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)

The SCA19 locus on chromosome 1p21-q21 was identified in a Dutch family in 2002. Affected individuals displayed a lateonset slowly progressive mild cerebellar ataxia, hyporeflexia, and signs of frontal lobe dysfunction. A postural head tremor and myoclonic movements were observed occasionally. Before the SCA19 locus was identified, the SCA22 symbol had been assigned to a locus on 1p21-q23 following a linkage study of a Chinese family with spinocerebellar ataxia. Although both SCA19 and SCA22 are linked to 1p21-q21, the clinical features are slightly different. While it cannot be excluded that the genes lie in close approximation at this locus, it is more likely that the same gene is mutated in both the Dutch and Chinese families, and that SCA19 and SCA22 represent the same condition.
Cerebellum 2005
PMID:Clinical, psychological, and genetic characteristics of spinocerebellar ataxia type 19 (SCA19). 1589 60

Spinocerebellar ataxia type 20 (SCA20) was reported in 2004 in a single Australian Anglo-Celtic pedigree. The phenotype is distinctive, with palatal tremor, and hypermetric saccades, and early dentate (but not pallidal) calcification in the absence of abnormalities of calcium metabolism. Dysarthria, rather than gait ataxia, was the initial symptom in most, and was typically conjoined with dysphonia, clinically resembling adductor spasmodic dysphonia. The onset of these speech abnormalities was abrupt in some cases. MRI scanning showed mild to moderate pancerebellar atrophy with dentate calcification, with olivary pseudohypertrophy in some cases, in the absence of other brainstem or cerebral changes. Nerve conduction studies were normal. Progression appeared to be slow. SCA20 is probably rare, as despite the distinctive phenotype, only this one pedigree has been described. The locus mapped to the pericentromeric region of chromosome 11 with a LOD score of 4.47, and its candidate region overlaps that of SCA5. It seems probable that these two SCAs may be separate genetic entities, on the basis of their divergent clinical features, but formal proof awaits discovery of one or both responsible genes.
Cerebellum 2005
PMID:Spinocerebellar ataxia type 20. 1589 61

Six forms of spinocerebellar ataxia (SCA) are caused by pathological cytosine-adenine-guanine (CAG) trinucleotide repeat expansions in the coding region of the mutated genes. The translated proteins contain abnormally long polyglutamine stretches, and SCA-1, SCA-2, SCA-3/Machado-Joseph disease (MJD), SCA-6, SCA-7, and SCA-17 are "polyglutamine diseases". Despite their clinical and genetic heterogeneity, the ataxia-causing lesions in the brain invariably affect the "cerebellar module" that is defined as a reciprocal circuitry between the cerebellar cortex, the dentate nuclei, and the inferior olivary nuclei. While the neurons of the basis pontis do not properly belong to this module, pontine atrophy is an important additional lesion in SCA-1, SCA-2, and SCA-7. The descriptive term olivopontocerebellar atrophy (OPCA) applies to these forms whereas SCA-6 is the prototype of "pure" cerebellar cortical or cerebello-olivary atrophy. Purkinje cells have an elaborate dendritic tree, and atrophy of these most remarkable cells has captured the attention of many morphologists. Almost invariably, the loss of Purkinje cells entails retrograde neuronal degeneration in the inferior olivary nuclei. However, SCA-6 is an exception, and many olivary neurons survive. Similarly, stellate, basket, and granule cells do not undergo commensurate retrograde atrophy when Purkinje cells disappear. The dentate nucleus displays "grumose" degeneration in SCA-3/MJD while the cerebellar cortex and the inferior olivary nuclei remain largely unaffected. The role of polyglutamine-containing intranuclear and cytoplasmic inclusion bodies in SCA remains unknown but protein aggregation may be the common step in the pathogenesis of these otherwise rather heterogeneous disorders.
Cerebellum 2005
PMID:The pathogenesis of spinocerebellar ataxia. 1589 63

Effective, pharmacologic approaches to the treatment of cerebellar ataxia are lacking or inadequate. We recently reported preliminary evidence that tandospirone citrate (tandospirone), a 5-HT1A agonist, improved cerebellar ataxia in patients with Machado-Joseph disease (MJD). In the course of that study, we found that such treatment also alleviated the pain associated with cold sensations in the legs, insomnia, anorexia, and depression, all of which are thought to be mediated through activation of the 5-HT1A receptor. In this paper, we reviewed the few published clinical trials that involved the use of 5-HT1A receptor agonists for the treatment of cerebellar ataxia, and discussed the current theories regarding their mechanism of action. Cortical cerebellar atrophy (CCA) was reported, in a double-blind study, to be amenable to treatment with tandospirone. Other types of spinocerebellar degeneration (SCD) i.e., olivopontocerebellar atrophy (OPCA) and Machado-Joseph disease (MJD) have also been reported to respond to the drug, but these have been small studies. Responsive patients exhibited only mild ataxia. The doses of 5-HT1A agonists that have been used successfully ranged from 12.5 mg/day to 60 mg/day (or 1 mg/kg), and were well tolerated by most patients.
Cerebellum 2005
PMID:Treatment of cerebellar ataxia with 5-HT1A agonist. 1614 54

The cerebellum regulates execution of skilled movements through neural connections with the primary motor cortex. A main projection from the cerebellum to the primary motor cortex is a disynaptic excitatory pathway relayed at the ventral thalamus. This dentatothalamocortical pathway receives inhibitory inputs from Purkinje cells of the cerebellar cortex. These pathways (cerebellothalamocortical pathways) have been characterized extensively using cellular approaches in animals. Advances in non-invasive transcranial activation of neural structures using electrical and magnetic stimulation have allowed us to investigate these neural connections in humans. This review summarizes various studies of the cerebellothalamocortical pathway in humans using current transcranial electrical and magnetic stimulation techniques. We studied effects on motor cortical excitability elicited by electrical or magnetic stimulation over the cerebellum by recording surface electromyographic (EMG) responses from the first dorsal interosseous (FDI) muscle. Magnetic stimuli were given with a round or figure eight coil (test stimulation) for primary motor cortical activation. For cerebellar stimulation, we gave high-voltage electrical stimuli or magnetic stimuli through a cone-shaped coil ipsilateral to the surface EMG recording (conditioning stimulation). We examined effects of interstimulus intervals (ISIs) with randomized condition-test paradigm, using a test stimulus given preceded by a conditioning stimulus by ISIs of several milliseconds. We demonstrated significant gain of EMG responses at an ISI of 3 ms (facilitatory effect) and reduced responses starting at 5 ms, which lasted 3-7 ms (inhibitory effect). We applied this method to patients with ataxia and showed that the inhibitory effect was only absent in patients with a lesion at cerebellar efferent pathways or dentatothalamocortical pathway. These results imply that this method activates the unilateral cerebellar structures. We confirmed facilitatory and inhibitory natures of cerebellothalamocortical pathways in humans. We can differentiate ataxia attributable to somewhere in the cerebello-thalamo-cortical pathways from that caused by other pathways.
Cerebellum 2005
PMID:The effects of cerebellar stimulation on the motor cortical excitability in neurological disorders: a review. 1632 76

Cerebellum has been assumed as an array of adjustable pattern generators (APGs). In recent years, electrophysiological researches have suggested the existence of modular structures in spinal cord called motor primitives. In our proposed model, each "adjustable primitive pattern generator" (APPG) module in the cerebellum is consisted of a large number of parallel APGs, the output of each module being the weighted sum of the outputs of these APGs. Each spinal field is tuned by a coefficient, representing a descending supraspinal command, which is modulated by ith APPG correspondingly. According to this model, motor control can be interpreted in terms of the modification of these coefficients. Vector summation of force fields implies that the complex nonlinearities in neuronal behavior are eliminated, causing our model to be simple and linear. The force field vectors, derived from motor primitives, depend on the state of movement and its derivative and the time that causes different repertoire of movement. This is physiologically plausible. Our model agrees with virtual trajectory hypothesis, stating that dynamics are not computed explicitly in central nervous system, but the desired trajectory, is fed into the spinal cord. We think that the dysmetria and the ataxia seen in some cerebellar diseases may be the result of local disruption of some APPGs. Accordingly, determining the exact location of related motor primitives in human spinal cord and stimulating them by functional neurostimulation may provide a good management for these clinical signs. Surely, experimental researches and clinical trials are needed to validate our hypothesis.
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PMID:Adjustable primitive pattern generator: a novel cerebellar model for reaching movements. 1693 Aug 35

The cerebellum is important for movement control and plays a critical role in balance and locomotion. As such, one of the most characteristic and sensitive signs of cerebellar damage is gait ataxia. How the cerebellum normally contributes to locomotor behavior is unknown, though recent work suggests that it helps generate appropriate patterns of limb movements, dynamically regulate upright posture and balance, and adjust the feedforward control of locomotor output through error-feedback learning. The purpose of this review is to examine mechanisms of cerebellar control of locomotion, emphasizing studies of humans and other animals. Implications for rehabilitation are also considered.
Cerebellum 2007
PMID:Mechanisms of cerebellar gait ataxia. 1736 69

Over the last decade, increasing evidence of cognitive functions of the cerebellum during development and learning processes could be ascertained. Posterior fossa malformations such as cerebellar hypoplasia or Joubert syndrome are known to be related to developmental problems in a marked to moderate extent. More detailed analyses reveal special deficits in attention, processing speed, visuospatial functions and language. A study about Dandy Walker syndrome states a relationship of abnormalities in vermis lobulation with developmental problems. Further lobulation or volume abnormalities of the cerebellum and/or vermis can be detected in disorders as fragile X syndrome, Downs's syndrome or William's syndrome. Neuropsychological studies reveal a relation of dyslexia and attention deficit disorder with cerebellar functions. These functional studies are supported by structural abnormalities in neuroimaging in these disorders. Acquired cerebellar or vermis atrophy was found in groups of children with developmental problems such as prenatal alcohol exposure or extreme prematurity. Also focal lesions during childhood or adolescence such as cerebellar tumour or stroke are related with neuropsychological abnormalities, which are most pronounced in visuo-spatial, language and memory functions. In addition, cerebellar atrophy was shown to be a bad prognostic factor considering cognitive outcome in children after brain trauma and leukaemia. In ataxia teleangiectasia, a neurodegenerative disorder affecting primarily the cerebellar cortex, a reduced verbal IQ and problems of judgment of duration are a hint of the importance of the cerebellum in cognition. In conclusion, the cerebellum seems to play an important role in many higher cognitive functions especially in learning. There is a suggestion that the earlier the incorrect influence the more pronounced the problems.
Cerebellum 2007
PMID:The cerebellum in cognitive processes: supporting studies in children. 1778 20

A central aspect of the cerebellar cognitive affective syndrome is the dysregulation of affect that occurs when lesions involve the 'limbic cerebellum' (vermis and fastigial nucleus). In this case series we describe neuropsychiatric disturbances in adults and children with congenital lesions including cerebellar agenesis, dysplasia, and hypoplasia, and acquired conditions including cerebellar stroke, tumor, cerebellitis, trauma, and neurodegenerative disorders. The behaviors that we witnessed and that were described by patients and families included distractibility and hyperactivity, impulsiveness, disinhibition, anxiety, ritualistic and stereotypical behaviors, illogical thought and lack of empathy, as well as aggression and irritability. Ruminative and obsessive behaviors, dysphoria and depression, tactile defensiveness and sensory overload, apathy, childlike behavior, and inability to appreciate social boundaries and assign ulterior motives were also evident. We grouped these disparate neurobehavioral profiles into five major domains, characterized broadly as disorders of attentional control, emotional control, and social skill set as well as autism spectrum disorders, and psychosis spectrum disorders. Drawing on our dysmetria of thought hypothesis, we conceptualized the symptom complexes within each putative domain as reflecting either exaggeration (overshoot, hypermetria) or diminution (hypotonia, or hypometria) of responses to the internal or external environment. Some patients fluctuated between these two states. We consider the implications of these neurobehavioral observations for the care of patients with ataxia, discuss the broader role of the cerebellum in the pathogenesis of these neuropsychiatric symptoms, and revisit the possibility of using cerebellar stimulation to treat psychiatric disorders by enhancing cerebellar modulation of cognition and emotion.
Cerebellum 2007
PMID:The neuropsychiatry of the cerebellum - insights from the clinic. 1778 22

The spinocerebellar ataxia type 17 (SCA17) is characterized by cerebellar ataxia, dementia, and involuntary movements, including chorea and dystonia. In addition, psychiatric symptoms, pyramidal signs, and rigidity are common. MRI shows variable atrophy of the cerebrum, brainstem, and cerebellum. The autosomal dominantly inherited progressive neurodegenerative disorder is caused by an expanded CAA/CAG repeat coding for glutamine. Alleles of the normal range carry 25 to 42 glutamine residues, disease causing alleles 43 to 63. Alleles with 43 to 48 glutamine codons may be associated with incomplete penetrance. The mean age of onset is about 30 years for individuals with full-penetrance alleles, but ranges from three to 55 years.
Cerebellum 2007
PMID:Spinocerebellar ataxia type 17 is caused by mutations in the TATA-box binding protein. 1785 80


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