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)

Phase three of the Quebec Cooperative Study of Friedreich's Ataxia was devoted to an understanding of the physiopathology of individual symptoms on the basis of previously discovered biochemical leads. The present paper attempts to pull these results together by presenting, as a hypothesis, a unifying scheme of possible interactions and relationships. The central core of this hypothesis is the demonstration in Friedreich's ataxia of a state of mitochondrial energy deprivation. This is indirectly responsible for such associated and important symptoms as muscle weakness, dying-back neuropathy, scoliosis and hypertrophic cardiomyopathy. Secondarily, and possibly as an independent but linked-event, the entry of glucose into cells and pyruvate oxidation, are slowed down, favoring the development of diabetes. As a consequence, tissue concentrations of glutamic acid and aspartic acid are decreased, particularly in more vulnerable areas such as the cerebellum, brain stem and dorsal root ganglia. This tissue deficiency in putative excitatory neurotransmitters is directly responsible for the symptom of ataxia. This conclusion is reinforced by the correction of the ataxia in experimental animals, by the intraventricular injection of the same amino acids, and not by the injection of other stimulants of motricity. The observed mitochondrial energy deprivation could be the metabolic consequence of major changes in the linoleic acid (18.2) composition of inner mitochondrial membrane phospholipids, such as cardiolipin. Such decreases in membrane 18:2 could be the result of interference with the normal incorporation of this fatty acid to lipoproteins and/or cell membranes. It is at this level that the search for the specific enzyme defect in Friedreich's ataxia is continuing.
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PMID:Friedreich's ataxia 1980. An overview of the physiopathology. 678 90

The clinical features of 115 patients from 90 families with Friedreich's ataxia are described. Onset of symptoms was before the age of 25 (mean 10.52) years in all the index cases. An analysis of early cases suggested that limb and truncal ataxia and absent tendon reflexes in the legs were the only consistent diagnostic criteria within five years of presentation. Dysarthria, signs of pyramidal tract dysfunction in the legs and loss of joint position and vibration sense are not necessarily present during the first five years of symptoms, but appear to develop eventually in all cases. Scoliosis and ECG evidence of cardiomyopathy were found in over two-thirds of the patients studied; pes cavus, distal amyotrophy, optic atrophy, nystagmus and deafness were all less frequent. The disorder was gradually progressive in all cases. The mean age of losing the ability to walk was 25 years; 95 per cent were chair-bound by the age of 44 years. About 10 per cent of the patients had diabetes mellitus which was controlled by oral hypoglycaemic drugs in one quarter. Diabetes appeared to be associated with a higher incidence of optic atrophy and deafness. Diabetes also clustered within sibships; the risk of an individual with Friedreich's ataxia developing diabetes if an affected sib has it is over 40 per cent. Similarly, cardiomyopathy ran true within affected members of the same sibship, but there were instances of discordance which suggest that the development of the non-neurological features of Friedreich's ataxia may be controlled by modifying genes rather than heterogeneity of the main gene. Segregation analysis and an increased consanguinity rate amongst parents of patients (5.55 per cent) confirmed that this disorder is of autosomal recessive inheritance. A study of 101 first degree relatives of the patients with Friedreich's ataxia failed to demonstrate any neurological or electrocardiographic abnormalities which could be ascribed to the heterozygous state.
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PMID:Friedreich's ataxia: a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features. 727 14

Twenty patients are described with a distinctive clinical syndrome characterised by progressive cerebellar ataxia developing within the first two decades. This is associated with dysarthria, pyramidal signs in the limbs, normal or increased knee jerks and upper limb reflexes and in some instances sensory loss. Inheritance is probably autosomal recessive in the majority, if not all, of the cases. The preservation of tendon reflexes distinguishes this disorder from Friedreich's ataxia. Other important differences from Friedreich's ataxia are absence of optic atrophy, cardiomyopathy, diabetes mellitus and severe skeletal deformity. The prognosis was better in the present series than in cases of Friedreich's ataxia; patients remained ambulant, on average, for more than 10 years longer.
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PMID:Early onset cerebellar ataxia with retained tendon reflexes: a clinical and genetic study of a disorder distinct from Friedreich's ataxia. 727 63

As part of an ongoing search for diabetes susceptibility loci, we tested linkage with non-insulin-dependent diabetes mellitus (NIDDM) for 19 candidate loci or regions chosen for their potential to affect directly or indirectly the action of insulin. Loci were associated with insulin resistance, known effects on lipid metabolism, or effects on glucose metabolism or insulin action. Loci included the insulin-responsive (GLUT4) glucose transporter, hexokinase 2, glucagon, growth hormone, insulin receptor substrate 1 (IRS1), phosphoenolpyruvate carboxykinase, hepatic and muscle forms of pyruvate kinase, hepatic phosphofructokinase, the apolipoprotein B and the apolipoprotein A2 cluster, lipoprotein lipase, hepatic triglyceride lipase, the very-low-density-lipoprotein receptor, and the Pima insulin resistance locus on chromosome 4. For several candidates, no specific informative marker was available; consequently, we tested the surrounding region with highly informative markers. These regions included the diabetes-associated ras-like gene, rad, and the cholesterol ester-transfer gene, both mapped to chromosome 16. Additionally, we tested for linkage with markers at the tumor necrosis factor-alpha gene and the Friedreich's ataxia region. All regions were tested for linkage with microsatellite polymorphisms in > 450 individuals from a minimum of 16 Caucasian families under parametric (LINKAGE 5.1) and nonparametric (affected pedigree member) models.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1995 Nov
PMID:Linkage analysis of 19 candidate regions for insulin resistance in familial NIDDM. 758 21

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

Recently, a new syndrome of early onset cerebellar ataxia with hypoalbuminemia (EOCA-HA) was reported in Japan. The clinical features of EOCA-HA overlap with those of Friedreich's ataxia (FA), and primary hypoalbuminemia is a characteristic laboratory finding of this syndrome. Genetic linkage analysis of EOCA-HA including this newly reported family revealed that the gene for EOCA-HA is located on the long arm of chromosome 9 as FA. However, several recombination events were observed between D9S15 in EOCA-HA, whereas no recombination events were seen in FA. We report on two siblings with EOCA-HA and discuss the clinical and laboratory features. The patients were a 25-year-old man (patient 1) and a 23-year-old man (patient 2). Their parents marriage was non-consanguineous. The mode of inheritance is compatible with autosomal recessive mode. Clinically, they showed cerebellar ataxia as the initial symptom in the late infantile period and subsequently showed choreoathetosis and ocular motor apraxia at the age of approximately fifteen years. Deep tendon reflexes were reduced in late infancy and finally disappeared. Amyotrophy and sensory impairment of the legs developed at approximately twenty. Abnormal electrocardiogram and diabetes mellitus were not observed. On X-ray CT scan or MRI, the cerebella of both patients were mildly atrophic. Clinical features in these siblings were indistinguishable from those of ataxia telangiectasia, but immunodeficiency syndrome was absent.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Siblings of early onset cerebellar ataxia with hypoalbuminemia]. 778 Dec 24

Friedreich's ataxia is associated with a high incidence of diabetes mellitus. We have previously demonstrated that insulin resistance is present in nondiabetic patients with Friedreich's ataxia. This was associated with a reduction in the affinity of insulin receptors on freshly isolated monocytes. In this study we investigated the ability of the monocyte insulin receptor to acutely alter its affinity in response to oral glucose. Glucose and insulin concentrations were higher in the patients with Friedreich's ataxia after an oral glucose load, consistent with the presence of insulin resistance. The normal increase in the affinity of insulin receptors on monocytes 5 h after oral glucose was absent in the five patients with Friedreich's ataxia. Receptor affinity actually decreased in three of the five patients. These findings support the concept that a membrane abnormality that alters the binding function of the insulin receptor is present in these patients.
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PMID:Evidence for abnormal regulation of insulin receptors in Friedreich's ataxia. 842 Nov 4

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

We performed a retrospective study on a series of 119 of our patients who have Friedreich's disease to assess the predictive value of age at onset, gender, and left ventricular hypertrophy in regard to disease progression. Outcome variables were survival, time to loss of independent gait, and time to confinement in a wheelchair. Diabetes was considered to be an outcome variable when defining time to diabetes and an explanatory variable when testing its effect on survival. Eleven patients died. The median estimated survival from onset was 36 years, and the median time to loss of independent gait was 8 years and to confinement in a wheelchair was 15 years from onset. Nineteen patients developed diabetes after a median time of 16 years. The presence of left ventricular hypertrophy or diabetes significantly reduced survival based on univariate analysis. Onset at the age of < or = 20 years and the presence of left ventricular hypertrophy predicted a faster rate of progression of the disease.
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PMID:Age of onset, sex, and cardiomyopathy as predictors of disability and survival in Friedreich's disease: a retrospective study on 119 patients. 890 40


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