Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UMLS:C0004134 (ataxia)
15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Spinocerebellar ataxias (SCAs) belong to a group of autosomal dominant, late-onset neurodegenerative disorders characterized by slowly progressive ataxia that eventually leads to severe gait, speech, coordination and sensory loss. The majority of these diseases result from expanded polyglutamine tracts in the encoded protein as seen in SCA1, SCA2, SCA3, SCA6, SCA7 and Dentatorubral-Pallidoluysian Atrophy (DRPLA). However, two novel forms of SCAs, SCA8 and SCA12, are associated with trinucleotide repeat expansions in non-translated regions of the genes. In the case of SCA8, the CUG expansion occurs at the 3' end of a processed non-coding RNA. While understanding of how expanded polyglutamine tracts compromise or alter protein function has advanced rapidly in the last five years, understanding of how trinucleotide repeat expansions alter the function of the non-coding SCA8 RNA and lead to human disease remains quite limited. Encouragingly, as discussed in this review, recent studies from murine and Drosophila models have provided new insights into both the cellular context in which SCA8 normally operates and the potential role of CTG expansion in the disease. Continued exploration of these genetically tractable model systems will further illuminate the biology underlying SCA8 disease, ultimately providing the necessary foundation on which to develop effective therapeutic interventions.
...
PMID:Molecular genetics of spinocerebellar ataxia type 8 (SCA8). 1713 42

The actin-binding protein Kelch-like 1 (KLHL1) is a neuronal protein that belongs to the evolutionarily-conserved Kelch protein super-family. The mammalian KLHL1 is brain-specific, cytosolic and can form multimers and bind actin filaments. KLHL1's function is likely that of an actin-organizing protein, possibly modulating neurite outgrowth, the dynamic morphology of dendritic spine heads; or anchoring proteins essential for post-synaptic function, like ion channels. Targeted deletion of the KLHL1 gene in Purkinje neurons results in dendritic deficits in these neurons, abnormal gait, and progressive loss of motor coordination in mice [He Y, Zu T, Benzow KA, Orr HT, Clark HB, Koob MD (2006) Targeted deletion of a single SCA8 ataxia locus allele in mice causes abnormal gait, progressive loss of motor coordination, and Purkinje cell dendritic deficits. J Neurosci 26:9975-9982]. Here we tested the hypothesis that KLHL1 may interact and modulate voltage-gated calcium channels by assessing the interaction of the principal subunit of P/Q-type channels, alpha(1A), with KLHL1. Experiments in human embryonic kidney line HEK 293 (HEK) cells and cerebellar primary cultures revealed co-incidence of alpha(1A) and KLHL1 immunoreactivity when testing both the endogenous or epitope-tagged versions of the proteins. Similarly, co-immunoprecipitation experiments in HEK cells and brain tissue exposed the presence of KLHL1 in protein samples immunoprecipitated with FLAG-tagged or alpha(1A) antibodies. Functional studies of KLHL1 on P/Q-type current properties probed with whole-cell patch clamp revealed a significant increase in mean current density in the presence of KLHL1 (80% increase; from -13.2+/-2.0 pA/pF to -23.7+/-4.2 pA/pF, P<0.02), as well as a shift in steady state activation V(50) of -5.5 mV (from 12.8+/-1.8 mV to 7.3+/-1.0 mV, P<0.02). Our data are consistent with a modulatory effect of KLHL1 on the P/Q-type calcium channel function and suggest a possible novel role for KLHL1 in cellular excitability.
...
PMID:The Kelch-like protein 1 modulates P/Q-type calcium current density. 1728 72

Hereditary spinocerebellar ataxia (SCA) is a cluster of heterogeneous disorders. At now, 29 dominant loci have been assigned. Responsible genes and mutations are determined in at least 14 of them. In recessive and X-linked SCAs, 15 loci have been mapped, and mutation in each gene is determined by 6 disorders. Molecular mechanism of those SCAs are variable. Generally, deletion, insertion, or substitution in a gene modifies the primary structure of mRNA, subsequently resulting in disturbance of transcription or in translation of mutant proteins showing loss-of-function or dominant negative effect. Large expansion of tandem repeat in promotor region or intron suppress translation of the gene, thus causing similar effect. Expansion of (CAG)n in coding exon is translated into proteins containing elongated poly-Q. Since the poly-Q fragment is cytotoxic, this kind of mutation causes protein toxic gain-of-function. In addition, RNA toxic gain-of-function mechanism recently gains attention as a new molecular mechanism of SCA8 and SCA10. Clinically, dominant SCA with dynamic mutation shows variable onset of age, severity, and variation of clinical phenotypes. Among this clinical complexity, vocal cord abductor paralysis in SCA1, familial parkinsonism in SCA2, vestibular dysfunction and axonal neuropathy in MJD, and axial myoclonus in SCA14, are reviewed for potential usefulness in clinical practice.
...
PMID:[Clinical feature and molecular genetics of hereditary spinocerebellar ataxia]. 1821 Aug 1

We administered a large battery of neuropsychological tests to an heterogeneous cohort of genetically defined spinocerebellar ataxia (SCA) patients in order to assess their cognitive profile and to compare cognitive impairment among different SCA genotypes, particularly between SCA with the classical pattern of olivo-ponto-cerebellar atrophy (SCA1 and SCA2) and those with a relatively "pure" olivo-cerebellar atrophy (SCA6 and SCA8). Our data revealed a neuropsychological picture characterized by fronto-parietal involvement with mnestic, linguistic, visuospatial, attentional, executive, and mood changes, in agreement with the cerebellar cognitive affective syndrome definition. We found a homogeneous neuropsychological profile among SCA subgroups with a prominent role of frontal dysfunction--particularly, attention, memory, and executive functions. We analyzed the possible interactions between neuropsychological pattern and clinical, demographical, and genetic variables. We found the presence of a cognitive impairment at the early stages of the disease, without visuospatial alterations, which appeared later. Age and education represented the most important demographic factors to predict the neuropsychological performance in SCA and in controls, but their effect in patients had definitely more impact. In our sample education could represent a protective factor and a marker of an enriched environment or a better developmental cognitive differentiation. We demonstrated that in our patients there was a distinct subgroup of high functional subjects and that triplet repeats modulated the effect of aging on cognition and progression of motor disability.
...
PMID:Neuropsychological picture of 33 spinocerebellar ataxia cases. 2130 72

Type I autosomal dominant cerebellar ataxia (ADCA) is a type of spinocerebellar ataxia (SCA) characterized by ataxia with other neurological signs, including oculomotor disturbances, cognitive deficits, pyramidal and extrapyramidal dysfunction, bulbar, spinal and peripheral nervous system involvement. The global prevalence of this disease is not known. The most common type I ADCA is SCA3 followed by SCA2, SCA1, and SCA8, in descending order. Founder effects no doubt contribute to the variable prevalence between populations. Onset is usually in adulthood but cases of presentation in childhood have been reported. Clinical features vary depending on the SCA subtype but by definition include ataxia associated with other neurological manifestations. The clinical spectrum ranges from pure cerebellar signs to constellations including spinal cord and peripheral nerve disease, cognitive impairment, cerebellar or supranuclear ophthalmologic signs, psychiatric problems, and seizures. Cerebellar ataxia can affect virtually any body part causing movement abnormalities. Gait, truncal, and limb ataxia are often the most obvious cerebellar findings though nystagmus, saccadic abnormalities, and dysarthria are usually associated. To date, 21 subtypes have been identified: SCA1-SCA4, SCA8, SCA10, SCA12-SCA14, SCA15/16, SCA17-SCA23, SCA25, SCA27, SCA28 and dentatorubral pallidoluysian atrophy (DRPLA). Type I ADCA can be further divided based on the proposed pathogenetic mechanism into 3 subclasses: subclass 1 includes type I ADCA caused by CAG repeat expansions such as SCA1-SCA3, SCA17, and DRPLA, subclass 2 includes trinucleotide repeat expansions that fall outside of the protein-coding regions of the disease gene including SCA8, SCA10 and SCA12. Subclass 3 contains disorders caused by specific gene deletions, missense mutation, and nonsense mutation and includes SCA13, SCA14, SCA15/16, SCA27 and SCA28. Diagnosis is based on clinical history, physical examination, genetic molecular testing, and exclusion of other diseases. Differential diagnosis is broad and includes secondary ataxias caused by drug or toxic effects, nutritional deficiencies, endocrinopathies, infections and post-infection states, structural abnormalities, paraneoplastic conditions and certain neurodegenerative disorders. Given the autosomal dominant pattern of inheritance, genetic counseling is essential and best performed in specialized genetic clinics. There are currently no known effective treatments to modify disease progression. Care is therefore supportive. Occupational and physical therapy for gait dysfunction and speech therapy for dysarthria is essential. Prognosis is variable depending on the type of ADCA and even among kindreds.
...
PMID:Autosomal dominant cerebellar ataxia type I: a review of the phenotypic and genotypic characteristics. 2161 91

Autosomal dominant cerebellar ataxias (ADCAs) encompass a heterogeneous group of rare diseases that affect the cerebellum and its connections. The most common forms have been associated with dynamic mutations while some rarer forms with conventional mutations. Studies in different populations revealed differences in their relative frequencies both within and between the studied populations, showing that the frequencies are depended on ethnic and geographical factors. Previous investigation of triplet repeat expansion SCAs (SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17 and DRPLA) in the Cypriot population, revealed no pathogenic expansion in the Cypriot SCA patients. We hereby present our recent investigation of the SCA10 pentanucleotide repeat expansion. Forty-two ascertained Cypriot sporadic ataxia patients, the index case from 1 ADCA and 14 ARCA families and a cohort of normal population individuals were included in the study. All our patients have normal range ATXN10 gene ATTCT repeat numbers (10-19). In the normal population group, repeat lengths ranged from 11 to 20 with the 14 repeats allele being the most frequent. Therefore, all currently established dynamic repeat SCA mutations are absent from the Cypriot population, indicating distinct genetic causes.
...
PMID:Investigation of SCA10 in the Cypriot population: further exclusion of SCA dynamic repeat mutations. 2302 38

Dominantly inherited ataxias (spinocerebellar ataxias, SCAs) are a genetically heterogeneous group of neurologic diseases characterized by progressive cerebellar and spinal tract degeneration with ataxia and other signs, common to all known subtypes. Several types are relatively frequent worldwide, but in several countries, one specific SCA may show a higher prevalence owing to founder phenomena. In Venezuela, genetic epidemiological features of SCAs have been assessed during the last 30 years; mutations in ATXN1 (SCA1), ATXN2 (SCA2), ATXN3 (SCA3), CACNA1A (SCA6), ATXN7 (SCA7), ATXN8 (SCA8), ATXN10 (SCA10), TBP (SCA17) and ATN1 (dentatorubral pallidoluysian atrophy, DRPLA) loci were searched among 115 independent families. SCA7 was the most frequent subtype (26.6%), followed by SCA3 (25.0%), SCA2 (21.9%), SCA1 (17.2%), SCA10 (4.7%) and DRPLA (3.1%); in 43% of the families, the subtype remained unidentified. SCA7 mutations displayed strong geographic aggregation in two independent founder foci, and SCA1 showed a very remote founder effect for a subset of families. SCA10 families were scattered across the country, but all had an identical in-phase haplotype carried also by Mexican, Brazilian and Sioux patients, supporting a very old common Amerindian origin. Prevalence for dominant SCAs in Venezuela was estimated as 1:25 000 nuclear families, provenances of which are either Caucasoid, African or Amerindian.
...
PMID:Spinocerebellar ataxias in Venezuela: genetic epidemiology and their most likely ethnic descent. 2653 2

Spinocerebellar degeneration (SCD) is a group of disorders characterized by progressive ataxia caused by dysfunction and atrophy of the cerebellum or its projections. Approximately one-third of SCD cases are familial SCD, the majority of which are attributed to CAG triplet repeat expansions including spinocerebellar ataxia (SCA)1, SCA2, Machado-Joseph disease (MJD)/SCA3, SCA6, SCA8, SCA12, SCA17, and dentate-rubro-pallido-luysian atrophy (DRPLA). The triplet repeat number of the alleles representing complete penetrance varies among diseases. Generally, there is a gap between the normal alleles and the complete penetrance alleles. Rarely, intermediate alleles with the repeat numbers between the abnormal and normal ranges are observed, although the implications of these intermediate alleles remain ambiguous.
...
PMID:Compound heterozygous intermediate MJD alleles cause cerebellar ataxia with sensory neuropathy. 2789 16

Trinucleotide repeat disorders comprise a variable group of inherited neurodegenerative diseases, with a large range in prevalence figures. There is a broad range in clinical presentations, but many of these diseases lead to some form of ataxia or other movement disorders, which are frequently combined with cognitive or psychiatric disturbances. This group can be divided into CAG- versus non-CAG-repeat diseases. Apart from spinocerebellar ataxia type 6 and 12 (SCA6 and SCA12), these CAG-repeat diseases, as well as Huntington disease-like 2 (HDL2) and SCA8, can be neuropathologically identified using 1C2 polyglutamine antibodies. In fragile X-associated tremor and ataxia, SCA6 and SCA12 ubiquitin/p62-positive and 1C2-negative inclusion bodies can be observed. In the other diseases proteinaceous inclusions are not found. For definite diagnosis genetic analysis is necessary.
...
PMID:Trinucleotide repeat disorders. 2898 84

Oculomotor abnormalities are common in the spinocerebellar ataxias (SCAs). In studies of SCAs 1, 2, 3, and 6, eye movement abnormalities correlate with disease severity. Oculomotor abnormalities may be the sole motor manifestation of early and/or premanifest disease; however, not all ataxia rating scales include oculomotor assessment. We sought to identify the prevalence and characteristics of oculomotor abnormalities at first presentation in a large SCA cohort, including those in earlier stages of disease. We performed a retrospective assessment of initial clinical examinations of SCA patients followed in the Massachusetts General Hospital Ataxia Unit and assessed with the Brief Ataxia Rating Scale (BARS). One hundred thirty-four SCA patients were assessed: 17 SCA1, 13 SCA2, 55 SCA3, 2 SCA5, 22 SCA6, 11 SCA7, 9 SCA8, and 5 SCA17, mainly in the early stages of disease (67.2% stage 0-1). Oculomotor abnormalities were present on initial assessment in 94.8%, including 7/9 stage 0 and 77/81 stage 1 patients. Stage 0/1 patients had frequent saccadic intrusions, nystagmus, and hypo/hypermetric saccades. Saccadic slowing was present even in early stage SCA7 and SCA2, eventually leading to ophthalmoplegia. The burden of oculomotor abnormalities correlated with disease stage, duration, and severity, remaining highly significant even when controlling for age. The ubiquitous presence of oculomotor abnormalities in the SCAs, particularly early in the course, underscores the importance of oculomotor assessment in ataxia rating scales such as BARS. These findings highlight the potential for quantitative physiological oculomotor measures as clinical biomarkers in natural history studies and clinical trials.
...
PMID:Eye Movement Abnormalities Are Ubiquitous in the Spinocerebellar Ataxias. 3117 30


<< Previous 1 2 3 4 Next >>

---