Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.7 (acetylcholinesterase)
 28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Congenital Myasthenic Syndromes (CMS) are a heterogeneous group of diseases caused by genetic defects affecting neuromuscular transmission. The twenty five past Years saw major advances in identifying different types of CMS due to abnormal presynaptic, synaptic, and postsynaptic proteins. CMS diagnosis requires two steps: 1) positive diagnosis supported by myasthenic signs beginning in neonatal period, efficacy of anticholinesterase medications, positive family history, negative tests for anti-acetylcholine receptor (AChR) antibodies, electromyographic studies (decremental response at low frequency, repetitive CMAP after one single stimulation); 2) pathophysiological characterisation of CMS implying specific studies: light and electron microscopic analysis of endplate (EP) morphology, estimation of the number of AChR per EP, acetylcholinesterase (AChE) expression, molecular genetic analysis. Most CMS are postsynaptic due to mutations in the AChR subunits genes that alter the kinetic properties or decrease the expression of AChR. The kinetic mutations increase or decrease the synaptic response to ACh resulting respectively in Slow Channel Syndrome (characterized by a autosomal dominant transmission, repetitive CMAP, refractoriness to anticholinesterase medication) and fast channel, recessively transmitted. AChR deficiency without kinetic abnormalities is caused by recessive mutations in AChR genes (mostly epsilon subunit) or by primary rapsyn deficiency, a post synaptic protein involved in AChR concentration. Recently, mutations in SCN4A sodium channel have been reported in one patient. AChE deficiency is identified on the following data: recessive transmission, presence of repetitive CMAP, refractoriness to cholinesterase inhibitors, slow pupillary response to light and absent expression of the enzyme at EP. This synaptic CMS is caused by mutations in the collagenic tail subunit (ColQ) that anchors the catalytic subunits in the synaptic basal lamina. The most frequent presynaptic CMS is caused by mutations of choline acetyltransferase. Several CMS are still not characterized. Many EP molecules are potential etiological candidates. In these unidentified cases, other methods of investigations are required: linkage analysis, when sufficient number of informative relatives are available, microelectrophysiological studies performed in intercostal or anconeus muscles. Prognosis of CMS, depending on severity and evolution of symptoms, is difficult to assess, and it cannot not be simply derived from mutation identification. Most patients respond favourably to anticholinesterase medications or to 3,4 DAP which is effective not only in presynaptic but also in postsynaptic CMS. Specific therapies for slow channel CMS are quinidine and fluoxetine that normalize the prolonged opening episodes. Clinical benefits derived from the full characterisation of each case include genetic counselling and specific therapy.
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PMID:[Congenital myasthenic syndromes: phenotypic expression and pathophysiological characterisation]. 1503 73

Congenital myasthenic syndromes comprise heterogeneous genetic diseases characterized by compromised neuromuscular transmission. Congenital myasthenic syndromes are classified as presynaptic, synaptic, or postsynaptic, depending on the primary defect's location within the neuromuscular junction. Presynaptic forms are the rarest, affecting an estimated 7-8% of patients; synaptic forms account for approximately 14-15% of patients; and the remaining 75-80% are attributable to postsynaptic defects. Clinical manifestations vary by congenital myasthenic syndrome subtype. Electrophysiologic, morphologic, and molecular descriptions of various forms of congenital myasthenic syndromes have led to an enhanced understanding of clinical manifestations and disease pathophysiology. Although congenital myasthenic syndromes are indicated by clinical manifestations, family history, electrophysiologic studies, and responses to acetylcholinesterase inhibitors, overlap in some presentations occurs. Therefore, genetic testing may be necessary to identify specific mutations in CHAT, COLQ, LAMB2, CHRNA, CHRNB, CHRND, CHRNE, CHRNG, RAPSN, DOK7, MUSK, AGRN, SCN4A, GFPT1, or PLEC1 genes. The identification of congenital myasthenic syndromes subtypes will prove important in the treatment of these patients. Different drugs may be beneficial, or should be avoided because they are ineffective or worsen some forms of congenital myasthenic syndromes. We explore the classification, clinical manifestations, electrophysiologic features, genetics, and treatment responses of each congenital myasthenic syndrome subtype.
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PMID:Congenital myasthenic syndrome: a brief review. 2235 87