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)

Much confusion and disagreement exists regarding the classification and characteristics of inherited disorders manifesting neurogenic muscular atrophy. Many authors consider Charcot-Marie-Tooth syndrome (CMTS) and Roussy Levy syndrome (RLS) forme fruste or variants of Friedreich's ataxia (FA). Familial kyphoscoliosis has often been described in FA and RLS but not with CMTS. The purpose of this paper is to present detailed clinical and laboratory findings in a family with three cases of Scheuermann's kyphoscoliosis and CMTS in three generations. In all cases Scheuermann's kyphoscoliosis was associated with pes cavus, markedly diminished vibratory and position sensation in the lower extremities, absent deep tendon reflexes and muscular atrophy, predominantly of the distal muscles. Fine rhythmic tremor of outstretched hands and positive Romberg sign were present in one case only. Serum creating phosphokinase was elevated in two cases. Motor nerve conduction studies revealed impaired function in the median, ulnar, tibial and peroneal nerves. Sensory nerve conduction wal also impaired in median and ulnar nerves. There was evidence of left ventricular hypertrophy in one case only. The nosology and relationship between CMTS, RLS and FA are discussed.
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PMID:Scheuermann's kyphoscoliosis associated with Charcot-Marie-Tooth syndrome. 94 37

After decades of confusion as a result of the marked clinical variability of spinocerebellar degeneration, molecular analyses have permitted the identification of loci and genes, which constitute the basis of a new classification. However, even greater genetic heterogeneity is suspected and several phenotypes, such as complex forms of spastic paraplegia and autosomal recessive ataxias, have not yet been thoroughly explored. Unexpectedly, the genes responsible for Friedreich's ataxia and a form of autosomal recessive spastic paraplegia place these diseases in the category of mitochondrial disorders. The unstable mutations caused by trinucleotide repeat expansions are responsible for a growing number of inherited cerebellar ataxias.
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PMID:Clinical and genetic aspects of spinocerebellar degeneration. 1097 57

The central nervous system (CNS) is, after the peripheral nervous system, the second most frequently affected organ in mitochondrial disorders (MCDs). CNS involvement in MCDs is clinically heterogeneous, manifesting as epilepsy, stroke-like episodes, migraine, ataxia, spasticity, extrapyramidal abnormalities, bulbar dysfunction, psychiatric abnormalities, neuropsychological deficits, or hypophysial abnormalities. CNS involvement is found in syndromic and non-syndromic MCDs. Syndromic MCDs with CNS involvement include mitochondrial encephalomyopathy, lactacidosis, stroke-like episodes syndrome, myoclonic epilepsy and ragged red fibers syndrome, mitochondrial neuro-gastrointestinal encephalomyopathy syndrome, neurogenic muscle weakness, ataxia, and retinitis pigmentosa syndrome, mitochondrial depletion syndrome, Kearns-Sayre syndrome, and Leigh syndrome, Leber's hereditary optic neuropathy, Friedreich's ataxia, and multiple systemic lipomatosis. As CNS involvement is often subclinical, the CNS including the spinal cord should be investigated even in the absence of overt clinical CNS manifestations. CNS investigations comprise the history, clinical neurological examination, neuropsychological tests, electroencephalogram, cerebral computed tomography scan, and magnetic resonance imaging. A spinal tap is indicated if there is episodic or permanent impaired consciousness or in case of cognitive decline. More sophisticated methods are required if the CNS is solely affected. Treatment of CNS manifestations in MCDs is symptomatic and focused on epilepsy, headache, lactacidosis, impaired consciousness, confusion, spasticity, extrapyramidal abnormalities, or depression. Valproate, carbamazepine, corticosteroids, acetyl salicylic acid, local and volatile anesthetics should be applied with caution. Avoiding certain drugs is often more beneficial than application of established, apparently indicated drugs.
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PMID:Central nervous system manifestations of mitochondrial disorders. 1694 41

Deficiency in the nuclear-encoded mitochondrial protein frataxin causes Friedreich ataxia (FRDA), a progressive neurodegenerative disorder associating spinocerebellar ataxia and cardiomyopathy. Although the exact function of frataxin is still a matter of debate, it is widely accepted that frataxin is a mitochondrial iron chaperone involved in iron-sulfur cluster and heme biosynthesis. Frataxin is synthesized as a precursor polypeptide, directed to the mitochondrial matrix where it is proteolytically cleaved by the mitochondrial processing peptidase to the mature form via a processing intermediate. The mature form was initially reported to be encoded by amino acids 56-210 (m(56)-FXN). However, two independent reports have challenged these studies describing two different forms encoded by amino acids 78-210 (m(78)-FXN) and 81-210 (m(81)-FXN). Here, we provide evidence that mature human frataxin corresponds to m(81)-FXN, and can rescue the lethal phenotype of fibroblasts completely deleted for frataxin. Furthermore, our data demonstrate that the migration profile of frataxin depends on the experimental conditions, a behavior which most likely contributed to the confusion concerning the endogenous mature frataxin. Interestingly, we show that m(56)-FXN and m(78)-FXN can be generated when the normal maturation process of frataxin is impaired, although the physiological relevance is not clear. Furthermore, we determine that the d-FXN form, previously reported to be a degradation product, corresponds to m(78)-FXN. Finally, we demonstrate that all frataxin isoforms are generated and localized within the mitochondria. The clear identification of the N-terminus of mature FXN is an important step for designing therapeutic approaches for FRDA based on frataxin replacement.
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PMID:The in vivo mitochondrial two-step maturation of human frataxin. 1872 97

Histone deacetylase (HDAC) inhibitors, including various benzamides and hydroxamates, are currently in clinical development for a broad range of human diseases, including cancer and neurodegenerative diseases. We recently reported the identification of a family of benzamide-type HDAC inhibitors that are relatively non-toxic compared with the hydroxamates. Members of this class of compounds have shown efficacy in cell-based and mouse models for the neurodegenerative diseases Friedreich ataxia and Huntington disease. Considerable differences in IC(50) values for the various HDAC enzymes have been reported for many of the HDAC inhibitors, leading to confusion as to the HDAC isotype specificities of these compounds. Here we show that a benzamide HDAC inhibitor, a pimelic diphenylamide (106), is a class I HDAC inhibitor, demonstrating no activity against class II HDACs. 106 is a slow, tight-binding inhibitor of HDACs 1, 2, and 3, although inhibition for these enzymes occurs through different mechanisms. Inhibitor 106 also has preference toward HDAC3 with K(i) of approximately 14 nm, 15 times lower than the K(i) for HDAC1. In comparison, the hydroxamate suberoylanilide hydroxamic acid does not discriminate between these enzymes and exhibits a fast-on/fast-off inhibitory mechanism. These observations may explain a paradox involving the relative activities of pimelic diphenylamides versus hydroxamates as gene activators.
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PMID:Pimelic diphenylamide 106 is a slow, tight-binding inhibitor of class I histone deacetylases. 1895 21