Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0013421 (dystonia)
 8,418 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Four naturally occurring sequence variations have been found in the coding region of the DYT1 gene encoding torsinA. One of these, a 3 bp (DeltaGAG) deletion, underlies dominantly inherited cases of early-onset torsion dystonia. Others, including a single nucleotide polymorphism that replaces aspartic acid (D) at residue 216 with histidine (H) in 12% of normal alleles and two other rare deletions, have not been clearly associated with disease. To gain insight into how these sequence variations affect torsinA, we used the structure of the related protein ClpB to provide a model of torsinA's AAA+ domain. Motifs important for ATP hydrolysis-sensor 1 and sensor 2-were identified, mutagenized and used to validate predictions of this model. Inspection revealed that the DeltaGAG deletion associated with dystonia removes one residue from an alpha-helix in the C-terminal portion of the AAA+ domain. The resulting distortion in torsinA structure may underlie this mutant's known tendency to produce ER-derived inclusions as well as its proposed loss of function. The D/H polymorphism at residue 216 falls in the N-terminal portion of the AAA+ domain near the sensor 1 motif. Surprisingly, cells expressing torsinA with the polymorphic histidine developed inclusions similar to those associated with DeltaGAG-torsinA, indicating that this change may also affect torsinA structure. Introducing H216 into DeltaGAG-torsinA reduced its tendency to form inclusions, suggesting that the two changes offset each other. Our findings point to a structural basis for the defects associated with the disease-linked DeltaGAG deletion in torsinA. They also suggest possible connections between the allelic polymorphism at residue 216 and the penetrance of DYT1 dystonia, as well as a possible role for this polymorphism in related disease states.
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PMID:Effects of genetic variations in the dystonia protein torsinA: identification of polymorphism at residue 216 as protein modifier. 1653 70

SOLUTIONS TO THE MAJOR RIDDLES IN MOVEMENT DISORDERS ARE APPEARING AT A BREATHTAKING PACE: 1) loss-of-function mutations in PRRT2, which encodes a cell surface protein expressed in neurons, have been found in many patients with paroxysmal kinesigenic dyskinesias; 2) mutations in CIZ1, which encodes a protein involved in cell-cycle control at the G1-S checkpoint, have been identified in a small percentage of patients with cervical dystonia; and 3) finally, after many years of genetics and identification of more than 25 disease-associated genes, cellular studies related to the pathobiology of hereditary spastic paraplegia are converging on defects in modeling the endoplasmic reticulum and membrane trafficking. On the treatment front, the distinctive syndromes of faciobrachial dystonic seizures with anti-LRI1 antibodies and anti-N-methyl-d-aspartic acid encephalitis with orobuccolingual dyskinesias are becoming increasingly recognized by clinicians as imminently treatable conditions. Also on the treatment front, the first phase I trial of MRI-guided high-intensity focused ultrasound for essential tremor has been completed and intraoperative MRI is currently being used to place electrodes in the brains of patients with medically intractable dystonia. Definitive etiologies and efficacious treatments for non-Parkinson disease movement disorders are no longer wishful thinking.
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PMID:Non-Parkinson movement disorders: Five new things. 2363 81

A 29-month-old boy presented to a pediatric emergency department with complaints of trouble sleeping for more than a week. History consisted of episodes of screaming while asleep from which he could not be awakened. A detailed physical examination revealed left arm dystonia and left plantar reflex to be upgoing. Upon admission, all imaging and an electroencephalogram were normal. Extensive laboratory work was done showing positive anti-N-methyl-D-Aspartate (NMDA) antibody in the cerebrospinal fluid. Inpatient care included intravenous immunoglobulin (IVIG) and Solumedrol. Cellcept was started after definitive diagnosis and continued on discharge. The patient was discharged with residual defects that will need long-term therapy. The varied presenting symptoms are easily misinterpreted as common clinical entities. Pediatric emergency physicians need to be aware of the wide spectrum of presenting symptoms for this clinical entity because earlier diagnosis and treatment have been shown to improve long-term morbidity.
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PMID:Two-Year-Old With Sleep Disturbance and Left Arm Movements. 3294 63