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Louis M Kunkel - One of the best experts on this subject based on the ideXlab platform.
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Analysis of human sarcospan as a candidate gene for CFEOM1
BMC Genetics, 2001Co-Authors: Kristine F O'brien, Elizabeth C Engle, Louis M KunkelAbstract:Background Congenital fibrosis of the extraocular muscles type 1 (CFEOM1) is an autosomal dominant Eye Movement Disorder linked to the pericentromere of chromosome 12 (12p11.2 - q12). Sarcospan is a member of the dystrophin associated protein complex in skeletal and extraocular muscle and maps to human chromosome 12p11.2. Mutations in the genes encoding each of the other components of the skeletal muscle sarcospan-sarcoglycan complex (α - δ sarcoglycan) have been shown to cause limb girdle muscular dystrophy (LGMD2C-F). To determine whether mutations in the sarcospan gene are responsible for CFEOM1 we: (1) attempted to map sarcospan to the CFEOM1 critical region; (2) developed a genomic primer set to directly sequence the sarcospan gene in CFEOM1 patients; and (3) generated an anti-sarcospan antibody to examine extraocular muscle biopsies from CFEOM1 patients. Results When tested by polymerase chain reaction, sarcospan sequence was not detected on yeast or bacterial artificial chromosomes from the CFEOM1 critical region. Sequencing of the sarcospan gene in CFEOM1 patients from 6 families revealed no mutations. Immunohistochemical studies of CFEOM1 extraocular muscles showed normal levels of sarcospan at the membrane. Finally, sarcospan was electronically mapped to bacterial artificial chromosomes that are considered to be outside of the CFEOM1 critical region. Conclusions In this report we evaluate sarcospan as a candidate gene for CFEOM1. We have found that it is highly unlikely that sarcospan is involved in the pathogenesis of this disease. As of yet no sarcospan gene mutations have been found to cause muscular abnormalities.
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Analysis of human sarcospan as a candidate gene for CFEOM1
2001Co-Authors: Kristine F. O&apos, Louis M Kunkel, Elizabeth C EngleAbstract:(c) 2001 O'Brien et al, licensee BioMed Central Ltd. Background: Congenital fibrosis of the extraocular muscles type 1 (CFEOM1) is an autosomal dominant Eye Movement Disorder linked to the pericentromere of chromosome 12 (12p11.2-q12). Sarcospan is a member of the dystrophin associated protein complex in skeletal and extraocular muscle and maps to human chromosome 12p11.2. Mutations in the genes encoding each of the other components of the skeletal muscle sarcospan-sarcoglycan complex (α- δ sarcoglycan) have been shown to cause limb girdle muscular dystrophy (LGMD2C-F). To determine whether mutations in the sarcospan gene are responsible for CFEOM1 we: (1) attempted to map sarcospan to the CFEOM1 critical region; (2) developed a genomic primer set to directly sequence the sarcospan gene in CFEOM1 patients; and (3) generated an anti-sarcospan antibody to examine extraocular muscle biopsies from CFEOM1 patients. Results: When tested by polymerase chain reaction, sarcospan sequence was not detected on yeast or bacterial artificial chromosomes from the CFEOM1 critical region. Sequencing of the sarcospan gene in CFEOM1 patients from 6 families revealed no mutations. Immunohistochemica
Sarah Guthrie - One of the best experts on this subject based on the ideXlab platform.
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axon guidance in the developing ocular motor system and duane retraction syndrome depends on semaphorin signaling via alpha2 chimaerin
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Juan E Ferrario, Pranetha Baskaran, Christopher Clark, Aenea C Hendry, Oleg Lerner, Mark Hintze, James A Van Allen, John K Chilton, Sarah GuthrieAbstract:Eye Movements depend on correct patterns of connectivity between cranial motor axons and the extraocular muscles. Despite the clinical importance of the ocular motor system, little is known of the molecular mechanisms underlying its development. We have recently shown that mutations in the Chimaerin-1 gene encoding the signaling protein α2-chimaerin (α2-chn) perturb axon guidance in the ocular motor system and lead to the human Eye Movement Disorder, Duane retraction syndrome (DRS). The axon guidance cues that lie upstream of α2-chn are unknown; here we identify candidates to be the Semaphorins (Sema) 3A and 3C, acting via the PlexinA receptors. Sema3A/C are expressed in and around the developing extraocular muscles and cause growth cone collapse of oculomotor neurons in vitro. Furthermore, RNAi knockdown of α2-chn or PlexinAs in oculomotor neurons abrogates Sema3A/C-dependent growth cone collapse. In vivo knockdown of endogenous PlexinAs or α2-chn function results in stereotypical oculomotor axon guidance defects, which are reminiscent of DRS, whereas expression of α2-chn gain-of-function constructs can rescue PlexinA loss of function. These data suggest that α2-chn mediates Sema3–PlexinA repellent signaling. We further show that α2-chn is required for oculomotor neurons to respond to CXCL12 and hepatocyte growth factor (HGF), which are growth promoting and chemoattractant during oculomotor axon guidance. α2-chn is therefore a potential integrator of different types of guidance information to orchestrate ocular motor pathfinding. DRS phenotypes can result from incorrect regulation of this signaling pathway.
Peter Rudge - One of the best experts on this subject based on the ideXlab platform.
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paroxysmal alternating skew deviation and nystagmus after partial destruction of the uvula
Journal of Neurology Neurosurgery and Psychiatry, 2001Co-Authors: A Radtke, M. Faldon, Adolfo M Bronstein, M A Gresty, W Taylor, J M Stevens, Peter RudgeAbstract:A patient with suspected brain stem glioma involving the area of the left vestibular nuclei and cerebellar peduncle, developed paroxysmal alternating skew deviation and direction changing nystagmus after biopsy of the inferior cerebellar vermis resulting in destruction of the uvula. Between attacks she had right over left skew deviation with asymptomatic right beating horizontal nystagmus. Slow phases of the resting nystagmus showed increasing velocity, similar to congenital nystagmus. At intervals of 40-50 seconds, paroxysmal reversal of her skew deviation occurred, accompanied by violent left beating horizontal torsional nystagmus lasting 10-12 seconds and causing severe oscillopsia. It is proposed that this complex paroxysmal Eye Movement Disorder results from (1) a lesion in the left vestibular nuclei causing right over left skew and right beating resting nystagmus and (2) a disruption of cerebellar inhibition of vestibular nuclei, causing alternating activity in the vestibular system with intermittent reversal of the skew deviation and paroxysmal nystagmus towards the side of the lesion.
Bettina Balint - One of the best experts on this subject based on the ideXlab platform.
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oculomotor apraxia and disrupted sleep with nocturnal ballistic bouts in adcy5 related disease
Parkinsonism & Related Disorders, 2018Co-Authors: Sofia H Eriksson, Elena Antelmi, Alexander M. Bronstein, Matthew C. Walker, Amit Batla, Niccolo E. Mencacci, Bettina Balint, Kailash P. BhatiaAbstract:Abstract Objective To characterise the distinctive Eye Movement Disorder and the sleep-related dyskinesia in Adenylate cyclase 5 (ADCY5) related disease. Methods Formal Eye Movement examination and video-polysomnography in a cohort of patients with ADCY5 mutations. Results All three patients had an Eye Movement Disorder characterised by oculomotor apraxia with gaze limitation most prominently in the vertical plane. All patients had disrupted sleep architecture with reduced sleep efficiency due to frequent and prolonged arousals and awakenings in the context of dyskinesia, which could arise from any sleep stage. The nocturnal Movements could last up to 30 min and be more severe than those seen during day-time. Conclusion Nocturnal exacerbations of dyskinesia (“ballistic bouts”) seem to be a characteristic feature of the disease, affect the quality of life of patients and therefore require awareness and symptomatic treatment approaches. Apraxia of Eye Movements, with predominant difficulties in the vertical plane, was a common finding in our patients with ADCY5 mutations. These features may prompt the diagnosis and help to distinguish ADCY5-related disease from other childhood-onset hyperkinetic Movement Disorders.
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progressive encephalomyelitis with rigidity and myoclonus a new variant with dppx antibodies
Neurology, 2014Co-Authors: Bettina Balint, Sven Jarius, Simon Nagel, Uwe Haberkorn, Christian Probst, Inga Blocker, Ramona Bahtz, Lars Komorowski, Winfried Stocker, Andreas KastrupAbstract:Objective: To describe a novel and distinct variant of progressive encephalomyelitis with rigidity and myoclonus (PERM) associated with antibodies directed against dipeptidyl peptidase-like protein 6 (DPPX), a regulatory subunit of the Kv4.2 potassium channels on the surface of neurons. Methods: Case series describing the clinical, paraclinical, and serologic features of 3 patients with PERM. A recombinant, cell-based indirect immunofluorescence assay with DPPX-expressing HEK293 cells was used to detect DPPX antibodies in conjunction with mammalian tissues. Results: All patients presented with a distinct syndrome involving hyperekplexia, prominent cerebellar ataxia with marked Eye Movement Disorder, and trunk stiffness of variable intensity. Additional symptoms comprised allodynia, neurogenic pruritus, and gastrointestinal symptoms. Symptoms began insidiously and progressed slowly. An inflammatory CSF profile with mild pleocytosis and intrathecal immunoglobulin G synthesis was found in all patients. High DPPX antibody titers were detected in the patients9 serum and CSF, with specific antibody indices suggestive of intrathecal synthesis of DPPX antibodies. Response to immunotherapy was good, but constant and aggressive treatment may be required. Conclusion: These cases highlight the expanding spectrum of both PERM and anti-neuronal antibodies. Testing for DPPX antibodies should be considered in the diagnostic workup of patients with acquired hyperekplexia, cerebellar ataxia, and stiffness, because such patients might benefit from immunotherapy. Further studies are needed to elucidate both the entire clinical spectrum associated with DPPX antibodies and their role in pathogenesis.
H C Hopf - One of the best experts on this subject based on the ideXlab platform.
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a new method to investigate brain stem structural functional correlations using digital post processing mri reliability in ischemic internuclear ophthalmoplegia
European Journal of Neurology, 2001Co-Authors: J J Marx, Sabine Fitzek, Clemens Fitzek, P P Urban, Peter Stoeter, F Thoemke, Goran Vucurevic, A Mikagruettner, H C HopfAbstract:We investigated the reliability of a new digital post-processing magnetic resonance imaging (MRI) technique in ischemic brain stem lesions to identify relations of the lesion to anatomical brain stem structures. The target was a medial longitudinal fasciculus (MLF) lesion, which was evident from ipsilateral internuclear ophthalmoplegia (INO). Sixteen patients with acute unilateral INO and an isolated acute brain stem lesion in T2- and EPI-diffusion weighted MRI within 2 days after the onset of symptoms were studied. The MRI slice direction was parallel and perpendicular to a slice selection of a stereotactic anatomical atlas. The individual slices were normalized and projected in the digitalized atlas. The Eye Movement Disorder was monitored by electro-oculography. In all patients with clinical or subclinical electro-oculographically documented INO and MRI proven brain stem infarction the lesion covered or at least partially overlapped the ipsilateral MLF at one or more atlas levels. We conclude that digital post-processing MRI with normalizing and projecting brain stem lesions in an anatomical atlas is a reliable method to demonstrate the anatomical structures involved by the lesion. Combined with electrophysiological brain stem testing, this method may be a useful tool to identify incompletely understood pathways mediating brain stem reflexes or the generators of evoked potentials.
