Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0013362 (dysarthria)
 3,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A systematic search for cases of adult-onset hereditary ataxia was conducted on location in Scotland. The investigation resulted in the discovery of eight pedigrees with 42 patients of whom 16 were alive in 1975. Nine patients were examined by the authors and recent hospital records were available on the remaining seven. The clinical features were quite variable. In declining order of frequency, findings were gait and limb ataxia, dysarthria, hyperreflexia, extrapyramidal motor disturbances, impaired vibratory sense, spasticity, defects of extraocular movements and nystagmus, reflex depression, Babinski signs, impaired joint position sense, muscle weakness, optic atrophy, and mental abnormalities. Foot deformity occurred only once. Inheritance was compatible with autosomal dominant transmission, but complicated by consanguinity in two families. The minimum prevalence was calculated as 0.31/100,000. Autopsy in two members in one family revealed olivopontocerebellar degeneration.
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PMID:Adult-onset hereditary ataxia in Scotland. 90 33

Patients with cerebellar disease may exhibit tremulous phonation as part of their dysarthria. The results of an acoustic analysis of cerebellar voice tremor in a patient with hereditary ataxia and presenting with a purely cerebellar syndrome are reported. Analysis included computation of speech intensity contours, fundamental frequency contours, and spectral parameters from sustained productions of vowels and voiceless fricatives. Fundamental frequency contours during sustained phonation of vowels showed rhythmic oscillations at a rate of about 3 Hz. No concomitant periodicity could be detected for the parameters characterising voiceless fricative production. The results indicate an impairment of phonatory control in relation to the maintenance of a constant isometric activity of the internal laryngeal muscles. Cerebellar voice tremor may therefore be classified as a form of postural tremor.
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PMID:Cerebellar voice tremor: an acoustic analysis. 201 Jul 64

Because linkage has been reported between HLA and the locus for hereditary ataxia in some families, we studied a 3-generation kindred in which several individuals had dominantly inherited spinopontine atrophy. Affected family members had upper and lower limb ataxia, hypoactive reflexes, loss of proprioception, dysarthria, dysphagia, and pronounced extraocular movement abnormalities. Linkage analysis, based on 25 markers in 28 people, gave strongly negative results with both HLA (z less than -2.0 for theta less than 0.15) and GLO1 (z less than -2.0, theta less than or equal to 0.01). The highest LOD score was for linkage to GPT on chromosome 16 (z = 0.42, theta = 0.0). To assess the relationship between HLA linkage and phenotype, 4 published kindreds with adequate clinical and neuropathological descriptions were used for comparison to the present family. Persons in the 3 families showing evidence for HLA linkage had clinical and pathologic changes consistent with olivopontocerebellar atrophy, type 1. The conditions in the 2 "nonlinked" families were phenotypically distinct from the HLA-linked condition with respect to extraocular movement findings and peripheral sensory nervous system signs. They differed markedly from each other in neuropathologic changes.
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PMID:Linkage analysis in spinopontine atrophy: correlation of HLA linkage with phenotypic findings in hereditary ataxia. 347 98

Joseph's disease is a hereditary ataxia found among descendants of Portuguese from the Azores Islands. We describe the clinical and pathological features of 4 members of a Japanese family who were diagnosed as having Joseph's disease. The illness began with cerebellar ataxia between the ages of 18 and 45 years. Nystagmus, dysarthria, and pyramidal signs were early manifestations. External ophthalmoplegia, dystonia and/or athetotic movements, and muscular atrophy appeared in the late stages. Neuropathological findings in one patient revealed degeneration of the dentatorubral and pallidoluysian systems, substantia nigra, pontocerebellar system, Clarke's column and spinocerebellar tracts, and anterior horn cells, as well as the cranial nuclei in the brainstem. Neurons in the inferior olivary nuclei, Purkinje's and granule cells, the cerebral cortex, thalamus, and striatum were spared. Involvement of the dentatorubral and pallidoluysian systems seems to be a characteristic feature of this disease in Japan.
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PMID:Joseph's disease: clinical and pathological studies in a Japanese family. 396 57

Spinocerebellar ataxia type 4 (SCA4), also known as 'hereditary ataxia with sensory neuropathy', represents a very rare, progressive and untreatable form of an autosomal dominant inherited cerebellar ataxia (ADCA). Due to a lack of autopsy cases, no neuropathological or clinicopathological studies had yet been performed in SCA4. In the present study, the first available cerebellar and brainstem tissue of a clinically diagnosed and genetically-confirmed German SCA4 patient was pathoanatomically studied using serial thick sections. During this systematic postmortem investigation, along with an obvious demyelinization of cerebellar and brainstem fiber tracts we observed widespread cerebellar and brainstem neurodegeneration with marked neuronal loss in the substantia nigra and ventral tegmental area, central raphe and pontine nuclei, all auditory brainstem nuclei, in the abducens, principal trigeminal, spinal trigeminal, facial, superior vestibular, medial vestibular, interstitial vestibular, dorsal motor vagal, hypoglossal, and prepositus hypoglossal nuclei, as well as in the nucleus raphe interpositus, all dorsal column nuclei, and in the principal and medial subnuclei of the inferior olive. Severe neuronal loss was seen in the Purkinje cell layer of the cerebellum, in the cerebellar fastigial nucleus, in the red, trochlear, lateral vestibular, and lateral reticular nuclei, the reticulotegmental nucleus of the pons, and the nucleus of Roller. In addition, immunocytochemical analysis using the anti-polyglutamine antibody 1C2 failed to detect any polyglutamine-related immunoreactivity in the central nervous regions of this SCA4 patient studied. In view of the known functional role of affected nuclei and related fiber tracts, the present findings not only offer explanations for the well-known disease symptoms of SCA4 patients (i.e. ataxic symptoms, dysarthria and somatosensory deficits), but for the first time help to explain why diplopia, gaze-evoked nystagmus, auditory impairments and pathologically altered brainstem auditory evoked potentials, saccadic smooth pursuits, impaired somatosensory functions in the face, and dysphagia may occur during the course of SCA4. Finally, the results of our immunocytochemical studies support the concept that SCA4 is not a member of the CAG-repeat or polyglutamine diseases.
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PMID:Spinocerebellar ataxia type 4 (SCA4): Initial pathoanatomical study reveals widespread cerebellar and brainstem degeneration. 1636 39

Dysarthria is a significant feature of the dominantly inherited spinocerebellar ataxias (SCA), but little is known about the patterns of brain activity associated with this disorder of motor speech control. Positron emission tomography (PET) was used to study regional cerebral blood flow during speech and rest in a group of 24 subjects with hereditary ataxia with mild-to-moderate dysarthria. These data were compared to the results obtained from a group of 13 age-matched, normal speakers. In the ataxic subjects, speech rates during scanning were significantly slowed compared to normal speakers. Significant reductions in mean regional blood flow were found in the cerebellum but not in supratentorial regions in the ataxic subjects. Multiple linear regression was used to model speech rate from regional blood flow. Four regions were identified as having significant relationships with speech rate in the model: the left inferior frontal and transverse temporal regions, and the right inferior cerebellar region and caudate nucleus. The relationship between flow and rate was positive in the inferior frontal and cerebellar regions and negative in the caudate and the transverse temporal region. The ataxic model represents an elaboration of the relationship previously reported for normal speakers, likely reflecting both the effects of, and compensation for, cerebellar degeneration in motor speech control. Although the mean regional blood flow values presented a pattern of functional organization for motor speech control at odds with lesion data, the performance-based model was in agreement with clinical experience. Incorporating performance data in functional image analysis may be more revealing of system characteristics than simply examining mean blood flow values.
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PMID:Mapping cerebral blood flow during speech production in hereditary ataxia. 1644 74

Friedreich's ataxia (FA) is one of the genetic syndromes sometimes associated with diabetes and the most common hereditary ataxia. It is a autosomal recessive neurodegenerative disease, caused by a mutation in the FRDA gene, which originates decreased expression of frataxin, a mitochondrial protein involved in iron metabolism. The disorder is usually manifest in childhood and is characterised by ataxia, dysarthria, scoliosis and feet deformity. About two thirds of patients have hypertrophic cardiomyopathy, 10% have diabetes and 20% have another glucose homeostasis disorder. Both insulin resistance and beta-cell dysfunction are implicated in this patients' diabetes pathophysiology. The mean half-life is 35 years. Cause of death is usually related to cardiomyopathy or diabetes' complications. We report the case study of two twin sisters with 28 years old, in whom FA was diagnosed in the first decade, both of them with diabetes since their early twenties. A third sister with FA is reported, with no glucose homeostasis disorder. They also have two healthy male brothers. Based in this cases, the FA associated diabetes pathophysiology is discussed, concerning the therapeutic approach to these patients and to their diabetic relatives without neurologic symptoms. The role of molecular genetic testing and genetic counselling are also debated.
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PMID:[Friedreich ataxia and diabetes mellitus--family study]. 1668 89

Friedreich ataxia is the most frequent hereditary ataxia, with an estimated prevalence of 3-4 cases per 100,000 individuals. This autosomal-recessive neurodegenerative disease is characterized by progressive gait and limb ataxia, dysarthria, lower-limb areflexia, decreased vibration sense, muscular weakness in the legs, and a positive extensor plantar response. Non-neurological signs include hypertrophic cardiomyopathy and diabetes mellitus. Symptom onset typically occurs around puberty, and life expectancy is 40-50 years. Friedreich ataxia is usually caused by a large GAA-triplet-repeat expansion within the first intron of the frataxin (FXN) gene. FXN mutations cause deficiencies of the iron-sulfur cluster-containing subunits of the mitochondrial electron transport complexes I, II, and III, and of the iron-sulfur protein aconitase. Mitochondrial dysfunction has been addressed in several open-label, non-placebo-controlled trials, which indicated that treatment with idebenone might ameliorate hypertrophic cardiomyopathy; a well-designed phase II trial suggested concentration-dependent functional improvements in non-wheelchair-bound children and adolescents. Other current experimental approaches address iron-mediated toxicity, or aim to increase FXN expression through the use of erythropoietin and histone deacetylase inhibitors. This Review provides guidelines, from a European perspective, for the diagnosis of Friedreich ataxia, differential diagnosis of ataxias and genetic counseling, and treatment of neurological and non-neurological symptoms.
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PMID:Diagnosis and treatment of Friedreich ataxia: a European perspective. 1934 27

The hereditary ataxias constitute a group of degenerative diseases that progress over years or decades. With principal pathology involving the cerebellum, dysarthria is an early feature of many of the ataxias. Positron emission tomography was used to study regional cerebral blood flow changes during speech production over a 21 month period in a group of seven right-handed subjects with hereditary ataxia (6 females and 1 male, 3 SCA1 and 4 SCA5, aged 38.3+/-18.9 years). The decline in blood flow was greatest in cerebellar regions. In contrast, blood flow actually increased during speech production in the classic speech area (Broca's area) but not in its right-hemisphere homologue at the second evaluation. This increase in cortical flow may have been compensatory for cerebellar degeneration as speech intelligibility did not decline significantly during this period. Compensation was not complete, though, as syllable timing shifted in the direction of equal syllable duration, one of the characteristics of ataxic dysarthria. These results are consistent with previous functional imaging studies of ataxia demonstrating a pattern of brain activity that reflects both loss of function and relative compensation when clinical signs and symptoms are still mild. The combination of disease-relevant tasks, behavioral measurement, and functional imaging may provide insight into the early changes associated with neurodegenerative disease.
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PMID:Longitudinal cerebral blood flow changes during speech in hereditary ataxia. 2041 59

Autosomal-recessive congenital cerebellar ataxia was identified in Roma patients originating from a small subisolate with a known strong founder effect. Patients presented with global developmental delay, moderate to severe stance and gait ataxia, dysarthria, mild dysdiadochokinesia, dysmetria and tremors, intellectual deficit, and mild pyramidal signs. Brain imaging revealed progressive generalized cerebellar atrophy, and inferior vermian hypoplasia and/or a constitutionally small brain were observed in some patients. Exome sequencing, used for linkage analysis on extracted SNP genotypes and for mutation detection, identified two novel (i.e., not found in any database) variants located 7 bp apart within a unique 6q24 linkage region. Both mutations cosegregated with the disease in five affected families, in which all ten patients were homozygous. The mutated gene, GRM1, encodes metabotropic glutamate receptor mGluR1, which is highly expressed in cerebellar Purkinje cells and plays an important role in cerebellar development and synaptic plasticity. The two mutations affect a gene region critical for alternative splicing and the generation of receptor isoforms; they are a 3 bp exon 8 deletion and an intron 8 splicing mutation (c.2652_2654del and c.2660+2T>G, respectively [RefSeq accession number NM_000838.3]). The functional impact of the deletion is unclear and is overshadowed by the splicing defect. Although ataxia lymphoblastoid cell lines expressed GRM1 at levels comparable to those of control cells, the aberrant transcripts skipped exon 8 or ended in intron 8 and encoded various species of nonfunctional receptors either lacking the transmembrane domain and containing abnormal intracellular tails or completely missing the tail. The study implicates mGluR1 in human hereditary ataxia. It also illustrates the potential of the Roma founder populations for mutation identification by exome sequencing.
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PMID:Autosomal-recessive congenital cerebellar ataxia is caused by mutations in metabotropic glutamate receptor 1. 2290 47


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