Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0016719 (Friedreich's ataxia)
 2,098 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Friedreich's ataxia (FRDA), the most common subtype of early onset hereditary ataxia, is an autosomal recessive neurodegenerative disorder caused by unstable GAA expansions. Two-dimensional, pulse, and pulse tissue Doppler echocardiographic examinations were performed on 21 patients with GAA expansion. There was no association between left ventricle ejection fraction, tissue Doppler systolic s wave, and left ventricle diastolic functions examined by pulse and tissue Doppler. The septum thickness of patients with Friedreich's ataxia was significantly increased when compared with that of the control group and wall thickness was found to be associated with GAA repeats. In patients with FRDA, despite a correlation between genetic abnormality with left ventricular early and late diastolic parameters, global diastolic functions were preserved when examined by tissue Doppler.
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PMID:The evaluation of left ventricular systolic and diastolic functions in patients with Friedreich ataxia. A pulse tissue Doppler study. 1604 40

The relative frequencies of different spinocerebellar ataxias (SCAs) vary widely among different ethnic groups, presumably due to a founder effect. We investigated the relative prevalence of SCA1-3, 6-8, 12, 17; dentate-rubro-pallidoluysian atrophy; and Friedreich's ataxia (FRDA) in Serbian patients with adult-onset (>20 years of age) hereditary and sporadic SCAs, and compared clinical features of patients with genetically confirmed SCAs. A total of 108 patients from 54 families (38 apparently dominant [ADCA] and 16 apparently recessive) with adult-onset hereditary ataxia and 75 apparently sporadic patients were assessed. Of 38 families with ADCA, 13 (34%) were positive for an expansion in an SCA1 and 5 families (13%) for an expansion in an SCA2 allele. In 20 families (53%), no expansions have been identified in any of the analyzed genes. Gaze palsy, spasticity, and hyperreflexia were significantly more common in SCA1, whereas slow saccades, hypotonia, hyporeflexia, and dystonia prevailed in SCA2 patients. Among the 16 families with an apparently recessive mode of ataxia inheritance, 4 (25%) were identified as having the FRDA mutation. Ataxia-causing mutations were identified in 8 (10.6%) of patients with apparently sporadic adult-onset ataxia.
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PMID:Frequency analysis and clinical characterization of different types of spinocerebellar ataxia in Serbian patients. 1670 60

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 common hereditary ataxia. The signs and symptoms of the disorder derive from decreased expression of the protein frataxin, which is involved in iron metabolism. Frataxin chaperones iron for iron-sulfur cluster biogenesis and detoxifies iron in the mitochondrial matrix. Decreased expression of frataxin is associated with impairments of iron-sulfur cluster biogenesis and heme synthesis, as well as with mitochondrial dysfunction and oxidative stress. Compounds currently in clinical trials are directed toward improving mitochondrial function and lessening oxidative stress. Iron chelators and compounds that increase frataxin expression are under evaluation. Further elucidation of frataxin's function should lead to additional therapeutic approaches.
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PMID:Iron dysregulation in Friedreich ataxia. 1710 55

Friedreich ataxia (FA), the most common form of hereditary ataxia, is caused by a deficit in the mitochondrial protein frataxin. While several hypotheses have been suggested, frataxin function is not well understood. Oxidative stress has been suggested to play a role in the pathophysiology of FA, but this view has been recently questioned, and its link to frataxin is unclear. Here, we report the use of RNA interference (RNAi) to suppress the Drosophila frataxin gene (fh) expression. This model system parallels the situation in FA patients, namely a moderate systemic reduction of frataxin levels compatible with normal embryonic development. Under these conditions, fh-RNAi flies showed a shortened life span, reduced climbing abilities, and enhanced sensitivity to oxidative stress. Under hyperoxia, fh-RNAi flies also showed a dramatic reduction of aconitase activity that seriously impairs the mitochondrial respiration while the activities of succinate dehydrogenase, respiratory complex I and II, and indirectly complex III and IV are normal. Remarkably, frataxin overexpression also induced the oxidative-mediated inactivation of mitochondrial aconitase. This work demonstrates, for the first time, the essential function of frataxin in protecting aconitase from oxidative stress-dependent inactivation in a multicellular organism. Moreover our data support an important role of oxidative stress in the progression of FA and suggest a tissue-dependent sensitivity to frataxin imbalance. We propose that in FA, the oxidative mediated inactivation of aconitase, which occurs normally during the aging process, is enhanced due to the lack of frataxin.
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PMID:Causative role of oxidative stress in a Drosophila model of Friedreich ataxia. 1716 74

Friedreich ataxia (FRDA), the most common hereditary ataxia, is caused by mutations in the frataxin (FXN) gene. The vast majority of FRDA mutations involve expansion of a GAA*TTC-repeat tract in intron 1, which leads to an FXN mRNA deficit. Bisulfite mapping demonstrates that the region adjacent to the repeat was methylated in both unaffected and affected individuals. However, methylation was more extensive in patients. Additionally, three residues were almost completely methylation-free in unaffected individuals but almost always methylated in those with FRDA. One of these residues is located within an E-box whose deletion caused a significant drop in promoter activity in reporter assays. Elevated levels of histone H3 dimethylated on lysine 9 were seen in FRDA cells consistent with a more repressive chromatin organization. Such chromatin is known to reduce transcription elongation. This may be one way in which the expanded repeats contribute to the frataxin deficit in FRDA. Our data also suggest that repeat-mediated chromatin changes may also affect transcription initiation by blocking binding of factors that increase frataxin promoter activity. Our results also raise the possibility that the repeat-mediated increases in DNA methylation in the FXN gene in FRDA patients are secondary to the chromatin changes.
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PMID:Repeat-induced epigenetic changes in intron 1 of the frataxin gene and its consequences in Friedreich ataxia. 1747 98

A population-based, cross-sectional study was performed in southeast Norway, between January 2002 and February 2008, to identify subjects with hereditary ataxia and hereditary spastic paraplegia, and to estimate the prevalence of these disorders. Patients were recruited through colleagues, families, searches in computerized hospital archives and the National Patients' Association for Hereditary Ataxia and Spastic Paraplegia. Strict criteria were used for inclusion of familial and isolated subjects. A project neurologist examined all index subjects and clinical and genetic data were registered. The source population on January 1, 2008 was 2.63 million and the prevalence day was set as February 1, 2008. One hundred seventy-one subjects from 87 unrelated families with hereditary ataxia and 194 subjects from 65 unrelated families with hereditary spastic paraplegia were included. The total prevalence was estimated at 13.9/100 000. Hereditary ataxia prevalence in the region was estimated at 6.5/100 000: 4.2/100 000 for autosomal-dominant and 2.3/100 000 for autosomal recessive, 0.15/100 000 for Friedreich's ataxia and 0.4/100 000 for ataxia telangiectasia. Hereditary spastic paraplegia prevalence was 7.4/100 000: 5.5/100 000 for autosomal dominant-hereditary spastic paraplegia, 0.6/100 000 for autosomal recessive-hereditary spastic paraplegia and 1.3/100 000 for isolated subjects. Marked differences were found in the frequencies of hereditary ataxia subtypes compared with other countries, while those of the most common autosomal dominant-hereditary spastic paraplegia genotypes, SPG4, SPG3 and SPG31, were similar to those previously reported. Clear variations between age groups and counties were observed, but no gender differences. Mean age on prevalence day was 48 years, mean age at onset was 24 years. We present the largest population study performed on hereditary ataxia and hereditary spastic paraplegia prevalence and report a higher prevalence than expected. Better inclusion criteria and multiple search strategies may explain the observed differences.
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PMID:Prevalence of hereditary ataxia and spastic paraplegia in southeast Norway: a population-based study. 1933 54

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

Mitochondrial dysfunction and oxidative damage are at the origin of numerous neurodegenerative diseases like Friedreich ataxia and Alzheimer and Parkinson diseases. Friedreich ataxia (FRDA) is the most common hereditary ataxia, with one individual affected in 50,000. This disease is characterized by progressive degeneration of the central and peripheral nervous systems, cardiomyopathy, and increased incidence of diabetes mellitus. FRDA is caused by a dynamic mutation, a GAA trinucleotide repeat expansion, in the first intron of the FXN gene. Fewer than 5% of the patients are heterozygous and carry point mutations in the other allele. The molecular consequences of the GAA triplet expansion is transcription silencing and reduced expression of the encoded mitochondrial protein, frataxin. The precise cellular role of frataxin is not known; however, it is clear now that several mitochondrial functions are not performed correctly in patient cells. The affected functions include respiration, iron-sulfur cluster assembly, iron homeostasis, and maintenance of the redox status. This review highlights the molecular mechanisms that underlie the disease phenotypes and the different hypothesis about the function of frataxin. In addition, we present an overview of the most recent therapeutic approaches for this severe disease that actually has no efficient treatment.
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PMID:Friedreich ataxia: molecular mechanisms, redox considerations, and therapeutic opportunities. 2015 11

Friedreich ataxia (FRDA) is the most common hereditary ataxia that is caused mainly by an unstable GAA trinucleotide expansion in the first intron of the frataxin gene. Molecular tests for FRDA diagnosis and carrier detection include polymerase chain reaction (PCR) for the GAA expansion, triplet repeat primed PCR (TP-PCR), and/or Southern blotting. TP-PCR is a method developed to detect trinucleotide expansions successfully applied to FRDA diagnosis. In our laboratory, we have included a PCR for the GAA expansion using fluorescent primers polymerase chain reaction (F-PCR) to identify normal heterozygous and affected individuals unambiguously. The purpose of our study was to reanalyze 310 samples previously diagnosed in our laboratory and compare the results with those obtained by F-PCR and TP-PCR. Eight percent of the discrepancies between the carrier and the normal individuals were identified correctly by this protocol. No discrepancy was detected in the affected individuals. These techniques are effective, and compared with Southern blotting, they are less labor-intensive and suitable for automation. We suggest a new routine protocol for FRDA diagnosis that includes F-PCR and TP-PCR.
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PMID:Protocol proposal for Friedreich ataxia molecular diagnosis using fluorescent and triplet repeat primed polymerase chain reaction. 2097 Jul 54


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