Identification of an Agrin Mutation that Causes Congenital Myasthenia and Affects Synapse Function

Huzé, Caroline; Bauché, Stéphanie; Richard, P.; Chevessier, Frédéric; Goillot, Evelyne; Gaudon, Karen; Ammar, Asma; Chaboud, Annie; Grosjean, Isabelle; Lecuyer, Heba-Aude; Bernard, Véronique; Rouche, Andrée; Alexandri, Nektaria; Küntzer, Thierry; Fardeau, Michel; Fournier, Emmanuel; Brancaccio, Andrea; Rüegg, Markus A.; Koenig, Jeanine; Eymard, B.; Schaeffer, Laurent; Hantaı̈, Daniel

doi:10.1016/j.ajhg.2009.06.015

Cited by 154 publications

(127 citation statements)

References 41 publications

Supporting

Mentioning

118

Contrasting

Order By: Relevance

“…In addition, thyroid function, anti-thyroid antibodies and connective tissue diseases associated autoantibodies were determined as well in all the cases. In the cases who presented as atypical manifestations, screening of mutations for Kearns-Sayre syndrome (KSS) and congenital myasthenic syndromes was performed and MRI of extra-ocular muscles was routinely carried out to exclude the possibility of atypical Graves's disease [9][10][11].…”

Section: Methods and Patientsmentioning

confidence: 99%

Long-term outcome of 424 childhood-onset myasthenia gravis patients

et al. 2015

View full text Add to dashboard Cite

The objective of this study was to describe the clinical characteristics, outcome and factors that may affect the outcome of childhood-onset myasthenia gravis (CMG) patients in China. We have followed up 424 patients with CMG for at least 5 years at Tongji Hospital. At the end of follow-up, the outcome of all the patients was measured according to MGFA Post-intervention Status. In this study, the patients have been followed up for 9.8 ± 5.4 years. The mean onset age was 5.4 ± 3.6 years. Ocular myasthenia gravis (OMG) was the major type of CMG within 2 years after onset (95%). Thymic hyperplasia was found in 116 patients, and thymoma was confirmed in 6 patients. Acetylcholine receptor antibodies were elevated in 69.5% of the patients. All the patients were routinely treated. Thymectomy was performed in 34 patients (8.0%). At the end of follow-up, seventy-one patients (16.7%) were significantly improved, 66 patients (15.6%) remained unchanged, 53 patients (12.5%) were worsened, and 234 patients (55.2%) were exacerbated. Importantly, fifty OMG patients (12.4%) had transformed into generalized myasthenia gravis (GMG) over 2 years after onset. Thymectomy did not effectively reduce the transformation from OMG to GMG. However, GMG cases significantly benefited from the surgery. This study indicated that the cases with autoimmune CMG account for over 50% in Chinese MG population. The long-term follow-up discloses that CMG patients have a low percentage of improvement, and a high percentage of worsening and exacerbation. The treatment should not be withdrawn too early after the patients obtain complete stable remission. More studies are needed to gain better control of CMG symptoms.

show abstract

Section: Methods and Patientsmentioning

confidence: 99%

Long-term outcome of 424 childhood-onset myasthenia gravis patients

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Only one patient (case 3) experienced a spontaneous and significant improvement of 7 years during the late teens. For all patients except cases 7 and 9, symptoms worsened with age: increase of limb/axial weakness and/or of bulbar symptoms (patients 1,2,4,5,6,7,8,11,14,15), and/or respiratory symptoms (patients 1, 2, 3, 5, 6, 8). As shown in case 7, the profile of deterioration was variable from one patient to another and an individual patient could display a variable disease course: progressive worsening, acute or subacute worsening with or without return to the previous state.…”

Section: Patientmentioning

confidence: 98%

“…Twelve genes have been described so far, coding for proteins involved in neuromuscular transmission [1][2][3][4]. Despite extensive testing of these genes, about half of the CMSs are not yet identified molecularly.…”

Section: Introductionmentioning

confidence: 98%

Phenotype genotype analysis in 15 patients presenting a congenital myasthenic syndrome due to mutations in DOK7

et al. 2009

View full text Add to dashboard Cite

Congenital myasthenic syndromes (CMSs) are a heterogeneous group of diseases caused by genetic defects affecting neuromuscular transmission. Mutations of DOK7 have recently been described in recessive forms of CMS. Dok-7 is a cytoplasmic post-synaptic protein co-activator of the muscle-specific receptor-tyrosine kinase (MuSK) involved in neuromuscular synaptogenesis and maintenance. We report clinical, morphological and molecular data on 15 patients with mutations in DOK7. Eleven different mutations (5 novel) were identified and all patients but one were found to carry at least the common c.1124_1127dupTGCC mutation. Patients with DOK7 mutations have a particular limb-girdle pattern, without tubular aggregates but a frequent lipidosis on the muscle biopsy. Changes in pre- and post-synaptic compartments of the neuromuscular junction were also observed in muscle biopsies: terminal axons showed defective branching which resulted in a unique terminal axon contacting en passant postsynaptic cups. Clinical features, muscle biopsy findings or response to therapy were confusing in several patients. Characterization of this distinct phenotype is essential to provide clues for targeted genetic screening and to predict the therapeutic response to anticholinesterase treatments or ephedrine as has been suggested.

show abstract

“…Agrin mutation can cause congenital myasthenia, with dramatic perturbations of the maintenance of the NMJ [31]. The expression of mutated proteins in muscles destabilizes the wild-type NMJ but not the induction of post-synaptic structures.…”

Section: An Extracellular Matrix Molecule: Agrinmentioning

confidence: 99%

Mechanisms controlling neuromuscular junction stability

Bloch‐Gallego

2014

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

The neuromuscular junction (NMJ) is the synaptic connection between motor neurons and muscle fibers. It is involved in crucial processes such as body movements and breathing. Its proper development requires the guidance of motor axons toward their specific targets, the development of multi-innervated myofibers, and a selective synapse stabilization. It first consists of the removal of excessive motor axons on myofibers, going from multi-innervation to a single innervation of each myofiber. Whereas guidance cues of motor axons toward their specific muscular targets are well characterized, only few molecular and cellular cues have been reported as clues for selecting and stabilizing specific neuromuscular junctions. We will first provide a brief summary on NMJ development. We will then review molecular cues that are involved in NMJ stabilization, in both pre- and post-synaptic compartments, considering motor neurons and Schwann cells on the one hand, and muscle on the other hand. We will provide links with pathologies and highlight advances that can be brought both by basic research on NMJ development and clinical data resulting from the analyses of neurodegeneration of synaptic connections to obtain a better understanding of this process. The goal of this review is to highlight the findings toward understanding the roles of poly- or single-innervations and the underlying mechanisms of NMJ stabilization.

show abstract

Identification of an Agrin Mutation that Causes Congenital Myasthenia and Affects Synapse Function

Cited by 154 publications

References 41 publications

Long-term outcome of 424 childhood-onset myasthenia gravis patients

Long-term outcome of 424 childhood-onset myasthenia gravis patients

Phenotype genotype analysis in 15 patients presenting a congenital myasthenic syndrome due to mutations in DOK7

Mechanisms controlling neuromuscular junction stability

Contact Info

Product

Resources

About