UMLS:C0011849 - FACTA Search

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Query: UMLS:C0011849 (diabetes)
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The mitochondrial A3243G mutation is most commonly related to the MELAS syndrome, but can cause many different clinical manifestations at various ages. Here, we present a family with maternally inherited diabetes and deafness (MIDD), the proband of which exhibits hearing loss, diabetes mellitus, cardiomyopathy and short stature. Four easily accessible samples (whole blood, hair roots, buccal scrapings and urinary sediment) from the proband and her 3 sons were simultaneously analyzed for heteroplasmic percentages of the A3243G mutation in their DNA. More than 10 subclones were sequenced and the percentage of clones possessing the A3243G mutation was calculated. The proportion of mutant genomes varied widely among the four samples tested. Blood DNA consistently had the lowest percentage of mutation load, while urinary sediment tended to have the highest. The 3 sons have not exhibited hearing disability or diabetes mellitus thus far. However, their mutation loads in all 4 tissue samples were higher than those in the corresponding samples from the proband. Follow-up of this family over time is necessary to understand the relationship between the heteroplasmic mutation loads in the 4 different samples and the clinical manifestations of MIDD/MELAS.
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PMID:Comparison of mitochondrial A3243G mutation loads in easily accessible samples from a family with maternally inherited diabetes and deafness. 2147 92

Mitochondrial diseases associated with mutations within mitochondrial genome are a subgroup of metabolic disorders since their common consequence is reduced metabolic efficiency caused by impaired oxidative phophorylation and shortage of ATP. Although the vast majority of mitochondrial proteins (approximately 1500) is encoded by nuclear genome, mtDNA encodes 11 subunits of respiratory chain complexes, 2 subunits of ATP synthase, 22 tRNAs and 2 rRNAs. Up to now, more than 250 pathogenic mutations have been described within mtDNA. The most common are point mutations in genes encoding mitochondrial tRNAs such as 3243A-->G and 8344T-->G that cause, respectively, MELAS (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes) or MIDD (maternally-inherited diabetes and deafness) and MERRF (myoclonic epilepsy with ragged red fibres) syndromes. There have been also found mutations in genes encoding subunits of ATP synthase such as 8993T-->G substitution associated with NARP (neuropathy, ataxia and retinitis pigmentosa) syndrome. It is worth to note that mitochondrial dysfunction can also be caused by mutations within nuclear genes coding for mitochondrial proteins.
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PMID:[Diseases caused by mutations in mitochondrial DNA]. 2191 24

The m.3243A>G mutation has become known as the MELAS mutation. However, many other clinical phenotypes associated with this mutation have been described,most frequently being Maternally Inherited Diabetes and Deafness (MIDD). The m.3243A>G mutation, can be detected in virtually all tissues, however heteroplasmy differs between samples. Recent reports indicate, a preference to perform mutation analysis in Urinary Epithelial Cells(UEC). To test this, and to study a correlation between the mutational load in different tissues with two mitochondrial scoring systems (NMDAS and NPMDS) we investigated 34 families carrying the m.3243A>G mutation. Heteroplasmy was determined in three non-invasively collected samples,namely leucocytes, UEC and buccal mucosa. We included 127 patients, of which 82 carried the m.3243A>G mutation.None of the children (n011) had specific complaints. In adults(n071), a median NMDAS score of 15 (IQR 10-24) was found. The most prevalent symptoms were hearing loss(68 %), gastro-intestinal problems (59 %), exercise intolerance(54 %) and glucose intolerance (52 %). Ten patients had neurologic involvement. Buccal mucosa had the best correlation with the NMDAS in all adults (r00.437, p<0.001),whereas UEC had the strongest correlation with the NMDAS in severely affected patients (r00.593, p00.002). Heteroplasmy declined significantly with increasing age in all three samples (leucocytes r0-0.705 (p<0.001), UEC r0-0.374 (p00.001), buccal mucosa r0-0.460 (p<0.001). In our cohort of 82 patients, the m.3243A>Gmutation causes a wide variety of signs and symptoms, MIDD being far more prevalent than MELAS. Looking at the characteristics of the three noninvasively available tissues for testing heteroplasmy we confirm that UEC are the preferred sample to test [corrected].
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PMID:Clinical features and heteroplasmy in blood, urine and saliva in 34 Dutch families carrying the m.3243A > G mutation. 2240 16

Mitochondrial diseases arise as a result of dysfunction of the respiratory chain, leading to inadequate ATP production required to meet the energy needs of various organs. On the other hand, nitric oxide (NO) deficiency can occur in mitochondrial diseases and potentially play major roles in the pathogenesis of several complications including stroke-like episodes, myopathy, diabetes, and lactic acidosis. NO deficiency in mitochondrial disorders can result from multiple factors including decreased NO production due to endothelial dysfunction, NO sequestration by cytochrome c oxidase, NO shunting into reactive nitrogen species formation, and decreased availability of the NO precursors arginine and citrulline. Arginine and citrulline supplementation can result in increased NO production and hence potentially have therapeutic effects on NO deficiency-related manifestations of mitochondrial diseases. Citrulline is a more efficient NO donor than arginine as it results in a greater increase in de novo arginine synthesis, which plays a major role in driving NO production. This concept is supported by the observation that the three enzymes responsible for recycling citrulline to NO (argininosuccinate synthase and lyase, and nitric oxide synthase) function as a complex that can result in compartmentalizing NO synthesis and channeling citrulline efficiently to NO synthesis. Clinical research evaluating the effect of arginine and citrulline in mitochondrial diseases is limited to uncontrolled open label studies demonstrating that arginine administration to subjects with MELAS syndrome results in improvement in the clinical symptoms associated with stroke-like episodes and a decrease in the frequency and severity of these episodes. Therefore, controlled clinical studies of the effects of arginine or citrulline supplementation on different aspects of mitochondrial diseases are needed to explore the potential therapeutic effects of these NO donors.
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PMID:Citrulline and arginine utility in treating nitric oxide deficiency in mitochondrial disorders. 2281 33

Renal dysfunction is increasingly recognized as a potential clinical feature of mitochondrial cytopathies such as mitochondrial encephalomyopathy, lacticacidosis and stroke-like episodes (MELAS) syndrome. Five cases of MELAS syndrome with renal involvement from 4 unrelated families are presented in this case series. Three of the 5 patients had a history of maternally-inherited diabetes and/or deafness. Focal and segmental glomerulosclerosis and arteriolar hyaline thickening were the most striking findings on renal biopsy. In addition to clinical presentation with the typical symptoms of MELAS syndrome, genetic testing in these patients identified the A3243G point mutation in the tRNALeu gene of the mitochondrial DNA (mtDNA). The diagnosis of MELAS syndrome was thus considered to be unequivocal. The incidence of kidney disease in MELAS syndrome may be underestimated although a study is required to investigate this hypothesis. As the A3243G mtDNA mutation leads to a progressive adult-onset form of focal segmental glomerulosclerosis (FSGS), screening for the MELAS A3243G mtDNA mutation should therefore be performed especially in patients with maternally-inherited diabetes or hearing loss presenting with FSGS.
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PMID:Renal involvement in MELAS syndrome - a series of 5 cases and review of the literature. 2290 80

Adipocytes play an integrative role in the regulation of energy metabolism and glucose homeostasis in the human body. Functional defects in adipocytes may cause systemic disturbance of glucose homeostasis. Recent studies revealed mitochondrial abnormalities in the adipose tissue of patients with type 2 diabetes. In addition, patients with mitochondrial diseases usually manifest systemic metabolic disorder. However, it is unclear how mitochondrial dysfunction in adipocytes affects the regulation of glucose homeostasis. In this study, we induced mitochondrial dysfunction and overproduction of reactive oxygen species (ROS) by addition of respiratory inhibitors oligomycin A and antimycin A and by knockdown of mitochondrial transcription factor A (mtTFA), respectively. We found an attenuation of the insulin response as indicated by lower glucose uptake and decreased phosphorylation of Akt upon insulin stimulation of adipocytes with mitochondrial dysfunction. Furthermore, the expression of glucose transporter 4 (Glut4) and secretion of adiponectin were decreased in adipocytes with increased ROS generated by defective mitochondria. Moreover, the severity of insulin insensitivity was correlated with the extent of mitochondrial dysfunction. These results suggest that higher intracellular ROS levels elicited by mitochondrial dysfunction resulted in impairment of the function of adipocytes in the maintenance of glucose homeostasis through attenuation of insulin signaling, downregulation of Glut4 expression, and decrease in adiponectin secretion. Our findings substantiate the important role of mitochondria in the regulation of glucose homeostasis in adipocytes and also provide a molecular basis for the explanation of the manifestation of diabetes mellitus or insulin insensitivity in a portion of patients with mitochondrial diseases such as MELAS or MERRF syndrome.
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PMID:Mitochondrial dysfunction leads to impairment of insulin sensitivity and adiponectin secretion in adipocytes. 2325 16

The m.3243A>G "MELAS" (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes) mutation is one of the most common point mutations of the mitochondrial DNA, but its phenotypic variability is incompletely understood. The aim of this study was to revise the phenotypic spectrum associated with the mitochondrial m.3243A>G mutation in 126 Italian carriers of the mutation, by a retrospective, database-based study ("Nation-wide Italian Collaborative Network of Mitochondrial Diseases"). Our results confirmed the high clinical heterogeneity of the m.3243A>G mutation. Hearing loss and diabetes were the most frequent clinical features, followed by stroke-like episodes. "MIDD" (maternally-inherited diabetes and deafness) and "PEO" (progressive external ophthalmoplegia) are nosographic terms without any real prognostic value, because these patients may be even more prone to the development of multisystem complications such as stroke-like episodes and heart involvement. The "MELAS" acronym is convincing and useful to denote patients with histological, biochemical and/or molecular evidence of mitochondrial disease who experience stroke-like episodes. Of note, we observed for the first time that male gender could represent a risk factor for the development of stroke-like episodes in Italian m.3243A>G carriers. Gender effect is not a new concept in mitochondrial medicine, but it has never been observed in MELAS. A better elucidation of the complex network linking mitochondrial dysfunction, apoptosis, estrogen effects and stroke-like episodes may hold therapeutic promises.
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PMID:The m.3243A>G mitochondrial DNA mutation and related phenotypes. A matter of gender? 2437 76

A clinical case of mitochondrial diabetes is reported in a young woman aged 26, also presenting with a neurosensorial deafness. A type MELAS 3243 A>G mutation was found and confirmed the diagnosis which was raised by the maternal history of diabetes and hearing impairment. Clinical description, associated co-morbidities, genetic analysis and differential diagnosis of this monogenic diabetes are presented. Early diagnosis and treatment are useful, and should be associated with a familial genetic diagnostic approach.
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PMID:[A clinical case of mitochondrial diabetes]. 2464 Mar 3

Pathological mutations in tRNA genes and tRNA processing enzymes are numerous and result in very complicated clinical phenotypes. Mitochondrial tRNA (mt-tRNA) genes are "hotspots" for pathological mutations and over 200 mt-tRNA mutations have been linked to various disease states. Often these mutations prevent tRNA aminoacylation. Disrupting this primary function affects protein synthesis and the expression, folding, and function of oxidative phosphorylation enzymes. Mitochondrial tRNA mutations manifest in a wide panoply of diseases related to cellular energetics, including COX deficiency (cytochrome C oxidase), mitochondrial myopathy, MERRF (Myoclonic Epilepsy with Ragged Red Fibers), and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). Diseases caused by mt-tRNA mutations can also affect very specific tissue types, as in the case of neurosensory non-syndromic hearing loss and pigmentary retinopathy, diabetes mellitus, and hypertrophic cardiomyopathy. Importantly, mitochondrial heteroplasmy plays a role in disease severity and age of onset as well. Not surprisingly, mutations in enzymes that modify cytoplasmic and mitochondrial tRNAs are also linked to a diverse range of clinical phenotypes. In addition to compromised aminoacylation of the tRNAs, mutated modifying enzymes can also impact tRNA expression and abundance, tRNA modifications, tRNA folding, and even tRNA maturation (e.g., splicing). Some of these pathological mutations in tRNAs and processing enzymes are likely to affect non-canonical tRNA functions, and contribute to the diseases without significantly impacting on translation. This chapter will review recent literature on the relation of mitochondrial and cytoplasmic tRNA, and enzymes that process tRNAs, to human disease. We explore the mechanisms involved in the clinical presentation of these various diseases with an emphasis on neurological disease.
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PMID:Transfer RNA and human disease. 2491 79

The m.3243A>G mutation in the mitochondrial gene MT-TL1 leads to a wide clinical spectrum ranging from asymptomatic carriers to MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) at the severe end. Diabetes mellitus (DM) occurs in mitochondrial diseases, with the m.3243A>G mutation being the most common mutation associated with mitochondrial DM. The pathogenesis of mitochondrial DM remains largely unknown, with previous studies suggesting that impaired insulin secretion is the major factor. In this study we used stable isotope infusion techniques to assess glucose metabolism in vivo and under physiological conditions in 5 diabetic and 11 non-diabetic adults with the m.3243A>G mutation and 10 healthy adult controls. Our results revealed increased glucose production due to increased gluconeogenesis in both diabetic and non-diabetic subjects with the m.3243A>G mutation. In addition, diabetic subjects demonstrated insulin resistance and relative insulin deficiency, resulting in an inability to increase glucose oxidation which can explain the development of DM in these subjects. Non-diabetic subjects showed normal insulin sensitivity; and therefore, they were able to increase their glucose oxidation rate. The ability to increase glucose utilization can act as a compensatory mechanism that explains why these subjects do not have DM despite the higher rate of glucose production. These results suggest that increased gluconeogenesis is not enough to cause DM and the occurrence of combined insulin resistance and relative insulin deficiency are needed to develop DM in individuals with the m.3243A>G mutation. Therefore, multiple defects in insulin and glucose metabolism are required for DM to occur in individuals with mitochondrial diseases. The results of this study uncover previously undocumented alterations in glucose metabolism in individuals with the m.3243A>G mutation that contribute significantly to our understanding of the pathogenesis of mitochondrial DM and can have significant implications for its management.
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PMID:Glucose metabolism derangements in adults with the MELAS m.3243A>G mutation. 2508 7

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