Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
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This review concerns the development of small molecule therapeutics for the inherited neurodegenerative disease Friedreich ataxia (FRDA). FRDA is caused by transcriptional repression of the nuclear FXN gene, encoding the essential mitochondrial protein frataxin and accompanying loss of frataxin protein. Frataxin insufficiency leads to mitochrondrial dysfunction and progressive neurodegeneration, along with scoliosis, diabetes and cardiomyopathy. Individuals with FRDA generally die in early adulthood from the associated heart disease, the most common cause of death in FRDA. While antioxidants and iron chelators have shown promise in ameliorating the symptoms of the disease, there is no effective therapy for FRDA that addresses the cause of the disease, the loss of frataxin protein. Gene therapy and protein replacement strategies for FRDA are promising approaches; however, current technology is not sufficiently advanced to envisage treatments for FRDA coming from these approaches in the near future. Since the FXN mutation in FRDA, expanded GAA.TTC triplets in an intron, does not alter the amino acid sequence of frataxin protein, gene reactivation would be of therapeutic benefit. Thus, a number of laboratories have focused on small molecule activators of FXN gene expression as potential therapeutics, and this review summarizes the current status of these efforts, as well as the molecular basis for gene silencing in FRDA.
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PMID:Small molecules affecting transcription in Friedreich ataxia. 1782 40

The aim of this study was to assess the incidence of point mutations in RAS oncogenes of papillary thyroid carcinoma (PTC). Tumour specimens were obtained from 29 PTCs. The fragments of exons 1 and 2 of RAS oncogenes family (H- RAS, K- RAS, N- RAS) were amplified and then, point mutations were detected by SSCP and/or by RFLP analysis. Several DNA samples were directly sequenced to confirm the results. Two mutations were found in this study (GAA/CAA at codon 31 of K- RAS and CAA/CAC at codon 61 of N- RAS oncogene). These data confirm the results of previous studies, showing that RAS mutations are more rarely found in PTC than in follicular neoplasms. The influence of a novel mutation at codon 31 of K- RAS oncogene on the development of PTC needs further studies.
Exp Clin Endocrinol Diabetes 2007 Oct
PMID:Prevalence of RAS point mutations in papillary thyroid carcinoma; a novel mutation at codon 31 of K-RAS. 1794 94

Diabetes mellitus is a disorder characterized by hyperglycemia in both the fasting and post-prandial states. The two most common forms of diabetes mellitus, type 1 and type 2 (previously called juvenile-onset and adult-onset, respectively), comprise the vast majority of cases. Type 1 diabetes (T1DM) has been shown to be a disease characterized by immune-mediated destruction of the insulin-secreting cells of the pancreas; it comprises the majority of cases of diabetes seen in childhood and approximately, 5-10% of all cases of diabetes mellitus in the USA and perhaps accounts for an even higher percentage in those nations with lower rates of obesity. The process of beta-cell destruction, marked by the production of autoantibodies to the beta-cell, occurs over many years and ultimately results in metabolic abnormalities first manifested as impaired glucose tolerance and then progressing to symptomatic hyperglycemia. It has been reported that approximately 50% of the genetic risk for T1DM can be attributed to the HLA region. The highest risk HLA-DR3/4 DQ8 genotype has been shown to be highly associated with beta-cell autoimmunity. The first antibodies described in association with the development of T1DM were islet cell autoantibodies (ICA). Subsequently, antibodies to insulin (IAA), glutamic acid decarboxylase (GAA or GAD) and protein tyrosine phosphatase (IA2 or ICA512) have all been defined. The number of antibodies, rather than the individual antibody, is thought to be most predictive of progression to overt diabetes.
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PMID:Autoantibodies in type 1 diabetes. 1817 60

Friedreich ataxia (FRDA) is a rare autosomal recessive hereditary disorder that affects approximately 1 in 50,000 Caucasians. It is caused by hyperexpansion of GAA repeats in the first intron of the frataxin gene. Initial symptoms of FRDA usually appear around the beginning of the second decade of life. In addition to neuropathological disabilities such as ataxia, sensory loss, and muscle weakness, common signs are scoliosis, foot deformity, and hypertrophic cardiomyopathy. Approximately 10 % of patients with FRDA develop diabetes. The neuronopathy in the dorsal root ganglia, accompanied by the loss of peripheral sensory nerve fibres and the degeneration of posterior columns of the spinal cord, is a hallmark of the disease and is responsible for the typical combination of signs and symptoms specific to FRDA. Variation in neurophysiological abnormalities is correlated with the size of the GAA repeat expansion and likely accounts for individual variation in the progression of FRDA. Despite a range of disease severity, most patients will lose their ability to walk, stand, or sit without support within 10 to 15 years of disease onset. In addition to a review of the clinicopathological features of FRDA, a discussion of recent advances in our understanding of the underlying molecular mechanisms is provided.
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PMID:Friedreich ataxia: the clinical picture. 1928 44

Friedreich ataxia is the most frequent hereditary ataxia, with an estimated prevalence of 3-4 cases per 100,000 individuals. This autosomal-recessive neurodegenerative disease is characterized by progressive gait and limb ataxia, dysarthria, lower-limb areflexia, decreased vibration sense, muscular weakness in the legs, and a positive extensor plantar response. Non-neurological signs include hypertrophic cardiomyopathy and diabetes mellitus. Symptom onset typically occurs around puberty, and life expectancy is 40-50 years. Friedreich ataxia is usually caused by a large GAA-triplet-repeat expansion within the first intron of the frataxin (FXN) gene. FXN mutations cause deficiencies of the iron-sulfur cluster-containing subunits of the mitochondrial electron transport complexes I, II, and III, and of the iron-sulfur protein aconitase. Mitochondrial dysfunction has been addressed in several open-label, non-placebo-controlled trials, which indicated that treatment with idebenone might ameliorate hypertrophic cardiomyopathy; a well-designed phase II trial suggested concentration-dependent functional improvements in non-wheelchair-bound children and adolescents. Other current experimental approaches address iron-mediated toxicity, or aim to increase FXN expression through the use of erythropoietin and histone deacetylase inhibitors. This Review provides guidelines, from a European perspective, for the diagnosis of Friedreich ataxia, differential diagnosis of ataxias and genetic counseling, and treatment of neurological and non-neurological symptoms.
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PMID:Diagnosis and treatment of Friedreich ataxia: a European perspective. 1934 27

Progressive signs of ataxia in a eight years old girl prompted neurological investigation. The girl had unstable gait with incoordination of limb movements, impairment of position and vibratory senses, dysarthria, pes cavus, positive Babinski sign and scoliosis. At the age of fourteen the girl was referred in a comatose condition, in a severe diabetic ketoacidosis. Ataxia and hypoactive knee and ankle jerks prompted the analysis of the frataxin gene (FXN; 606829). The most common molecular abnormality: GAA trinucleotide repeat expansion in intron 1 was found with + 300 GAA repeats (1490bp) (normal individuals have 5 to 30 GAA repeat expansions, whereas affected individuals have from 70 to more than 1,000 GAA triplets). Electrocardiogram showed diffuse T wave inversion with sinus bradycardia, while ultrasound revealed concentric, symmetric hypertrophy of left ventricle leading to the diagnosis of hyperthrophic cardiomyopathy. At the age of 14 years, the patient was bound to the wheel-chair, unable to walk. Her brother started to show ataxia at the age of 8 years, and subsequent analysis showed hyperthrophic cardiomyopathy, too. His mutational analysis revealed the same frataxin abnormality, with + 300 GAA repeats. So far, no signs of diabetes occurred. The parents are heterozygous with FXN of 9 -10 GAA (490 bp). Both children received a beta blocker, while the girl's diabetes mellitus was treated by insulin preparations. This is a report of two siblings with Fridreich ataxia and hyperthrophic cardiomyopathy. In addition, the girl developed type 1 diabetes mellitus.
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PMID:Friedreich ataxia (FA) associated with diabetes mellitus type 1 and hyperthrophic cardiomyopathy. 1948 41

Progressive signs of ataxia in a eight year old girl with hypo-active knee and ankle jerks, prompted the analysis of the frataxin gene (FXN; 606829). The most common molecular abnormality--GAA trinucleotide repeat expansion in intron 1--was found with +300 GAA repeats (1490 bp) (normal individuals have 5 to 30 GAA repeats expansions, whereas affected individuals have from 70 to more than 1000 GAA triplets). Additionally she had unstable gait with incoordination of limb movements, impairment of position and vibratory senses, dysarthria, pes cavus, positive Babinski sign and scoliosis. At the age of fourteen the girl was referred in a comatose condition, in severe diabetic ketoacidosis. Insulin dependent diabetes mellitus was since treated with insulin preparations. Electrocardiogram showed diffuse T wave inversion with sinus bradycardia, while ultrasound revealed concentric, symmetric hypertrophy of the left ventricle leading to the diagnosis of hypertrophic cardiomyopathy. At the age of 14, she is bound to the wheelchair, unable to walk. Her brother started to show ataxia at the age of 8 years and subsequent analysis also showed hypertrophic cardiomyopathy. His mutational analysis revealed the same frataxin abnormality with +300 GAA repeats. So far, no signs of diabetes occurred. The parental DNA was not available for analysis.
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PMID:Friedreich's ataxia (FA) associated with diabetes mellitus type 1 and hypertrophic cardiomyopathy: analysis of a FA family. 1953 71

Mitochondrial dysfunction and oxidative damage are at the origin of numerous neurodegenerative diseases like Friedreich ataxia and Alzheimer and Parkinson diseases. Friedreich ataxia (FRDA) is the most common hereditary ataxia, with one individual affected in 50,000. This disease is characterized by progressive degeneration of the central and peripheral nervous systems, cardiomyopathy, and increased incidence of diabetes mellitus. FRDA is caused by a dynamic mutation, a GAA trinucleotide repeat expansion, in the first intron of the FXN gene. Fewer than 5% of the patients are heterozygous and carry point mutations in the other allele. The molecular consequences of the GAA triplet expansion is transcription silencing and reduced expression of the encoded mitochondrial protein, frataxin. The precise cellular role of frataxin is not known; however, it is clear now that several mitochondrial functions are not performed correctly in patient cells. The affected functions include respiration, iron-sulfur cluster assembly, iron homeostasis, and maintenance of the redox status. This review highlights the molecular mechanisms that underlie the disease phenotypes and the different hypothesis about the function of frataxin. In addition, we present an overview of the most recent therapeutic approaches for this severe disease that actually has no efficient treatment.
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PMID:Friedreich ataxia: molecular mechanisms, redox considerations, and therapeutic opportunities. 2015 11

Friedreich's ataxia (FRDA) is an autosomal recessive inherited disorder characterized by progressive gait and limb ataxia, dysarthria, areflexia, loss of vibratory and position sense, and a progressive motor weakness of central origin. Additional features include hypertrophic cardiomyopathy and diabetes. Large GAA repeat expansions in the first intron of the FXN gene are the most common mutation underlying FRDA. Patients show severely reduced levels of a FXN-encoded mitochondrial protein called frataxin. Frataxin deficiency is associated with abnormalities of iron metabolism: decreased iron-sulfur cluster (ISC) biogenesis, accumulation of iron in mitochondria and depletion in the cytosol, enhanced cellular iron uptake. Some models have also shown reduced heme synthesis. Evidence for oxidative stress has been reported. Respiratory chain dysfunction aggravates oxidative stress by increasing leakage of electrons and the formation of superoxide. In vitro studies have demonstrated that Frataxin deficient cells not only generate more free radicals, but also show a reduced capacity to mobilize antioxidant defenses. The search for experimental drugs increasing the amount of frataxin is a very active and timely area of investigation. In cellular and in animal model systems, the replacement of frataxin function seems to alleviate the symptoms or even completely reverse the phenotype. Therefore, drugs increasing the amount of frataxin are attractive candidates for novel therapies. This review will discuss recent findings on FRDA pathogenesis, frataxin function, new treatments, as well as recent animal and cellular models. Controversial aspects are also discussed.
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PMID:Friedreich's ataxia: past, present and future. 2155 Jun 66

Friedreich ataxia, the most common hereditary ataxia, affects approximately 1 per 29,000 white individuals. In about 98% of these individuals, it is due to homozygosity for a GAA trinucleotide repeat expansion in intron 1 of FXN; in the other 2%, it is due to compound heterozygosity for a GAA expansion and point mutation or deletion. The condition affects multiple sites in the central and peripheral nervous system as well as a number of other organ systems, resulting in multiple signs and symptoms. Onset of this autosomal recessive condition is usually in the first 2 decades of life. Major clinical features include progressive ataxia, absent lower limb reflexes, upgoing plantar responses, and peripheral sensory neuropathy. The main nonneurological sites of morbidity are the heart, resulting in cardiomyopathy, and the pancreas, resulting in diabetes mellitus. In this review, we provide an overview of the clinical features of Friedreich ataxia and discuss differential diagnoses.
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PMID:Clinical features of Friedreich ataxia. 2275 93


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