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

Nine cases of mitochondrial myopathy are presented and the literature is reviewed. The clinical picture ranges from virtually pure ophthalmoplegia, through 'ophthalmoplegia plus' to predominantly central nervous system disturbance. Morphological mitochondrial abnormalities are likely to reflect generalised metabolic abnormalities of diverse aetiology, but producing common pathophysiological consequences. The association of mitochondrial myopathy with CNS disorders, which may ante-date muscle weakness, is emphasised. The myopathies constitute a clinical continuum within which the following syndromes may be delineated: (1) Kearns-Sayre syndrome (2) Luft's disease (3) a variant of Ramsay Hunt syndrome (4) relapsing febrile neurological deficits with headache and seizures. These may be specific diseases or artificially separated manifestations of some common metabolic disorder(s). There is a similarity between the CNS pathology, and also some clinical features, of Leigh's disease and the findings in certain of the mitochondrial myopathies. The review suggests that the following should be regarded as associations of mitochondrial myopathy and progressive external ophthalmoplegia (a) diabetes mellitus (b) cataracts, in which calcium deposits may, like basal ganglia calcification, be due to abnormal calcium metabolism. Diplopia, although unusual, does occur in progressive external ophthalmoplegia with mitochondrial myopathy.
 ...
PMID:The mitochondrial myopathies: 9 case reports and a literature review. 734 99

We review the main features of human mitochondrial function and structure, and in particular mitochondrial transcription, translation, and replication cycles. Furthermore, some pecularities such as mitochondria's high polymorphism, the existence of mitochondrial pseudogenes, and the various considerations to take into account when studying mitochondrial diseases will also be mentioned. Mitochondrial syndromes mostly affecting the nervous system have, during the past few years, been associated with mitochondrial DNA (mt DNA) alterations such as deletions, duplications, mutations and depletions. We suggest a possible classification of mitochondrial diseases according to the kind of mt DNA mutations: structural mitochondrial gene mutation as in LHON (Leber's Hereditary Optic Neuropathy) and NARP (Neurogenic muscle weakness, Ataxia and Retinitis Pigmentosa) as well as some cases of Leigh's syndrome; transfer RNA and ribosomal RNA mitochondrial gene mutation as in MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis and Strokelike Episodes) or MERRF (Myoclonic Epilepsy with Ragged Red Fibers) or deafness with aminoglycoside; structural with transfer RNA mitochondrial gene mutations as observed in large-scale deletions or duplications in Kearns-Sayre syndrome, Pearson's syndrome, diabetes mellitus with deafness, and CPEO (Chronic Progressive External Ophtalmoplegia). Depletions of the mt DNA may also be classified in this category. Even though mutations are generally maternally inherited, most of the deletions are sporadic. However, multiple deletions or depletions may be transmitted in a mendelan trait which suggests that nuclear gene products play a primary role in these processes. The relationship between a mutation and a particular phenotype is far from being fully understood. Gene dosage and energic threshold, which are tissue-specific, appear to be the best indicators. However, the recessive or dominant behavior of both the wild type or the mutated genome appears to play a significant role, which can be verified with in vitro studies.
 ...
PMID:Mitochondrial DNA alterations and genetic diseases: a review. 799 80

A variety of degenerative diseases involving deficiencies in mitochondrial bioenergetics have been associated with mitochondrial DNA (mtDNA) mutations. Maternally inherited mtDNA nucleotide substitutions range from neutral polymorphisms to lethal mutations. Neutral polymorphisms are ancient, having accumulated along mtDNA lineages, and thus correlate with ethnic and geographic origin. Mildly deleterious base substitutions have also occurred along mtDNA lineages and have been associated with familial deafness and some cases of Alzheimer's Disease and Parkinson's Disease. Moderately deleterious nucleotide substitutions are more recent and cause maternally-inherited diseases such as Leber's Hereditary Optic Neuropathy (LHON) and Myoclonic Epilepsy and Ragged-Red Fiber Disease (MERRF). Severe nucleotide substitutions are generally new mutations that cause pediatric diseases such as Leigh's Syndrome and dystonia. MtDNA rearrangements also cause a variety of phenotypes. The milder rearrangements generally involve duplications and can cause maternally-inherited adult-onset diabetes and deafness. More severe rearrangements frequently involving detections have been associated with adult-onset Chronic Progressive External Ophthalmoplegia (CPEO) and Kearns-Sayre Syndrome (KSS) or the lethal childhood disorder, Pearson's Marrow/Pancreas Syndrome. Defects in nuclear-cytoplasmic interaction have also been observed, and include an autosomal dominant mutation causing multiple muscle mtDNA deletions and a genetically complex disease resulting in the tissue depletion of mtDNAs. MtDNA nucleotide substitution and rearrangement mutations also accumulate with age in quiescent tissues. These somatic mutations appear to degrade cellular bioenergetic capacity, exacerbate inherited mitochondrial defects and contribute to tissue senescence. Thus, bioenergetic defects resulting from mtDNA mutations may be a common cause of human degenerative disease.
 ...
PMID:Mitochondrial DNA mutations in diseases of energy metabolism. 807 79

Clinical and biochemical classifications of mitochondrial disorders have given way to an as yet incomplete genetic classification system based on alterations of the mitochondrial genome, the nuclear genome, or both. The first group includes mitochondrial disorders due to specific mutations of mitochondrial DNA such as the MELAS, MERRF or NARP encephalomyopathies, various conditions involving deafness (non-syndromic or associated with diabetes), Leber's optic neuropathy and a small group of cases of maternally transmitted Leigh's syndrome. All these diseases are transmitted through maternal line. conditions which are usually sporadic are due to deletion or duplication of mitochondrial DNA, and give rise to myopathies, with or without ophthalmoplegia, and to more complex disorders such as Kearns Sayre syndrome are also included. The second group is composed of all the mitochondrial disorders in which the nuclear genes which codify sub-units of mitochondrial DNA contain a genetic defect. This includes most cases of Leigh's syndrome, Alpers polydystrophies, the myoneurogastrointestinal syndrome, Barth's syndrome and Friedreich's disease. Amongst the disorders secondary to defects in communication between the nuclear and mitochondrial genomes is a progressive external ophthalmoplegic form with autosomal dominance which arises secondary to mutations on chromosomes 3 and 10. Further mitochondrial disorders due to faults in the relationship between the two genomes will probably be found in the near future.
 ...
PMID:[Classification of mitochondrial diseases]. 981 May 85

Adult onset Leigh syndrome with a nucleotide (nt) 8993 mutation in mitochondrial (mt) DNA is reported. A 43-year-old woman with a 6-year-history of insulin-resistant diabetes mellitus developed muscular weakness, intractable nausea and vomiting, and anemia. These were followed vertigo, blindness, and deafness with nystagmus. Magnetic resonance imaging (MRI) revealed abnormal high intensities in the bilateral medial regions of the thalamus and periaqueductal gray matters. Autopsy disclosed well-demarcated necrotizing lesions with prominent capillaries in the areas detected by MRI, which were sufficiently diagnostic for Leigh syndrome. MtDNA analysis performed on DNAs extracted from formalin-fixed tissues including liver, heart, brain, muscle, kidney and pancreas showed a T-->G mutation at nt 8993. This is the first case of adult Leigh syndrome demonstrating on mtDNA mutations.
 ...
PMID:Adult Leigh syndrome with mitochondrial DNA mutation at 8993. 1020 83

We report an 8-year molecular study of mitochondrial DNA (mtDNA) mutations in patients with mitochondrial diseases in Taiwan. One hundred and seventy-seven patients met the diagnostic criteria of mitochondrial disease and were recruited into the study. The results showed that 32 patients, including 25 with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, one with Kearns-Sayre syndrome (KSS), one with diabetes mellitus and deafness, and five with chronic progressive external ophthalmoplegia (CPEO), harbored the A3243G mtDNA mutation. The A8344G mutation was found in nine patients, all of whom suffered from myoclonic epilepsy and ragged-red fibers (MERRF) syndrome. The G11778A mtDNA mutation was found in 18 of 22 patients with Leber's hereditary optic neuropathy. The T8993C and T8993G mutations were found, respectively, in one and two patients with Leigh syndrome. Large-scale deletions of mtDNA were found in 17 patients with CPEO, one with KSS, one with MELAS, and two with MERRF syndrome. The mtDNA mutations in patients with each of the mitochondrial diseases found in Taiwan were restricted mainly to a single site, while those reported for the same diseases in other ethnic groups occurred in many sites. Furthermore, significant levels of additional mtDNA mutations occurred in some patients with mitochondrial encephalomyopathies. We suggest that these additional (or secondary) mtDNA mutations are generated as a consequence of the preexisting primary mtDNA mutations and may contribute to the age-dependent progressive deterioration characteristic of mitochondrial diseases.
 ...
PMID:Molecular epidemiologic study of mitochondrial DNA mutations in patients with mitochondrial diseases in Taiwan. 1042 Jul

Five unrelated patients harboring the A3243G mutation in the mitochondrial DNA (mtDNA) but presenting with different clinical phenotype were studied for their percentage of mutation at the single muscle fiber levels. One patient had a clinically and pathologically defined Leigh syndrome (LS), two showed mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), another showed progressive external ophthalmoplegia (PEO), and the other showed mitochondrial diabetes mellitus (MDM). The mutation load was greater in the muscle from the patient with LS (92%), who showed more than 80% even in the non-ragged red fibers (RRF) and also presented the highest proportion of RRF. The patients with MELAS had lower mutation levels as well as a lower proportion of RRF, and these two parameters were even lower in the PEO and MDM patients. These results were consistent with the concept that differences in the mutation load and in the somatic distribution of the mutation among different cells and tissues are responsible for the differences in phenotypical expression of the disease.
 ...
PMID:Single-fiber analysis of mitochondrial A3243G mutation in four different phenotypes. 1067 26

Mutations in mitochondrial genes encoded by both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) genes have been implicated in a wide range of neuromuscular diseases. MtDNA base substitution and rearrangement mutations generally inactivate one or more tRNA or rRNA genes and can cause myopathy, cardiomyopathy, cataracts, growth retardation, diabetes, etc. nDNA mutations can cause Leigh syndrome, cardiomyopathy, and nephropathy, due to defects in oxidative phosphorylation (OXPHOS) enzyme complexes; cartilage-hair hypoplasia (CHH) and mtDNA depletion syndrome, through defects in mitochondrial nucleic acid metabolism; and ophthalmoplegia with multiple mtDNA deletions, caused by adenine nucleotide translocator-1 (ANT1) mutations. Mouse models have been prepared that recapitulate a number of these diseases. The mtDNA 16S rRNA chloramphenicol (CAP) resistance mutation was introduced into the mouse female germline and caused cataracts and rod and cone abnormalities in chimeras and neonatal lethal myopathy and cardiomyopathy in mutant animals. A mtDNA deletion was introduced into the mouse germline and caused myopathy, cardiomyopathy, and nephropathy. Conditional inactivation of the nDNA mitochondrial transcription factor (Tfam) gene in the heart resulted in neonatal lethal cardiomyopathy, while its inactivation in the pancreatic beta-cells caused diabetes. The ATP/ADP ratio was implicated in mitochondrial diabetes through transgenic modification of the beta-cell ATP-sensitive K(+) channel (K(ATP)). Mutational inactivation of the mouse Ant1 gene resulted in myopathy, cardiomyopathy, and multiple mtDNA deletions in association with elevated reactive oxygen species (ROS) production. Inactivation of uncoupler proteins (Ucp) 1-3 revealed that mitochondrial Delta Psi regulated ROS production. The role of mitochondrial ROS toxicity in disease and aging was confirmed by inactivating glutathione peroxidase (GPx1), resulting in growth retardation, and by total and partial inactivation of Mn superoxide dismutase (MnSOD; Sod2), resulting in neonatal lethal dilated cardiomyopathy and accelerated apoptosis in aging, respectively. The importance of mitochondrial ROS in degenerative diseases and aging was confirmed by treating Sod2 -/- mice and C. elegans with catalytic antioxidant drugs.
 ...
PMID:Mouse models for mitochondrial disease. 1157 27

Mutations in mitochondrial genes encoded by both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA have been implicated in a wide range of degenerative diseases. MtDNA base substitution and rearrangement mutations can cause myopathy, cardiomyopathy, ophthalmological defects, growth retardation, movement disorders, dementias, and diabetes. nDNA mutations can affect mtDNA replication and transcription, increase mtDNA mutations through defects in the adenine nucleotide translocator isoform 1 (ANT1), or cause Leigh's syndrome, as a result of defects in oxidative phosphorylation (OXPHOS) structural genes. Mouse models of mtDNA base substitution mutations have been created by introducing the mtDNA 16S rRNA chloramphenicol (CAP)-resistance mutation into the mouse female germline. This resulted in ophthalmological defects in chimeras and perinatal lethality resulting from myopathy and cardiomyopathy in mutant animals. Mouse models of mtDNA rearrangements have resulted in animals with myopathy, cardiomyopathy, and nephropathy. Conditional inactivation of the mouse nDNA mitochondrial transcription factor (Tfam) gene in the heart caused neonatal lethal cardiomyopathy, whereas its inactivation in the pancreatic beta-cells caused diabetes. Mutational inactivation of the mouse Ant1 gene resulted in myopathy, cardiomyopathy, and multiple mtDNA deletions in association with elevated reactive oxygen species (ROS) production. This suggests that multiple mtDNA deletion syndrome can be caused by increased ROS damage. The inactivation of the uncoupler protein genes (Ucp) 1-3 resulted in alterations in delta mu H+ and increased ROS production. Inactivation of the Ucp2 gene, which is expressed in the pancreatic beta-cells, resulted in increased islet ATP, increased serum insulin levels, and suppression of the diabetes of the ob/ob mouse genotype. Transgenic mice with altered beta-cell ATP-sensitive K+ channels (KATP) also developed diabetes. Mutational inactivation of the mitochondrial antioxidant genes for glutathione peroxidase (GPx1) and Mn superoxide dismutase (Sod2) caused reduced energy production and neonatal lethal dilated cardiomyopathy, respectively, the later being ameliorated by treatment with MnSOD mimics. Partial Sod2 deficiency (+/-) resulted in mice with increased mitochondrial damage during aging, and treatment of C. elegans with catalytic antioxidant drugs can extend their life-span. Mice deficient in cytochrome-c died early in embryogenesis, but cells derived from these embryos had a complete deficiency in mitochondrial apoptosis. Mice lacking the proapoptotic Bax and Bak genes were not able to release cytochrome-c from the mitochondrion and were blocked in apoptosis. Mice lacking Apaf1, Cas9, and Cas3 did release mitochondrial cytochrome-c and were blocked in the downstream steps of apoptosis. These animal studies confirm that alterations in mitochondrial energy generation, ROS production, and apoptosis can all contribute to the pathophysiology of mitochondrial disease.
 ...
PMID:Animal models for mitochondrial disease. 1201 5

Over 100 mutations of mitochondrial DNA (mtDNA) have been associated with human disease. The phenotypic manifestation of mtDNA mutations is extremely broad, from oligosymptomatic patients with isolated deafness, diabetes, ophthalmoplegia, etc., to complex encephalomyopathic disorders that may include dementia, seizures, ataxia, stroke-like episodes, etc. The genotype variants are also wide, with rearrangements (deletions, duplications) and point mutations affecting protein coding genes, tRNAs and rRNAs. There are some broad genotype/phenotype correlations but also substantial overlap. The pathogenetic mechanisms involved in the expression of mtDNA mutations are still not yet fully understood. More recently, mutations of nuclear genes encoding subunits of the respiratory chain, particularly those of complex I, have been identified. These predominantly, but not exclusively, involve infant onset disease with early death. Recently it has become clear that the function of the respiratory chain may be impaired by mutations affecting other mitochondrial proteins or as a secondary phenomenon to other intracellular biochemical derangements. Examples include Friedreich ataxia where a mutation of a nuclear encoded protein (frataxin), probably involved in iron homeostasis in mitochondria, results in severe deficiency of the respiratory chain in a pattern indicative of free radical mediated damage. Mutations of nuclear encoded proteins involved in cytochrome oxidase assembly and maintenance have been characterised and, as predicted, are associated with severe deficiency of cytochrome oxidase and, most frequently, Leigh syndrome. Defects of intracellular metabolism, with particularly excess-free radical generation including nitric oxide or peroxynitrite, may cause secondary damage to the respiratory chain. This is probably of relevance in Huntington disease, motor neuron disease (amyotrophic lateral sclerosis) and Wilson disease. These disorders seem to have defective oxidative phosphorylation as a common pathway in their pathogenesis and it may be that treatments designed to improve respiratory chain function may ameliorate the progression of these disorders.
 ...
PMID:Primary and secondary defects of the mitochondrial respiratory chain. 1213 29


1 2 3 Next >>