Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026827 (hypotonia)
 5,860 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The inherited neurometabolic disease d-2-hydroxyglutaric aciduria is complicated by progressive neurodegeneration of vulnerable brain regions during infancy and early childhood, frequently presenting with hypotonia, epilepsy and psychomotor retardation. Here, we report that the pathogenetic role of the endogenously accumulating metabolite d-2-hydroxyglutarate (D-2), which is structurally similar to the excitatory amino acid glutamate, is mediated by at least three mechanisms. (i) D-2-induced excitotoxic cell damage in primary neuronal cultures from chick and rat involved N-methyl-d-aspartate (NMDA) receptor activation. Indeed, D-2 activated recombinant NMDA receptors (NR1/NR2A, NR1/NR2B) but not recombinant alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) receptors in HEK293 cells. (ii) Fluorescence microscopy using fura-2 as a calcium indicator and the oxidant-sensitive dye dihydrorhodamine-123 revealed that D-2 disturbed intracellular calcium homeostasis and elicited the generation of reactive oxygen species. (iii) D-2 reduced complex V (ATP synthase) activity of the mitochondrial respiratory chain, reflecting an impaired energy metabolism due to inhibition of ATP synthesis but without affecting the electron-transferring complexes I-IV. Thus, D-2 stimulates neurodegeneration by mechanisms well-known for glutamate, NMDA or mitochondrial toxins. In conclusion, excitotoxicity contributes to the neuropathology of d-2-hydroxyglutaric aciduria, highlighting new neuroprotective strategies.
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PMID:NMDA receptor activation and respiratory chain complex V inhibition contribute to neurodegeneration in d-2-hydroxyglutaric aciduria. 1215 28

Autoantibodies to the extracellular domain of neuronal proteins cause different neurological conditions with movement disorders as a prominent feature. We reviewed the literature of autoantibody-mediated and autoantibody-associated diseases focusing on anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, autoimmune basal ganglia encephalitis, Sydenham chorea, and the rare syndrome of progressive encephalomyelitis with rigidity and myoclonus. NMDAR encephalitis is a diffuse encephalitis with psychiatric and cognitive features associated with autoantibodies against the NR1 subunit of the NMDAR. The movement disorder phenotype is diverse and often generalized in young children. Although orofacial dyskinesia was the initial movement phenotype, chorea, dystonia, catatonia, and stereotypical movements are now described. The stereotypical movements can be bizarre and include cycling movements and compulsive self-injurious behavior. Autoimmune basal ganglia encephalitis is an inflammatory encephalitis localizing to the basal ganglia that is sometimes associated with serum antibodies against dopamine-2 receptor. Although psychiatric features are common, the dominant problem is a movement disorder, with dystonia-parkinsonism being characteristic. Sydenham chorea is the prototypic poststreptococcal autoimmune neuropsychiatric disorder and several autoantibodies may be involved in disease generation. The syndrome is characterized by a pure chorea, although hypotonia, dysarthria, and emotional lability are common. Progressive encephalomyelitis with rigidity and myoclonus is a rare autoimmune disorder causing rigidity, stimulus sensitive spasms, and myoclonus of nonepileptic origin and is associated with autoantibodies of multiple types including those against the glycine receptor. These disorders are important to recognize and diagnose, as immune therapy can shorten disease duration and improve outcome.
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PMID:Autoantibody-associated movement disorders. 2420 56