Molecular Analysis of a Congenital Myasthenic Syndrome Due to a Pathogenic Variant Affecting the C-Terminus of ColQ.

Congenital Myasthenic Syndromes (CMSs) are rare inherited diseases of the neuromuscular junction characterized by muscle weakness. CMSs with acetylcholinesterase deficiency are due to pathogenic variants in COLQ, a collagen that anchors the enzyme at the synapse. The two COLQ N-terminal domains have been characterized as being biochemical and functional. They are responsible for the structure of the protein in the triple helix and the association of COLQ with acetylcholinesterase. To deepen the analysis of the distal C-terminal peptide properties and understand the CMSs associated to pathogenic variants in this domain, we have analyzed the case of a 32 year old male patient bearing a homozygote splice site variant c.1281 C > T that changes the sequence of the last 28 aa in COLQ. Using COS cell and mouse muscle cell expression, we show that the COLQ variant does not impair the formation of the collagen triple helix in these cells, nor its association with acetylcholinesterase, and that the hetero-oligomers are secreted. However, the interaction of COLQ variant with LRP4, a signaling hub at the neuromuscular junction, is decreased by 44% as demonstrated by in vitro biochemical methods. In addition, an increase in all acetylcholine receptor subunit mRNA levels is observed in muscle cells derived from the patient iPSC. All these approaches point to pathophysiological mechanisms essentially characterized by a decrease in signaling and the presence of immature acetylcholine receptors.

A TOR1AIP1 variant segregating with an early onset limb girdle myasthenia-Support for the role of LAP1 in NMJ function and disease.

Rare pathogenic variants in TOR1AIP1 (OMIM 614512), coding the inner nuclear membrane protein lamin-associated protein 1 (LAP1), have been associated with a spectrum of disorders including limb girdle muscular dystrophy with cardiac involvement and a severe multisystem phenotype. Recently, Cossins et al reported two siblings with limb girdle muscular dystrophy and impaired transmission of the neuromuscular synapse, demonstrating that defective LAP1 may lead to a congenital myasthenic syndrome. Herein, we describe the association of TOR1AIP1 deficiency with congenital myasthenic syndrome in three siblings.

Severe congenital myasthenic syndromes caused by agrin mutations affecting secretion by motoneurons.

Congenital myasthenic syndromes (CMS) are predominantly characterized by muscle weakness and fatigability and can be caused by a variety of mutations in genes required for neuromuscular junction formation and maintenance. Among them, AGRN encodes agrin, an essential synaptic protein secreted by motoneurons. We have identified severe CMS patients with uncharacterized p.R1671Q, p.R1698P and p.L1664P mutations in the LG2 domain of agrin. Overexpression in primary motoneurons cultures in vitro and in chick spinal motoneurons in vivo revealed that the mutations modified agrin trafficking, leading to its accumulation in the soma and/or in the axon. Expression of mutant agrins in cultured cells demonstrated accumulation of agrin in the endoplasmic reticulum associated with induction of unfolded protein response (UPR) and impaired secretion in the culture medium. Interestingly, evaluation of the specific activity of individual agrins on AChR cluster formation indicated that when secreted, mutant agrins retained a normal capacity to trigger the formation of AChR clusters. To confirm agrin accumulation and secretion defect, iPS cells were derived from a patient and differentiated into motoneurons. Patient iPS-derived motoneurons accumulated mutant agrin in the soma and increased XBP1 mRNA splicing, suggesting UPR activation. Moreover, co-cultures of patient iPS-derived motoneurons with myotubes confirmed the deficit in agrin secretion and revealed a reduction in motoneuron survival. Altogether, we report the first mutations in AGRN gene that specifically affect agrin secretion by motoneurons. Interestingly, the three patients carrying these mutations were initially suspected of spinal muscular atrophy (SMA). Therefore, in the presence of patients with a clinical presentation of SMA but without mutation in the SMN1 gene, it can be worth to look for mutations in AGRN.

Phenotypical variability and atypical presentations in a French cohort of Andersen-Tawil syndrome.

BACKGROUND AND PURPOSE: Andersen-Tawil syndrome (ATS) is a skeletal muscle channelopathy caused by KCNJ2 mutations, characterized by a clinical triad of periodic paralysis, cardiac arrhythmias and dysmorphism. The muscle phenotype, particularly the atypical forms with prominent permanent weakness or predominantly painful symptoms, remains incompletely characterized. METHODS: A retrospective clinical, histological, electroneuromyography (ENMG) and genetic analysis of molecularly confirmed ATS patients, diagnosed and followed up at neuromuscular reference centers in France, was conducted. RESULTS: Thirty-five patients from 27 unrelated families carrying 17 different missense KCNJ2 mutations (four novel mutations) and a heterozygous KCNJ2 duplication are reported. The typical triad was observed in 42.9% of patients. Cardiac abnormalities were observed in 65.7%: 56.5% asymptomatic and 39.1% requiring antiarrhythmic drugs. 71.4% of patients exhibited dysmorphic features. Muscle symptoms were reported in 85.7%, amongst whom 13.3% had no cardiopathy and 33.3% no dysmorphic features. Periodic paralysis was present in 80% and was significantly more frequent in men. Common triggers were exercise, immobility and carbohydrate-rich diet. Ictal serum potassium concentrations were low in 53.6%. Of the 35 patients, 45.7% had permanent weakness affecting proximal muscles, which was mild and stable or slowly progressive over several decades. Four patients presented with exercise-induced pain and myalgia attacks. Diagnostic delay was 14.4 ± 9.5 years. ENMG long-exercise test performed in 25 patients (71.4%) showed in all a decremental response up to 40%. Muscle biopsy performed in 12 patients revealed tubular aggregates in six patients (associated in two of them with vacuolar lesions), dystrophic features in one patient and non-specific myopathic features in one patient; it was normal in four patients. DISCUSSION: Recognition of atypical features (exercise-induced pain or myalgia and permanent weakness) along with any of the elements of the triad should arouse suspicion. The ENMG long-exercise test has a high diagnostic yield and should be performed. Early diagnosis is of utmost importance to improve disease prognosis.

Brody myopathy demonstrates a pseudo-increment on repetitive nerve stimulation.

INTRODUCTION: Brody myopathy (BM) is a recessive condition caused by mutations in the ATP2A1 gene and usually induces impaired muscle relaxation during and after exercise. Diagnosis relies on needle electromyography showing electrical silence, muscle biopsy with decreased sarcoplasmic reticulum calcium adenosine triphosphatase activity, and genetic analysis. Electrodiagnostic functional analyses are useful in the diagnosis of channelopathies, and thus may be impaired in BM. METHODS: We performed exercise tests and repetitive nerve stimulation (RNS; 10 supramaximal stimuli at 3 Hz) in 10 patients with BM. RESULTS: All participants showed incremental responses on RNS. Compound muscle action potential amplitude was increased and duration was decreased, especially in the ulnar nerve (+30.2 ± 7.1% and - 30.3 ± 2.8%, respectively; both P < .001). DISCUSSION: Easily accessible, this sign, referred to as the Arzel sign, could prove to be a very useful tool in BM diagnosis and in broadening its phenotype.

Motor chronic inflammatory demyelinating polyneuropathy (CIDP) in 17 patients: Clinical characteristics, electrophysiological study, and response to treatment.

Motor chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare and poorly described subtype of CIDP. We aimed to study their clinical and electrophysiological characteristics and response to treatment. From a prospective database of CIDP patients, we included patients with definite or probable CIDP with motor signs and without sensory signs/symptoms at diagnosis. Patients were considered to have pure motor CIDP (PM-CIDP) if sensory conductions were normal or to have motor predominant CIDP (MPred-CIDP) if ≥2 sensory nerve action potential amplitudes were abnormal. Among the 700 patients with CIDP, 17 (2%) were included (PM-CIDP n = 7, MPred-CIDP n = 10); 71% were male, median age at onset was 48 years (range: 13-76 years), 47% had an associated inflammatory or infectious disease or neoplasia. At the more severe disease stage, 94% of patients had upper and lower limb weakness, with distal and proximal weakness in 4 limbs for 56% of them. Three-quarters (75%) responded to intravenous immunoglobulins (IVIg) and four of five patients to corticosteroids including three of three patients with MPred-CIDP. The most frequent conduction abnormalities were conduction blocks (CB, 82%) and F-wave abnormalities (88%). During follow up, 4 of 10 MPred-CIDP patients developed mild sensory symptoms; none with PM-CIDP did so. Patients with PM-CIDP had poorer outcome (median ONLS: 4; range: 22-5) compared to MPred-CIDP (2, range: 0-4; P = .03) at last follow up. This study found a progressive clinical course in the majority of patients with motor CIDP as well as frequent associated diseases, CB, and F-wave abnormalities. Corticosteroids might be considered as a therapeutic option in resistant IVIg patients with MPred-CIDP.

The role of electrodiagnosis with long exercise test in mcardle disease.

INTRODUCTION: In this study we evaluated the role of an electrodiagnostic provocative test (long exercise test) in McArdle disease. METHODS: Twenty-five McArdle patients and 2 control groups underwent an electrodiagnostic protocol with long exercise test (LET), consisting of recording the compound muscle action potential (CMAP) before and after 5 minutes of isometric contraction. RESULTS: The LET disclosed a postexercise decrease in CMAP amplitude in 23 of 25 McArdle patients. The immediate and long-lasting decrease differentiated McArdle patients from controls. Patients with a normal LET demonstrated milder symptoms and/or residual myophosphorylase activity. DISCUSSION: The LET is a sensitive, safe, and noninvasive provocative test that may guide clinicians toward molecular analysis of the myophosphorylase gene. The abnormalities observed on LET point toward complex biochemical mechanisms determined by the absence of myophosphorylase, beyond simple glycolytic blockade (ionic pump dysfunction, sarcolemmal inexcitability). The normal LET in patients with milder symptoms indicates a relationship of the LET with clinical severity, thus identifying it as a potential outcome measure. Muscle Nerve, 2018.

Axonal Neuropathies due to Mutations in Small Heat Shock Proteins: Clinical, Genetic, and Functional Insights into Novel Mutations.

In this study, we describe the phenotypic spectrum of distal hereditary motor neuropathy caused by mutations in the small heat shock proteins HSPB1 and HSPB8 and investigate the functional consequences of newly discovered variants. Among 510 unrelated patients with distal motor neuropathy, we identified mutations in HSPB1 (28 index patients/510; 5.5%) and HSPB8 (four index patients/510; 0.8%) genes. Patients have slowly progressive distal (100%) and proximal (13%) weakness in lower limbs (100%), mild lower limbs sensory involvement (31%), foot deformities (73%), progressive distal upper limb weakness (29%), mildly raised serum creatine kinase levels (100%), and central nervous system involvement (9%). We identified 12 HSPB1 and four HSPB8 mutations, including five and three not previously reported. Transmission was either dominant (78%), recessive (3%), or de novo (19%). Three missense mutations in HSPB1 (Pro7Ser, Gly53Asp, and Gln128Arg) cause hyperphosphorylation of neurofilaments, whereas the C-terminal mutant Ser187Leu triggers protein aggregation. Two frameshift mutations (Leu58fs and Ala61fs) create a premature stop codon leading to proteasomal degradation. Two mutations in HSPB8 (Lys141Met/Asn) exhibited increased binding to Bag3. We demonstrate that HSPB1 and HSPB8 mutations are a major cause of inherited motor axonal neuropathy. Mutations lead to diverse functional outcomes further demonstrating the pleotropic character of small heat shock proteins.

Guillain-Barré Syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study.

BACKGROUND: Between October, 2013, and April, 2014, French Polynesia experienced the largest Zika virus outbreak ever described at that time. During the same period, an increase in Guillain-Barré syndrome was reported, suggesting a possible association between Zika virus and Guillain-Barré syndrome. We aimed to assess the role of Zika virus and dengue virus infection in developing Guillain-Barré syndrome. METHODS: In this case-control study, cases were patients with Guillain-Barré syndrome diagnosed at the Centre Hospitalier de Polynésie Française (Papeete, Tahiti, French Polynesia) during the outbreak period. Controls were age-matched, sex-matched, and residence-matched patients who presented at the hospital with a non-febrile illness (control group 1; n=98) and age-matched patients with acute Zika virus disease and no neurological symptoms (control group 2; n=70). Virological investigations included RT-PCR for Zika virus, and both microsphere immunofluorescent and seroneutralisation assays for Zika virus and dengue virus. Anti-glycolipid reactivity was studied in patients with Guillain-Barré syndrome using both ELISA and combinatorial microarrays. FINDINGS: 42 patients were diagnosed with Guillain-Barré syndrome during the study period. 41 (98%) patients with Guillain-Barré syndrome had anti-Zika virus IgM or IgG, and all (100%) had neutralising antibodies against Zika virus compared with 54 (56%) of 98 in control group 1 (p<0.0001). 39 (93%) patients with Guillain-Barré syndrome had Zika virus IgM and 37 (88%) had experienced a transient illness in a median of 6 days (IQR 4-10) before the onset of neurological symptoms, suggesting recent Zika virus infection. Patients with Guillain-Barré syndrome had electrophysiological findings compatible with acute motor axonal neuropathy (AMAN) type, and had rapid evolution of disease (median duration of the installation and plateau phases was 6 [IQR 4-9] and 4 days [3-10], respectively). 12 (29%) patients required respiratory assistance. No patients died. Anti-glycolipid antibody activity was found in 13 (31%) patients, and notably against GA1 in eight (19%) patients, by ELISA and 19 (46%) of 41 by glycoarray at admission. The typical AMAN-associated anti-ganglioside antibodies were rarely present. Past dengue virus history did not differ significantly between patients with Guillain-Barré syndrome and those in the two control groups (95%, 89%, and 83%, respectively). INTERPRETATION: This is the first study providing evidence for Zika virus infection causing Guillain-Barré syndrome. Because Zika virus is spreading rapidly across the Americas, at risk countries need to prepare for adequate intensive care beds capacity to manage patients with Guillain-Barré syndrome. FUNDING: Labex Integrative Biology of Emerging Infectious Diseases, EU 7th framework program PREDEMICS. and Wellcome Trust.

Physiological and ultrastructural features of human induced pluripotent and embryonic stem cell-derived skeletal myocytes in vitro.

Progress has recently been made toward the production of human skeletal muscle cells from induced pluripotent stem (iPS) cells. However, the functional and ultrastructural characterization, which is crucial for disease modeling and drug discovery, remains to be documented. We show, for the first time to our knowledge, that the electrophysiological properties of human iPS-derived skeletal myocytes are strictly similar to those of their embryonic stem (ES) cell counterparts, and both are typical of aneural mammalian skeletal muscle. In both cell types, intracellular calcium signaling that links membrane depolarization to contraction occurs in the absence of extracellular Ca(2+), a unique feature of skeletal muscle. Detailed analysis of the Ca(2+) signal revealed diverse kinetics of the rising phase, and hence various rates in the release of Ca(2+) from the sarcoplasmic reticulum. This was mirrored by ultrastructural evidence of Ca(2+) release units, which varied in location, shape, and size. Thus, the excitation-contraction coupling machinery of both iPS- and ES-derived skeletal myocytes was functional and specific, but did not reach full maturity in culture. This is in contrast with the myofibrillar network, which displayed the same organization as in adult skeletal muscle. Overall, the present study validates the human iPS-based skeletal myocyte model in comparison with the embryonic system, and provides the functional and ultrastructural basis for its application to human skeletal muscle diseases.

Peripheral neuropathy in glycogen storage disease type III: Fact or myth?

INTRODUCTION: The aim of this study was to assess whether peripheral neuropathy is a feature of glycogen storage disease type IIIa (GSD IIIa) in adult patients. METHODS: Medical records of a cohort of adult GSD IIIa patients who underwent electromyography (EMG) and nerve conduction studies (NCS) were reviewed, and the results were correlated with physical examination findings. RESULTS: Sixteen patients underwent EMG and NCS; 4 complained of exercise intolerance, 1 of foot paresthesia, and 11 of muscle weakness (3 proximal, 8 distal). None of the patients had sensory deficits on clinical examination. All motor and sensory conduction velocities and sensory amplitudes were within reference ranges. EMG showed myopathic motor unit potentials in 15 of the 16 patients. CONCLUSIONS: Based on the clinical examination and the NCS and EMG results, we did not identify any peripheral nerve involvement in our adult patients diagnosed with GSD III.

Synthesis and activities towards resistant cancer cells of sulfone and sulfoxide griseofulvin derivatives.

Griseofulvin, an antifungal drug, has been shown in recent years to have anti-proliferative activities. We report here the synthesis of new analogs of griseofulvin, substituted in 2' by a sulfonyl group or in 3' by a sulfinyl or sulfonyl group. These compounds exhibit good anti-proliferative activities against SCC114 cells, an oral squamous carcinoma cell line showing pronounced centrosome amplification, and unexpected cytotoxic activities on HCC1937 cells, a triple negative breast cancer cell line resistant to microtubule inhibitors.

Agrin mutations lead to a congenital myasthenic syndrome with distal muscle weakness and atrophy.

Congenital myasthenic syndromes are a clinically and genetically heterogeneous group of rare diseases resulting from impaired neuromuscular transmission. Their clinical hallmark is fatigable muscle weakness associated with a decremental muscle response to repetitive nerve stimulation and frequently related to postsynaptic defects. Distal myopathies form another clinically and genetically heterogeneous group of primary muscle disorders where weakness and atrophy are restricted to distal muscles, at least initially. In both congenital myasthenic syndromes and distal myopathies, a significant number of patients remain genetically undiagnosed. Here, we report five patients from three unrelated families with a strikingly homogenous clinical entity combining congenital myasthenia with distal muscle weakness and atrophy reminiscent of a distal myopathy. MRI and neurophysiological studies were compatible with mild myopathy restricted to distal limb muscles, but decrement (up to 72%) in response to 3 Hz repetitive nerve stimulation pointed towards a neuromuscular transmission defect. Post-exercise increment (up to 285%) was observed in the distal limb muscles in all cases suggesting presynaptic congenital myasthenic syndrome. Immunofluorescence and ultrastructural analyses of muscle end-plate regions showed synaptic remodelling with denervation-reinnervation events. We performed whole-exome sequencing in two kinships and Sanger sequencing in one isolated case and identified five new recessive mutations in the gene encoding agrin. This synaptic proteoglycan with critical function at the neuromuscular junction was previously found mutated in more typical forms of congenital myasthenic syndrome. In our patients, we found two missense mutations residing in the N-terminal agrin domain, which reduced acetylcholine receptors clustering activity of agrin in vitro. Our findings expand the spectrum of congenital myasthenic syndromes due to agrin mutations and show an unexpected correlation between the mutated gene and the associated phenotype. This provides a good rationale for examining patients with apparent distal myopathy for a neuromuscular transmission disorder and agrin mutations.

Increase in cases of Guillain-Barré syndrome during a Chikungunya outbreak, French Polynesia, 2014 to 2015.

During the recent chikungunya fever outbreak in French Polynesia in October 2014 to March 2015, we observed an abnormally high number of patients with neurological deficit. Clinical presentation and complementary exams were suggestive of Guillain-Barré syndrome (GBS) for nine patients. All nine had a recent dengue-like syndrome and tested positive for chikungunya virus (CHIKV) in serology or RT-PCR. GBS incidence was increased four- to nine-fold during this period, suggesting a link to CHIKV infection.

Chronic inflammatory demyelinating polyradiculoneuropathy: search for factors associated with treatment dependence or successful withdrawal.

BACKGROUND: About 40% of responders to treatment for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) remain treatment dependent and have a relapse if treatment is interrupted. OBJECTIVE: To look for factors associated with treatment dependence or successful withdrawal in CIDP patients. METHODS: We retrospectively studied 70 responder CIDP patients comprising 34 patients who remained treatment dependent (treatment-dependent group) and 36 patients whose treatment could be discontinued (treatment withdrawal group). Clinical, biological, electrophysiological and therapeutic features were compared between these groups. RESULTS: A multifocal deficit was more frequent in the treatment-dependent group (35%) than in the treatment withdrawal group (8%) (p<0.01). The most frequent effective treatment was intravenous immunoglobulin (IVIG) for the treatment-dependent group (79%). In this group, more patients were resistant to corticosteroids in first-line therapy (93%) than in the treatment withdrawal group (40%) (p=0.002). The delay to effective treatment was significantly shorter for the treatment withdrawal group than for the treatment-dependent group (mean 11.1 vs 31.2 months; p<0.01). The rate of successful withdrawal was lower with IVIG (29%) than with corticosteroids (83%) (p<0.001). CONCLUSIONS: When compared with the treatment withdrawal group, the treatment-dependent group was more frequently responsive to IVIG, more frequently resistant to corticosteroids in first-line treatment, had a longer delay to effective treatment and was more likely to present a multifocal deficit. The rate of successful withdrawal seems to be higher with corticosteroids, but a prospective study with a long-term follow-up is needed to confirm these features.

Is total duration of distal compound muscle action potential better than negative peak duration in the diagnosis of chronic inflammatory demyelinating polyneuropathy?

INTRODUCTION: The diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) is difficult, and the role of electrophysiology is crucial. Distal compound muscle action potential (CMAP) duration is a useful tool that is assessed by measuring negative peak duration (NP). The value of total distal CMAP duration (T), which seems more precise from a physiological standpoint, has not been studied. METHODS: We reviewed retrospectively the records of 50 patients with CIDP and 50 controls with chronic axonal neuropathy. We constructed ROC curves for NP and T. RESULTS: Comparison of AUC for T vs. NP showed an advantage for the former (P=0.026 for the fibular nerve). Our derived cut-offs offered a sensitivity of 42.3% for T vs. 35.3% for NP. CONCLUSION: This study suggests a slight advantage for T over NP duration of the distal CMAP in the diagnosis of CIDP. However, the clinical relevance of this result must be weighed against the feasibility of this measurement.

Muscle histone deacetylase 4 upregulation in amyotrophic lateral sclerosis: potential role in reinnervation ability and disease progression.

Amyotrophic lateral sclerosis is a typically rapidly progressive neurodegenerative disorder affecting motor neurons leading to progressive muscle paralysis and death, usually from respiratory failure, in 3-5 years. Some patients have slow disease progression and prolonged survival, but the underlying mechanisms remain poorly understood. Riluzole, the only approved treatment, only modestly prolongs survival and has no effect on muscle function. In the early phase of the disease, motor neuron loss is initially compensated for by collateral reinnervation, but over time this compensation fails, leading to progressive muscle wasting. The crucial role of muscle histone deacetylase 4 and its regulator microRNA-206 in compensatory reinnervation and disease progression was recently suggested in a mouse model of amyotrophic lateral sclerosis (transgenic mice carrying human mutations in the superoxide dismutase gene). Here, we sought to investigate whether the microRNA-206-histone deacetylase 4 pathway plays a role in muscle compensatory reinnervation in patients with amyotrophic lateral sclerosis and thus contributes to disease outcome differences. We studied muscle reinnervation using high-resolution confocal imaging of neuromuscular junctions in muscle samples obtained from 11 patients with amyotrophic lateral sclerosis, including five long-term survivors. We showed that the proportion of reinnervated neuromuscular junctions was significantly higher in long-term survivors than in patients with rapidly progressive disease. We analysed the expression of muscle candidate genes involved in the reinnervation process and showed that histone deacetylase 4 upregulation was significantly greater in patients with rapidly progressive disease and was negatively correlated with the extent of muscle reinnervation and functional outcome. Conversely, the proposed regulator of histone deacetylase 4, microRNA-206, was upregulated in both patient groups, but did not correlate with disease progression or reinnervation. We conclude that muscle expression of histone deacetylase 4 may be a key factor for muscle reinnervation and disease progression in patients with amyotrophic lateral sclerosis. Specific histone deacetylase 4 inhibitors may then constitute a therapeutic approach to enhancing motor performance and slowing disease progression in amyotrophic lateral sclerosis.

[Channels: a new way to revisit pathology]. / La pathologie revisitée par les canaux.

Many "essential" diseases that manifest themselves in the form of crises or fits (epilepsies, episodic ataxia, periodic paralyses, myotonia, heart rhythm disorders, etc.) are due to ionic channel dysfunction and are thus referred to as "channelopathies". Some of these disorders are congenital, due to mutations of genes encoding channel subunits, while others result from toxic, immune or hormonal disturbances affecting channelfunction. Channelopathies take on a wide variety of clinical forms, depending on the type of channel (sodium, potassium, calcium, chloride...) and the type of dysfunction (loss or gain of function). Some apparently unrelated diseases affecting distinct organs are due to a similar dysfunction of the same channel, revealing unsuspected relationships between organs and between medical specialties. In addition, a given syndrome can be caused by distinct channel dysfunctions. This provides new opportunities for diferential diagnosis and specific correction of the causal defects, although some treatments find applications across multiple medical specialties.

[Congenital myasthenic syndromes; French experience]. / Syndromes myasthéniques congénitaux - L'expérience française.

Congenital myasthenic syndromes CMS) form a heterogeneous group of genetic diseases characterized by abnormal neuromuscular transmission. The associated muscular weakness is exacerbated by exertion and usually starts during infancy/childhood In 2002 a national Congenital Myasthenic Syndromes Network was created in France, composed of neurologists, neuropediatricians, pathologists, molecular geneticists and neurobiologists. The network has now identified nearly 300 cases of CMS, as well as three new culprit genes. Based on our personal experience and data from the most recent studies, we describe the 18 principal culprit genes so far identified, along with diagnostic pitfalls, the disease course, prognosis and treatment. The underlying genetic defect remains to be identified in nearly half of CMS patients.