Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917801 (insomnia)
 10,606 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The prion protein (PrP) is a glycosylphosphatidylinositol-anchored membrane glycoprotein that plays a vital role in prion diseases, a class of fatal neurodegenerative disorders of humans and animals. Approximately 20% of human prion diseases display autosomal dominant inheritance and are linked to mutations in the PrP gene on chromosome 20. PrP mutations are thought to favor the conformational conversion of PrP into a misfolded isoform that causes disease by an unknown mechanism. The PrP mutation D178N/Met-129 is linked to fatal familial insomnia, which causes severe sleep abnormalities and autonomic dysfunction. We showed by immunoelectron microscopy that this mutant PrP accumulates abnormally in the endoplasmic reticulum and Golgi of transfected neuroblastoma N2a cells. To investigate the impact of intracellular PrP accumulation on cellular homeostasis, we did a two-dimensional gel-based differential proteomics analysis. We used wide range immobilized pH gradient strips, pH 4-7 and 6-11, to analyze a large number of proteins. We found changes in proteins involved in energy metabolism, redox regulation, and vesicular transport. Rab GDP dissociation inhibitor alpha (GDI) was one of the proteins that changed most. GDI regulates vesicular protein trafficking by acting on the activity of several Rab proteins. We found a specific reduction in the level of functional Rab11 in mutant PrP-expressing cells associated with impaired post-Golgi trafficking. Our data are consistent with a model by which mutant PrP induces overexpression of GDI, activating a cytotoxic feedback loop that leads to protein accumulation in the secretory pathway.
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PMID:Mutant prion protein expression is associated with an alteration of the Rab GDP dissociation inhibitor alpha (GDI)/Rab11 pathway. 1999 23

This report describes the case of a 49-year-old man who presented to the hospice with severe neuropathic pain, cramps, muscle twitching, generalised sweating, insomnia and anxiety in the context of metastatic thymoma. The symptoms were exquisitely corticosteroid sensitive raising the possibility of an immunogenic aetiology. Morvan's syndrome, a paraneoplastic, immune-mediated syndrome characterised by peripheral nerve hyperexcitability, dysautonomia and central nervous system dysfunction was thus considered. Nerve conduction studies and electromyography were negative as were initial serological assays. Subsequent assays for antibodies to leucine-rich, glioma inactivated one protein and contactin-associated protein-2, recently discovered to be associated with Morvan's syndrome, confirmed the diagnosis. By the time the diagnosis of Morvan's syndrome was reached the patient was too unwell to receive disease-modifying treatments. An awareness of Morvan's syndrome in Palliative and Supportive care is essential to improve the outcome of patients with this devastating syndrome.
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PMID:A complicated case of metastatic thymoma. 2539 17

Voltage-gated potassium channel (VGKC) complex auto-antibodies were initially identified in Isaacs' syndrome (IS), which is characterized by muscle cramps and neuromyotonia. These antibodies were subsequently identified in patients with Morvan's syndrome (MoS), which includes IS in conjunction with psychosis, insomnia, and dysautonomia. The antibodies have also been detected in a patient with limbic encephalopathy (LE) presenting with prominent amnesia and frequent seizures. Typical cases of LE have adult-onset, with frequent, brief dystonic seizures that predominantly affect the arms and ipsilateral face, and has recently been termed faciobrachial dystonic seizures. Autoantibodies against the extracellular domains of VGKC complex proteins, leucine-rich glioma-inactivated 1 (LGI1), and contactin-associated protein-2 (Caspr2), occur in patients with IS, MoS, and LE. However, routine testing has detected VGKC complex antibodies without LGI1 or Caspr2 reactivities (double-negative) in patients with other diseases, such as Creutzfeldt-Jakob disease and amyotrophic lateral sclerosis. Furthermore, double-negative VGKC complex antibodies are often directed against cytosolic epitopes of Kv1 subunits. Therefore, these antibodies should no longer be classified as neuronal-surface antibodies and lacking pathogenic potential. Novel information has been generated regarding autoantibody disruption of the physiological functions of target proteins. LGI1 antibodies neutralize the interaction between LGI1 and ADAM22, thereby reducing the synaptic AMPA receptors. It may be that the main action is on inhibitory neurons, explaining why the loss of AMPA receptors causes amnesia, neuronal excitability and seizures.
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PMID:[Current Perspective on Voltage-gated Potassium Channel Complex Antibody Associated Diseases]. 2963 80

Research in the last few years has indicated that most voltage-gated potassium channel- (VGKC-) complex antibodies without leucine-rich glioma-inactivated protein 1 or contactin-associated protein-like 2 antibody specificity lack pathogenic potential and are not clear markers for autoimmune inflammation. Here we report on a patient with double-negative VGKC who developed severe peripheral nerve hyperexcitability, central nervous system symptoms with agitation and insomnia, dysautonomia, and systemic symptoms with weight loss, itch, and skin lesions. The disease started acutely one month after an episode of enteroviral pericarditis and responded well to immunotherapy. The patient is presumed to have developed a postinfectious immunotherapy-responsive autoimmune disease. In the setting of anti-VGKC positivity, it seems likely that anti-VGKC contributed to the pathogenesis of the patient's symptoms of nerve hyperexcitability and that the disease was caused by an acquired autoimmune effect on the neuronal kinetics of VGKC. It is still unknown whether or not there are unidentified extracellular molecular targets within the VGKC-complex, i.e., a novel surface antigen and a pathogenic antibody that can cause affected individuals to develop a peripheral nerve hyperexcitability syndrome. This case highlights the fact that less well-characterized autoimmune central and peripheral nervous system syndromes may have infectious triggers.
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PMID:A Patient with Double-Negative VGKC, Peripheral Nerve Hyperexcitability, and Central Nervous System Symptoms: A Postinfectious Autoimmune Disease. 3312 94

Objective: Sleep disorders are common in voltage-gated potassium channel complex antibody (VGKC-Ab) diseases. The aim was to investigate the sleep disturbances and polysomnography (PSG) characteristics in patients with VGKC-Ab-associated diseases. Methods: Twenty-seven patients with leucine-rich glioma-inactivated protein 1 antibody (LGI1-Ab) encephalitis, seven patients with contactin protein-like 2 antibody (Caspr2-Ab)-associated diseases, and 14 healthy controls with at least one PSG or actigraphy recording were recruited at Peking Union Medical College Hospital from January 2014 to July 2019. Results: Sleep disorders including insomnia, hypersomnia, rapid eye movement (REM) sleep behavior disorder (RBD), periodic limb movements in sleep (PLMS), agrypnia excitata, and obstructive sleep apnea syndrome were observed. Twenty-one PSG recordings from patients with LGI1-Ab encephalitis demonstrated a decrease in total sleep time (TST) (median 365.5, range 184.5-495.5 min), sleep efficiency (70.0%, 47-92%), N3 sleep (9.7%, 0-32.9%), and REM sleep (9.9%, 0.4-27.9%). Of five patients with Caspr2-Ab-associated diseases, TST was found to be 329.5 (167.0-377.5 min), and sleep efficiency was found to be 61.7% (34.6-71.7%). The percentage for N3 and REM sleep was found to be 15.0% (0-34.6%) and 12.7% (0-22.2%), respectively. Both RBD and PLMS were observed more frequently in patients with LGI1-Ab encephalitis. We identified status dissociatus (SD) in five (23.8%) patients with LGI1-Ab encephalitis and two (40%) patients with Caspr2-Ab diseases. The former is more likely to have simple limb movements rather than complex movements, which mimic the contents of their dreams. Continuous insomnia was more common in patients with Caspr2-Ab diseases than patients with LGI1-Ab encephalitis. Patients reported clinical and PSG improvements following immunotherapy. Conclusion: Sleep disorders in patients with VGKC-Ab-associated diseases include decreased TST and poor sleep efficiency. Our studies provide evidence of SD in patients with LGI1-Ab encephalitis.
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PMID:Sleep Disorders in Leucine-Rich Glioma-Inactivated Protein 1 and Contactin Protein-Like 2 Antibody-Associated Diseases. 3319 70