Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interest in senataxin biology began in 2004 when mutations were first identified in what was then a novel protein. Dominantly inherited mutations were documented in rare juvenile-onset, motor neuron disease pedigrees in a familial form of amyotrophic lateral sclerosis (ALS4), while recessive mutations were found to cause a severe early-onset ataxia with oculomotor apraxia (AOA2) that is actually the second most common recessive ataxia after Freidreich's ataxia. From earlier studies of sen1p, the yeast ortholog of senataxin, a range of important RNA processing functions have been attributed to this protein. Like sen1p, senataxin contains a helicase domain to interact with RNA and an amino-terminal domain for critical protein interactions. Senataxin also joins a group of important proteins responsible for maintaining RNA transcriptome homeostasis, including FUS, TDP-43, and SMN that can all cause familial forms of motor neuron disease (MND). Independent of this association, senataxin is gaining attention for its role in maintaining genomic stability. Senataxin has been shown to resolve R-Loop structures, which form when nascent RNA hybridizes to DNA, displacing the non-transcribed strand. But in cycling cells, senataxin is also found at nuclear foci during the S/G2 cell-cycle phase, and may function at sites of specific collision between components of the replisome and transcription machinery. Which of these important processes is most critical to prevent neurodegeneration remains unknown, but our evolving understanding of these processes will be crucial not only for understanding senataxin's role in neurological disease, but also in a number of fundamentally important cellular functions.
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PMID:Unwinding the role of senataxin in neurodegeneration. 2572 27

A 30 months-old boy with Farber disease developed nystagmus 12 months after hematopoietic stem cell transplantation (HSCT). At 40 months, gait ataxia was evident, and brain MRI showed increased size of pericerebellar sulci and 4th ventricle. EMG showed denervation in the tongue and upper limb muscles, consistent with motor neuron disease. HSCT improves the peripheral manifestations of Farber disease, but may not prevent the progressive neurological deterioration.
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PMID:Nervous system involvement in Farber disease. 2637 51

Senataxin (SETX) is a DNA-RNA helicase whose C-terminal region shows homology to the helicase domain of the yeast protein Sen1p. Genetic discoveries have established the importance of SETX for neural function, as recessive mutations in the SETX gene cause Ataxia with Oculomotor Apraxia type 2 (AOA2) (OMIM: 606002), which is the third most common form of recessive ataxia, after Friedreich's ataxia and Ataxia-Telangiectasia. In addition, rare, dominant SETX mutations cause a juvenile-onset form of Amyotrophic Lateral Sclerosis (ALS), known as ALS4. SETX performs a number of RNA regulatory functions, including maintaining RNA transcriptome homeostasis. Over the last decade, altered RNA regulation and aberrant RNA-binding protein function have emerged as a central theme in motor neuron disease pathogenesis, with evidence suggesting that sporadic ALS disease pathology may overlap with the molecular pathology uncovered in familial ALS. Like other RNA processing proteins linked to ALS, the basis for SETX gain-of-function motor neuron toxicity remains ill-defined. Studies of yeast Sen1p and mammalian SETX protein have revealed a range of important RNA regulatory functions, including resolution of R-loops to permit transcription termination, and RNA splicing. Growing evidence suggests that SETX may represent an important genetic modifier locus for sporadic ALS. In cycling cells, SETX is found at nuclear foci during the S/G2 cell-cycle transition phase, and may function at sites of collision between components of the replisome and transcription machinery. While we do not yet know which SETX activities are most critical to neurodegeneration, our evolving understanding of SETX function will undoubtedly be crucial for not only understanding the role of SETX in ALS and ataxia disease pathogenesis, but also for delineating the mechanistic biology of fundamentally important molecular processes in the cell.
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PMID:Senataxin, A Novel Helicase at the Interface of RNA Transcriptome Regulation and Neurobiology: From Normal Function to Pathological Roles in Motor Neuron Disease and Cerebellar Degeneration. 2991 23

Spinal and bulbar (bulbospinal) muscular atrophy (BSMA, SBMA, Kennedy's disease) is a progressive motor neuron disease with rare involvement of structures other than the lower motor neuron, such as the endocrine system and the central nervous system (CNS). Aim of the review was to study type and frequency of clinical, imaging, and functional (CNS) abnormalities in SBMA patients. The most frequent clinical CNS manifestations in SBMA are postural or kinetic tremor predominantly of the hands and mild cognitive impairment. The most frequent instrumental CNS abnormality in SBMA patients are white matter lesions, visible on voxel-based morphometry, magnetic resonance spectroscopy, or diffusion tensor imaging. Single patients with enlarged pituitary volume, or diminished somato-sensory representation in the cortex have been also reported. Seizures, epilepsy, ataxia, spasticity, dystonia, or migraine have not been found in SBMA patients. Only supportive treatment is available for CNS manifestations in SBMA. It is concluded that the most frequent CNS abnormalities in SBMA are tremor, cognitive impairment, and white matter lesions on new imaging modalities. CNS involvement in SBMA should not be neglected as a phenotypic manifestation of SBMA and, apart from cognitive involvement, may help to differentiate clinically SBMA from other types of motor neuron disease.
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PMID:Central nervous system abnormalities in spinal and bulbar muscular atrophy (Kennedy's disease). 3135 Dec 15


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