Background and purpose
Generalized myasthenia gravis (gMG) continues to present significant challenges for clinical management due to an unpredictable disease course, frequent disease fluctuations, ...and varying response to therapy. The recent availability of new pharmacologic therapies presents a valuable opportunity to reevaluate how this disease is classified, assessed, and managed and identify new ways to improve the clinical care of patients with gMG.
Methods
Narrative review was made of publications identified via searches of PubMed and selected congresses (January 2000–September 2022).
Results
New consensus definitions are required to ensure consistency, to better characterize patients, and to identify patients who will benefit from specific drugs and earlier use of these agents. There is a need for more frequent, standardized patient assessment to identify the cause of motor function deficits, provide a clearer picture of the disease burden and its impact on daily living and quality of life (QoL), and better support treatment decision‐making. Novel approaches that target different components of the immune system will play a role in more precise treatment of patients with gMG, alongside the development of new algorithms to guide individualized patient management.
Conclusions
gMG has a physical, mental, and social impact, resulting in a considerable burden of disease and substantially decreased QoL, despite standard treatments. The availability of novel, targeted treatments that influence key pathological mediators of gMG, together with new biomarkers, offers the potential to optimize patient management and ultimately enables a greater number of patients to achieve minimal manifestation status and a reduced burden of disease.
•The triple stimulation technique is useful to reveal proximal conduction blocks in Guillain–Barré syndrome (GBS).•Triple stimulation is useful for diagnosis of GBS in the early stages of the ...disease.•The combination of nerve conduction studies and triple simulation improves greatly diagnosis.
Current diagnostic electrophysiological criteria can miss the early stages of Guillain–Barré syndrome (GBS). We evaluated the diagnostic efficiency of the triple stimulation technique (TST) in highlighting proximal conduction blocks (CBs) in patients who do not meet the electrophysiological criteria for GBS.
All patients with a diagnosis of clinical GBS referred to our center between September 2014 and January 2016 were included in the study. For patients who did not fulfill the electrophysiological criteria of GBS, we performed the TST examination.
Among the 44 included patients, 86% fulfilled the electrophysiological criteria of GBS during the initial nerve conduction study (NCS). The six remaining patients had proximal CBs revealed by TST examination. Therefore, a combination of a conventional NCS and the TST allowed 100% of the patients to be electrophysiologically diagnosed.
TST is useful for the diagnosis of GBS in association with NCS, particularly in the early stages of the disease.
TST is a useful tool for GBS diagnosis at the early stages of the disease.
Background
Fat infiltration in individual muscles of sporadic inclusion body myositis (sIBM) patients has rarely been assessed.
Methods
Sixteen sIBM patients were assessed using MRI of the thighs and ...lower legs (LL). The severity of fat infiltration, proximal‐to‐distal and side asymmetries, and the correlations with clinical and functional parameters were investigated.
Results
All the patients had fat‐infiltrated muscles, and thighs were more severely affected than LL. A proximal‐to‐distal gradient of fat infiltration was mainly observed for adductors, quadriceps, sartorius, and medial gastrocnemius muscles. A strong negative correlation was observed between the whole muscle fat fraction in the thighs and LL and the Inclusion Body Myositis Functional Rating Scale and Medical Research Council scores for the lower limbs.
Conclusions
Fat infiltration in individual muscles of sIBM patients is heterogeneous in terms of proximal‐to‐distal gradient and severity was correlated with clinical scores. These results should be considered for both natural history investigation and clinical trials.
Abstract
The DNA methylation epigenetic signature is a key determinant during development. Rules governing its establishment and maintenance remain elusive especially at repetitive sequences, which ...account for the majority of methylated CGs. DNA methylation is altered in a number of diseases including those linked to mutations in factors that modify chromatin. Among them, SMCHD1 (Structural Maintenance of Chromosomes Hinge Domain Containing 1) has been of major interest following identification of germline mutations in Facio-Scapulo-Humeral Dystrophy (FSHD) and in an unrelated developmental disorder, Bosma Arhinia Microphthalmia Syndrome (BAMS). By investigating why germline SMCHD1 mutations lead to these two different diseases, we uncovered a role for this factor in de novo methylation at the pluripotent stage. SMCHD1 is required for the dynamic methylation of the D4Z4 macrosatellite upon reprogramming but seems dispensable for methylation maintenance. We find that FSHD and BAMS patient's cells carrying SMCHD1 mutations are both permissive for DUX4 expression, a transcription factor whose regulation has been proposed as the main trigger for FSHD. These findings open new questions as to what is the true aetiology for FSHD, the epigenetic events associated with the disease thus calling the current model into question and opening new perspectives for understanding repetitive DNA sequences regulation.
Facioscapulohumeral dystrophy (FSHD), one of the most common hereditary neuromuscular disorders, is associated with a complex combination of genetic variations at the subtelomeric 4q35 locus. As ...molecular diagnosis relying on Southern blot (SB) might be challenging in some cases, molecular combing (MC) was recently developed as an additional technique for FSHD diagnosis and exploration of the genomic organization of the 4q35 and 10q26 regions. In complement to the usual SB, we applied MC in a large cohort of 586 individuals with clinical FSHD. In 332 subjects, the two 4q alleles were normal in size, allowing exclusion of FSHD1 while we confirmed FSHD1 in 230 patients. In 14 patients from 10 families, we identified a recurrent complex heterozygous rearrangement at 4q35 consisting of a duplication of the D4Z4 array and a 4qA haplotype, irresolvable by the SB technique. In five families, we further identified variations in the SMCHD1 gene. Impact of the different mutations was tested using a minigene assay and we analyzed DNA methylation after sodium bisulfite modification and NGS sequencing. We discuss the involvement of this rearrangement in FSHD since all mutations in SMCHD1 are not associated with D4Z4 hypomethylation and do not always segregate with the disease.
By using molecular combing and a ‘morse’ bar code corresponding to the 4q35 subtelomeric locus we identified a novel and recurrent rearrangement consisting in the duplication of the D4Z4 array and flanking qA allele in individuals affected with Facio‐Scapulo Humeral Dystrophy. These results reveal the variability of molecular data among subjects and within families and highlight the complexity one might face in analyzing FSHD families for molecular diagnosis but also genetic counseling.
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.
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
Conduction blocks (CB) are the diagnostic hallmark of multifocal motor neuropathy (MMN). Conventional nerve conduction studies cannot detect CB above Erb's point. Our purpose was to ...compare the performance of the motor evoked potential with triple stimulation technique (MEP‐TST) and MRI in the detection of abnormalities of the brachial plexus.
Methods
Examinations were performed on 26 patients with MMN (11 definite, 6 probable, 9 possible), of whom 7 had no CB.
Results
MEP‐TST detected proximal CB in 19/26 patients. Plexus MRI showed T2 hyperintensity in 18/26 patients, with nerve enlargement in 14/18. A combination of both techniques increased the detection rate of brachial plexus abnormalities to 96% of patients (25/26).
Conclusions
MEP‐TST and MRI have high sensitivities for detecting brachial plexus abnormalities. A combination of the two techniques increases the detection rate of supportive criteria for the diagnosis of MMN.
X-Linked Charcot-Marie-Tooth disease type 1 (CMTX1) is characterized by gender differences in clinical severity. Women are usually clinically affected later and less severely than men. However, their ...clinical presentation appears to be heterogenous. Our aim was to extend the phenotypic description in a large series of women with CMTX1.
We retrospectively evaluated 263 patients with CMTX1 from 11 French reference centers. Demographic, clinical, and nerve conduction data were collected. The severity was assessed by CMT Examination Score (CMTES) and Overall Neuropathy Limitations Scale (ONLS) scores. We looked for asymmetrical strength, heterogeneous motor nerve conduction velocity (MNCV), and motor conduction blocks (CB).
The study included 137 women and 126 men from 151 families. Women had significantly more asymmetric motor deficits and MNCV than men. Women with an age of onset after 19 years were milder. Two groups of women were identified after 48 years of age. The first group represented 55%, with women progressing as severely as men, however, with a later onset age. The second group had mild or no symptoms. Some 39% of women had motor CB. Four women received intravenous immunoglobulin before being diagnosed with CMTX1.
We identified two subgroups of women with CMTX1 who were over 48 years of age. Additionally, we have demonstrated that women with CMTX can exhibit an atypical clinical presentation, which may result in misdiagnosis. Therefore, in women presenting with chronic neuropathy, the presence of clinical asymmetry, heterogeneous MNCV, and/or motor CB should raise suspicion for X-linked CMT, particularly CMTX1, and be included in the differential diagnosis.
Introduction/Aims
There is debate about whether and to what extent either respiratory or cardiac dysfunction occurs in patients with dysferlinopathy. This study aimed to establish definitively ...whether dysfunction in either system is part of the dysferlinopathy phenotype.
Methods
As part of the Jain Foundation's International Clinical Outcome Study (COS) for dysferlinopathy, objective measures of respiratory and cardiac function were collected twice, with a 3‐y interval between tests, in 188 genetically confirmed patients aged 11–86 y (53% female). Measures included forced vital capacity (FVC), electrocardiogram (ECG), and echocardiogram (echo).
Results
Mean FVC was 90% predicted at baseline, decreasing to 88% at year 3. FVC was less than 80% predicted in 44 patients (24%) at baseline and 48 patients (30%) by year 3, including ambulant participants. ECGs showed P‐wave abnormalities indicative of delayed trans‐atrial conduction in 58% of patients at baseline, representing a risk for developing atrial flutter or fibrillation. The prevalence of impaired left ventricular function or hypertrophy was comparable to that in the general population.
Discussion
These results demonstrate clinically significant respiratory impairment and abnormal atrial conduction in some patients with dysferlinopathy. Therefore, we recommend that annual or biannual follow‐up should include FVC measurement, enquiry about arrhythmia symptoms and peripheral pulse palpation to assess cardiac rhythm. However, periodic specialist cardiac review is probably not warranted unless prompted by symptoms or abnormal pulse findings.
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