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)

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.
 ...
PMID:Kearns syndrome: a heterogeneous group of disorders with CPEO, or a nosological entity? 706 93

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

Molecular diagnosis for mitochondrial diseases offers a powerful means to clarify that mitochondrial DNA (mtDNA) defects have different characteristics from those of nuclear DNA. Regarding the relationship between genotype and phenotype, there is a dual heterogeneity. It means that one mutation, for example, a 3243 mutation, has several clinical phenotypes, including MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes), myopathy only, diabetes and/or deafness and even CPEO (chronic progressive external ophthalmoplegia). Conversely, one phenotype, for instance, MELAS has several genetypes; 3243, 3271, and 3291 mutations. The second unique event in mitochondrial DNA mutation is heterogenous distribution of mutant mtDNA in a mitochondrion or a cell that is called heteroplasmy. The extend of heteroplasmy seems different from tissue to tissue providing clues to explain the variability of tissue impairment and heterogenous clinical symptoms. The above evidence suggests that we should take care in selecting tissues to be tested. The third problem remained is on maternal inheritance. It makes the genetic counselling on mitochondrial diseases at clinics difficult and laborious. In conclusion, mtDNA analysis must be used as a last resort to get final diagnosis.
 ...
PMID:[Mitochondrial encephalomyopathies: 3243 mutation as a central matter]. 875 18

The accumulation of multiple mitochondrial DNA (mtDNA) deletions in stable tissues is a distinctive feature of several autosomal disorders, characterized by Progressive External Ophthalmoplegia (PEO), ptosis, and proximal myopathy. At least three nuclear genes are responsible for these disorders: ANT1 and C10orf2 cause autosomal dominant PEO, while mutations of DNA polymerase gammaA (POLG1 or POLG) gene on chromosome 15q25 causes both autosomal dominant and recessive forms of PEO. To investigate the contribution of these genes to the sporadic cases of PEO with multiple mtDNA deletions, we studied 31 mitochondrial myopathy patients without any family history for the disorder: 23 had PEO with myopathy, with or without the additional features of pigmentary retinopathy, ataxia, neurosensorial hypoacusia and diabetes mellitus, 7 presented isolated myopathy and one a peripheral neuropathy with ptosis. In all patients Southern blot of muscle DNA showed multiple mtDNA deletions; screening for ANT1 and C10ORF2 genes was negative. POLG analysis revealed mutations in eight patients; in six of them the mutations were allelic, while two patients were heterozygous. Five mutations were new, namely one stop codon (c.2407C>T/p.R709X) and four missense mutations (c.1085G>C/p.G268A; c.1967G>A/p.R562Q; c.2702G>C/p.R807P; c.3076C>T/p.H932W). A high degree of conservation was observed for all the new missense mutations. Only patients presenting PEO as part of their clinical phenotype had POLG mutations, in seven of them together with myopathic signs and in one with a sensori-motor peripheral neuropathy.
 ...
PMID:POLG mutations in sporadic mitochondrial disorders with multiple mtDNA deletions. 1463 18

We report a patient with mitochondrial diabetes mellitus associated with the A3243G mutation (MDM3243). The patient is a 77-year man with diabetes. At age 68, he noticed diplopia, due to superior rectus muscle palsy of the right eye. At age 70, he noticed lipoma on the right arm. The pathology of his muscle revealed some ragged-red fibers, and focal cytochrome c oxidase deficiency. Hence, he may have a pathogenetic mechanism in common with CPEO (chronic progressive external ophthalmoplegia) or mitochondria-related autoimmune disorder associated with mononeuropathy. He had the rate of 0.102% for heteroplasmy of 3243 mitochondrial DNA mutation in leukocytes. This case's heteroplasmy level is the smallest among the reported cases of MDM3243 in the literature. 3243 mitochondrial DNA mutation is known to induce a lack of uridine-modification in tRNA(Leu(UUR)) at the first letter of the anticodon, with which the third letter of the codon pairs, and decline of the pairing of the anticodon of tRNA with the codon of mRNA, suggesting the termination of polypeptide-elongation to generate premature proteins. Therefore, we speculate that these premature proteins may accumulate overtime, thereby affecting cells in target organs.
Diabetes Res Clin Pract 2004 Mar
PMID:Lipoma and opthalmoplegia in mitochondrial diabetes associated with small heteroplasmy level of 3243 tRNA(Leu(UUR)) mutation. 1475 94

Progressive external ophthalmoplegia (PEO) can be caused by a disorder characterized by multiple mitochondrial DNA (mtDNA) deletions due to mutations in the TWINKLE gene, encoding a mtDNA helicase. We describe a 71-year-old woman who had developed PEO at age 55 years. She had cataracts, diabetes, paresthesias, cognitive defects, memory problems, hearing loss, and sensory ataxia. She had muscle weakness with ragged red fibers on biopsy. MRI showed static white matter changes. A c.908G>A substitution (p.R303Q) in the TWINKLE gene was identified. Multiple mtDNA deletions were detected in muscle but not blood by a PCR-based method, but not by Southern blot analysis. MtDNA copy number was maintained in blood and muscle. A systematic literature search was used to identify the genotypic and phenotypic spectrum of dominant TWINKLE-related disease. Patients were adults with PEO and symptoms including myopathy, neuropathy, dysarthria or dysphagia, sensory ataxia, and parkinsonism. Diabetes, cataract, memory loss, hearing loss, and cardiac problems were infrequent. All reported mutations clustered between amino acids 303 and 508 with no mutations at the N-terminal half of the gene. The TWINKLE gene should be analyzed in adults with PEO even in the absence of mtDNA deletions in muscle on Southern blot analysis, and of a family history for PEO. The pathogenic mutations identified 5' beyond the linker region suggest a functional role for this part of the protein despite the absence of a primase function in humans. In our patient, the pathogenesis involved multiple mtDNA deletions without reduction in mtDNA copy number.
 ...
PMID:Finding twinkle in the eyes of a 71-year-old lady: a case report and review of the genotypic and phenotypic spectrum of TWINKLE-related dominant disease. 1935 76

No association between mitochondrial disease and pancreatitis has yet been established, although diabetes mellitus and diseases caused by exocrine insufficiency, such as Pearson syndrome, are the commonest pancreatic complications of mitochondrial diseases. Here, we report 2 cases of mitochondrial disease complicated by pancreatitis as an unusual pancreatic exocrine manifestation. One patient was a 10-year-old girl with mild retardation of psychomotor development who had experienced recurrent pancreatitis since the age of 4years. Chronic progressive external ophthalmoplegia (CPEO) due to m.8344A>G mutation was diagnosed when the patient was 10years old. The other patient was a 28-year-old woman who was diagnosed with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) due to m.3243A>G mutation at 10years of age. She had experienced regular recurrent vomiting since the age of 16 and suffered an episode of critical pancreatitis at 23years. In both cases, no possible etiological, morphological, or genetic factors for pancreatitis were identified, including anomalous pancreaticobiliary duct. A combination therapy of the standard treatment for chronic pancreatitis and supportive therapy for mitochondrial energy production may be beneficial to prevent the recurrence of acute pancreatitis complicating mitochondrial diseases. The pathophysiological mechanism of pancreatitis in mitochondrial disease has not been adequately established; however, our observations suggest that pancreatitis should be included in the list of pancreatic complications of mitochondrial disease.
...
PMID:Unusual exocrine complication of pancreatitis in mitochondrial disease. 2318 49

Chronic progressive external ophthalmoplegia (CPEO) is one of the most common mitochondrial disorders. It is characterized by bilateral, slowly progressing loss of extraocular muscle mobility, orbicularis oculi weakness, ptosis, and other neuromuscular symptoms, which are caused by the accumulation of multiple mitochondrial DNA (mtDNA) deletions. Many mutations in different nuclear genes, such as POLG1, POLG2, ANT1, and others, have been described as causing autosomal-inherited CPEO with multiple mtDNA deletions. Most causative genes are involved in mtDNA replication impairment. Here, we report a family with CPEO-like symptoms characterized by multiple muscle mtDNA deletions, ptosis, diabetes, hearing loss, mental retardation, and emotional instability. We performed genetic analyses to identify nuclear gene mutations in the family. DNA from the proband was analyzed by whole-exome sequencing. In addition to possible pathogenic mutations, rare variants were prioritized for gene-functional phenotype interpretation. We found possible pathogenetic mutations in the PRIMPOL, BRCA1, CPT2, and GJB2 genes, and functional polymorphisms in the CARD8, and MEFV genes. Multiple functional polymorphisms and possible pathogenic mutations may contribute to mitochondrial-disease-like phenotypes in a composite manner.
 ...
PMID:A PRIMPOL mutation and variants in multiple genes may contribute to phenotypes in a familial case with chronic progressive external ophthalmoplegia symptoms. 3134 95