Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Friedreich ataxia (FRA) is an autosomal recessive neuromuscular disorder in which nearly all affected homozygotes eventually develop significant cardiomyopathy and a substantial proportion also develop diabetes mellitus. Diabetes and early heart disease have been observed previously in close blood relatives of FRA patients. To test the hypothesis that FRA heterozygotes may have elevated rates of heart disease mortality and diabetes incidence, we compared the rates of these conditions in 1,191 adult blood relatives to those in 745 nonblood relative spouse controls in 27 families of FRA patients. We found no evidence for an excess of diabetes in the blood relatives. For three broad categories of circulatory disease mortality, the FRA blood relatives had significantly higher rates than the spouse controls. However, when each relative's prior probability of heterozygosity for the FRA gene was taken into account, the resulting estimates of relative risk of dying from circulatory disease for FRA heterozygotes compared to nonheterozygotes were not significantly elevated. Since the latter analysis provides the best test of the hypothesis, our data did not strongly support the hypothesis that FRA heterozygotes are at increased risk of cardiac death.
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PMID:Circulatory disease mortality and diabetes incidence in 27 families with Friedreich ataxia. 320 55

Friedreich ataxia is an autosomal recessive ataxia with onset usually before puberty whose characteristic clinical features include progressive ataxia of gait and limbs, dysarthria, loss of joint position and vibratory sense, absent knee and ankle jerks, and Babinski signs. Foot deformity, scoliosis, diabetes mellitus, and cardiac involvement are common and characteristic. Patients survive until about age 30 years although longer survivals occur. A later onset, more slowly progressive form seems to be an allelic variant. The basic process seems to be a dying-back of neuronal processes. Using linkage mapping techniques, the classical form of Friedreich ataxia has been localized to 9q13-q21, a region on the long arm of chromosome 9. Haplotype analysis, analysis of recombinants, and physical mapping techniques, including construction of a YAC contig, have narrowed the interval for the Friedreich ataxia gene, FRDA, to a few hundred thousand base pairs. Candidate genes in the region are being studied by techniques of mutation analysis. It is likely that the Freidreich ataxia gene will be cloned soon. A condition resembling Friedreich ataxia with decreased vitamin E levels has been localized to chromosome 8 and is discussed elsewhere.
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PMID:Friedreich ataxia. 761 92

The onset of Friedreich ataxia (FA) was before 10 years of age in 36 out of 95 personally observed patients. We studied the clinical and laboratory findings of these childhood onset patients. Mean onset age +/- SD was 6.3 +/- 2.4 years. Gait and stance ataxia and lower limb areflexia were constant, dysmetria, dysarthria, Babinski sign, pes cavus, scoliosis and decreased vibration sense were present in the majority of patients. Higher occurrence of diabetes in childhood onset cases (25%) was the only statistical difference in comparison with later onset patients. Mean onset age of diabetes was 21.1 +/- 6.9 years and all patients required insulin. ECG was abnormal in 72% of the patients and echocardiographic evidence of hypertrophic cardiomyopathy was found in 43%. Linkage analysis, performed in 10 families, showed no recombination between the polymorphic markers of the 9q13-21.1 region and the disease locus with a peak lod score of 4.21 at a recombination fraction = 0.00.
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PMID:Childhood onset of Friedreich ataxia: a clinical and genetic study of 36 cases. 867 22

Friedreich ataxia (FA) is associated with the expansion of a GAA trinucleotide repeat in the first intron of the X25 gene. We found both alleles expanded in 67 FA patients from 48 Italian families. Five patients from three families were compound heterozygotes with expansion on one allele and an isoleucine-->phenylalanine change at position 154 on the other one. We found neither expansions nor point mutations in three patients. The length of FA alleles ranged from 201 to 1,186 repeat units, with no overlap with the normal range, and showed a negatively skewed distribution with a peak between 800 and 1,000 repeats. The FA repeat showed meiotic instability with a median variation of 150 repeats. The lengths of both larger and smaller alleles in each patient inversely correlated with age at onset of the disorder. Smaller alleles showed the best correlation, accounting for approximately 50% of the variation of age at onset. Mean allele length was significantly higher in patients with diabetes and in those with cardiomyopathy.
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PMID:The relationship between trinucleotide (GAA) repeat length and clinical features in Friedreich ataxia. 875 56

The clinical relevance of neurological disorders associated with impaired glucose tolerance(IGT) is reviewed. In this review some neurological diseases, such as, myotonic dystrophy, Crow-Fukase syndrome, Wolfram syndrome (DIDMOAD), Friedreich ataxia, spinal muscular atrophy of the Kennedy-Alter-Sung type, amyotrophic lateral sclerosis, Parkinson-dementia, and MELAS are discussed in relation to, glucose intolerance. Although the etiology of these disorders still remains an enigma, MELAS was caused by an A-to-G mutation at nucleotide position 3243 of the mitochondria genome. An association of "diabetic neuropathy" with IGT appears to be negative. Peripheral nerve function did not differ between IGT and control subjects, whereas autonomic nerve function deviated; an abnormal expiration to inspiration ratio of R-R interval was significantly more common in IGT than in control subjects. In conclusion, diabetes, but not IGT, is associated with peripheral nerve dysfunction.
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PMID:[Neurological disorders associated with impaired glucose tolerance]. 891 31

Friedreich's ataxia is the most common hereditary ataxia and is frequently associated with disturbances of glucose metabolism. This autosomal recessive disease is caused by the decreased expression of a mitochondrial protein, frataxin, encoded by the X25 gene. Homozygous expansion of a GAA repeat in the first intron of X25 inhibits frataxin expression and is associated with clinical disease. We evaluated whether heterozygous expansions of the triplet repeat in the frataxin gene X25 may be associated with NIDDM in two genetically distinct populations--one in Germany (n = 358) and the other in the U.S. (n = 292)--using a polymerase chain reaction-based assay. Intermediate expansions (10-36 repeats), which are longer than normal but not sufficient for the appearance of the ataxia phenotype, were found in 24.7 and 27.3% of these two NIDDM cohorts compared with 7.6 and 6.3% of the matched control subjects (both P < 0.001). The odds ratios were 3.36 (95% CI 1.72-6.55) for the German group and 4.01 (2.08-7.74) for the U.S. group. Therefore, we conclude that the X25/frataxin GAA repeat polymorphism is associated with NIDDM in a frequency higher than any other mutation heretofore described. Further studies are needed to elucidate the possible role of frataxin in the pathogenesis of NIDDM.
Diabetes 1998 May
PMID:An association between NIDDM and a GAA trinucleotide repeat polymorphism in the X25/frataxin (Friedreich's ataxia) gene. 958 63

Mutations of mitochondrial DNA (mtDNA) are associated with a wide spectrum of disorders encompassing the myopathies, encephalopathies and cardiomyopathies, in addition to organ specific presentations such as diabetes mellitus and deafness. The pathogenesis of mtDNA mutations is not fully understood although it is assumed that their final common pathway involves impaired oxidative phosphorylation. The identification of a specific respiratory chain defect (complex I deficiency) in Parkinson's disease (PD) 10 years ago focused attention on the aetiological and pathogenetic roles that mitochondria may play in neurodegenerative diseases. There is evidence now emerging that mtDNA abnormalities may determine the complex I defect in a proportion of PD patients and it may prove possible to use biochemical analysis of platelet and cybrid complex I function to identify those that lie within this group. Respiratory chain defects of a different pattern have been identified in Huntington's disease (HD) (complex II/III deficiency) and Friedreich's ataxia (FA) complex I-III deficiency). In both these disorders, the mitochondrial abnormality is secondary to the primary nuclear mutation:CAG repeat in the huntingtin gene in HD, and GAA repeat in the frataxin gene in FA. Nevertheless, it appears that the mitochondrion may be the target of the biochemical defects that are the consequence of these mutations. There is a close and reciprocal relationship between respiratory chain dysfunction and free radical generation, and there is evidence for oxidative stress and damage in PD, HD and FA, which together with the mitochondrial defect may result in cell damage. Impaired oxidative phosphorylation and free radical generation may independently adversely affect the maintenance of mitochondrial transmembrane potential (Deltapsim). A fall in Deltapsim is an early event (preceding nuclear fragmentation) in the apoptotic pathway. It is possible therefore that mitochondrial dysfunction in the neurodegenerative disorders may result in a fall in the apoptotic threshold of neurones which, in some, may be sufficient to induce cell death whilst, in others, additional factors may be required. In any event, mitochondria present an important target for future strategies for 'neuroprotection' to prevent or retard neurodegeneration.
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PMID:Mitochondrial dysfunction in neurodegenerative disorders. 971 16

A variable expansion of a GAA repeat is present in the first intron of the frataxin gene, also termed FRDA1 or X25. Long repeat lengths (>66 repeats) are present in patients with Friedreich's ataxia, while an intermediate expansion (10-66 repeats) has recently been reported to be highly associated with type 2 diabetes. Using a polymerase chain reaction-based assay, we found that 32.4% (95%CI 29.9-34.9) of 636 Danish Caucasian type 2 diabetic patients were carriers of an intermediate expansion, whereas the frequency was 30.4% (26.4-34.4) among 224 matched glucose-tolerant control subjects (P = 0.6). In the control subjects, the values of serum insulin and C-peptide responses during an oral glucose tolerance test were similar between the 69 carriers and 155 noncarriers. Furthermore, we investigated a possible relationship between expansions of the FRDA1 gene and glucose-induced beta-cell function in 338 young Caucasians (33.7% [30.1-37.3] carriers) and in 215 glucose-tolerant subjects (31.0% [26.6-35.4] carriers) with a type 2 diabetic parent. In neither population did the carriers differ from noncarriers according to values of fasting plasma glucose, serum insulin, or C-peptide, acute serum insulin, or C-peptide responses after intravenous glucose. In conclusion, intermediate expansion of the frataxin trinucleotide repeat is not associated with type 2 diabetes or altered glucose-induced insulin secretion in Danish Caucasians.
Diabetes 1999 Apr
PMID:Intermediate expansions of a GAA repeat in the frataxin gene are not associated with type 2 diabetes or altered glucose-induced beta-cell function in Danish Caucasians. 1010 12

Friedreich's ataxia is associated with GAA trinucleotide repeat expansions in the frataxin gene. In the general population, these trinucleotide expansions are variable in length, and three types of expansions are seen: short, intermediate, and long repeats. Friedreich's ataxia patients are generally homozygous for the long repeats and exhibit diabetes as pronounced comorbidity. Ristow et al. recently reported an association between the intermediate-length normal allele in the frataxin gene and type 2 diabetes. We have investigated in 94 subjects with impaired glucose tolerance (IGT) as to whether the length of the GAA trinucleotide repeat polymorphism in the frataxin gene associates with parameters reflecting beta-cell function. A hyperglycemic clamp at 10 mmol/l glucose for 3 h was used to quantitate beta-cell characteristics. Carriers of one or two intermediate repeat alleles (n = 32) had a 50% higher median first- phase insulin response to glucose than the noncarriers. Furthermore, they needed less time to reach peak insulin. An analysis of the distribution of the various repeat lengths in elderly type 2 diabetic (n = 179) and control subjects (n = 183), with the same age and ethnic background, did not provide evidence for an association of the intermediate-length repeat allele with type 2 diabetes in Dutch Caucasians.
Diabetes 1999 Apr
PMID:Altered beta-cell characteristics in impaired glucose tolerant carriers of a GAA trinucleotide repeat polymorphism in the frataxin gene. 1010 15

Friedreich's ataxia (FRDA) is the most frequent cause of recessive ataxias. Neurological examination shows oculo-motor ataxia, dysarthria, limbs ataxia, tendon areflexia, pyramidal signs and sensory deficits. Extra-neurological involvement consists in osteoarticular deformities, cardiomyopathy and diabetes mellitus. Neurological deficits and osteoarticular deformities both contribute to the gait disorder, which is the main disabling deficit. In 98% of the cases, a trinucleotide repeat is found in chromosome 9. Gene implicated in FRDA codes for a protein called frataxin. Experimental studies have revealed iron accumulation in mitochondria of neurons and cardiomyocytes, suggesting that frataxin plays a determinant role in intramitochondrial iron homeostasis. These discoveries are now considered as a clue for new strategies of treatment in this hereditary disease.
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PMID:[Friedreich's ataxia: recent developments and prospects for treatment]. 1033


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