UNASSIGNED: Maternally inherited diabetes and deafness (MIDD) is caused by the m.3243A>G pathogenic variant in maternally inherited mitochondrial DNA. Diabetes is prevalent in our setting; however, MIDD is rarely diagnosed. This study, undertaken in Pretoria, South Africa, highlights the variable presentation of MIDD in different patients within the same family.
UNASSIGNED: A 45-year-old man (proband) with hearing impairment was referred to the endocrine unit in July 2015 due to poor glycaemic control (HbA1c = 13%). His clinical and biochemical features were in keeping with MIDD. A genetic study of accessible maternal relatives was pursued. His mother had difficulty hearing and reportedly died from an unspecified cardiovascular cause. Two sisters with diabetes and deafness died of cardiac-related conditions. One nephew had diabetes (HbA1c = 7.7%), hearing loss and tested positive for m.3243A>G. A third sister tested positive for m3243A>G, but aside from bilateral mild hearing loss in higher frequencies, showed no other signs of target organ damage. Her daughter developed end-stage kidney failure necessitating a transplant, while her son had no biochemical abnormalities and was negative for m.3243A>G.
UNASSIGNED: A multidisciplinary team managed and screened for complications of the patient and his maternal relatives. Proband died prior to genetic testing.
UNASSIGNED: Most MIDD patients initially present with symptoms of diabetes only, and it is probable that many cases remain undiagnosed. A high index of suspicion is necessary when encountering a family history of both diabetes and impaired hearing, and screening should be offered to the patient\'s maternal relatives.
UNASSIGNED: This study demonstrates the importance of proper assessment when evaluating a patient with diabetes and a family history of hearing loss.

OBJECTIVE: Nearly 85% of maternally inherited diabetes and deafness (MIDD) are caused by the m.3243A>G mutation in the mitochondrial DNA. However, the clinical phenotypes of MIDD may also be influenced by the nuclear genome, this study aimed to investigate nuclear genome variants that influence clinical phenotypes associated with m.3243A>G mutation in MIDD based on whole-genome sequencing of the patients belonging to pedigrees.
METHODS: We analyzed a whole-genome sequencing (WGS) dataset from blood samples of 38 MIDD patients with the m.3243A > G mutation belonging to 10 pedigrees, by developing a Kinship-graph convolutional network approach, called Ki-GCN, integrated with the conventional genome-wide association study (GWAS) methods.
RESULTS: We identified eight protective alleles in the nuclear genome that have protective effects against the onset of MIDD, related deafness, and also type 2 diabetes. Based on these eight protective alleles, we constructed an effective logistic regression model to predict the early or late onset of MIDD patients.
CONCLUSIONS: There are protective alleles in the nuclear genome that are associated with the onset-age of MIDD patients and might also provide protective effects on the deafness derived from MIDD patients.

UNASSIGNED: To present results of contemporary multimodal ophthalmic imaging in a case of maternally inherited diabetes and deafness (MIDD) and a literature review of MIDD.
UNASSIGNED: A case of a 47-year-old female with diabetes mellitus, severe insulin resistance, familial lipodystrohy, deafness and increasing problems with vision is reported. A full ophthalmic examination was done, including best corrected visual acuity (BCVA, LogMAR), funduscopy, and imaging studies: optical coherence tomography (OCT), OCT angiography (OCT-A), fundus autofloresence (FAF), visual fields (HVF) 10-2 , electrophysiology (EP) and genetic testing were performed. Literature available on the topic was reviewed.
UNASSIGNED: BCVA was 0.06 LogMAR in the right eye and 0.1 LogMAR in the left. Funduscopy revealed atrophy (AT) and pigmentary changes but no diabetic retinopathy. HVF confirmed corresponding defects. The imaging and diagnostic tests showed the following abnormalities: FAF: hypoautofluoresence in areas of AT and mottled appearance in the macular and peripapillary area; OCT: attenuation of outer retinal layers and retinal pigment epithelium (RPE) in the AT; OCT-A: thinning of the deep capillary plexus and choriocapillaris; EP: abnormalities on full field electroretinogram (ERG), 30 Hz flicker and single cone flash response; multifocal ERG: reduced responses; genetic testing: A-to-G transition mutation at position 3243 of the mitochondrial genome, typical for MIDD. After one year OCT ganglion cell analysis showed loss of thickness.
UNASSIGNED: Genetic testing should be considered in diabetic patients with pigmentary retinopathy. Imaging studies and diagnostic testing showed structural and functional retinal changes, confined to the macula and progressive in nature.

Whole genome sequencing (WGS) from large clinically unselected cohorts provides a unique opportunity to assess the penetrance and expressivity of rare and/or known pathogenic mitochondrial variants in population. Using WGS from 179 862 clinically unselected individuals from the UK Biobank, we performed extensive single and rare variant aggregation association analyses of 15 881 mtDNA variants and 73 known pathogenic variants with 15 mitochondrial disease-relevant phenotypes. We identified 12 homoplasmic and one heteroplasmic variant (m.3243A>G) with genome-wide significant associations in our clinically unselected cohort. Heteroplasmic m.3243A>G (MAF = 0.0002, a known pathogenic variant) was associated with diabetes, deafness and heart failure and 12 homoplasmic variants increased aspartate aminotransferase levels including three low-frequency variants (MAF ~0.002 and beta~0.3 SD). Most pathogenic mitochondrial disease variants (n = 66/74) were rare in the population (<1:9000). Aggregated or single variant analysis of pathogenic variants showed low penetrance in unselected settings for the relevant phenotypes, except m.3243A>G. Multi-system disease risk and penetrance of diabetes, deafness and heart failure greatly increased with m.3243A>G level ≥ 10%. The odds ratio of these traits increased from 5.61, 12.3 and 10.1 to 25.1, 55.0 and 39.5, respectively. Diabetes risk with m.3243A>G was further influenced by type 2 diabetes genetic risk. Our study of mitochondrial variation in a large-unselected population identified novel associations and demonstrated that pathogenic mitochondrial variants have lower penetrance in clinically unselected settings. m.3243A>G was an exception at higher heteroplasmy showing a significant impact on health making it a good candidate for incidental reporting.

OBJECTIVE: Maternally inherited diabetes and deafness (MIDD) is a rare form of adult-onset diabetes that can be difficult to diagnose due to its variable clinical phenotype. Transfer RNA-derived small fragments are a novel, emerging class of small non-coding RNAs (sncRNAs) that have significant potential as serum biomarkers due to their stress-induced generation, abundance, stability and ease of detection.
METHODS: We investigated the levels of tiRNA 5\'ValCAC (alone and in combination with miR-23b-3p) identified from small RNA sequencing studies in serum samples from healthy controls, type 1 diabetes, type 2 diabetes and MIDD subjects.
RESULTS: Serum levels of 5\'ValCAC were reduced in MIDD and type 2 diabetes subjects compared to controls. Type 2 diabetes subjects had higher serum levels of miR-23b-3p compared to all other subjects. Receiver Operating Characteristic analysis showed the potential of 5\'ValCAC and miR-23b-3p as MIDD biomarkers, with the combination showing excellent separation from type 2 diabetes subjects.
CONCLUSIONS: This is the first report showing altered serum levels of tiRNAs in diabetes subjects. The combined use of 5\'ValCAC and miR-23b-3p as serum biomarkers could potentially differentiate between MIDD subjects and type 2 diabetes subjects.

Mitochondrial dysfunction causes maternally inherited deafness and diabetes (MIDD). Herein, we report improved glycemic control in a 47-year-old Japanese woman with MIDD using imeglimin without major adverse effects. Biochemical tests and metabolome analysis were performed before and after imeglimin administration. Blood glucose level fluctuations were determined. Sulfonylureas, dipeptidyl peptidase-4 inhibitors (DPP4is), and sodium glucose transporter-2 inhibitors (SGLT2i) were administered to evaluate the efficacy of their combination with imeglimin. Imeglimin decreased the HbA1c and ammonia levels and increased the time-in-range, C-peptide reactivity, and glucagon level. Elevated citrulline and histamine levels were decreased by imeglimin. The hypoglycemic effect was not enhanced by imeglimin when combined with sulfonylurea or DPP4i, but the blood glucose level was improved when combined with SGLT2i. Imeglimin improved glucose concentration-dependent insulin secretion and maximized the insulin secretory capacity by improving mitochondrial function and glutamine metabolism and urea circuit abnormalities by promoting glucagon secretion. Imeglimin could improve glycemic control in MIDD.

UNASSIGNED: Mitochondrial diseases are a group of genetic disorders caused by nuclear or mitochondrial DNA gene mutations and characterized by multiorgan disorders, including cardiomyopathy. Mitochondrial cardiomyopathy is occasionally complicated by hypertrophic cardiomyopathy with/without left ventricular systolic dysfunction, dilated cardiomyopathy, and left ventricular non-compaction. In such cases, the dilated left ventricle impairs coaptation of the mitral leaflets and leads to functional mitral regurgitation. To date, valvular interventions in patients with mitochondrial cardiopathy have not been investigated.
UNASSIGNED: A 64-year-old woman with mitochondrial cardiopathy was referred to our hospital owing to dyspnoea. She experienced her first admission with heart failure at age 60 years. At 62 years old, she was diagnosed with maternally inherited diabetes and deafness with mitochondrial cardiomyopathy based on mitochondrial DNA sequencing. Despite administration of guideline-directed medical therapy and high-dose taurine supplementation, she was repeatedly hospitalized for heart failure. At admission, transthoracic echocardiography revealed severe functional mitral regurgitation due to left ventricular dilatation. Surgical risk was considered high (Society of Thoracic Surgeons score of 12.6%); therefore, transcatheter edge-to-edge repair with the MitraClip system was performed. Two devices deployed at the middle segment of the anterior and posterior leaflet successfully reduced mitral regurgitation. The patient was free from cardiovascular events during the 2-year follow-up period.
UNASSIGNED: Transcatheter edge-to-edge repair is a less invasive and effective treatment for severe drug-refractory mitral regurgitation in patients with mitochondrial disease. Given the limited therapeutic options for mitochondrial cardiopathy, further studies are required to uncover the mechanism underlying mitochondrial diseases and establish disease-specific treatments.

Large single mitochondrial DNA (mtDNA) deletion syndrome is a rare inborn error of metabolism with variable heteroplasmy levels and clinical phenotype among affected individuals. Chronic progressive external ophthalmoplegia (CPEO) is the most common phenotype in adults with this form of mitochondrial disease [J Intern Med. 2020;287(6):592-608 and Biomed Rep. 2016;4(3):259-62]. The common CPEO clinical manifestations are ptosis and ophthalmoplegia. More variable phenotypic manifestations of CPEO (CPEO plus) include involvement of the peripheral nervous system and myopathy. Here, we describe a 62-year-old female with CPEO and the major mtDNA deletion present at 40% heteroplasmy, who had a coexistent previously undescribed CPEO phenotypic feature of persistent unexplained macrocytosis without anemia. Building on this case, we reviewed other major mtDNA deletion cases seen in our Adult Metabolic Diseases Clinic (AMDC) at the University of British Columbia, Vancouver, Canada, from 2016 to 2022. The major mtDNA deletion cases (n = 26) were compared with mtDNA missense variants identified in the clinic over the same period who acted as the comparison group (n = 16). Of these, the most frequent diagnosis was maternally inherited diabetes and deafness and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes. Ten out of 26 (38%) of mtDNA deletion patients had macrocytosis with elevated mean corpuscular volume (MCV), median (interquartile range) of 108 fL (102-114 fL). Seven of the patients with macrocytosis had no pertinent etiology. None of the comparison group had macrocytosis. There was a significant difference (p = 0.000) between the MCV and MCH in the mtDNA deletion group compared to the comparison group. This communication sheds light on the association of macrocytosis with the mtDNA deletion syndrome. It would be of great interest to determine if the association is found in other mitochondrial disease clinic populations.

Maternally inherited diabetes and deafness (MIDD) is a rare diabetic syndrome mainly caused by a point mutation in the mitochondrial DNA. It affects up to 1% of patients with diabetes but is often unrecognized by physicians. We report a case of MIDD in a 29-year-old man with coexisting imaging of cerebellar vermis hypoplasia and bilateral basal ganglia calcification.

BACKGROUND: The amino acid 5-aminolevulinic acid (5-ALA) is the first heme biosynthetic precursor. The combination of 5-ALA with sodium ferrous citrate (SFC) enhances heme production, leading to increased adenosine triphosphate (ATP) production in mitochondria. We investigated whether administering 5-ALA/SFC improves glucose tolerance with an increase in insulin secretion in patients with maternally inherited diabetes and deafness (MIDD), which is characterized by an insulin secretory disorder due to impaired mitochondrial ATP production.
METHODS: This was a single-arm, open-label, interventional study. We prospectively administered the oral glucose tolerance test (OGTT) twice in five patients with MIDD who had received intensive insulin therapy: before and 24 weeks after an administration of 5-ALA/SFC (200/232 mg per day). We measured the concentrations of glucose, insulin, C-peptide, and proinsulin at fasting, and 30, 60, and 120 min after glucose load in each OGTT. The primary endpoint was the changes in the area under the curve (AUC) of serum insulin from 0 to 120 min during OGTT from baseline to 24 weeks.
RESULTS: The serum insulin AUC (µU/mL) during the 120-min OGTT tended to increase from baseline to 24 weeks but not significantly (17.1 ± 13.7 versus 22.3 ± 13.4, p = 0.077). The plasma glucose AUC (mg/dL) during the 120-min OGTT at 24 weeks was not significantly decreased; the late phase of glucose excursion from 60 to 120 min was significantly decreased compared with baseline (357 ± 42 versus 391 ± 50, p = 0.041). The mean level of glycated hemoglobin (HbA1c) decreased from 8.3 ± 1.2% at baseline to 7.9 ± 0.3% at 24 weeks (p = 0.36) without increasing the daily dose of insulin injections.
CONCLUSIONS: The 24-week administration of 5-ALA/SFC did not demonstrate a significant improvement in insulin secretion in patients with MIDD. Further investigations with a larger number of patients and a placebo control group are required to clarify the potential efficacy of 5-ALA/SFC for ameliorating mitochondrial dysfunctions in MIDD.
BACKGROUND: UMIN-CTR000040581 and jRCT071200025.