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

Friedreich's ataxia, the most common autosomal recessive inherited ataxia, is characterized by progressive gait and limb ataxia. Friedreich's ataxia is known for its occurrence within the first or second decade of life and is associated with hypertrophic cardiomyopathy, and in some cases with diabetes. Genetically, it is identified by the expression of an unstable trinucleotide GAA repeat expansion located in the first intron of the X25 gene on chromosome 9. Two brothers with very late adult-onset ataxia, and their unaffected sister, were examined for the clinical presentation of FA and for the presence of the mutated FA gene. The relationship of the expanded gene sequence to the severity of disease and age of onset were evaluated. Clinical examination revealed that the two brothers had mild ataxia and proprioceptive loss, with age of onset between 60 and 70 years of age. DNA from peripheral blood nucleated cells demonstrated a small homozygous expansion, with approximately 120-130 GAA repeats in the X25 gene in both patients. The expanded repeats were interrupted either with GAAGAG, GAAGGA, or GAAGAAAA sequences. The unaffected sister carried a normal FA genotype with 8-uninterrupted GAA repeat, observed by sequence analysis. In addition, the levels of FA gene transcript in both brothers were relatively lower than that in the unaffected sister. No detectable cardiomyopathy or diabetes was observed. Phenotypic diversity of FA is increasingly expanding. The age of onset and the structure of GAA repeat expansion plays an important role in determining the clinical features and the differential diagnosis of FA. The confirmation of the FA gene mutation in the atypical case, broadens the clinical spectrum of FA, and supports the idea that patients with even a mild form of ataxia of late adult onset should be considered for molecular testing.
 ...
PMID:Sequence variation in GAA repeat expansions may cause differential phenotype display in Friedreich's ataxia. 1174 52

Friedreich Ataxia (FA) is a neurodegenerative disorder characterised by progressive gait disturbance, dysarthria, dysmetria and other coordination disorders. The genetic defect is represented by an expansion of GAA repeats in the frataxin gene (FRDA or X25). Hypertrophic cardiomyopathy is a common finding in FA, and it is widely recognised as specific for the diagnosis of disease status. In this study, we report the co-existence, in a 5-year old boy with FA, of a double mutation in two distinct genes [X25 (A allele: 850 triplets; B allele: 1000 triplets), and cardiac troponin T (TNNT2) (287G>A)]. TNNT2 gene mutations have been previously identified in individuals with a familial form of hypertrophic cardiomyopathy (FHC), an autosomal dominant inherited disease characterised by unexplained cardiac hypertrophy and high incidence of sudden death. Although we cannot rule out the impact of each gene defect on cardiac morphology, it is of interest that these two mechanisms may be acting in a synergistic fashion to produce the extreme degree of cardiac hypertrophy detected in the child. This is, to our knowledge, the first description of a double gene defect in individuals with FA and FHC.
 ...
PMID:Co-existence of frataxin and cardiac troponin T gene mutations in a child with Friedreich Ataxia and familial hypertrophic cardiomyopathy. 1185 53

Friedreich's ataxia (FRDA) is a neuro-degenerative disease causing limb and gait ataxia and hypertrophic cardiomyopathy. It results from a triplet expansion in the first intron of the frataxin gene encoding a mitochondrial protein of yet unknown function. Cells with low frataxin content display generalized deficiency of mitochondrial iron-sulfur cluster-containing proteins, which presumably denotes overproduction of superoxide radicals in these organelles. Idebenone, a short-chain quinone, may act as a potent free radical scavenger protecting mitochondria against oxidative stress. We therefore carried out an open trial of idebenone (oral supplementation; 5mg/kg/day) in a large series of FRDA patients and followed their left ventricular mass and function. Consistent and definitive worsening being observed in the natural course of the disease and cardiac hypertrophy having no chance of spontaneous reversal and to be subject to a placebo effect, the patient's heart status before and after the treatment was used to unambiguously establish the effect of the drug. After six months, heart ultrasound revealed more than 20% reduction of left ventricular mass in about half of the patients (p < 0.001) and no significant change in the other half. Since any measurable reversion of this pathogenic trait is highly significant, this demonstrates the efficiency of idebenone in controlling heart hypertrophy in FRDA. Owing to the absence of side effects of the drug, idebenone (up to 15mg/kg/day) should be prescribed for FRDA patients continuously as early as possible.
 ...
PMID:Heart hypertrophy and function are improved by idebenone in Friedreich's ataxia. 1206 12

Friedreich Ataxia (FRDA), the most prevalent of the inherited ataxias, is a multi-systemic disease with loss of sensory neurons and life-threatening hypertrophic cardiomyopathy as its most severe manifestations. Reduced levels of the mitochondrial protein frataxin lead to cell-damaging oxidative stress and consequently FRDA is considered as a model for more common neurodegenerative disorders in which reactive radicals and oxidative stress are involved. We have developed a cellular assay system that discriminates between fibroblasts from FRDA patients and unaffected donors on the basis of their sensitivity to pharmacological inhibition of de novo synthesis of glutathione. With this assay we observed that supplementation with selenium effectively improved the viability of FRDA fibroblasts, indicating that basal selenium concentrations are not sufficient to allow an adequate increase in the activity of certain detoxification enzymes (such as GPX). Furthermore, we characterized potential drug candidates and found that idebenone, a mitochondrially localized antioxidant that ameliorates cardiomyopathy in FRDA patients, as well as other lipophilic antioxidants protected FRDA cells from cell death. Our results also demonstrate for the first time that small-molecule GPX mimetics have potential as a novel treatment strategy for Friedreich Ataxia and presumably also for other neurodegenerative diseases with mitochondrial impairment.
 ...
PMID:A cellular model for Friedreich Ataxia reveals small-molecule glutathione peroxidase mimetics as novel treatment strategy. 1241 27

Friedreich's ataxia is a neurodegenerative disease frequently associated with hypertrophic cardiomyopathy. We have determined mitochondrial ATP, phosphocreatine, and intracellular inorganic phosphate levels by 31P nuclear magnetic resonance spectroscopy in the heart of 11 Friedreich's ataxia patients and 11 healthy controls. For the first time, to our knowledge, we showed a significant correlation between the extent of myocardial energy deficiency and the degree of myocardial hypertrophy. When combining our results with previous works on Friedreich's ataxia, these novel findings suggest that energy metabolism is most likely the cause and hypertrophy the effect in Friedreich's ataxia.
 ...
PMID:Cardiac energetics correlates to myocardial hypertrophy in Friedreich's ataxia. 1452 Jun 74

Cardiomyopathy and neuromuscular abnormalities may simultaneously coexist and present with defects in mitochondrial DNA and bioenergetic function. We sought to evaluate the relationship between clinical and mitochondrial phenotypes in 28 young patients with both cardiomyopathy and neurologic disorders including seizures, dystonia, ophthalmoplegia, Kearns-Sayre syndrome, Leigh disease, and Friedreich's ataxia. All tissues examined displayed marked defects in respiratory complex activities. Five patients had abundant large-scale mitochondrial DNA deletions and one patient displayed a pathogenic point mutation previously reported with mitochondrial cytopathy. In this cohort, patients with hypertrophic cardiomyopathy displayed a higher incidence of complex I defects, fewer DNA deletions and mitochondrial structural abnormalities and were less often associated with developmental delay phenotype compared with patients with dilated cardiomyopathy. Although structural abnormalities are present in a subset of patients, evaluation of respiratory enzyme activity appears to be most informative whether tissues examined were derived from heart or skeletal muscle. Defects in mitochondrial DNA and bioenergetics are frequently present in children with cardiomyopathy presenting with a variety of neurologic abnormalities and are amenable to biochemical and molecular analysis.
 ...
PMID:Cardiomyopathy associated with neurologic disorders and mitochondrial phenotype. 1254 31

The authors report the case of a 21 year old woman admitted to hospital for congestive cardiac failure due to concentric hypertrophic cardiomyopathy. Echocardiography showed severe systolo-diastolic left ventricular dysfunction without obstruction to ejection. Neurological examination showed a stato-kinetic cerebellar syndrome, a posterior radiculo-cordonal syndrome and a dysmorphic syndrome which characterise Friedreich's disease. In the light of this case and a review of the literature, the authors underline the rarity of cardiomyopathy in Friedreich's disease, its particular presentation and its poor prognostic significance in this disease.
 ...
PMID:[Hypertrophic cardiomyopathy disclosing Friedreich's disease. Report of a case]. 1462 38

Hypertrophic cardiomyopathy is a Mendelian disease characterized by cardiac hypertrophy. It has a prevalence of 1:500 individuals and is the most common cause of sudden death in the young. Other complications include heart failure and the need for heart transplantation. Hypertrophic cardiomyopathy is due to sarcomeric gene mutations, however, phenocopies with myocardial hypertrophy can be due to triplet-repeat syndromes (Friedreich ataxia and myotonic dystrophy), mitochondrial and metabolic diseases. In a peculiar form associated with Wolf-Parkinson-White syndrome, the disease is caused by mutations in the gamma2 regulatory subunit of the AMP-activated protein kinase gene, leading to a glycogen storage cardiomyopathy. In spite of the growing knowledge about the molecular basis of hypertrophic cardiomyopathy, very little is still known about the genotype-phenotype correlations and their clinical implications. In this review, the clinical and molecular genetics of hypertrophic cardiomyopathy are described.
 ...
PMID:Familial hypertrophic cardiomyopathy: clinical features, molecular genetics and molecular genetic testing. 1471 53

Friedreich's ataxia is one of the most frequent ataxias of childhood. The disease is inherited in autosomal recessive mode. It is caused by deficiency of mitochondrial protein frataxin, which is responsible for the degenerative impairment of the spinocerebellar and corticospinal tracts and posterior columns of the spinal cord and for the heart damage. We present a case report of a patient with a complete clinical syndrome. Patient experienced slowly progressive neurological symptomatology from the age of 6 years, which consisted of instability, gait abnormalities, tremor and ataxia. Adult patient became immobile with severe quadruparesis and dysarthria. Cardiac involvement presented in adulthood with multifocal atrial tachycardia became the chief symptom. Hypertrophic cardiomyopathy was diagnosed. Diagnosis of Friedreich's ataxia was confirmed by genetic analysis. Pharmacotherapy with coenzyme Q10 and carnitine was introduced with effort to slow down progression of cardiac impairment. Causal treatment is still impossible.
 ...
PMID:[Cardiac manifestations of Friedreich's ataxia]. 1506 Nov 20

We report the anaesthetic management of vaginal delivery in a woman with Friedreich's ataxia, who had hypertrophic cardiomyopathy and had previously undergone thoracic spinal fusion with Harrington rod fixation. Combined spinal-epidural analgesia was used. Options for the anaesthetic management of labour and delivery are discussed.
 ...
PMID:Anaesthetic management of vaginal delivery in a woman with Friedreich's ataxia complicated by cardiomyopathy and scoliosis. 1532 Dec 15


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>