Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1762617 (weakness)
 37,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in ion channels, or channelopathies, often lead to neurological disorders in which normal behavior is interrupted by attacks of debilitating symptoms such as pain, weakness or abnormal motor control. Attacks are often precipitated by similar stimuli, including stress, caffeine, ethanol, exercise or fatigue. The tottering mouse inherits a mutation in P/Q-type calcium channels and reliably exhibits attacks of abnormal movements, or dyskinesia. To determine if this mouse mutant is an appropriate model to study episodic neurological disorders, tottering mice were exposed to different environmental conditions or drugs known to precipitate attacks in humans. Stress, caffeine and ethanol all reliably induced attacks in tottering mice. Since calcium influx has previously been implicated in stress-induced tottering mouse attacks, the L-type calcium channel antagonist, nimodipine, and the NMDA receptor antagonist, MK 801, were tested for their ability to prevent attacks caused by caffeine or ethanol administration. Nimodipine blocked both caffeine- and ethanol-induced attacks, while MK 801 was effective against stress- and caffeine-induced attacks. These results support a common role for excess neuronal excitability and increased calcium influx in attacks triggered by diverse agents. Together, these results suggest that the tottering mouse is a novel model to investigate triggers of episodic neurological disorders.
 ...
PMID:Triggers of paroxysmal dyskinesia in the calcium channel mouse mutant tottering. 1215 Oct 38

A high index of suspicion is essential in arriving at the correct diagnosis of Lambert-Eaton myasthenic syndrome (LEMS). LEMS should be considered in the differential in any patient who has proximal weakness, reduced or absent muscle stretch reflexes, and dry mouth. Weakness predominates in hip and shoulder muscles, but may also affect ocular and oropharyngeal muscles to a lesser extent. The diagnosis is confirmed by demonstrating characteristic electromyographic findings-low-amplitude muscle responses that increase dramatically after activation. Most patients also have circulating antibodies to the voltage-gated calcium channel. Half the patients with LEMS have a malignancy, usually small-cell lung cancer. The diagnosis should trigger an intensive search for malignancy, especially in older patients with a history of smoking. Younger, nonsmoking patients are likely to have LEMS as part of a more general autoimmune state. Successful treatment of the underlying cancer leads to improvement in many patients. More than 85% of patients have clinically significant benefit from 3,4-diaminopyridine (DAP). In over half of these, the improvement is marked. If severe weakness persists despite DAP, immunotherapy should be considered. Plasma exchange and high-dose immunoglobulin induce transient improvement in many patients, but function rarely becomes normal. Combinations of prednisone, azathioprine, or cyclosporine have been used with variable success. Improvement, if any, occurs only after many months and requires chronic administration of immunosuppressive medications at significant doses. The long-term prognosis in LEMS is determined by the presence of cancer or other autoimmune disease.
 ...
PMID:Lambert-eaton myasthenic syndrome: diagnosis and treatment. 1459 20

Lambert-Eaton myasthenic syndrome (LEMS) is an idiopathic or paraneoplastic syndrome producing antibodies against presynaptic voltage-gated P/Q calcium channels. This decreases calcium entry into the presynaptic terminal, which prevents binding of vesicles to the presynaptic membrane and acetylcholine release. LEMS is most often associated with small cell lung cancer, although idiopathic presentations comprise approximately 40% of the cases. The most common initial complaint is proximal muscle weakness involving the lower extremities more than the upper extremities. Depressed deep tendon reflexes and autonomic dysfunction are frequently present. Involvement of the bulbar or respiratory muscles is rare. Diagnosis is confirmed by electrophysiological testing, which demonstrates small compound muscle action potentials and facilitation with exercise or 20-Hz repetitive stimulation. A serum test for voltage-gated calcium channel antibodies is commercially available. Treatment involves removing the cancer associated with the disease. If cancer is not found, immunosuppressive medications and acetylcholinesterase inhibitors are used with moderate success. Patients with idiopathic LEMS should be screened every 6 months with chest imaging for cancer.
 ...
PMID:Lambert-Eaton myasthenic syndrome. 1525 11

We encountered a very rare case of cT0N2M0 small cell lung cancer (SCLC) with Lambert-Eaton myasthenic syndrome (LEMS). A 69-year-old man with a complaint of muscle weakness was admitted to our hospital. Although his chest radiograph on admission showed no abnormal findings, CT scanning detected a mediastinal lymphadenopathy. Also, 2-[18F]-2-fluorodeoxy-D-glucose position emission tomography (FDG-PET) revealed increased accumulation in the same portion in the mediastinum. A diagnosis of LEMS was made from the distinctive electromyogram (EMG) findings (waning and waxing phenomenon in response to low-and high-frequency repetitive stimulation, respectively) in combination with the increased serum level of a P/Q-type anti-voltage-gated calcium channel (VGCC) antibody. Subsequent histopathological diagnosis by mediastinoscopic resection of a paraaortic lymph node was small cell carcinoma. No distant metastasis was detected by MRI of the brain, abdominal CT scan or an FDG-PET. Eight courses of chemotherapy (carboplatin + etoposide) with radiotherapy of the mediastinum (for a total dose of 45 Gy) was performed. A decreased serum level of P/Q-type anti-VGCC antibody titers followed by marked improvement of neurological dysfunction (muscle weakness, gait disturbance and scanning speech) and of an EMG finding (a loss of waning phenomenon) was observed. A close relationship between reduction of the antibody titers and improvement of neurological symptoms after the therapy was noticed. It was suggested that monitoring the level of a P/Q-type anti-VGCC antibody titer in the serum is important for evaluating the efficacy of chemotherapy for LEMS associated with SCLC.
 ...
PMID:[A case of cT0N2M0 small cell lung cancer with Lambert-Eaton myasthenic syndrome]. 1550 Jan 50

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder of neuromuscular and autonomic transmission in which IgG autoantibodies lead to presynaptic voltage-gated calcium channel (VGCC) loss, or as a paraneoplastic disorder in association with small cell lung carcinoma (SCLC). Recent results strongly suggest that the antibodies to P/Q-type VGCC are the principal pathogenic factors in LEMS. Here, we present diagnosis and treatment of LEMS patients. Proximal weakness, depressed tendon reflexes, autonomic symptoms, and electrical posttetanic potentiation together are essential to accurately diagnose LEMS. The diagnosis is established immunologically by the presence of anti-P/Q-type VGCC antibodies, detected using the (125)I-omega-conotoxin MVIIC radioimmunoassay, which will be present in 85% of LEMS patients. The drug 3,4-diaminopyridine with anti-cholinesterase inhibitor is most effective in LEMS patients with or without SCLC. In LEMS with SCLC, specific tumor therapy will often improve the neurological disorder. In some cases plasmapheresis or intravenous immunoglobulin may be indicated.
 ...
PMID:[Lambert-Eaton myasthenic syndrome: diagnosis and treatment]. 1577 66

Lambert-Eaton myasthenic syndrome (LEMS) is an autoinmune idiopathic or paraneoplastic syndrome producing antibodies agaisnt presynaptic voltage calcium channels. The clinical features of patients with LEMS are muscle weakness and autonomic dysfunction. We report a 40 years old man with a four years history of proximal weakness, absent tendon reflexes and dry mouth. The diagnosis was confirmed by characteristic electromyographic findings, showing a low-amplitude muscle response that increased dramatically after activation. Circulating antibodies to voltage-gated calcium channel were present. The search for malignant tumors was negative. The patient was treated with prednisone and azathioprine and after four months, he was able to walk and signs of autonomic dysfunction started to subside.
 ...
PMID:[Idiopathic Lambert-Eaton myasthenic syndrome: report of one case]. 1655 31

A case of adult-onset ataxia-telangiectasia (AT) is presented, with debut at the age of 18 years and survival into the fourth decade. The clinical picture included cerebellar ataxia, distal weakness and hypopalesthesia in the lower limbs, oculomotor apraxia, dysarthria, and conjunctival telangiectasiae. Carcinoembrionic antigen was raised in plasma. MR imaging showed atrophy of the cerebellar vermis and thinning of the spinal cord. Deficiencies of gamma-aminobutyric acid and glutamate have been found in the cerebellar cortex in a case of AT. These were attributed to the loss of Purkinje cells and granule cells. In spite of some ataxias having improved with the gabaergic drugs gabapentin and tiagabine, the administration of gabapentin, acetazolamide and a placebo, did not benefit this patient. Pregabalin, 225 mg/day, ameliorated the ataxia unexpectedly, with further improvement after the addition of tiagabine. The authors suggest that the beneficial effect observed might have been due, either to the higher affinity of pregabalin towards alpha2-delta, a subtype of the alpha2-delta subunit which forms part of the voltage-gated calcium channel; either to the profusion of this subtype in the Purkinje cell layer, or to its larger capacity to let calcium into the neuron; or to the combination of these. These differences with gabapentin could explain the higher power of pregabalin in the stimulation of the cerebellar structures, thus justifying the improvement of ataxia in this case of AT. A synergistic effect with pregabalin is proposed as the cause of the improvement obtained with the addition of tiagabine.
 ...
PMID:[Adult-onset ataxia-telangiectasia. A clinical and therapeutic observation]. 1701 92

Hypokalemic periodic paralysis (HypoPP) is a skeletal muscle disorder in which episodic attacks of muscle weakness occur; they are associated with decreased serum potassium (K+) levels. Recent molecular approaches have clarified that the condition is caused by mutations in the skeletal muscle voltage-gated calcium channel 1 subunit (CACNA1S). We describe two unrelated patients with HypoPP, followed by their relevant clinical studies and gene analysis. Clinical studies included an oral glucose tolerance test (OGTT), food-loading and insulin tolerance tests (ITT). For Case 1, serum K+ levels were extremely decreased following insulin tolerance testing compared with levels for controls. These results support the hypothesis that no efflux of K+ ion occurs in patients because of low activity of adenosine triphosphate (ATP)-sensitive K+ channel (KATP) channels. Mutational analysis of the CACNA1S gene showed a duplicate insertion of 14 base pairs (bp) from 52 to 65 in intron 26, present in the heterozygous state in both patients. No other mutations were detected in the CACNA1S gene, the muscle sodium channel gene (SCN4A) or the voltage-gated K+ channel gene (KCN3) of either patient. Further analysis showed that this duplicate insertion of 14 bp in intron 26 of the CACNA1S gene was found in 23.7% of healthy subjects. K+ dynamics studies are useful for confirming this syndrome, while further gene analysis for various ion channels using amplification and direct sequencing are required to evaluate the molecular basis of the disorder in the individual patient.
 ...
PMID:Gene analysis of the calcium channel 1 subunit and clinical studies for two patients with hypokalemic periodic paralysis. 1718 4

The Lambert-Eaton myasthenic syndrome (LEMS) is a disease of neuromuscular transmission in which autoantibodies against the P/Q-type voltage-gated calcium channel (VGCC) at the presynaptic nerve terminal play a major role in decreasing quantal release of acetylcholine (ACh), resulting in skeletal muscle weakness and autonomic symptoms. It is associated with cancer, particularly small-cell lung carcinoma (SCLC), in 50-60% of LEMS patients; the nerve terminal and carcinoma cells apparently share a common antigen (VGCC), suggesting an immunological cross-reactivity that may lead to the neurological abnormality. Non-tumor LEMS has a strong association with HLA-DR3-B8. In approximately 15% of LEMS patients, no anti-P/Q-type VGCC antibodies are found, suggesting recognition of other targets(s). The VGCC-associated protein synaptotagmin could be one candidate, because it acts as an exocytotic calcium receptor, is implicated in fast ACh release; its N-terminus is exposed extracellularly during exocytosis and it is expressed in SCLC. Antibodies against synaptotagmin-1 were detected in both anti-VGCC-positive and -negative LEMS patients (20%), and it can be immunogenic, allowing induction of an animal model of LEMS. Another candidate target is the M1-type presynaptic muscarinic ACh receptor (M1 mAChR), also expressed extracellularly on motor nerve terminals; it modulates cholinergic transmission, linking to P/Q-type VGCC. In our series of 25 LEMS patients with and without SCLC, anti-M1 mAChR antibodies were prevalent in both anti-VGCC-positive and -negative LEMS patients. Autonomic symptoms seemed more frequent in the latter; serum from one of them passively transferred LEMS-type electrophysiological defects to mice. As a compensatory mechanism, researchers in Oxford suggested a shift in the dependence of ACh release from the P/Q-type to other types of VGCC. We have also focused on G protein-coupled mAChRs and neurotrophins, which may affect both P/Q-type VGCC and clathrin-independent "kiss-and-run" synaptic vesicle recycling (fast-mode of endocytosis) via protein kinase C activation. We hypothesize that these signaling cascades help to compensate for the immune-mediated defects in calcium entry in LEMS, compensation that may frequently be restricted by the coincident anti-M1 mAChR antibodies in this disease.
 ...
PMID:Lambert-Eaton myasthenic syndrome: search for alternative autoimmune targets and possible compensatory mechanisms based on presynaptic calcium homeostasis. 1865 48

A 67-year-old man was admitted with a 2-year history of dropped head. Neurological examination revealed ptosis, dysarthria, neck weakness, hyporeflexia of all limbs, and autonomic failure. Electrophysiologic study showed a 400% increment response to high-rate repetitive nerve stimulation. Serum anti-P/Q-voltage-gated calcium channel antibody was positive, confirming the diagnosis of Lambert-Eaton myasthenic syndrome (LEMS). His symptoms and electrophysiological abnormalities improved with oral prednisolone following plasmapheresis. This is the first report of LEMS as a cause of dropped head syndrome.
 ...
PMID:"Dropped head syndrome" caused by Lambert-Eaton myasthenic syndrome. 1953 55


<< Previous 1 2 3 4 5 Next >>