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)

The traditional role of iron chelation therapy has been to reduce body iron burden via chelation of excess metal from organs and fluids and its excretion via biliary-fecal and/or urinary routes. In their present use for hemosiderosis, chelation regimens might not be suitable for treating disorders of iron maldistribution, as those are characterized by toxic islands of siderosis appearing in a background of normal or subnormal iron levels (e.g., sideroblastic anemias, neuro- and cardio-siderosis in Friedreich ataxia- and neurosiderosis in Parkinson's disease). We aimed at clearing local siderosis from aberrant labile metal that promotes oxidative damage, without interfering with essential local functions or with hematological iron-associated properties. For this purpose we introduced a conservative mode of iron chelation of dual activity, one based on scavenging labile metal but also redeploying it to cell acceptors or to physiological transferrin. The "scavenging and redeployment" mode of action was designed both for correcting aberrant iron distribution and also for minimizing/preventing systemic loss of chelated metal. We first examine cell models that recapitulate iron maldistribution and associated dysfunctions identified with Friedreich ataxia and Parkinson's disease and use them to explore the ability of the double-acting agent deferiprone, an orally active chelator, to mediate iron scavenging and redeployment and thereby causing functional improvement. We subsequently evaluate the concept in translational models of disease and finally assess its therapeutic potential in prospective double-blind pilot clinical trials. We claim that any chelator applied to diseases of regional siderosis, cardiac, neuronal or endocrine ought to preserve both systemic and regional iron levels. The proposed deferiprone-based therapy has provided a paradigm for treating regional types of siderosis without affecting hematological parameters and systemic functions.
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PMID:Regional siderosis: a new challenge for iron chelation therapy. 2442 36

Cardiomyopathy is a frequent cause of death in patients with Friedreich ataxia (FA), and a characteristic pathological feature is the focal accumulation of iron (Fe) in cardiomyocytes. This restricted localization of the metal contrasts with the diffuse cardiac Fe overload in hemochromatosis and transfusion siderosis. Nevertheless, heart Fe in FA contributes to cardiomyocyte necrosis, inflammation, and scarring as the disease progresses. A putative mechanism of cardiomyopathy in FA is Fe-mediated oxidative damage. Two other transition metals zinc (Zn) and copper (Cu), are diffusely distributed throughout normal hearts and the hearts of patients with FA. The myocardium in FA is also prone to deposits of calcium in the form of scattered concretions. In this study, heart tissues (left and right ventricular walls and ventricular septum) of 23 patients with genetically confirmed FA and 8 normal controls were obtained at autopsy and analyzed for Fe, Zn, Cu, and calcium. The principal assay methods were inductively coupled plasma optical emission spectrometry and plasma mass spectrometry. Total levels of Fe in bulk extracts were not significantly higher than normal, and the concentrations of Zn also remained in the normal range. Cu levels, however, were significantly lower in FA. In conclusion, the decrease of Cu may be important in consideration of the potential benefit of Cu supplements in FA cardiomyopathy.
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PMID:Abundance and Significance of Iron, Zinc, Copper, and Calcium in the Hearts of Patients With Friedreich Ataxia. 2718 13

Magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT) and positron emission tomography (PET) are the main instruments for neuroimaging investigation of patients with chronic ataxia. MRI has a predominant diagnostic role in the single patient, based on the visual detection of three patterns of atrophy, namely, spinal atrophy, cortical cerebellar atrophy and olivopontocerebellar atrophy, which correlate with the aetiologies of inherited or sporadic ataxia. In fact spinal atrophy is observed in Friedreich ataxia, cortical cerebellar atrophy in Ataxia Telangectasia, gluten ataxia and Sporadic Adult Onset Ataxia and olivopontocerebellar atrophy in Multiple System Atrophy cerebellar type. The 39 types of dominantly inherited spinocerebellar ataxias show either cortical cerebellar atrophy or olivopontocerebellar atrophy. T2 or T2* weighted MR images can contribute to the diagnosis by revealing abnormally increased or decreased signal with a characteristic distribution. These include symmetric T2 hyperintensity of the posterior and lateral columns of the cervical spinal cord in Friedreich ataxia, diffuse and symmetric hyperintensity of the cerebellar cortex in Infantile Neuro-Axonal Dystrophy, symmetric hyperintensity of the peridentate white matter in Cerebrotendineous Xanthomatosis, and symmetric hyperintensity of the middle cerebellar peduncles and peridentate white matter, cerebral white matter and corpus callosum in Fragile X Tremor Ataxia Syndrome. Abnormally decreased T2 or T2* signal can be observed with a multifocal distribution in Ataxia Telangectasia and with a symmetric distribution in the basal ganglia in Multiple System Atrophy. T2 signal hypointensity lining diffusely the outer surfaces of the brainstem, cerebellum and cerebrum enables diagnosis of superficial siderosis of the central nervous system. The diagnostic role of nuclear medicine techniques is smaller. SPECT and PET show decreased uptake of radiotracers investigating the nigrostriatal system in Multiple System Atrophy and in patients with Fragile X Tremor Ataxia Syndrome. Semiquantitative or quantitative MRI, SPECT and PET data describing structural, microstructural and functional changes of the cerebellum, brainstem, and spinal cord have been widely applied to investigate physiopathological changes in patients with chronic ataxias. Moreover they can track diseases progression with a greater sensitivity than clinical scales. So far, a few small-size and single center studies employed neuroimaging techniques as surrogate markers of treatment effects in chronic ataxias.
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PMID:Neuroimaging Applications in Chronic Ataxias. 3047 93