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.
Mitochondrial DNA instability disorders are responsible for a large clinical spectrum, among which amyotrophic lateral sclerosis-like symptoms and frontotemporal dementia are extremely rare. We ...report a large family with a late-onset phenotype including motor neuron disease, cognitive decline resembling frontotemporal dementia, cerebellar ataxia and myopathy. In all patients, muscle biopsy showed ragged-red and cytochrome c oxidase-negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V. The multiple mitochondrial DNA deletions found in skeletal muscle revealed a mitochondrial DNA instability disorder. Patient fibroblasts present with respiratory chain deficiency, mitochondrial ultrastructural alterations and fragmentation of the mitochondrial network. Interestingly, expression of matrix-targeted photoactivatable GFP showed that mitochondrial fusion was not inhibited in patient fibroblasts. Using whole-exome sequencing we identified a missense mutation (c.176C>T; p.Ser59Leu) in the CHCHD10 gene that encodes a coiled-coil helix coiled-coil helix protein, whose function is unknown. We show that CHCHD10 is a mitochondrial protein located in the intermembrane space and enriched at cristae junctions. Overexpression of a CHCHD10 mutant allele in HeLa cells led to fragmentation of the mitochondrial network and ultrastructural major abnormalities including loss, disorganization and dilatation of cristae. The observation of a frontotemporal dementia-amyotrophic lateral sclerosis phenotype in a mitochondrial disease led us to analyse CHCHD10 in a cohort of 21 families with pathologically proven frontotemporal dementia-amyotrophic lateral sclerosis. We identified the same missense p.Ser59Leu mutation in one of these families. This work opens a novel field to explore the pathogenesis of the frontotemporal dementia-amyotrophic lateral sclerosis clinical spectrum by showing that mitochondrial disease may be at the origin of some of these phenotypes.
In this preliminary study, our objective was to investigate the potential of high‐resolution anatomical imaging, diffusion tensor imaging (DTI) and conventional/inhomogeneous magnetization transfer ...imaging magnetization transfer (MT)/inhomogeneous magnetization transfer (ihMT) at 3 T, analyzed with template‐extracted regions of interest, to measure the atrophy and structural changes of white (WM) and gray (GM) matter spinal cord (SC) occurring in patients with amyotrophic lateral sclerosis (ALS). Ten patients with ALS and 20 age‐matched healthy controls were recruited. SC GM and WM areas were automatically segmented using dedicated templates. Atrophy indices were evaluated from T2*‐weighted images at each vertebral level from cervical C1 to C6. DTI and ihMT metrics were quantified within the corticospinal tract (CST), posterior sensory tract (PST) and anterior GM (aGM) horns at the C2 and C5 levels. Clinical disabilities of patients with ALS were evaluated using the Revised ALS Functional Rating Scale, upper motor neuron (UMN) and Medical Research Council scorings, and correlated with MR metrics. Compared with healthy controls, GM and WM atrophy was observed in patients with ALS, especially at lower cervical levels, where a strong correlation was also observed between GM atrophy and the UMN score (R = −0.75, p = 0.05 at C6). Interestingly, a significant decrease in ihMT ratio was found in all regions of interest (p < 0.0008), fractional anisotropy (FA) and MT ratios decreased significantly in CST, especially at C5 (p < 0.005), and λ// (axial diffusivity) decreased significantly in CST (p = 0.0004) and PST (p = 0.003) at C2. Strong correlations between MRI metrics and clinical scores were also found (0.47 < |R| < 0.87, p < 0.05). Altogether, these preliminary results suggest that high‐resolution anatomical imaging and ihMT imaging, in addition to DTI, are valuable for the characterization of SC tissue impairment in ALS. In this study, in addition to an important SC WM demyelination, we also observed, for the first time in ALS, impairments of cervical aGM.
A high‐resolution, multi‐parametric magnetic resonance (MR) protocol, including diffusion tensor imaging and inhomogeneous magnetization transfer imaging, was combined with an atlas‐based analysis using dedicated spinal cord templates to evaluate region‐specific impairments of the cervical spinal cord in amyotrophic lateral sclerosis (ALS). The preliminary results suggested that this high‐resolution, multi‐parametric MR protocol is valuable for the characterization of spinal cord tissue impairment in ALS. More particularly, evidence for important white matter demyelination and impairment of cervical anterior gray matter, reported for the first time in ALS, was observed.
Emery-Dreifuss muscular dystrophy (EDMD) is a rare disorder characterized by early joint contractures, muscular dystrophy, and cardiac involvement with conduction defects and arrhythmias. So far, ...only 35% of EDMD cases are genetically elucidated and associated with
EMD or
LMNA gene mutations, suggesting the existence of additional major genes. By whole-genome scan, we identified linkage to the Xq26.3 locus containing the
FHL1 gene in three informative families belonging to our
EMD- and
LMNA-negative cohort. Analysis of the
FHL1 gene identified seven mutations, in the distal exons of
FHL1 in these families, three additional families, and one isolated case, which differently affect the three FHL1 protein isoforms: two missense mutations affecting highly conserved cysteines, one abolishing the termination codon, and four out-of-frame insertions or deletions. The predominant phenotype was characterized by myopathy with scapulo-peroneal and/or axial distribution, as well as joint contractures, and associated with a peculiar cardiac disease characterized by conduction defects, arrhythmias, and hypertrophic cardiomyopathy in all index cases of the seven families. Heterozygous female carriers were either asymptomatic or had cardiac disease and/or mild myopathy. Interestingly, four of the
FHL1-mutated male relatives had isolated cardiac disease, and an overt hypertrophic cardiomyopathy was present in two. Expression and functional studies demonstrated that the FHL1 proteins were severely reduced in all tested patients and that this was associated with a severe delay in myotube formation in the two patients for whom myoblasts were available. In conclusion,
FHL1 should be considered as a gene associated with the X-linked EDMD phenotype, as well as with hypertrophic cardiomyopathy.
Collagen type VI-related dystrophies (COL6-RD) are rare diseases with a wide phenotypic spectrum ranging from severe Ullrich's congenital muscular dystrophy Ullrich congenital muscular dystrophy to ...much milder Bethlem myopathy Both dominant and recessive forms of COL6-RD are caused by pathogenic variants in three collagen VI genes (
,
and
). The prognosis of these diseases is variable and difficult to predict during early disease stages, especially since the genotype-phenotype correlation is not always clear. For this reason, studies with long-term follow-up of patients with genetically confirmed COL6-RD are still needed. In this study, we present phenotypic and genetic data from 25 patients (22 families) diagnosed with COL6-RD and followed at a single French center, in both adult and pediatric neurology departments. We describe three novel pathogenic variants and identify
:c.1970-9G>A as the most frequent variant in our series (29%). We also observe an accelerated progression of the disease in a subgroup of patients. This large series of rare disease patients provides essential information on phenotypic variability of COL6-RD patients as well as on frequency of pathogenic
gene variants in Southern France, thus contributing to the phenotypic and genetic description of Collagen type VI-related dystrophies.
ABSTRACT
Introduction: The diagnostic sensitivity of repetitive nerve stimulation (RNS) in patients with myasthenia gravis (MG) varies as a function of the number of muscles or the choice of muscles ...studied. Methods: By exploring 12 muscles bilaterally, we evaluated the global sensitivity of RNS at rest, the sensitivity in different clinical forms, and the sensitivity of different combinations of muscles studied. Results: The global sensitivity of RNS was 82%, and specificity was 100%. The sensitivity in the MG subgroups was as follows: ocular (O) = 67%; oculobulbar (OB) = 86%; and generalized (G) = 89%. The most sensitive muscles were the anconeus in group O, orbicularis oculi (OO) or nasalis in group OB, and the trapezius in group G. Maximum sensitivity was obtained by exploring OO, trapezius, and anconeus bilaterally. Conclusions: We recommend bilateral exploration of at least 3 muscles, a facial muscle, trapezius, and anconeus. Muscle Nerve 55: 532–538, 2017
Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disorder. Diffusion magnetic resonance imagining (MRI) studies have consistently showed widespread alterations in ...both motor and non-motor brain regions. However, connectomics and graph theory based approaches have shown inconsistent results. Hub-centered lesion patterns and their impact on local and large-scale brain networks remain to be established. The objective of this work is to characterize topological properties of structural brain connectivity in ALS using an array of local, global and hub-based network metrics.
Magnetic resonance imagining data were acquired from 25 patients with ALS and 26 age-matched healthy controls. Structural network graphs were constructed from diffusion tensor MRI. Network-based statistics (NBS) and graph theory metrics were used to compare structural networks without
regions of interest.
Patients with ALS exhibited global network alterations with decreased global efficiency (Eglob) (
= 0.03) and a trend of reduced whole brain mean degree (
= 0.05) compared to controls. Six nodes showed significantly decreased mean degree in ALS: left postcentral gyrus, left interparietal and transverse parietal sulcus, left calcarine sulcus, left occipital temporal medial and lingual sulcus, right precentral gyrus and right frontal inferior sulcus (
< 0.01). Hub distribution was comparable between the two groups. There was no selective hub vulnerability or topological reorganization centered on these regions as the hub disruption index (κ) was not significant for the relevant metrics (degree, local efficiency and betweenness centrality). Using NBS, we identified an impaired motor subnetwork of 11 nodes and 10 edges centered on the precentral and the paracentral nodes (
< 0.01). Significant clinical correlations were identified between degree in the frontal area and the disease progression rate of ALS patients (
< 0.01).
Our study provides evidence that alterations of structural connectivity in ALS are primarily driven by node degree and white matter tract degeneration within an extended network around the precentral and the paracentral areas without hub-centered reorganization.
In this study we report three patients with facial‐onset sensory and motor neuronopathy (FOSMN), including the first female to be described. A fourth rather atypical case of a pyramidal syndrome with ...a fast rate of progression is also described. These cases raise the question as to whether upper motor neuron impairment is involved in FOSMN and whether there is a link between this syndrome and amyotrophic lateral sclerosis. The existence of this syndrome suggests that it may be wise to monitor all patients with isolated idiopathic trigeminal sensory neuropathy to ensure that this type of motor neuron disease is not overlooked. Muscle Nerve, 2011
Abstract Background : Myotonic muscular dystrophy type 1 (MMD1) is the most common form of adult MD, with a mean prevalence of 1 in 8000. Excessive daytime sleepiness (ie, hypersomnia) is a common ...complication of MMD1. Objective : The aim of this study was to evaluate the efficacy and tolerability of modafinil for the treatment of hypersomnia in adults with MMD1. Methods : This multicenter, prospective, randomized, double-blind, placebo-controlled study consisted of a prerandomization period (90 to 2 days before randomization) and a 4-week randomization period in which patients were assigned to receive either active treatment (modafinil 300 mg/d) or placebo. The study was conducted at 3 clinics in France between February 2000 and June 2002. Adult patients aged ≥18 years, with genetically proven MMD1, an Epworth Sleepiness Scale (ESS) score >10, and a mean latency to sleep onset ≤8 minutes measured by the Multiple Sleep Latency Test (MSLT) were eligible. The primary efficacy end point was the Maintenance of Wakefulness Test (MWT) score at 4 weeks. Secondary end points included the mean MSLT score and scores from the ESS, physician's assessment of the therapeutic effect and the patient's global self-assessment via visual analog scale, the 17-item Hamilton Depression Rating Scale, and the Short Form Health Survey (SF-36) quality-of-life assessment. Results : A total of 28 patients (15 men, 13 women; mean SD age, 40 12.7 years range, 18–69 years; 100% white; modafinil group, 13; placebo group, 15) completed the study without protocol violations. Of the 28 patients with MMD1 included in the analysis, 21 had adult-onset MMD1. At 4 weeks, the mean MWT score was 16.4 (3.3) minutes in the modafinil group and 15.8 (3.8) minutes in the placebo group ( P = NS). At the end of the randomization period, there were no significant between-group differences in any secondary outcome. A total of 8 patients (4 in each group) reported ≥1 adverse event, including digestive, neurologic, and skin symptoms. Weight loss was reported in 1 patient (2 kg). Conclusion : In this small study conducted in an adult population with MMD1 and a high prevalence of hyper-somnia, modafinil had no significant effects on daytime somnolence measured using objective MWTs.
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