrying biallelic VRK1 variants were evaluated. In most cases (66%), symptom onset occurred during the first decade of life. All patients presented with gradually progressive distal muscle weakness. Mean Medical Research Council (MRC) scores were 2.8 for ankle dorsiflexion and 1.9 for plantar flexion. Sensory nerve conduction studies were normal in all individuals evaluated (8/9), although mild sensory complaints were reported in four patients. Muscle cramps were observed in two-thirds of the cohort, while fasciculations were uncommon (11%). EMG findings consistently demonstrated a neurogenic pattern with predominant distal involvement, and evidence of both acute and chronic denervation was present in four patients. Whole-body muscle MRI, available for all patients, revealed a consistent pattern of fatty infiltration predominantly affecting posterior muscle compartments, with minimal STIR signal changes. Brain and spinal imaging, performed in all individuals, showed no abnormalities. INTERPRETATIONS:Biallelic mutations in VRK1 are associated with a recognizable form of motor neuron disease characterized by features of dHMN combined with upper motor neuron involvement, along with a distinctive posterior-predominant pattern on muscle MRI. Identifying this phenotype, a known presentation of VRK1-related disorders, highlights the importance of targeted genetic testing in unresolved cases of hereditary motor neuropathy.
BACKGROUND:Guillain-Barré syndrome (GBS) typically presents with symmetric weakness, but marked asymmetry can mimic stroke and delay diagnosis, especially when unilateral onset progresses to bilateral asymmetric involvement. We aimed to characterize this phenotype and identify features that facilitate early recognition. METHODS:We retrospectively analyzed 611 consecutive patients with GBS over 10 years. Asymmetry was defined as a difference of ≥ 2 points on the Medical Research Council (MRC) scale between contralateral limbs. Clinical features, electrophysiological subtypes, and diagnostic timelines were compared between asymmetric and symmetric cases. RESULTS:Thirty-two patients (5.2%) exhibited asymmetric onset. Compared with symmetric cases, asymmetric GBS had fewer antecedent respiratory infections (12.5% vs. 32.1%; p = 0.02) and no facial weakness (0% vs. 13.6%; p = 0.049). Twenty-two patients progressed to symmetric weakness; among 10 patients with persistent asymmetry, 6 unilateral onset cases evolved into bilateral asymmetric involvement, all initially misdiagnosed as stroke. Of these 10, 6 (60%) lacked sensory involvement, 7 (70%) had axonal GBS, and 4/7 (57%) were anti-ganglioside antibody positive. Asymmetric GBS was associated with longer diagnostic delays (median 3 vs. 2 days; p < 0.001), longer admission-to-immunotherapy intervals (median 4 vs. 3 days; p < 0.001), and greater disability at nadir (median 4 vs. 3; p = 0.01). CONCLUSIONS:Within asymmetric GBS, unilateral-onset cases that evolve into bilateral asymmetric involvement are the subgroup most likely to mimic stroke. The absence of facial weakness, few antecedent respiratory infections, axonal electrophysiologic subtype, and positive anti-ganglioside antibodies may aid recognition and timely immunotherapy.
