Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 8 de 8
Filter
1.
BMJ ; 379: e066326, 2022 12 01.
Article in English | MEDLINE | ID: mdl-36455938
4.
Neuromuscul Disord ; 22(2): 112-7, 2012 Feb.
Article in English | MEDLINE | ID: mdl-21940170

ABSTRACT

Fast channel congenital myasthenic syndromes are rare, but frequently result in severe weakness. We report a case of 12 fast channel patients to highlight clinical features and management difficulties. Patients were diagnosed through genetic screening and identification of mutations shown to cause fast channel syndrome. Data was obtained from clinical notes, history, examination and follow up. Patterns of muscle weakness involved limb, trunk, bulbar, respiratory, facial and extraocular muscles. Patients responded to treatment with anticholinesterase medication and 3,4-diaminopyridine. Fast channel syndrome contrasted with AChR deficiency in the occurrence of severe respiratory crises in infancy and childhood. The death of two children even when on treatment and the family histories of sibling deaths re-inforces the need for accurate genetic diagnosis, optimised pharmacological treatment and additional supportive measures to manage acute respiratory crises. Referral to a specialist paediatric respiratory centre and regular resuscitation training for parents are recommended.


Subject(s)
Myasthenic Syndromes, Congenital/diagnosis , 4-Aminopyridine/analogs & derivatives , 4-Aminopyridine/pharmacology , 4-Aminopyridine/therapeutic use , Adult , Amifampridine , Child , Child, Preschool , Humans , Infant , Middle Aged , Muscle Weakness/physiopathology , Mutation/genetics , Myasthenic Syndromes, Congenital/drug therapy , Myasthenic Syndromes, Congenital/genetics
6.
Ann N Y Acad Sci ; 1132: 99-103, 2008.
Article in English | MEDLINE | ID: mdl-18567858

ABSTRACT

The congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders affecting neuromuscular transmission. Underlying mutations have been identified in at least 11 different genes. The majority of CMS patients have disorders due to mutations in postsynaptic proteins. Initial studies focused on dysfunction of the acetylcholine receptor (AChR) itself as the major cause of CMS. However, it is becoming apparent that mutations of proteins involved in clustering the AChR and maintaining neuromuscular junction structure form important subgroups. Analysis of the mutations in the AChR-clustering protein, rapsyn, show diverse causes for defective AChR localization and suggest that the common mutation rapsyn-N88K results in AChR clusters that are less stable than those generated by wild-type rapsyn. More recently, mutations in the newly identified endplate protein Dok-7 have been shown to affect AChR clustering and the generation and maintenance of specialized structures at the endplate. Dok-7 binds MuSK and many of the mutations of DOK7 impair the MuSK signaling pathway. Components of this pathway will provide attractive gene candidates for additional forms of CMS. The phenotypic characteristics of the different CMS in which muscle groups may be differentially affected not only provide clues for targeted genetic screening, but also pose further intriguing questions about underlying molecular mechanisms.


Subject(s)
Myasthenic Syndromes, Congenital/pathology , Neuromuscular Junction/pathology , Animals , Gene Expression Regulation , Humans , Muscle Proteins/genetics , Muscle Proteins/metabolism , Myasthenic Syndromes, Congenital/genetics , Myasthenic Syndromes, Congenital/metabolism , Neuromuscular Junction/metabolism , Receptors, Cholinergic/genetics , Receptors, Cholinergic/metabolism
7.
Brain ; 130(Pt 6): 1507-15, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17452375

ABSTRACT

Mutations in DOK7 have recently been shown to underlie a recessive congenital myasthenic syndrome (CMS) associated with small simplified neuromuscular junctions ('synaptopathy') but normal acetylcholine receptor and acetylcholinesterase function. We identified DOK7 mutations in 27 patients from 24 kinships. Mutation 1124_1127dupTGCC was common, present in 20 out of 24 kinships. All patients were found to have at least one allele with a frameshift mutation in DOK7 exon 7, suggesting that loss of function(s) associated with the C-terminal region of Dok-7 underlies this disorder. In 15 patients, we were able to study the clinical features in detail. Clinical onset was usually characterized by difficulty in walking developing after normal motor milestones. Proximal muscles were usually more affected than distal, leading to a 'limb-girdle' pattern of weakness; although ptosis was often present from an early age, eye movements were rarely involved. Patients did not show long-term benefit from anticholinesterase medication and sometimes worsened, and where tried responded to ephedrine. The phenotype can be distinguished from 'limb-girdle' myasthenia associated with tubular aggregates, where DOK7 mutations were not detected and patients respond to anticholinesterase treatments. CMS due to DOK7 mutations are common within our UK cohort and is likely to be under-diagnosed; recognition of the phenotype will help clinical diagnosis, targeted genetic screening and appropriate management.


Subject(s)
Muscle Proteins/genetics , Mutation , Myasthenic Syndromes, Congenital/genetics , Neuromuscular Junction/pathology , Adult , Alleles , Amino Acid Sequence , Biopsy , Cholinesterase Inhibitors/therapeutic use , DNA Mutational Analysis , Female , Humans , Male , Middle Aged , Molecular Sequence Data , Muscle, Skeletal/pathology , Muscular Dystrophies, Limb-Girdle/drug therapy , Muscular Dystrophies, Limb-Girdle/genetics , Muscular Dystrophies, Limb-Girdle/pathology , Myasthenic Syndromes, Congenital/drug therapy , Myasthenic Syndromes, Congenital/pathology , Pedigree , Polymerase Chain Reaction/methods , Sequence Alignment , Treatment Outcome
8.
Congenit Heart Dis ; 2(6): 410-5, 2007.
Article in English | MEDLINE | ID: mdl-18377433

ABSTRACT

OBJECTIVE: To reproduce in an adult population a pediatric study that found an association between aortic arch geometry and late systemic hypertension following successful repair of aortic coarctation. DESIGN AND RESULTS: Fifty-one patients with successful repair of coarctation of the aorta had blood pressure measurement at rest and during exercise. After cross-sectional imaging of the aortic arch, patients were assigned to 1 of 3 previously defined morphological categories: normal, gothic, or crenel. The degree of residual stenosis and the ratio of the height/transverse diameter of the arch (A/T ratio) were calculated. No relationship was found between arch geometry and either resting- or exercise-induced hypertension. CONCLUSIONS: We found the classification into 3 morphological types difficult and did not find an association between gothic arch or a high A/T ratio and hypertension.


Subject(s)
Aorta, Thoracic/pathology , Aortic Coarctation/surgery , Aortic Diseases/complications , Cardiovascular Surgical Procedures/adverse effects , Hypertension/etiology , Adult , Blood Pressure , Constriction, Pathologic , Female , Follow-Up Studies , Humans , Hypertension/physiopathology , Magnetic Resonance Imaging , Male , Middle Aged , Tomography, X-Ray Computed
SELECTION OF CITATIONS
SEARCH DETAIL
...