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)

Friedreich ataxia (FRDA) is a common autosomal recessive degenerative disease (1/50,000 live births) characterized by a progressive-gait and limb ataxia with lack of tendon reflexes in the legs, dysarthria and pyramidal weakness of the inferior limbs. Hypertrophic cardiomyopathy is observed in most FRDA patients. The gene associated with the disease has been mapped to chromosome 9q13 (ref. 3) and encodes a 210-amino-acid protein, frataxin. FRDA is caused primarily by a GAA repeat expansion within the first intron of the frataxin gene, which accounts for 98% of mutant alleles. The function of the protein is unknown, but an increased iron content has been reported in hearts of FRDA patients and in mitochondria of yeast strains carrying a deleted frataxin gene counterpart (YFH1), suggesting that frataxin plays a major role in regulating mitochondrial iron transport. Here, we report a deficient activity of the iron-sulphur (Fe-S) cluster-containing subunits of mitochondrial respiratory complexes I, II and III in the endomyocardial biopsy of two unrelated FRDA patients. Aconitase, an iron-sulphur protein involved in iron homeostasis, was found to be deficient as well. Moreover, disruption of the YFH1 gene resulted in multiple Fe-S-dependent enzyme deficiencies in yeast. The deficiency of Fe-S-dependent enzyme activities in both FRDA patients and yeast should be related to mitochondrial iron accumulation, especially as Fe-S proteins are remarkably sensitive to free radicals. Mutated frataxin triggers aconitase and mitochondrial Fe-S respiratory enzyme deficiency in FRDA, which should therefore be regarded as a mitochondrial disorder.
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PMID:Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia. 932 46

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.
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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 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.
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PMID:[Cardiac manifestations of Friedreich's ataxia]. 1506 Nov 20