母系遗传性糖尿病伴耳聋发病机制及诊治

母系遗传性糖尿病伴耳聋(MIDD)是一种线粒体疾病,在糖尿病患者中约占1％.其中tRNALeu(UUR) A3243G突变引起胰岛β细胞胰岛素分泌功能障碍是其致糖尿病的主要原因,但具体机制仍不明确.近年EndoC-βH1细胞系的建立为研究其机制提供了途径.尿道上皮细胞与线粒体疾病表型相关性最好,尿液可作为临床诊断和检测线粒体DNA异质性首选的样本,而MIDD的治疗仍以抗氧化剂和预防糖尿病并发症为主.A3243G突变的临床表型和MIDD突变的组织异质性仍是研究的热点,其研究对MIDD的诊断和治疗具有重要的指导意义.     

A detailed investigation of maternally inherited diabetes and deafness (MIDD) including clinical characteristics,C‐peptide secretion,HLA‐DR and ‐DQ status and autoantibody pattern

Background This article presents a clinically characterization of the mitochondrial DNA mutation (A3243G) associated with maternally inherited diabetes and deafness (MIDD) syndrome in two families. Methods Six patients with MIDD and one mutation‐positive relative with normal glucose tolerance (NGT) were examined. Fasting serum C‐peptide was measured in all subjects and compared with controls having NGT (n = 14). C‐peptide response to an intravenous glucose tolerance test (IVGTT) was investigated in the diabetic patients not treated with insulin (n = 3) and in the mutation‐positive healthy individual and compared with the controls. Results The A3243G heteroplasmy value varied between 5 and 30%. All A3243G carriers had HLA‐DR1‐DQ5 haplotype, and either the ‐DQ5 or the ‐DQ6 allele. The fasting and the serum C‐peptide levels at 120 min during the IVGTT did not differ between the A3243G carriers and the controls. A missing first phase and a decreased total C‐peptide response was detected in the mutation‐positive diabetics compared with controls (p < 0.0001). The same abnormality was found in the A3243G carrier with NGT. Circulating islet cell antibody (ICA) was present in three patients with MIDD. Glutamic acid decarboxylase (GAD), tyrosine phosphatase‐like protein IA‐2 (IA‐2) and mitochondrial antibodies were missing. The diagnosis of MIDD was delayed in each case. Conclusions A missing first phase and a decreased total C‐peptide response during an IVGTT was characteristic for the A3243G mutation. The fasting C‐peptide level of the carriers did not differ from the controls. Circulating ICA was present in some patients, but GAD, IA‐2 and mitochondrial antibodies were absent. All subjects had HLA‐DR1‐DQ5 haplotype, and either ‐DQ5 or ‐DQ6 alleles. Copyright © 2008 John Wiley & Sons, Ltd.     

Mitochondrial DNA mutation at np 3243 in a family with maternally inherited diabetes mellitus

Mitochondrial DNA (mtDNA) gene defects may play a role in the development of maternally inherited diabetes mellitus and deafness (MIDD). A family from Southern Italy who showed maternal transmission of type 2 diabetes mellitus with three individuals affected is described. A 10.4 kb deletion and mutations at nucleotide positions (np) 3243, 7445 and 11778 in the mtDNA of six relatives were sought. The mitochondrial np 3243 mutation of the tRNA Leu (UUR) gene was identified in a boy affected by optic atrophy and mental retardation, as well as in his diabetic mother. No other mutations or deletions were found. Our study points out the variable phenotypic expression of the np 3243 mtDNA mutation. This may suggest the presence of other mitochondrial or nuclear mutations required to modulate the phenotype. A clinical and metabolic follow-up of all family members was necessary to understand the role of the np 3243 mutation, especially in one child affected by optic atrophy and mental retardation. Further studies will be aimed at investigating the prevalence of mutations and deletions of mtDNA in type 2 diabetes mellitus. Received: 20 November 1998 / Accepted in revised form: 20 July 1999     

Diabetes mellitus associated with the mitochondrial mutation A3243G: frequency and clinical presentation

Maternal inherited diabetes and deafness (MIDD) has been related to an A to G transition in the mitochondrial RNA Leu (UUR) at base pair 3243. The prevalence of MIDD in the diabetes population ranges between 0.5-3.0% depending on the ethnic background. AIM: To examine the frequency and clinical features of diabetes associated with this mutation in Brazilian patients with glucose intolerance. METHODS: The study population comprised: 78 type 1 diabetic subjects (group I), 148 patients with type 2 diabetes (group II), 15 patients with either type 1 or type 2 diabetes and hearing loss (group III) and 492 Japanese Brazilians with varying degrees of glucose intolerance. DNA was extracted from peripheral blood leucocytes and the A3243G mutation was determined by PCR amplification and Apa 1 digestion. In some individuals DNA was also extracted from buccal mucosa and hair follicles. The 3243 bp mutation was found in three individuals, all from group III, resulting in a prevalence of 0.4%. These subjects had an early age of diagnosis of diabetes, low or normal body mass index and requirement of insulin therapy. In conclusion MIDD is rare in our population and should be investigate in patients with diabetes and deafness.     

Prevalence of mitochondrial diabetes in southwestern Finland: a molecular epidemiological study

Mitochondrial diabetes and deafness (MIDD) is a subtype of diabetes mellitus (DM) that most commonly results from the m.3243A > G mutation in mitochondrial DNA (mtDNA). Sensorineural hearing loss is a typical accompanying feature. Previous studies have suggested a prevalence of ~1–1.5 % for MIDD. We studied the molecular epidemiology of MIDD among young (aged 18–45 years) adults in a defined population in southwestern Finland. Of the identified cohort of 1,532 patients with DM, we received blood samples of 299 patients and analyzed them for the m.3243A > G mutation and for mtDNA haplogroups. We found three DM patients (1.0 %) with the m.3243A > G mutation. All the three patients with DM and m.3243A > G also had severe hearing impairment that required use of hearing aid. MtDNA haplogroup U was more prevalent among patients with maternal family history of DM. We conclude that among young adults, ~1 % of all DM is associated with the m.3243A > G mutation. We suggest that all patients with both DM and hearing impairment, at least in this age group, should undergo investigation for this mutation. Furthermore, our results suggest that mtDNA haplogroup U is associated with maternal family history of DM.     

Diabetes mellitus, deafness, muscle weakness and hypocalcemia in a patient with an A3243G mutation of the mitochondrial DNA

In a 54-year-old woman with diabetes mellitus, hearing loss, muscle weakness and hypocalcemia, caused by idiopathic hypoparathyroidism, an A to G transition at the nucleotide position of 3243 (A3243G mutation) was found in the mitochondrial DNA from her leukocytes. Clinical features of diabetes mellitus and hearing loss in association with the A3243G mutation are compatible with a diagnosis of maternally inherited diabetes and deafness (MIDD). Although hypoparathyroidism is rarely seen in MIDD, we consider that hypoparathyroidism in this patient is a possible phenotype caused by the A3243G mutation of mitochondrial DNA.     

Heteroplasmic ratio of the A3243G mitochondrial DNA mutation in single pancreatic beta cells

AIMS/HYPOTHESIS: To examine whether there is a high content of mutated mitochondrial DNA in individual pancreatic beta cells from a patient with the A3243G mitochondrial DNA mutation. METHODS: Tissues were available from a patient with diabetes and the A3243G mutation including pancreatic tissue. We quantified the amount of mutated mitochondrial DNA in tissue homogenates and single pancreatic beta cells using hot last cycle PCR. RESULTS: The percentage ratio of mutated to wild-type mtDNA was high in tissues such as muscle and brain (>60%), but surprisingly low in both pancreatic islets and in individual beta cells from these islets. The islets were smaller in the patient than in control subjects in keeping with a decreased beta-cell mass. CONCLUSIONS/INTERPRETATION: These observations suggest that either the beta cells show increased sensitivity to the effects mtDNA mutations on respiratory chain function, and/or cells with a high mutant load are preferentially removed leading to a progressive decrease in the islet beta-cell mass.     

Maternally inherited diabetes and deafness: prevalence in a hospital diabetic population

Maternally inherited diabetes and deafness (MIDD) is a new sub-type of diabetes and results from an A to G substitution at position 3243 of the mitochondrial tRNA^Leu(UUR) gene. This mutation is also associated with a neurological syndrome (MELAS). Recent studies have screened carefully selected diabetic populations and have reported MIDD prevalence rates ranging from undetectable to 60 %. The aim of this work was to determine the importance of this sub-type in clinical practice by screening a routine hospital diabetic population. A total of 1440 patients (IDDM and NIDDM) of North European extraction attending two hospital diabetes services were initially screened by questionnaire. This identified 445 patients with one or more features of MIDD and/or MELAS and these subjects were then genotyped. Two patients were identified with the mutation giving a prevalence rate of 0.13 % for the whole study population, and 0.45 % for the sample with phenotypic features of MIDD. In conclusion, therefore, the 3243 mutation is associated with the phenotypically distinct MIDD sub-type, but this is rare in the routine hospital diabetic population. © 1997 by John Wiley & Sons, Ltd.     

Comparison of the level of mitochondrial DNA A3243G mutation in esophageal epithelium and myocardium from individuals of very advanced age

The A3243G mutation, one of the changes of human mitochondrial DNA (mtDNA) that accumulates in cells during aging, is a useful marker for investigating the aging of cells. We measured the mutation level of the mtDNA A3243G mutation using DNAs from two different tissues (esophageal epithelium and myocardium) from advanced elderly individuals. The mean level of the A3243G mutation for the esophageal epithelium was 0.0063+/-0.0019, and that for the myocardium was 0.0098+/-0.0031. The mutation level in the myocardium was significantly higher than that in the esophageal epithelium, indicating that more mtDNA A3243G mutations accumulated in the myocardium than in the esophageal epithelium. Since the myocardium is static with respect to cell turnover, but in the esophageal epithelium renewal is very rapid, it is possible that the mtDNA A3243G mutation in the myocardium accumulates more rapidly than in the esophageal epithelium. This phenomenon may reflect the difference in the longevity of cells in each of these tissues and their different levels of oxidative stress.     

Insulin resistance in patients with the mitochondrial tRNA(Leu(UUR)) gene mutation at position 3243.

SUMMARY: The point mutation at position 3243 of the tRNA Leu(UUR) of the mitochondrial DNA is associated with mitochondrial encephalomyopathy, lactic acidosis and strokes (MELAS) as well as with mitochondrial diabetes and deafness (MIDD). A defect in insulin secretion has been found in most of these patients. However, there have been controversial findings to which extent insulin resistance contributes to pathogenesis. The aim of the present investigation was to study the insulin sensitivity index (SI), insulin secretion (AIR(Glucose)) and glucose effectiveness (Sg) in patients with the 3243-mutation. MATERIAL AND METHODS: 7 patients of a large pedigree (some of the members who were not investigated had MELAS) and 3 siblings of another family in whom the 3243-mutation had been detected, as well as 23 non-related, healthy control subjects underwent a modified intravenous glucose tolerance test (Bergman's minimal model). In addition, a screening of islet cell antibodies (ICA) was performed. RESULTS: All patients except for one with known diabetes mellitus revealed normal glucose tolerance. There was no difference between patients and controls for SI, AIR(Glucose) or Sg. However, when looking at the individual results, there were 4 closely related members of the large family with very poor insulin sensitivity. The other 2 patients of this pedigree were more distantly related and extremely insulin sensitive. The siblings of the other family revealed normal or even a very good insulin sensitivity. In one patient, ICA were detected. CONCLUSIONS: The 3243-mutation does not seem to be causative for insulin resistance in our patients. Whether nuclear genes are involved and indirectly influence the expression of the 3243-mutation or, more likely, directly lead to impaired insulin sensitivity in some of our patients cannot be answered by our data. It remains open whether there is a difference in the pathogenesis of diabetes between patients with MIDD and those with MELAS.     

线粒体DNA变异与老年2型糖尿病患者易感性的相关性

目的 研究湖北地区老年2型糖尿病(T2DM)患者中线粒体基因突变的发生率及其相关性.方法 采用PCR-RFLP、基因测序技术,对175例老年T2DM患者和200例糖耐量正常的健康老年对照组进行检测.结果 MIND1 3316(G→A)、MTTL1 3243(A→G)、MIND13394( T→C)、MIND14216(T→C) MIND14164(A→G)和MIND2 5178( T→C)变异率分别为3.26％、2.72％、1.71％、4％、34.9％;对照组检出3316(G→A)突变2例(0.99％)、4164 5例(0.99％)、5718(T→C)变异64例(32.3％),未检出3394、4216的点突变;两组间3394(T→C)变异率差别有统计学意义(P＜0.05);且T2DM组5178A基因型血清TC水平低于5178C基因型(P＜0.05),但TG、LDL-C、HDL-C、apoA、apoB、Lp(a)水平两组无统计学意义.结论 3394( T→C)与老年T2DM患者的易感性有一定关联,5178(T→C)变异与湖北地区老年汉族人T2DM的脂代谢相关.     

Clinical phenotype of mitochondrial diabetes due to rare mitochondrial DNA mutations

ObjectiveWhile the most frequent mutation responsible for mitochondrial diabetes is the point mutation m.3243 A>G of mitochondrial DNA (mtDNA), few data are available about the role of rare mtDNA mutations in the pathophysiology of diabetes. The main objective of our study was to describe the phenotypic characteristics of patients suffering from diabetes linked to rare mtDNA mutations.Research design and methodsWe performed a post-hoc analysis of a prospective multicenter cohort of 743 patients with mitochondrial disorder (previously published by the French Network of Mitochondrial Diseases), associated to a literature review of the PubMed database from 1992 to May 2016. We extracted all reported patients with diabetes and identified rare mtDNA mutations and described their clinical and metabolic phenotypes.ResultsThe 50 identified patients (10 from the princeps study; 40 from the review of the literature) showed a heterogeneous metabolic phenotype in terms of age, symptoms prior to diagnosis, treatments, and associated clinical and biological signs. However, neurological symptoms were more frequent in case of rare mtDNA mutations compared to the classical m.3243 A > G mutation (P = 0.024). In contrast, deafness (65% vs. 95%, P = 3.7E-5), macular pattern dystrophy (20% vs. 86%, P = 1.6E-10) and nephropathy (8% vs. 28%, P = 0.018) were significantly less frequent than in case of the classical m.3243 A>G mutation.ConclusionAlthough no specific metabolic phenotype could be identified suggesting or eliminating implication of rare mtDNA mutations in diabetes, clinical phenotypes featured more frequent neurological signs.     

Mitochondrial diabetes is associated with insulin resistance in subcutaneous adipose tissue but not with increased liver fat content

We recently showed that patients with mitochondrial diabetes are insulin resistant in skeletal muscle before the decline in insulin secretion is observed. In this study, we further evaluate whether insulin resistance is associated with increased ectopic fat accumulation and altered adipose and hepatic tissue insulin sensitivity. We studied 15 nonobese patients with the m.3243A > G mutation. Five were without diabetes (group 1), three had newly diagnosed diabetes (group 2), and seven had previously diagnosed diabetes (group 3). Thirteen healthy volunteers of similar age and body mass index (BMI) served as controls. Insulin-stimulated glucose uptake was measured with positron emission tomography using 2- [¹⁸F]-fluoro-2-deoxyglucose during euglycemic hyperinsulinemia. Fat masses and liver fat content were measured with magnetic resonance imaging and spectroscopy. Compared with controls, insulin-stimulated glucose uptake in adipose tissue was decreased by ∼50% in all groups with the m.3243A > G mutation. In addition, fat masses were not different, but insulin-mediated suppression of lipolysis and adiponectin metabolism were blunted in patients with the m.3243A > G mutation. Hepatic fat content was normal (<5.6%) in 80% of patients and significantly elevated in one case only. Hepatic glucose metabolism in patients with m.3243A > G did not differ from that of controls. In conclusion, m.3243A > G mutation affects subcutaneous adipose tissue metabolism. This seems to occur before aberrant liver metabolism, if any, can be observed or before beta-cell failure results in mitochondrial diabetes.     

Functional and morphological abnormalities of mitochondria harbouring the tRNALeu(UUR) mutation in mitochondrial DNA derived from patients with maternally inherited diabetes and deafness (MIDD) and progressive kidney disease

Aims/hypothesis. An A to G transition at nucleotide position 3243 in the mitochondrial tRNA ^Leu(UUR) gene has been identified in patients with maternally inherited diabetes and deafness, as well as in patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes, chronic progressive external ophpthalmoplegia, cardiomyopathy and progressive kidney disease. Variations in the mitochondrial DNA haplotype as well as differences in the degree and distribution of heteroplasmy in a certain tissue are factors that may contribute to the variety in phenotypical expression of the 3243 tRNA ^Leu(UUR) mutation. We have done morphological and functional experiments on mitochondria carrying the 3243 mutation derived from patients with either maternally inherited diabetes and deafness or progressive kidney disease to prove the pathogenicity of the 3243 mutation and to examine whether the mtDNA haplotype modulates the pathobiochemistry of this mutation. Methods. We constructed clonal cell lines that contain predominantly mutated or exclusively wild-type mtDNA with a distinct mtDNA haplotype by the methodology of mitochondria-mediated transformation. Cells lacking mitochondrial DNA (ϱ°) were used as recipients and donor mitochondria were derived from fibroblasts of a patient with either maternally inherited diabetes and deafness or progressive kidney disease. The fibroblasts from these clinically distinct patients carry different mitochondrial DNA haplotypes with the 3243 mutation in heteroplasmic form. Results. Heteroplasmy in the clonal cybrid cells ranged from 0 to 100 %, reflecting the heterogeneity of the mitochondrial donor cell. Cybrid cells containing predominantly mutant mitochondrial DNA showed lactic acidosis, poor respiration and marked defects in mitochondrial morphology and respiratory chain complex I and IV activities. No differences were observed in the extent of the mitochondrial dysfunction between the mutant cells derived from the two donors. Conclusion/interpretation. These results provide evidence for a pathogenic effect of the tRNA ^Leu(UUR) mutation in maternally inherited diabetes and deafness and progressive kidney disease, and show no evidence of a contribution of the mitochondrial DNA haplotype as a modulating the biochemical expression of the mutation. [Diabetologia (1999) 42: 485–492] Received: 13 August 1998 and in final revised form: 7 December 1998     

Clinical features and heteroplasmy in blood, urine and saliva in 34 Dutch families carrying the m.3243A > G mutation

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 (n?=?11) had specific complaints. In adults (n?=?71), a median NMDAS score of 15 (IQR 10-24) was found. The most prevalent symptoms were hearing loss(48%), gastro-intestinal problems(42%), exercise intolerance(38%) and glucose intolerance(37%). Ten patients had neurologic involvement. Buccal mucosa had the best correlation with the NMDAS in all adults (r?=?0.437,p? G mutation causes a wide variety of signs and symptoms, MIDD being far more prevalent than MELAS. Looking at the characteristics of the three non-invasively available tissues for testing heteroplasmy we confirm that UEC are the preferred sample to test.     

The effects of coenzyme Q10 treatment on maternally inherited diabetes mellitus and deafness, and mitochondrial DNA 3243 (A to G) mutation

Summary The characteristic clinical features of diabetes mellitus with mitochondrial DNA (mtDNA) 3243(A-G) mutation are progressive insulin secretory defect, neurosensory deafness and maternal inheritance, referred to as maternally inherited diabetes mellitus and deafness (MIDD). A treatment for MIDD to improve insulin secretory defects and reduce deafness has not been established. The effects of coenzyme Q₁₀ (CoQ₁₀) treatment on insulin secretory response, hearing capacity and clinical symptoms of MIDD were investigated. 28 MIDD patients (CoQ₁₀-DM), 7 mutant subjects with impaired glucose tolerance (IGT), and 15 mutant subjects with normal glucose tolerance (NGT) were treated daily with oral administration of 150 mg of CoQ₁₀ for 3 years. Insulin secretory response, blood lactate after exercise, hearing capacity and other laboratory examinations were investigated every year. In the same way we evaluated 16 MIDD patients (control-DM), 5 mutant IGT and 5 mutant NGT subjects in yearly examinations. The insulin secretory response assessed by glucagon-induced C-peptide secretion and 24 h urinary C-peptide excretion after 3 years in the CoQ₁₀-DM group was significantly higher than that in the control-DM group. CoQ₁₀ therapy prevented progressive hearing loss and improved blood lactate after exercise in the MIDD patients. CoQ₁₀ treatment did not affect the diabetic complications or other clinical symptoms of MIDD patients. CoQ₁₀ treatment did not affect the insulin secretory capacity of the mutant IGT and NGT subjects. There were no side effects during therapy. This is the first report demonstrating the therapeutic usefulness of CoQ₁₀ on MIDD. [Diabetologia (1998) 41: 584–588] Received: 16 October 1997 and in revised form: 21 January 1998     

Heterogeneity of diabetes phenotype in patients with 3243 bp mutation of mitochondrial DNA (Maternally Inherited Diabetes and Deafness or MIDD)

OBJECTIVE: In patients with maternally inherited diabetes and deafness (MIDD), due to 3 243 A > G mutation of mitochondrial DNA (mtDNA), diabetes may present with variable phenotypes. OBJECTIVE: To ascertain the existence of two distinct phenotypes, MIDD1 and MIDD2, in a series of patients with MIDD. DESIGN: Multicenter prospective study. PATIENTS: 77 patients with diabetes and the mtDNA 3243 mutation and 139 control patients with type 1 (T1D) or type 2 (T2D) diabetes, matched according to initial presentation of diabetes, age at onset, sex, and duration of diabetes (24 T1D and 115 T2D, including 55 treated with insulin). MEASUREMENTS: Anthropometric characteristics (height, body weight, body mass index [BMI], sex), family history of diabetes, and characteristics of diabetes (age at onset, treatment, hemoglobin A1c [HbA1c]), extrapancreatic manifestations. RESULTS: In 13 cases (17%, MIDD1), diabetes presented as insulin-dependent from the onset, with ketoacidosis in 6 cases. In 64 cases (83%, MIDD2), diabetes resembled T2D, and was treated with diet in 12 cases, oral hypoglycemic agents in 21 cases, or insulin in 31 cases. Compared with patients with MIDD2, patients with MIDD1 were characterized by lower age at onset of first manifestation of MIDD (25.4 +/- 9.6 vs 33.7 +/- 13.2 Years, P<0.0005), lower body weight (49.1 +/- 7.4 vs 56.3 +/- 10.9 kg, P<0.0025), lower BMI (18.2 +/- 2.3 vs 20.9 +/- 3.6 kg/m2, P<0.0005), and higher HbA1c levels (9.5 +/- 2.0 vs 7.5 +/- 1.6%, P<0.0005). Frequency of family history of diabetes and of extrapancreatic manifestations was the same in both MIDD subtypes. No difference was found within the MIDD2 subtype when comparing patients treated with or without insulin. Compared with matched controls, patients with MIDD had a lower BMI (MIDD1/T1D 18.2 +/- 2.3 vs 24.0 +/- 3.6 kg/m2 and MIDD2/T2D 20.9 +/- 3.6 vs 30.2 +/- 5.9 kg/m2, P<0.0025). Lastly, male patients with MIDD had a shorter height than controls (MIDD1/T1D: 166.1 +/- 3.2 vs 177.3 +/- 6.6 cm and MIDD2/T2D: 168.4 +/- 7.2 vs 173.6 +/- 6.6 cm P<0.025). CONCLUSIONS: These results confirm the existence of two different phenotypes in MIDD, MIDD1 and MIDD2, which may be related to the severity of the mitochondrial disease. The role of other genetic and/or environmental factors in the variable phenotype of MIDD remains to be elucidated.     

Prevalence and progression of diabetes in mitochondrial disease

Aims/Hypothesis The aims of this study were (1) to determine the prevalence and rate of progression in diabetes secondary to mitochondrial DNA (mtDNA) mutations; and (2) to determine whether percentage heteroplasmy predicts clinical outcome in patients carrying the m.3243A>G mutation. Methods We prospectively assessed 242 patients attending a specialist neuromuscular clinic using a validated mitochondrial disease rating scale. Retrospective clinical data on these patients from up to 25 years of follow-up were also included. Percentage heteroplasmy in blood, urine and muscle was determined for the m.3243A>G group and correlated against clinical features. Results Patients carrying the m.3243A>G mutation formed the largest group of patients with diabetes (31/81 patients). The highest prevalence of diabetes was in the m.12258C>A group (2/2 patients), the lowest in the multiple mtDNA deletions group (3/43 patients). The earliest age of onset was in the m.3243A>G group (37.9 years) with the highest age of presentation in the multiple deletion group (56.3 years). Of patients presenting with m.3243A>G, 12.9% required insulin; an additional 32.3% progressed to insulin requirement over a mean of 4.2 years after presentation. Percentage heteroplasmy in blood, urine or muscle did not predict progression of diabetes or risk of developing complications. Early age of presentation with diabetes did predict poor clinical outcome. Conclusions/Interpretation Although patients carrying the m.3243A>G mutation account for the majority of cases of diabetes secondary to mtDNA mutations, several other genotypes are also associated with the development of diabetes, some with high penetrance. All show a gradual progression to insulin requirement. Percentage heteroplasmy is a poor predictor of severity of diabetes in the m.3243A>G group.     

Dilated cardiomyopathy, diabetes and deafness related to a mutation of mitochondrial DNA

Mitochondrial diseases may cause hypertrophic cardiomyopathy or, less commonly, dilated cardiomyopathy. The authors describe a case of a 46 year old woman with dilated cardiomyopathy associated with diabetes and deafness. This association is suggestive of the MIDD syndrome and the demonstration of metabolic abnormalities (raised serum lactic acid, abnormal lactate/pyruvate ratio) was compatible with a mitochondrial disease. This diagnosis was confirmed by finding an A3243G mutation of the mitochondrial DNA.