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Hereditary neuropathy with liability to pressure palsies (HNPP) is characterized by recurrent sensory and motor neuropathy in individual nerves starting in adolescence or young adulthood, focal conduction abnormalities at entrapment sites on nerve conduction studies, and sausage-like swellings (tomacula) of the myelin sheaths by nerve biopsy. It is characterized genetically by the deletion of the chromosome 17p11.2–p12 region including the peripheral myelin protein-22 gene in the overwhelming majority of cases. HNPP may be frequently underdiagnosed or misdiagnosed owing to the heterogeneity of clinical and electrophysiological appearance. The main objective of this review is to describe clinical manifestations, paraclinical features such as electrodiagnostic, pathological, radiological and genetics findings, and possible treatments.

This monocentric prospective study of patient suffering from Amyotrophic lateral sclerosis (ALS) aims to evaluate the prognosis and diagnostic potential of both Neurofilament-Light (Nf-L) and neuroinflammatory biomarkers in serum and CSF. Candidate markers levels were measured using multiplex method in serum of 60 ALS patients, 94 healthy controls of 43 patients suffering from Inflammatory Peripheral Neuropathies (IPN). A comparative CSF analysis was performed for 20 ALS and 17 IPN patients. Among the altered biomarkers, CSF Nf-L level remains the best marker of ALS severity, while serum levels correlate strongly with disease progression. The combination of Nf-L and ICAM-1 concentrations in the CSF and IFN-γ concentration in the serum differentiate ALS patients from IPN patients with improved sensibility and specificity relative to individual biomarkers. A cutoff value of 0.49 for the fitted values of these 3 biomarkers discriminate ALS from IPN patients with a specificity of 100% (78.20–100%) and a sensibility of 85.71% (57.19–98.22%) with an AUC of 0.99 ± 0.01. The measure of Nf-L and neuroinflammatory biomarkers in CSF and serum can be useful biomarkers panel in the differential diagnosis of ALS.

Distinguishing between hereditary and inflammatory neuropathy is usually straightforward on clinical grounds with the help of a family history. There are nevertheless cases where the distinction is less clear. The advent of molecular genetics has in the past several years aided confirmatory diagnosis for an increasing proportion of patients with genetic neuropathy. Various reports have described associations of Charcot-Marie-Tooth disease with a suspected or confirmed inflammatory neuropathy occasionally responding to immunotherapy. Possible predisposition to an inflammatory component was suggested in a subset of patients. Such reports have, however, been relatively few in number, suggesting the rarity of such associations and of such a predisposition if it exists. There have been a number of publications detailing clinical presentations suggestive of inflammatory neuropathy in patients with a known or later proven genetic aetiology, and subsequently felt to be part of the phenotype rather than representing an association. A number of genetically mediated multisystemic diseases with neuropathy have otherwise been reported as mimicking chronic inflammatory demyelinating polyneuropathy (CIDP). The most common example is that of familial amyloid polyneuropathy, of particular concern for the clinician when misdiagnosed as CIDP, in view of the therapeutic implications. We review the literature on reported associations, mimics and misdiagnoses of hereditary and inflammatory neuropathy and attempt to determine a practical approach to the problem in clinical practice using clinical features, electrophysiology, histopathology and targeted early genetic testing. The issue of attempting immunomodulatory therapy is discussed in view of the published literature.

Introduction IgG4 antibodies against neurofascin (Nfasc155 and Nfasc140/186), contactin (CNTN1) and contactin-associated protein (Caspr1) are described in specific subtypes of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Our objective was to assess, in a real-life practice, the incidence, the clinical features and the response to treatment of these forms of CIDP. Methods 1500 sera of patients suspected of having CIDP from France, Belgium and Switzerland were prospectively tested using a flow cytometry technique. The characteristics of patients with antibodies against the node of Ranvier were compared to 100 seronegative CIDP from our department. Results IgG4 antibodies against Nfasc155, CNTN1, and Caspr1 were, respectively, detected in 15 (prevalence 1%), 10 (0.7%) and 2 (0.2%) sera. Antibodies specific of the Nfasc140/186 were not detected. All subjects with antibodies against the node of Ranvier fulfilled diagnostic criteria for CIDP. CIDP with anti-Nfasc155 were younger, had more sensory ataxia and postural tremor than seronegative CIDP. CIDP with anti-CNTN1 had more frequent subacute onset and facial paralysis, commoner renal involvement with membranous glomerulonephritis and greater disability, than seronegative CIDP. CIDP with anti-Caspr1 had more frequent respiratory failure and cranial nerve involvement but not more neuropathic pain than seronegative CIDP. Intravenous immunoglobulins were ineffective in most seropositive patients. Rituximab produced dramatic improvement in disability and decreased antibodies titres in 13 seropositive patients (8 with anti-Nfasc155 and 5 with anti-CNTN1 antibodies). Conclusions Although rare, anti-paranodal antibodies are clinically valuable, because they are associated with specific phenotypes and therapeutic response.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by significant heterogeneity among patients. 23Na MRI maps abnormal sodium homeostasis that reflects metabolic alterations and energetic failure contributing to the neurodegenerative process. In this study, we investigated disease severity at the individual level in ALS patients using brain 23Na MRI. 1H and 23Na brain MRI were collected prospectively from 28 ALS patients. Individual map of abnormal total sodium concentration (TSC) was computed using voxel-based statistical mapping for each patient compared to a local database of 62 healthy controls. Clinical data included the revised ALS functional rating scale (ALSFRS-R), ALSFRS-R slope, ALSFRS-R at 6-month and survival time. Individual maps quantifying voxels with TSC increase evidenced a high heterogeneity between patients consistent with clinical presentation. The main areas involved were the corticospinal tracts. Half of patients showed abnormal TSC increase within more than 1% of whole brain voxels. Patients with TSC increase had worse clinical severity: higher ALSFRS-R slope (p = 0.02), lower ALSFRS-R at 6-month (p = 0.04), and shorter survival (p = 0.04). ALS patients with limited TSC increase had slower progression of disability or predominant lower motor neuron phenotype or shorter disease duration. This study mapping sodium homeostasis disturbances at the individual level in ALS patients through 23Na MRI evidenced heterogeneity of TSC increase among patients associated with clinical presentation and disease severity. These findings suggest that TSC increase detected at the individual level by 23Na MRI may be a useful marker of the clinical heterogeneity of ALS patients, a factor that is likely to greatly influence the results of therapeutic trials.

Background Charcot–Marie–Tooth disease type 1A (CMT1A) is a rare, orphan, hereditary neuromuscular disorder with no cure and for which only symptomatic treatment is currently available. A previous phase 2 trial has shown preliminary evidence of efficacy for PXT3003 in treating CMT1A. This phase 3, international, randomized, double-blind, placebo-controlled study further investigated the efficacy and safety of high- or low-dose PXT3003 (baclofen/naltrexone/D-sorbitol [mg]: 6/0.70/210 or 3/0.35/105) in treating subjects with mild to moderate CMT1A. Methods In this study, 323 subjects with mild-to-moderate CMT1A were randomly assigned in a 1:1:1 ratio to receive 5 mL of high- or low-dose PXT3003, or placebo, orally twice daily for up to 15 months. Efficacy was assessed using the change in Overall Neuropathy Limitations Scale total score from baseline to months 12 and 15 (primary endpoint). Secondary endpoints included the 10-m walk test and other assessments. The high-dose group was discontinued early due to unexpected crystal formation in the high-dose formulation, which resulted in an unanticipated high discontinuation rate, overall and especially in the high-dose group. The statistical analysis plan was adapted to account for the large amount of missing data before database lock, and a modified full analysis set was used in the main analyses. Two sensitivity analyses were performed to check the interpretation based on the use of the modified full analysis set. Results High-dose PXT3003 demonstrated significant improvement in the Overall Neuropathy Limitations Scale total score vs placebo (mean difference: − 0.37 points; 97.5% CI [− 0.68 to − 0.06]; p  = 0.008), and consistent treatment effects were shown in the sensitivity analyses. Both PXT3003 doses were safe and well-tolerated. Conclusion The high-dose group demonstrated a statistically significant improvement in the primary endpoint and a good safety profile. Overall, high-dose PXT3003 is a promising treatment option for patients with Charcot–Marie–Tooth disease type 1A.

Facioscapulohumeral muscular dystrophy type 1 (FSHD1) is the third most common inherited muscular dystrophy. Considering the highly variable clinical expression and the slow disease progression, sensitive outcome measures would be of interest. Using muscle MRI, we assessed muscular fatty infiltration in the lower limbs of 35 FSHD1 patients and 22 healthy volunteers by two methods: a quantitative imaging (qMRI) combined with a dedicated automated segmentation method performed on both thighs and a standard T1-weighted four-point visual scale (visual score) on thighs and legs. Each patient had a clinical evaluation including manual muscular testing, Clinical Severity Score (CSS) scale and MFM scale. The intramuscular fat fraction measured using qMRI in the thighs was significantly higher in patients (21.9 ± 20.4%) than in volunteers (3.6 ± 2.8%) (p<0.001). In patients, the intramuscular fat fraction was significantly correlated with the muscular fatty infiltration in the thighs evaluated by the mean visual score (p<0.001). However, we observed a ceiling effect of the visual score for patients with a severe fatty infiltration clearly indicating the larger accuracy of the qMRI approach. Mean intramuscular fat fraction was significantly correlated with CSS scale (p ≤ 0.01) and was inversely correlated with MMT score, MFM subscore D1 (p ≤ 0.01) further illustrating the sensitivity of the qMRI approach. Overall, a clustering analysis disclosed three different imaging patterns of muscle involvement for the thighs and the legs which could be related to different stages of the disease and put forth muscles which could be of interest for a subtle investigation of the disease progression and/or the efficiency of any therapeutic strategy. The qMRI provides a sensitive measurement of fat fraction which should also be of high interest to assess disease progression and any therapeutic strategy in FSHD1 patients.

Background and aims Hereditary transthyretin amyloidosis (ATTRv) should be considered in patients diagnosed with intravenous immunoglobulin (IVIg)-resistant chronic inflammatory demyelinating polyradiculoneuropathy (IVIg-NR CIDP). In this 1-year long, retrospective, multicentric study, an online questionnaire was sent to 1100 French healthcare professionals (HCPs) investigating: (i) how many IVIg-NR CIDP patients they followed; (ii) how many IVIg-NR CIDP patients had undergone TTR gene analysis; and (iii) how many IVIg-NR CIDP patients were eventually diagnosed with ATTRv. The questionnaire was sent every 3 months for 1 year and contained information on ATTRv clinical manifestations and diagnosis. Results One-hundred and ten (10%) HCPs responded. A total of 2131 patients with CIDP were identified, including 315 (22.1%) with IVIg-NR CIDP. TTR gene analysis was performed in 144 patients and was positive in 43 cases (29.9%). Conclusions This study demonstrates that ATTRv should be investigated systematically in patients diagnosed with IVIg-NR CIDP. HCP-directed information campaigns are useful for modifying diagnostic practices.

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common hereditary muscular disorders. Currently FSHD has no known effective treatment and detailed data on the natural history are lacking. Determination of the efficacy of a given therapeutic approach might be difficult in FSHD given the slow and highly variable disease progression. Magnetic resonance imaging (MRI) has been widely used to qualitatively and quantitatively evaluate in vivo the muscle alterations in various neuromuscular disorders. The main aim of the present study was to investigate longitudinally the time-dependent changes occurring in thigh muscles of FSHD patients using quantitative MRI and to assess the potential relationships with the clinical findings. Thirty-five FSHD1 patients (17 females) were enrolled. Clinical assessment tools including manual muscle testing using medical research council score (MRC), and motor function measure (MFM) were recorded each year for a period ranging from 1 to 2 years. For the MRI measurements, we used a new quantitative index, i.e., the mean pixel intensity (MPI) calculated from the pixel-intensity distribution in T1 weighted images. The corresponding MPI scores were calculated for each thigh, for each compartment and for both thighs totally (MPItotal). The total mean pixel intensity (MPItotal) refers to the sum of each pixel signal intensity divided by the corresponding number of pixels. An increased MPItotal indicates both a raised fat infiltration together with a reduced muscle volume thereby illustrating disease progression. Clinical scores did not change significantly over time whereas MPItotal increased significantly from an initial averaged value of 39.6 to 41.1 with a corresponding rate of 0.62/year. While clinical scores and MPItotal measured at the start of the study were significantly related, no correlation was found between the rate of MPItotal and MRC sum score changes, MFMtotal and MFM subscores. The relative rate of MPItotal change was 2.3% (0.5-4.3)/year and was significantly higher than the corresponding rates measured for MRCS 0% (0-1.7) /year and MFMtotal 0% (0-2.0) /year (p = 0.000). On the basis of these results, we suggested that muscle MRI and more particularly the MPItotal index could be used as a reliable biomarker and outcome measure of disease progression. In slowly progressive myopathies such as FSHD, the MPItotal index might reveal subclinical changes, which could not be evidenced using clinical scales over a short period of time.

Background Pompe disease is a rare, severe genetic multisystem disorder. It was one of the first genetic muscle diseases to benefit from an innovative therapy—enzyme replacement therapy (ERT)—more than 15 years ago. Despite this progress, data on patient management in community healthcare settings remain scarce, yet essential to understanding the dual economic and clinical burden of the disease. In this context, the French national healthcare claims database offers a valuable resource for comprehensive data collection. To our knowledge, this study is the first to provide a detailed, patient-level analysis of healthcare resource utilization for patients with Pompe disease. Our objective was to estimate the number of patients receiving ERT with alglucosidase alfa (Myozyme®), describe their care pathways, and assess associated medical expenses in both community settings and healthcare facilities across France. Method Cases of Pompe disease were identified using the French national healthcare claims database aims for expensive drugs. All patients with at least one hospitalization for ERT with Myozyme® in France in 2022 were included. Healthcare resource utilization in 2022 was documented, and costs were assessed from the perspective of public health insurance. Costs drivers were analyzed using a generalised linear model. A supplementary analysis using 2023 data was also conducted. Results A total of 154 patients were analyzed, including 24 with classic infantile-onset Pompe disease (IOPD) and 130 with late-onset Pompe disease (LOPD), with a mean age of 48.0 years. The annual healthcare cost per patient was €232,117 for IOPD patients and €358,768 for LOPD patients, nearly 96% of the costs were incurred inside hospitals. In addition to the unit cost of Myozyme® and related hospitalization, ventilator dependence and female sex emerged as major cost drivers. The 2023 data confirmed the robustness of the main findings, showing no substantial year-specific variations. Conclusion This study provides robust real-world data to assess both hospital and non-hospital costs associated with Pompe disease in patients treated with Myozyme®. With an average of 81.9 medical or paramedical consultations per year and 49 days of hospitalization in 2022, the clinical burden imposed by Pompe disease is substantial, yet essential for patient care.