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)

In connection with 4 new cases of Kearns syndrome (multisystem form of mitochondrial CPEO), the condition was found to be present in slight to oligosymptomatic form in all 4 families. The marker symptom in subclinical patients was nearly always ptosis (sometimes very slight) and occasionally diabetes. In the literature other endocrine disorders, retinal anomalies, deafness, growth disturbances, etc., have been noted as subclinical symptoms in former generations. Heredity appears to be autosomal dominant in these 4 families, with very variable expressivity. The possibility that one gene is responsible for the disease seems to be plausible, but the marked variation in expressivity suggests a modifying influence of other alleles; in this sense, therefore, one may speak of multifactor inheritance. Supporting facts could also be found in the literature, where there was autosomal dominant heredity of the disease-carrying gene, but for its complete expression 'amplifying' factors (alleles) were needed. The pleiotropia of the disease-carrying gene is explained by a mitochondrial disorder of various organs. On the basis of the heredity, therefore, Kearns syndrome is not a syndrome but a disease. The most serious, most progressive and most extensive (multisystem) variant of Kearns disease is the infantile form, known as the 'Kearns-Sayre syndrome. When the expressivity of the disease is less extensive it usually occurs later in life and is less progressive: the adult form of Kearns disease.
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PMID:Kearns syndrome: a heterogeneous group of disorders with CPEO, or a nosological entity? 706 93

An A to G transition at nucleotide 3,243 in the tRNA(Leu)(UUR) gene of mitochondrial DNA has recently been identified as a pathogenic point mutation which is associated with diabetes mellitus and sensorineural deafness in several pedigrees. We have also reported a family showing the association of deafness and diabetes mellitus as the predominant clinical features with this mutation. Audiologic data from two patients in this family are presented. Both had a bilaterally symmetrical sensorineural hearing loss at all frequencies. As is often the case with deafness associated with a mitochondrial disorder, the pure-tone threshold values were maximal at high frequencies in both patients. The audiologic work-up presented not only cochlear characteristics but also signs suggestive of retrocochlear disturbance with poor speech discrimination scores as compared to pure-tone thresholds, although auditory brain-stem responses showed neither wave delay nor prolonged interpeak latencies.
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PMID:[Audiologic evaluation in a family showing diabetes mellitus and deafness associated with a mutation in mitochondrial DNA]. 747 62

We report the clinical, biochemical, and molecular genetic findings in a family with an unusual mitochondrial disease phenotype harboring a novel mtDNA tRNA glutamic acid mutation at position 14709. The proband and his sister presented with congenital myopathy and mental retardation and subsequently developed cerebellar ataxia. Other family members had either adult-onset diabetes mellitus with muscle weakness or adult-onset diabetes mellitus alone. Ragged-red and cytochrome c oxidase (COX)-negative fibers were present in muscle biopsies. Biochemical studies of muscle mitochondria showed reduced complex I and IV activities. The mtDNA mutation was heteroplasmic in blood and muscle in all matrilineal relatives analyzed. Primary myoblast, but not fibroblast, cultures containing high proportions of mutant mtDNA exhibited impaired mitochondrial translation. These observations indicate that mtDNA tRNA point mutations should be considered in the differential diagnosis of congenital myopathy. In addition they illustrate the diversity of phenotypes associated with this mutation in the same family and further highlight the association between mtDNA mutations and diabetes mellitus.
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PMID:Congenital encephalomyopathy and adult-onset myopathy and diabetes mellitus: different phenotypic associations of a new heteroplasmic mtDNA tRNA glutamic acid mutation. 772 55

DIDMOAD is usually considered an autosomal recessive condition, with wide phenotypic variation, but the possibility of mitochondrial mutations occurring in this condition has been considered. A 19 year old man presented with long standing diabetes mellitus, optic atrophy, and grand mal seizures. Further investigations showed unilateral sensorineural hearing loss and the most common mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy, which was inherited from his mother. This suggests the DIDMOAD phenotype is a mitochondrial disorder in some cases and is likely to have a heterogeneous aetiology.
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PMID:Mitochondrial mutation commonly associated with Leber's hereditary optic neuropathy observed in a patient with Wolfram syndrome (DIDMOAD). 807 60

We identified two patients with pathogenic single nucleotide changes in two different mitochondrial tRNA genes: the first mutation in the tRNA(Asn) gene, and the ninth known mutation in the tRNA(Leu(UUR)) gene. The mutation in tRNA(Asn) was associated with isolated ophthalmoplegia, whereas the mutation in tRNA(Leu(UUR)) caused a neurological syndrome resembling MERRF (myoclonus epilepsy and ragged-red fibers) plus optic neuropathy, retinopathy, and diabetes. Both mutations were heteroplasmic, with higher percentages of mutant mtDNA in affected tissues, and undetectable levels in maternal relatives. Analysis of single muscle fibers indicated that morphological and biochemical alterations appeared only when the proportions of mutant mtDNA exceeded 90% of the total cellular mtDNA pool. The high incidence of mutations in the tRNA(Leu(UUR)) gene suggests that this region is an "etiologic hot spot" in mitochondrial disease.
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PMID:Two novel pathogenic mitochondrial DNA mutations affecting organelle number and protein synthesis. Is the tRNA(Leu(UUR)) gene an etiologic hot spot? 825 46

Recent discoveries in mitochondrial clinical genetics have revealed that a broad spectrum of clinical phenotypes are associated with mutations in mitochondrial DNA. Diseases caused by mutations in mitochondrial DNA are by nature quantitative. Myoclonic epilepsy and ragged-red fiber disease are caused by a mutation in the transfer RNA gene lysine. Although everyone in a maternal lineage will harbor the same mutation, the nature and severity of the symptoms vary markedly among individuals. This variability correlates with the inherited percentage of mutations in the individual's mitochondrial DNA and the individual's age. Age-related expression of mitochondrial disease has also been demonstrated for mitochondrial DNA deletions. Although deletions that retain both origins of replication result in late-onset disease because of the progressive enrichment of the deleted mitochondrial DNA, a 10.4-kb deletion that lacks the light-strand replication origin and maintains a stable mutant percentage in both tissues and cultured cells has been discovered. This deletion is associated with adult-onset diabetes and deafness, but not with ophthalmoplegia, ptosis, or mitochondrial myopathy. Biochemically, it causes a generalized defect in mitochondrial protein synthesis and oxidative phosphorylation. The age-related decline in oxidative phosphorylation could reflect the accumulation of somatic mitochondrial DNA mutations. Inhibition of oxidative phosphorylation stimulates this accumulation. The general paradigm for mitochondrial DNA diseases may be that inherited mutations inhibit the electron transport chain. This damages the mitochondrial DNA, further reducing oxidative phosphorylation. Ultimately, oxidative phosphorylation drops below the expression threshold of cells and tissues, and clinical symptoms appear.
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PMID:Mitochondrial DNA mutations in epilepsy and neurological disease. 829 23

Mitochondrial gene mutations are found to cause certain forms of diabetes mellitus and related syndromes. To study the prevalence of mitochondrial gene mutations in subjects with non-insulin-dependent diabetes mellitus (NIDDM) in Taiwan, 23 pedigrees with multiple siblings affected with NIDDM were consecutively collected from patients living in northern Taiwan. The A-to-G mutation at position 3243 np in the tRNA Leu gene and the mutation at position 8344 were screened by PCR-RFLP methods and confirmed by direct DNA sequence analysis. Among 23 NIDDM pedigrees, one pedigree was found to carry the 3243 np mutation. There was no 8344 np mutation in this series. Clinical features of this pedigree were consistent with mitochondrial disease in terms of maternal transmission, relatively early onset, non-obesity, insulin-requirement and association with hearing impairment. There was no correlation between the degree of heteroplasmy of mitochondrial gene mutation in leukocyte DNA and clinical severity. We conclude that a mitochondrial gene defect is an important genetic factor in familial cases with NIDDM in Taiwan.
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PMID:Mitochondrial gene mutations in familial non-insulin-dependent diabetes mellitus in Taiwan. 882 3

Mitochondrial diseases are a group of disorders characterized by morphological or functional defects of the mitochondria, the organelles producing most of our cellular energy. As the only extranuclear site carrying genetic information, the mitochondria add an important chapter into the inheritance patterns of genetic diseases. Mitochondrial DNA (mtDNA) is exclusively maternally inherited in humans, but a mitochondrial disorder may follow either maternal or Mendelian inheritance, depending on the site of the primary gene defect. After the initial finding of mtDNA mutations in rare ocular myopathies in 1988, an explosion in the amount of information on mitochondrial diseases has occurred. Because the mitochondria produce energy in all the tissues, symptoms resulting from mtDNA mutations may originate from any organ system, and the clinical spectrum of mitochondrial diseases has expanded to virtually all branches of medicine. Subgroups of several common diseases, such as diabetes, deafness and inherited cardiomyopathies, have been found to be caused by mtDNA mutations, and some mtDNA defects have been suggested to modify the outcome of diseases primarily caused by other factors, such as Parkinson's or Alzheimer's disease. Although no breakthroughs in the therapeutic trials on the devastating mitochondrial diseases have so far been achieved, detection of mtDNA mutations offers an accurate diagnosis and is a prerequisite for genetic counselling, being now accessible to most clinicians.
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PMID:Mitochondrial DNA and disease. 924 Jun 29

We have mapped the chromosomal locations of three human nuclear genes for putative components of the apparatus of mitochondrial gene expression, using a combination of in situ hybridization and interspecies hybrid mapping. The genes RPMS12 (mitoribosomal protein S12, a conserved protein component of the mitoribosomal accuracy center), TUFM (mitochondrial elongation factor EF-Tu), and AFG3L1 (similar to the yeast genes Afg3 and Rca1 involved in the turnover of mistranslated or misfolded mtDNA-encoded polypeptides) were initially characterized by a combination of database sequence analysis, PCR, cloning, and DNA sequencing. RPMS12 maps to chromosome 19q13.1, close to the previously mapped gene for autosomal dominant hearing loss DFNA4. The TUFM gene is located on chromosome 16p11.2, with a putative pseudogene or variant (TUFML) located very close to the centromere of chromosome 17. AFG3L1 is located on chromosome 16q24, very close to the telomere. By virtue of their inferred functions in mitochondria, these genes should be regarded as candidates of disorders sharing features with mitochondrial disease syndromes, such as sensorineural deafness, diabetes, and retinopathy.
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PMID:Chromosomal locations of three human nuclear genes (RPSM12, TUFM, and AFG3L1) specifying putative components of the mitochondrial gene expression apparatus. 954 47

Mitochondrial disorders can affect any organ system, but certain tissues, such as skeletal muscle, heart, and brain are more susceptible to oxidative phosphorylation defects because of their high energy requirements. Endocrinological manifestations, especially diabetes mellitus, are common but they rarely dominate the clinical picture. We describe a 5-year-old girl who died of primary adrenal insufficiency with a mitochondrial disease. Biochemical studies in muscle showed decreased respiratory chain enzyme activities. We detected a novel 7.0 kb mtDNA deletion in muscle form the proband, but not in her mother's white blood cells. Our findings further enlarge the spectrum of clinical presentation associated with mitochondrial DNA deletions.
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PMID:Primary adrenal insufficiency in a child with a mitochondrial DNA deletion. 958 67


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