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)

Trace elements might be related with the pathogenesis of spinocerebellar degeneration (SCD). Mercury produce cerebellar ataxia. However, it was reported that the content of mercury in the hair of patients with SCD was normal. Therefore, mercury may not be directly related with SCD. It was reported that the content of copper in the hair might be high in patients with Friedreich's disease, or low in patients with late cortical cerebellar atrophy. The normal content of zinc in the hair was reported in patients with SCD. The low content of manganese in the hair was suggested in patients with SCD. Usually Parkinsonism was observed in manganese intoxication in man. Lead may produce cerebellar ataxia. These trace elements might cause SCD. However, the relation is still obscure. The further study should be conducted.
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PMID:[Trace elements in spinocerebellar degeneration]. 858 79

In Parkinson's disease (PD) and its neurotoxin-induced models, 6-hydroxydopamine (6-OHDA) and N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), significant accumulation of iron occurs in the substantia nigra pars compacta. The iron is thought to be in a labile pool, unbound to ferritin, and is thought to have a pivotal role to induce oxidative stress-dependent neurodegeneration of dopamine neurons via Fenton chemistry. The consequence of this is its interaction with H(2)O(2) to generate the most reactive radical oxygen species, the hydroxyl radical. This scenario is supported by studies in both human and neurotoxin-induced parkinsonism showing that disposition of H(2)O(2) is compromised via depletion of glutathione (GSH), the rate-limiting cofactor of glutathione peroxide, the major enzyme source to dispose H(2)O(2) as water in the brain. Further, radical scavengers have been shown to prevent the neurotoxic action of the above neurotoxins and depletion of GSH. However, our group was the first to demonstrate that the prototype iron chelator, desferal, is a potent neuroprotective agent in the 6-OHDA model. We have extended these studies and examined the neuroprotective effect of intracerebraventricular (ICV) pretreatment with the prototype iron chelator, desferal (1.3, 13, 134 mg), on ICV induced 6-OHDA (250 micro g) lesion of striatal dopamine neurons. Desferal alone at the doses studied did not affect striatal tyrosine hydroxylase (TH) activity or dopamine (DA) metabolism. All three pretreatment (30 min) doses of desferal prevented the fall in striatal and frontal cortex DA, dihydroxyphenylacetic acid, and homovalinic acid, as well as the left and right striatum TH activity and DA turnover resulting from 6-OHDA lesion of dopaminergic neurons. A concentration bell-shaped neuroprotective effect of desferal was observed in the striatum, with 13 micro g being the most effective. Neither desferal nor 6-OHDA affected striatal serotonin, 5-hydroxyindole acetic acid, or noradrenaline. Desferal also protected against 6-OHDA-induced deficit in locomotor activity, rearing, and exploratory behavior (sniffing) in a novel environment. Since the lowest neuroprotective dose (1.3 micro g) of desferal was 200 times less than 6-OHDA, its neuroprotective activity may not be attributed to interference with the neurotoxin activity, but rather iron chelation. These studies led us to develop novel brain-permeable iron chelators, the VK-28 series, with iron chelating and neuroprotective activity similar to desferal for ironing iron out from PD and other neurodegenerative diseases, such as Alzheimer's disease, Friedreich's ataxia, and Huntington's disease.
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PMID:Ironing iron out in Parkinson's disease and other neurodegenerative diseases with iron chelators: a lesson from 6-hydroxydopamine and iron chelators, desferal and VK-28. 1510 75

Defects of mitochondrial metabolism cause a wide range of human diseases that include examples from all medical subspecialties. This review updates the topic of mitochondrial diseases by reviewing the most important recent advances in this area. The factors influencing inheritance, maintenance and replication of mtDNA are reviewed and the genotype-phenotype of mtDNA disorders has been expanded, with new insights into epidemiology, pathogenesis and its role in ageing. Recently identified nuclear gene mutations of mitochondrial proteins include mutations of frataxin causing Friedreich's ataxia, PINK1, DJ1 causing Parkinson's disease and POLG causing infantile mtDNA depletion syndrome, ophthalmoplegia, parkinsonism, male subfertility and, in a transgenic mouse model, premature senescence. Mitochondrial defects in neurodegenerative diseases include Parkinson's, Alzheimer's and Huntington's disease. Improved understanding of mtDNA inheritance and mutation penetrance patterns, and novel techniques for mtDNA modification offer significant prospects for more accurate genetic counselling and effective future therapies.
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PMID:Mitochondrial disease. 1681 81

We present a 36-year-old Dutch woman who suffered from a progressive form of cerebellar ataxia since school age. In her childhood she was diagnosed with Friedreich's ataxia. Genetic analysis of the frataxin gene at 34 years of age, however, had revealed no abnormal GAA triplet expansion. We identified two point mutations in the alpha-tocopherol transport protein (alpha-TTP) gene on chromosome 8q13, and the diagnosis ataxia with isolated vitamin E deficiency (AVED) was made. This report illustrates the diagnosis AVED and its relation to vitamin E metabolism. It is important to evaluate previously made diagnoses when newly developed tests can be performed for confirmation.
Parkinsonism Relat Disord 2007 Jul
PMID:First case of ataxia with isolated vitamin E deficiency in the Netherlands. 1704 53

There is compelling evidence for the direct involvement of mitochondria in certain neurodegenerative disorders, such as Morbus Parkinson, FRDA (Friedreich's ataxia), ALS (amyotrophic lateral sclerosis), and temporal lobe epilepsy with Ammon's horn sclerosis. This evidence includes the direct genetic evidence of pathogenic mutations in mitochondrial proteins in inherited Parkinsonism {such as PARK6, with mutations in the mitochondrial PINK1 [PTEN (phosphatase and tensin homologue deleted on chromosome 10)-induced kinase 1]} and in FRDA (with mutations in the mitochondrial protein frataxin). Moreover, there is functional evidence of impairment of the respiratory chain in sporadic forms of Parkinsonism, ALS, and temporal lobe epilepsy with Ammon's horn sclerosis. In the sporadic forms of the above-mentioned neurodegenerative disorders, increased oxidative stress appears to be the crucial initiating event that affects respiratory chain function and starts a vicious cycle finally leading to neuronal cell death. We suggest that the critical factor that determines the survival of neurons in neurodegenerative disorders is the degree of mitochondrial DNA damage and the maintenance of an appropriate mitochondrial DNA copy number. Evidence for a depletion of intact copies of the mitochondrial genome has been provided in all above-mentioned neurodegenerative disorders including ALS and temporal lobe epilepsy with Ammon's horn sclerosis. In the present study, we critically review the available data.
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PMID:Mitochondrial dysfunction in neurodegenerative disorders. 1795 19

The ataxias are a group of progressive neurodegenerative disorders with ataxia as the leading symptom. Current classifications distinguish between hereditary and non-hereditary ataxias. The hereditary ataxias are further divided into the autosomal recessive ataxias, the most frequent of which is Friedreich's ataxia, and the autosomal dominant spinocerebellar ataxias. The non-hereditary ataxias are separated into the acquired ataxias, such as alcoholic cerebellar degeneration or paraneoplastic cerebellar degeneration, and the sporadic degenerative ataxias, such as multiple system atrophy or sporadic adult onset ataxia. The causative mutations of many hereditary ataxias have recently been identified. Therapies based on the knowledge of the underlying molecular pathogenesis are available for a number of ataxia disorders.
Parkinsonism Relat Disord 2007
PMID:Parkinsonism & related disorders. Ataxias. 1826 70

Inherited ataxias are a heterogeneous group of disorders characterized by autosomal dominant and recessive inheritance. Recent advances in genetic research have resulted in an improved comprehension of their clinical presentation. Autosomal dominant cerebellar ataxias (ADCAs) include spinocerebellar ataxias (SCAs) and dentatorubral-pallidoluysian atrophy (DRPLA); six of these have been found to be trinucleotide repeat disorders. Episodic ataxia, types 1 and 2, are at present recognized to be channelopathies, caused by point mutations. Friedreich's ataxia (FA) which is an autosomal recessive disorder, resulting from a a unique trinucleotide repeat, is now recognized to have a wide age of onset and clinical spectrum. Ataxia-telangiectasia (AT), also an autosomal recessive cerebellar ataxia, is characterized by immunodeficiency. In this article, the genetic and clinical characteristics of these diseases are reviewed in detail.
Parkinsonism Relat Disord 1998 Dec
PMID:A review of the inherited ataxias: recent advances in genetic, clinical and neuropathologic aspects. 1859 Nov 6

An increasing number of inherited neurodegenerative diseases are known to be caused by the expansion of unstable trinucleotide repeat tracts. Spinocerebellar ataxia type 8 (SCA8) has been identified as being partly caused by a CTG expansion in an untranslated, endogenous antisense RNA that overlaps the Kelch-like 1 (KLHL1) gene. Clinically, SCA8 patients show similar features to those with the other SCAs, including limb and truncal ataxia, ataxic dysarthria and horizontal nystagmus, all of which are signs of dysfunction of the cerebellar system. However, allele sizes within the SCA8 proposed pathogenic range have been reported in patients with ataxia of unknown etiology, in individuals from pedigrees with other SCA or Friedreich's ataxia, and in patients with Alzheimer's disease, schizophrenia or parkinsonism. These observations suggest that mutation of the SCA8 locus might affect neurons other than the cerebellum. Antisense transcripts are known to regulate complementary sense transcripts and are involved in several biologic functions, such as development, adaptive response, and viral infection. In order to test whether SCA8 affects the KLHL1 expression by antisense RNA in brain cells, we examined the expression pattern of KLHL1 and SCA8 in human tissues and in mouse brain regions. SCA8 expression was colocalized with KLHL1 transcript in many brain regions whose functions are correlated to the clinical symptoms of SCA8 patients. These findings lead to the hypothesis of a possible relevance that SCA8 transcript downregulates KLHL1 expression through an antisense mechanism, which then leads to SCA8 neuropathogenesis.
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PMID:SCA8 mRNA expression suggests an antisense regulation of KLHL1 and correlates to SCA8 pathology. 1870 37

Deferiprone was shown to reverse iron deposition in Friedreich's ataxia. This multi-center, unblinded, single-arm pilot study evaluated safety and efficacy of deferiprone for reducing cerebral iron accumulation in neurodegeneration with brain iron accumulation. Four patients with genetically-confirmed pantothenate kinase-associated neurodegeneration, and 2 with parkinsonism and focal dystonia, but inconclusive genetic tests, received 15 mg/kg deferiprone bid. Magnetic resonance imaging and neurological examinations were conducted at baseline, six and 12 months. Chelation treatment caused no apparent hematologic or neurological side effects. Magnetic resonance imaging revealed decreased iron accumulation in the globus pallidus of 2 patients (one with pantothenate kinase-associated neurodegeneration). Clinical rating scales and blinded video rating evaluations documented mild-to-moderate motor improvement in 3 patients (2 with pantothenate kinase-associated neurodegeneration). These results underline the safety and tolerability of deferiprone, and suggest that chelating treatment might be effective in improving neurological manifestations associated with iron accumulation. (Clinicaltrials.gov Identifier: NTC00907283).
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PMID:A pilot trial of deferiprone for neurodegeneration with brain iron accumulation. 2205 78

Mitochondrial diseases (MIDs) are a large group of heterogeneous disorders due to mutations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) genes, the latter encoding proteins involved in mitochondrial function. A multisystem clinical picture that involves several organs, including both the peripheral and central nervous systems, is a common presentation of MID. Movement disorders, even isolated ones, are not rare. Cerebellar ataxia is common in myoclonic epilepsy with ragged red fibers (MERFF) due to mutations in the mitochondrial transfer RNA (tRNA) lysine gene, in Kearns-Sayre syndrome due to mtDNA deletions, in sensory ataxic neuropathy with dysarthria and ophthalmoplegia (SANDO) due to nuclear POLG1 gene mutations, and also in ARCA2, Friedreich's ataxia, SPG7, SCA28 and autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) due to mutations in nuclear genes involved in mitochondrial morphology or function. Myoclonus is a key feature of MERFF, but may also be encountered in mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), ARCA2, POLG1 mutations and Leigh syndrome. Dystonia is common in Leigh syndrome (which may be caused by 75 different genes) and in Leber hereditary ocular neuropathy (LHON) plus disease, due to mutations in mtDNA genes that encode subunits of NADH dehydrogenase, as well as in ARCA2, pantothenate kinase-associated neurodegeneration (PKAN), mitochondrial membrane protein-associated neurodegeneration (MPAN) and POLG1 mutations. Other movement disorders are rarer (such as parkinsonism, tremor, chorea). Although parkinsonism is more frequent in POLG1 mutations, and myoclonus in MERFF, most movement disorders are found either isolated or combined in numerous MIDs. The presence of associated neurological signs, whether central or peripheral, or of evocative magnetic resonance imaging (MRI) abnormalities (striatal necrosis) should prompt a search for MID. In cases of a particular clinical spectrum (LHON, MERFF, Kearns-Sayre, SANDO, SPG7, ARCA2, ARSACS), a search for the most frequently implicated mutation(s) is recommended. In other cases, muscle biopsies followed by metabolic and genetic studies may be useful for arriving at a diagnosis.
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PMID:Movement disorders in mitochondrial diseases. 2777 46


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