Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029089 (ophthalmoplegia)
 3,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inherited, autosomal-dominant cerebellar ataxia (ADCA) comprises a genetically and clinically heterogenous group of neurodegenerative disorders. Clinical classification of these disorders was an important step [2] in differentiation among several types, the most common one being ADCA-I, accompanied with supranuclear ophthalmoplegia, optic nerve atrophy, symptoms of the basal ganglia lesions, dementia and amyotrophia. Molecular-genetic studies indicated genetic heterogeneity of ADCA-I with mutations of genetic loci on chromosome 6p (spinocerebellar ataxia type 1; SCA1), 12q (SCA2), 14q (SCA3), 19p (SCA6) and 16q (SCA4) [3]. Spinocerebellar ataxia type 1 (SCA1) is characterized by cerebellar ataxia, ophthalmoplegia and pyramidal signs [4], but also with other neurological findings that tend to prevent clinical differentiation among patients with SCA1, SCA2 and SCA3. The mutation inducing SCA1 is an instable expansion of trinucleotide (CAG) repeats in the coding region on chromosome 6 [5]. Herein, we report clinical features in patients from two families with SCA1: family I with 15 and family II with 8 affected members in 4 consecutive generations. The acceptable data (history, examination and/or insight into medical records) were obtained for 9 patients in family I and 7 patients in family II. The age at the onset of the disease was 37.8 +/- 11.3 years (mean value +/- SD) (range: 27-60) for all the patients, or 31.8 +/- 10.7 years (range: 7-60) for family I and 45.0 +/- 8.4 years (range: 35-55) for family II. Duration of the disease was 8.9 +/- 4.6 years (range: 3-15); 10.8 +/- 4.1 (range 5-15) and 5.7 +/- 3.8 years (range: 3-10) for families I and II, respectively. The mean number of CAG repeats in the mutated allele for SCA1 of the affected individuals was 50.5 +/- 6.2 (range 45-64). A significant inverse correlation (p < 0.05) was noted between the number of CAG repeats and the age at the onset of the disease (Figure 3). Similarity of initial symptoms in SCA1 was noted. They include simultaneous gait-related problems and dysarthria (usually slurred speech). Occurrence of other neurological signs (Table 3) was also predictable in most cases and depended on the phase of SCA1 at the time of examination. Generally, it is believed that intra- and interfamilial phenotypic heterogeneity in SCA1 is lower than in SCA2 and SCA3 [12]). In conclusion, typical clinical manifestations of SCA1, at least in early phases of the disease, according to our study, include gait ataxia, dysarthria, brisk muscle reflexes and marked hand ataxia; the age at the onset of the disease was inverse, and clinical progression was directly related to the number of CAG repeats in the mutated allele on chromosome 6. Nevertheless, significant differences in clinical properties of this inherited disease are possible among different affected families.
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PMID:[Clinico-genetic study of type I spinocerebelllar ataxia]. 1050 Apr 22

Spinocerebellar ataxias (SCAs) are a clinically heterogeneous group of disorders. Current molecular classification corresponds to the order of gene description (SCA1-SCA 25). The prevalence of SCAs is estimated to be 1-4/100,000. Patients exhibit usually a slowly progressive cerebellar syndrome with various combinations of oculomotor disorders, dysarthria, dysmetria/kinetic tremor, and/or ataxic gait. They can present also with pigmentary retinopathy, extrapyramidal movement disorders (parkinsonism, dyskinesias, dystonia, chorea), pyramidal signs, cortical symptoms (seizures, cognitive impairment/behavioral symptoms), peripheral neuropathy. SCAs are also genetically heterogeneous and the clinical diagnosis of subtypes of SCAs is complicated by the salient overlap of the phenotypes between genetic subtypes. The following clinical features have some specific values for predicting a gene defect: slowing of saccades in SCA2, ophthalmoplegia in SCA1, SCA2 and SCA3, pigmentary retinopathy in SCA7, spasticity in SCA3, dyskinesias associated with a mutation in the fibroblast growth factor 14 (FGF 14) gene, cognitive impairment/behavioral symptoms in SCA17 and DRPLA, seizures in SCA10, SCA17 and DRPLA, peripheral neuropathy in SCA1, SCA2, SCA3, SCA4, SCA8, SCA18 and SCA25. Neurophysiological findings are compatible with a dying-back axonopathy and/or a neuronopathy. Three patterns of atrophy can be identified on brain MRI: a pure cerebellar atrophy, a pattern of olivopontocerebellar atrophy, and a pattern of global brain atrophy. A remarkable observation is the presence of dentate nuclei calcifications in SCA20, resulting in a low signal on brain MRI sequences. Several identified mutations correspond to expansions of repeated trinucleotides (CAG repeats in SCA1, SCA2, SCA3, SCA6, SCA7, SCA17 and DRPLA, CTG repeats in SCA8). A pentanucleotide repeat expansion (ATTCT) is associated with SCA10. Missense mutations have also been found recently. Anticipation is a main feature of SCAs, due to instability of expanded alleles. Anticipation may be particularly prominent in SCA7. It is estimated that extensive genetic testing leads to the identification of the causative gene in about 60-75 % of cases. Our knowledge of the molecular mechanisms of SCAs is rapidly growing, and the development of relevant animal models of SCAs is bringing hope for effective therapies in human.
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PMID:The wide spectrum of spinocerebellar ataxias (SCAs). 1589 52

Autosomal Dominant Cerebellar Ataxia (ADCA) Type III is a type of spinocerebellar ataxia (SCA) classically characterized by pure cerebellar ataxia and occasionally by non-cerebellar signs such as pyramidal signs, ophthalmoplegia, and tremor. The onset of symptoms typically occurs in adulthood; however, a minority of patients develop clinical features in adolescence. The incidence of ADCA Type III is unknown. ADCA Type III consists of six subtypes, SCA5, SCA6, SCA11, SCA26, SCA30, and SCA31. The subtype SCA6 is the most common. These subtypes are associated with four causative genes and two loci. The severity of symptoms and age of onset can vary between each SCA subtype and even between families with the same subtype. SCA5 and SCA11 are caused by specific gene mutations such as missense, inframe deletions, and frameshift insertions or deletions. SCA6 is caused by trinucleotide CAG repeat expansions encoding large uninterrupted glutamine tracts. SCA31 is caused by repeat expansions that fall outside of the protein-coding region of the disease gene. Currently, there are no specific gene mutations associated with SCA26 or SCA30, though there is a confirmed locus for each subtype. This disease is mainly diagnosed via genetic testing; however, differential diagnoses include pure cerebellar ataxia and non-cerebellar features in addition to ataxia. Although not fatal, ADCA Type III may cause dysphagia and falls, which reduce the quality of life of the patients and may in turn shorten the lifespan. The therapy for ADCA Type III is supportive and includes occupational and speech modalities. There is no cure for ADCA Type III, but a number of recent studies have highlighted novel therapies, which bring hope for future curative treatments.
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PMID:Autosomal dominant cerebellar ataxia type III: a review of the phenotypic and genotypic characteristics. 2333 13

Hereditary spinocerebellar degenerations (SCD) are a group of neurodegenerative disorders characterized by slowly progressive ataxia associated with non-cerebellar neurological signs and symptoms. In the Japanese population, dominantly inherited SCDs are much more common than recessively inherited or X-linked SCDs. The most common dominantly inherited SCD in Japan, as well as in many other countries, is Machado-Joseph disease, also known as spinocerebellar ataxia type 3 (MJD/SCA3). MJD/SCA3 is frequently accompanied by non-cerebellar symptoms, including progressive external ophthalmoplegia, pyramidal signs, dystonia, rigidity, dysarthria, and distal muscle atrophies. SCA6 and SCA31 represent a pure cerebellar subtype of SCD, occasionally accompanied by non-cerebellar signs. Detailed medical history and neurological examination are important for clinicians to diagnose hereditary SCDs, although genetic testing can help confirm the diagnosis. Despite increasing understanding of the molecular mechanisms underlying these fatal diseases, preventive therapies are currently lacking.
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PMID:[Overview of Hereditary Spinocerebellar Ataxias in Japan]. 2881 72

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.
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PMID:Eye Movement Abnormalities Are Ubiquitous in the Spinocerebellar Ataxias. 3117 30