Journal ArticleDOI
Spinocerebellar ataxia type 6: Gaze‐evoked and vertical nystagmus, Purkinje cell degeneration, and variable age of onset
Christopher M. Gomez,Randall Thompson,Jason T. Gammack,Susan Perlman,William B. Dobyns,Charles L. Truwit,David S. Zee,H. Brent Clark,John H. Anderson +8 more
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TLDR
Clinical and quantitative measurement of extraocular movements demonstrated a characteristic pattern of ocular motor and vestibular abnormalities, including horizontal and vertical nystagmus and an abnormal vestibulo‐ocular reflex, which identifies a distinct phenotype associated with this newly recognized form of dominant SCA.Abstract:
Spinocerebellar ataxia type 6 (SCA6) was recently identified as a form of autosomal dominant cerebellar ataxia associated with small expansions of the trinucleotide repeat (CAG)n in the gene CACNL1A4 on chromosome 19p13, which encodes the α1 subunit of a P/Q-type voltage-gated calcium channel. We describe clinical, genetic, neuroimaging, neuropathological, and quantitative oculomotor studies in four kindreds with SCA6. We found strong genetic linkage of the disease to the CACNL1A4 locus and strong association with the expanded (CAG)n alleles in two large ataxia kindreds. The expanded alleles were all of a single size (repeat number) within the two large kindreds, numbering 22 and 23 repeat units. It is noteworthy that the age of onset of ataxia ranged from 24 to 63 years among all affected individuals, despite the uniform repeat number. Radiographically and pathologically, there was selective atrophy of the cerebellum and extensive loss of Purkinje cells in the cerebellar cortex. In addition, clinical and quantitative measurement of extraocular movements demonstrated a characteristic pattern of ocular motor and vestibular abnormalities, including horizontal and vertical nystagmus and an abnormal vestibulo-ocular reflex. These studies identify a distinct phenotype associated with this newly recognized form of dominant SCA.read more
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Journal ArticleDOI
Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis.
TL;DR: The identification of ataxia genes raises hope that essential pathogenetic mechanisms causing SCA will become more and more apparent, and will enable the development of rational therapies for this group of disorders, which currently can only be treated symptomatically.
Journal ArticleDOI
Sensory Prediction Errors Drive Cerebellum-Dependent Adaptation of Reaching
TL;DR: Adaptation to visuomotor perturbations depends on the cerebellum and is driven by the mismatch between predicted and actual sensory outcome of motor commands, suggesting that only sensory prediction errors influence this process.
Journal ArticleDOI
Molecular basis of the neurodegenerative disorders.
TL;DR: Mendelian inheritance can be demonstrated in many of these disorders and senile plaques, neurofibrillary tangles, neuronal loss, and acetylcholine deficiency define Alzheimer's disease and Parkinson's disease.
Journal ArticleDOI
Use-Dependent and Error-Based Learning of Motor Behaviors
TL;DR: This work shows that error-based and use-dependent learning can change motor behavior simultaneously in opposing directions by physically constraining the direction of active movements and determines the solution the motor system adopts when learning a motor task.
Journal ArticleDOI
Brain pathology of spinocerebellar ataxias
TL;DR: The genetic and clinical background of the known SCAs are reported, the state of neuropathological investigations of brain tissue from SCA patients in the final disease stages are presented, and detailed molecular and pathogenetic consequences remain to be determined.
References
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Book
The neurology of eye movements
R. John Leigh,David S. Zee +1 more
TL;DR: The Neurology of Eye Movements: Characteristics and Teleology by R. John Leigh, M.D., and David S. Zee MD as mentioned in this paper is a survey of eye movement.
Journal ArticleDOI
Familial Hemiplegic Migraine and Episodic Ataxia Type-2 Are Caused by Mutations in the Ca2+ Channel Gene CACNL1A4
Roel A. Ophoff,Gisela M. Terwindt,Monique N. Vergouwe,Ronald van Eijk,Peter J. Oefner,Susan M.G. Hoffman,Jane Lamerdin,Harvey W. Mohrenweiser,Dennis E. Bulman,Maurizio Ferrari,Joost Haan,Dick Lindhout,Gert-Jan B. van Ommen,Marten H. Hofker,Michel D. Ferrari,Rune R. Frants +15 more
TL;DR: A brain-specific P/Q-type Ca2+ channel alpha1-subunit gene, CACNL1A4, covering 300 kb with 47 exons is characterized, revealing polymorphic variations, including a (CA)n-repeat (D19S1150), a (CAG) n-repeat in the 3'-UTR, and different types of deleterious mutations in FHM and EA-2.
Journal ArticleDOI
CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1
Yoshiya Kawaguchi,Toshihiro Okamoto,Masafumi Taniwaki,Megumi Aizawa,Miho Inoue,Sadao Katayama,Hideshi Kawakami,Shigenobu Nakamura,Masaki Nishimura,Ichiro Akiguchi,Jun Kimura,Shuh Narumiya,Akira Kakizuka +12 more
TL;DR: Southern blot analyses and genomic cloning demonstrates the existence of related genes, raising the possibility that similar abnormalities in related genes may give rise to diseases similar to Machado-Joseph disease.
Journal ArticleDOI
Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1.
Harry T. Orr,Ming Yi Chung,Sandro Banfi,Thomas J. Kwiatkowski,Antonio Servadio,Arthur L. Beaudet,Alanna E. McCall,Lisa A. Duvick,Laura P.W. Ranum,Huda Y. Zoghbi +9 more
TL;DR: There is a direct correlation between the size of the (CAG)n repeat expansion and the age–of–onset of SCA1, with larger alleles occurring in juvenile cases.
Journal ArticleDOI
Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the α(1A)-voltage-dependent calcium channel
Olga Zhuchenko,Jennifer Bailey,Penelope E. Bonnen,T. Ashizawa,T. Ashizawa,David W. Stockton,Christopher I. Amos,William B. Dobyns,S. H. Subramony,Huda Y. Zoghbi,Cheng Chi Lee +10 more
TL;DR: It is concluded that a small polyglutamine expansion in the human α1A calcium channel is most likely the cause of a newly classified autosomal dominant spinocerebellar ataxia, SCA6.
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