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

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

The authors describe a family (mother, son and two daughters) with mitochondrial myopathy. The mother was asymptomatic. Two daughters had lactic acidosis and myoclonic epilepsy, mild dementia, ataxia, weakness and sensory neuropathy. The son suffered one acute hemiplegic episode due to an ischemic infarct in the right temporal region. All the patients studied had hypertension. EEG disclosed photomyoclonic response in the proband patient. Muscle biopsy disclosed ragged-red fibers and abnormal mitochondria by electron microscopy. Biochemical analysis showed a defect of cytochrome C oxidase in mitochondria isolated from skeletal muscle. Several clinical and genetic aspects of the mitochondrial encephalomyopathies are discussed.
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PMID:Mitochondrial myopathy and myoclonic epilepsy. 216 73

We have investigated electron transfer activities of respiratory chain complexes in platelet mitochondria of a patient with intermittent ataxia and lactic acidosis who was previously reported to be deficient in the E1 (decarboxylase) component of the pyruvate dehydrogenase complex. Electron transfer from succinate to cytochrome c was normal, but the mitochondria exhibited moderately decreased (63% of control) quinol: cytochrome-c oxidoreductase activity, suggesting a defect in complex III. Consistent with some perturbation in complex III, electron flux through complex III was resistant to inhibition by myxothiazol compared to normal controls. In contrast, titration with antimycin revealed a less abnormal pattern of inhibition. The extreme specificity of myxothiazol binding at or near the quinol oxidase domain of mitochondrial cytochrome b, i.e., b-566, suggests a defect in this region of complex III which may perturb the kinetics or thermodynamics of quinol oxidation in the complex. These data suggest that the patient's illness results from a mutation in the quinol oxidase domain of mitochondrial cytochrome b (b-566).
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PMID:Myxothiazol resistance in human mitochondria. 284 49

Thirty-four children with lactic acidosis and Leigh encephalopathy due to cytochrome C oxidase (COX) deficiency distributed in 28 families have recently been identified in northeastern Quebec, particularly in the Saguenay-Lac-Saint-Jean (SLSJ) region. The segregation analysis was consistent with an autosomal recessive mode of inheritance. The incidence was estimated at 1/2,063 live births between 1979 and 1990, and the carrier rate was estimated at 1/23 inhabitants in SLSJ. In SLSJ, the places of origin of the COX-deficient children and their parents did not show a clustered nonuniform distribution. The genealogical reconstruction of 54 obligate carriers identified 26 ancestors common to all of them. Twenty-two were 17th-century Europeans, suggesting that the COX-deficient gene was introduced in the French-Canadian population by early settlers. These results support the hypothesis of a founder effect for COX deficiency in northeastern Quebec. Clinical findings are reported for 15 of these COX-deficient patients, age 6 mo to 11 years. Moderate developmental delay, hypotonia, ataxia, strabismus, and mild facial dysmorphism were frequent. Eleven children died in episodes of fulminant metabolic acidosis. The patients had elevated blood and cerebrospinal fluid lactate levels, decreased blood bicarbonate levels, and normal blood pH. Leigh disease and microvesicular steatosis of the liver were present in all affected patients for whom postmortem examination was performed. This biochemically uniform group of patients showed a wide range of clinical severity.
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PMID:Clinical, metabolic, and genetic aspects of cytochrome C oxidase deficiency in Saguenay-Lac-Saint-Jean. 839 91

Two families of dogs (Australian cattle dogs and Shetland sheepdogs) with an inherited "spongiform leukoencephalomyelopathy" were identified, with widespread vacuolation of white matter of the brain and spinal cord. Affected dogs of both breeds developed tremors at 2-9 weeks of age followed by progressive neurological worsening with ataxia, paresis, paralysis, spasticity, and cranial nerve dysfunction. The modes of inheritance of both families were most likely maternal. The cerebrospinal fluid (CSF) analysis showed elevated ratio of 3-OH butyrate to acetoacetic acid. Mitochondrial DNA sequencing showed a G to A transition at 14,474 nt (G14474A, GenBank accession no. NC002008 ) that results in an amino acid change of valine-98 to methionine (V98M) of mitochondrial encoded cytochrome b. Western blot analysis showed increased levels of core I and core II but decreased level of cytochrome c1 of the complex III and cytochrome c oxidase of the complex IV of the respiratory chain.
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PMID:Canine spongiform leukoencephalomyelopathy is associated with a missense mutation in cytochrome b. 1602 96

Mitochondrial reactive oxygen species (ROS) are proposed to play a central role in aging and age-associated disorders, although direct in vivo evidence is lacking. We recently generated a mouse mutant with mutated inner mitochondrial membrane peptidase 2-like (Immp2l) gene, which impairs the signal peptide sequence processing of mitochondrial proteins cytochrome c1 and glycerol phosphate dehydrogenase 2. The mitochondria from mutant mice generate elevated levels of superoxide ion and cause impaired fertility in both sexes. Here, we design experiments to examine the effects of excessive mitochondrial ROS generation on health span. We show that Immp2l mutation increases oxidative stress in multiple organs such as the brain and the kidney, although expression of superoxide dismutases in these tissues of the mutants is also increased. The mutants show multiple aging-associated phenotypes, including wasting, sarcopenia, loss of subcutaneous fat, kyphosis, and ataxia, with female mutants showing earlier onset and more severe age-associated disorders than male mutants. The loss of body weight and fat was unrelated to food intake. Adipose-derived stromal cells (ADSC) from mutant mice showed impaired proliferation capability, formed significantly less and smaller colonies in colony formation assays, although they retained adipogenic differentiation capability in vitro. This functional impairment was accompanied by increased levels of oxidative stress. Our data showed that mitochondrial ROS is the driving force of accelerated aging and suggested that ROS damage to adult stem cells could be one of the mechanisms for age-associated disorders.
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PMID:Mitochondrial peptidase IMMP2L mutation causes early onset of age-associated disorders and impairs adult stem cell self-renewal. 2133 23

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting carriers of premutation forms of the FMR1 gene, resulting in a progressive development of tremor, ataxia and neuropsychological problems. The disease is caused by an expanded CGG repeat in the FMR1 gene, leading to an RNA gain-of-function toxicity mechanism. In order to study the pathogenesis of FXTAS, new inducible transgenic mouse models have been developed that expresses either 11CGGs or 90CGGs at the RNA level under control of a Tet-On promoter. When bred to an hnRNP-rtTA driver line, doxycycline (dox) induced expression of the transgene could be found in almost all tissues. Dox exposure resulted in loss of weight and death within 5 d for the 90CGG RNA expressing mice. Immunohistochemical examination of tissues of these mice revealed steatosis and apoptosis in the liver. Decreased expression of GPX1 and increased expression of cytochrome C is found. These effects were not seen in mice expressing a normal sized 11CGG repeat. In conclusion, we were able to show in vivo that expression of an expanded CGG-repeat rather than overexpression of a normal CGG-repeat causes pathology. In addition, we have shown that expanded CGG RNA expression can cause mitochondrial dysfunction by regulating expression levels of several markers. Although FTXAS patients do not display liver abnormalities, our findings contribute to understanding of the molecular mechanisms underlying toxicity of CGG repeat RNA expression in an animal model. In addition, the dox inducible mouse lines offer new opportunities to study therapeutic interventions for FXTAS.
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PMID:Induced expression of expanded CGG RNA causes mitochondrial dysfunction in vivo. 2548 75

Defects in mitochondrial cytochrome c oxidase or respiratory chain complex IV (CIV) assembly are a frequent cause of human mitochondrial disorders. Specifically, mutations in four conserved assembly factors impinging the biogenesis of the mitochondrion-encoded catalytic core subunit 2 (COX2) result in myopathies. These factors afford stability of newly synthesized COX2 (the dystonia-ataxia syndrome protein COX20), a protein with two transmembrane domains, and maturation of its copper center, Cu_A (cardiomyopathy proteins SCO1, SCO2, and COA6). COX18 is an additional COX2 assembly factor that belongs to the Oxa1 family of membrane protein insertases. Here, we used a gene-editing approach to generate a human COX18 knock-out HEK293T cell line that displays isolated complete CIV deficiency. We demonstrate that COX20 stabilizes COX2 during insertion of its N-proximal transmembrane domain, and subsequently, COX18 transiently interacts with COX2 to promote translocation across the inner membrane of the COX2 C-tail that contains the apo-Cu_A site. The release of COX18 from this complex coincides with the binding of the SCO1-SCO2-COA6 copper metallation module to COX2-COX20 to finalize COX2 biogenesis. Therefore, COX18 is a new candidate when screening for mitochondrial disorders associated with isolated CIV deficiency.
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PMID:Human mitochondrial cytochrome c oxidase assembly factor COX18 acts transiently as a membrane insertase within the subunit 2 maturation module. 2833 Aug 71

Spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of cerebellar degenerative disorders, characterized by progressive gait unsteadiness, hand incoordination, and dysarthria. Ataxia type 1 (SCA1) is caused by the expansion of a CAG trinucleotide repeat in the SCA1 gene resulting in the atypical extension of a polyglutamine (polyQ) tract within the ataxin-1 protein. Our main objective was to investigate the mitochondrial oxidative metabolism in the cerebellum of transgenic SCA1 mice. SCA1 transgenic mice develop clinical features in the early life stages (around 5 weeks of age) presenting pathological cerebellar signs with concomitant progressive Purkinje neuron atrophy and relatively little cell loss; this evidence suggests that the SCA1 phenotype is not the result of cell death per se, but a possible effect of cellular dysfunction that occurs before neuronal demise. We studied the mitochondrial oxidative metabolism in cerebellar cells from both homozygous and heterozygous transgenic SCA1 mice, aged 2 and 6 months. Histochemical examination showed a cytochrome-c-oxidase (COX) deficiency in the Purkinje cells (PCs) of both heterozygous and homozygous mice, the oxidative defect being more prominent in older mice, in which the percentage of COX-deficient PC was up to 30%. Using a laser-microdissector, we evaluated the mitochondrial DNA (mtDNA) content on selectively isolated COX-competent and COX-deficient PC by quantitative Polymerase Chain Reaction and we found mtDNA depletion in those with oxidative dysfunction. In conclusion, the selective oxidative metabolism defect observed in neuronal PC expressing mutant ataxin occurs as early as 8 weeks of age thus representing an early step in the PC degeneration process in SCA1 disease.
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PMID:Purkinje cell COX deficiency and mtDNA depletion in an animal model of spinocerebellar ataxia type 1. 3011 22

Both nuclear and mitochondrial DNA defects can cause isolated cytochrome c oxidase (COX; complex IV) deficiency, leading to the development of the mitochondrial disease. We report a 52-year-old female patient who presented with a late-onset, progressive cerebellar ataxia, tremor and axonal neuropathy. No family history of neurological disorder was reported. Although her muscle biopsy demonstrated a significant COX deficiency, there was no clinical and electromyographical evidence of myopathy. Electrophysiological studies identified low frequency sinusoidal postural tremor at 3 Hz, corroborating the clinical finding of cerebellar dysfunction. Complete sequencing of the mitochondrial DNA genome in muscle identified a novel MT-CO2 variant, m.8163A>G predicting p.(Tyr193Cys). We present several lines of evidence, in proving the pathogenicity of this heteroplasmic mitochondrial DNA variant, as the cause of her clinical presentation. Our findings serve as an important reminder that full mitochondrial DNA analysis should be included in the diagnostic pipeline for investigating individuals with spinocerebellar ataxia.
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PMID:A Novel Pathogenic Variant in MT-CO2 Causes an Isolated Mitochondrial Complex IV Deficiency and Late-Onset Cerebellar Ataxia. 3116 10

Mitochondrial complex III deficiency nuclear type 2 is an autosomal-recessive disorder caused by mutations in TTC19 gene. TTC19 is involved in the preservation of mitochondrial complex III, which is responsible for transfer of electrons from reduced coenzyme Q to cytochrome C and thus, contributes to the formation of electrochemical potential and subsequent ATP generation. Mutations in TTC19 have been found to be associated with a wide range of neurological and psychological manifestations. Herein, we report on a 15-year-old boy born from first-degree cousin parents, who initially presented with psychiatric symptoms. He subsequently developed progressive ataxia, spastic paraparesis with involvement of caudate bodies and lentiform nuclei with cerebellar atrophy. Eventually, the patient developed gastrointestinal involvement. Using whole-exome sequencing (WES), we identified a novel homozygous frameshift mutation in the TTC19 gene in the patient (NM_017775.3, c.581delG: p.Arg194Asnfs^*16). Advanced genetic sequencing technologies developed in recent years have not only facilitated identification of novel disease genes, but also allowed revelations about novel phenotypes associated with mutations in the genes already linked with other clinical features. Our findings expanded the clinical features of TTC19 mutation to potentially include gastrointestinal involvement. Further functional studies are needed to elucidate the underlying pathophysiological mechanisms.
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PMID:A Novel TTC19 Mutation in a Patient With Neurological, Psychological, and Gastrointestinal Impairment. 3155 10


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