Around 1% of all cases of diabetes are due to mutations in the mitochondrial DNA (mtDNA). The commonest mutation is the m.3243A>G, associated with the maternally inherited diabetes and deafness (MIDD) syndrome. Patients with MIDD are often misclassified as type 2 or type 1 diabetes by physicians unaware of the syndrome. The presence of diabetes, deafness and a family history of the above in maternal relatives should raise suspicion of MIDD and genetic testing should be pursued in view of the implications for personalised management and genetic counselling for patients and relatives. Diabetes is treated initially with oral hypoglycaemics, but early use of insulin is commonly needed due to insulin deficiency.
Maternally inherited diabetes and deafness (MIID/; MIM no. 520000) is a rare form of diabetes, accounting for approximately 1% of all diabetes cases , first described in 1992 by van den Ouweland et al in a Dutch family and by Reardon et al in a UK family . This quite heterogeneous syndrome results from an A to G substitution at the conserved position 3243 (m.3243A>G) of the mitochondrial DNA. The age and the mode of presentation of diabetes result in this entity being often misdiagnosed as either T1D or T2D.
Clinical features of diabetes in MIDD
The presence of diabetes and sensorineural deafness in a patient with family history of similar problems in maternal relatives should raise suspicion of MIDD. However, a number of other features may co-exist (see below). The clinical characteristics of diabetes can be similar to either T1D or T2D depending on the degree of insulinopenia. The presentation is usually insidious as in T2D, however around 20% of cases present acutely, even with ketoacidosis in a small proportion. Interestingly, in the vast majority of MIDD patients there is lack of autoimmunity as evidenced by the absence of pancreatic auto-antibodies and high-risk HLA polymorphisms associated with T1D. Among carriers of the m.3243A>G mutation, the penetrance of diabetes is high (estimated as over 85% by the age of 70 years) but the age of onset varies; the average age is 35 to 40 years with a range of 11 to 68 years old. The mitochondrial dysfunction in the metabolically demanding pancreatic islets leads to β-cell dysfunction which progresses gradually to a reduction in the β-cell mass and subsequently to insulin deficiency. Insulin sensitivity is not usually affected.
Other clinical features in MIDD
Sensorineural deafness is the other main characteristic in MIDD and is due to cochlear involvement. It is present in about 75% of diabetic patients, from early adulthood. It commonly precedes the diagnosis of diabetes, is more common and is often more severe and rapidly progressive in men than in women. Initially, it affects higher frequencies and subsequently all frequencies.
The syndrome of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS: MIM no 540000) was first described in patients with the m.3243A>G mutation, however it is very rarely seen in patients with MIDD, albeit more often in Japanese carriers of the mutation. It has been suggested that the presence of the m.3243A>G mutation results to a continuum of clinical manifestations from the presence of diabetes or deafness only to MIDD and MELAS.
Psychiatric disorders including severe depression, schizophrenia and various phobias have been described in these patients but it is unclear whether they are distinct to the presence of diabetes per se.
Macular retinal dystrophy is the commonest ophthalmic manifestation of the m.3243A>G mutation seen in more than 80% of MIDD who had a retinal examination. The presence of both pigmented lesions in the retina and atrophy of either the choroid or the retinal epithelium have been reported. Visual symptoms do not occur unless there is severe damage of the retinal epithelium. Also, the severity of the disease has not been shown to correlate with either the age of onset or the duration of diabetes.
Muscular involvement with proximal, exercise-induced muscle cramps or weakness has been reported in around 40% of MIDD patients.
Cardiac involvement includes premature cardiac death due to a number of possible reasons. Left ventricular hypertrophy, cardiac autonomic neuropathy along with various arrhythmias (e.g. Wolff-Parkinson-White syndrome, atrial fibrillation) are more commonly seen in MIDD patients compared to diabetic cases matched for age, sex and duration of diabetes.
Moreover, end-stage renal failure without features of diabetic nephropathy often develops before the diagnosis of diabetes or deafness. The presence of deafness occasionally leads to misclassification of these patients as X-linked Alport disease, however MIDD associated nephropathy does not present with microscopic haematuria and is also present in women, features that should prompt the consideration of MIDD.
With regards to endocrine manifestations, often these patients have short stature and low BMI. The former is due to deficiency of the Growth Hormone Releasing Hormone (GHRH) from the hypothalamus. The low BMI can be either due to insulin deficiency, particularly in cases where progression to insulin requirement is rapid, or due to loss of adipose or muscle tissue mass, depending on the severity of the mitochondrial dysfunction.
Mitochondrial DNA is only inherited from the mother (due to the degradation of mitochondria in the spermatic cells upon fertilisation). Therefore, the m.3243A>G mutation can only be transmitted via the mother, however both sexes can harbor the mutation and have manifestations of the disease. There has been one report of a de novo m.3243A>G mutation resulting to MIDD.
A number of possible explanations for the diabetogenic effect of the m.3243A>G mutation have been proposed. It is known that this mutation affects the tertiary structure of the mitochondrial tRNALeu leading to abnormal function of the complex 1 and 4 of the mitochondrial respiratory chain. As a result, metabolically active organs such as the pancreatic islets and the cochlea along with the retina, muscles, kidneys, heart and brain are affected. The degree of heteroplasmy in various tissues [a] partly explains the large variability in clinical phenotypes mentioned above.
A study used hyperglycaemic clamps and showed impaired insulin secretion in carriers of the m.3243A>G mutation (4). The attenuated production of ATP from ADP by mutant mitochondria in β-cells is thought to affect the closure of the KATP channel and subsequently the release of insulin. However, it seems likely that mitochondrial diabetes is an age-related process leading to the gradual deterioration of the β-cell function.
The confirmation of MIDD is possible with genetic testing to identify the m.3243A>G mutation in cases with a clinical suspicion of the syndrome. In view of the fact that leucocytes contain the lowest level of heteroplasmy, in some cases a false negative result can be generated. Therefore, other readily available tissues like urine or mouth swab are preferable. The detection of the mutation is performed by real time PCR that can detect heteroplamsy levels down to 1-5%. The cost of the test is approximately £75/€90/$120 .
MIDD patients are initially treated with diet or/and_ oral hypoglycaemic agents_ however progression to insulin is rather quick within 2 years from diagnosis. The theoretical risk of lactic acidosis in mitochondrial diabetes with metformin has been suggested but there is no robust evidence to support it. Moreover, based on our experience with a number of MIDD patients treated with metformin, no lactic acidosis has occurred. Similarly, the use of statins, for treatment of hyperlipidaemia in the presence of diabetes, is debatable in view of the increased risk of muscle-related side-effects.
Given the high risk of renal complications, tight blood pressure control and ACE-inhibitors are recommended early in the natural history of the disease. Careful monitoring of the cardiac function with a baseline electrocardiogram (ECG) and echocardiogram (ECHO) at the age of 35 or earlier if clinical manifestations exist, is recommended. Annual ECHOs thereafter should also be considered.
Medications to be avoided include antibiotics such as tetracyclines and chloramphenicol; anti-epileptics such as valproate, phenytoin and phenobarbitone, and nucleoside analogues reverse transcriptase inhibitors.
It is advisable that because maternal relatives of patients with MIDD are at high risk of developing diabetes, deafness, renal failure or cardiomyopathy they should be offered long-term follow-up. A negative result on a blood test may be falsely reassuring in view of the low heteroplasmy in leucocytes.
MIDD is maternally inherited therefore an affected male cannot transmit the mutation to his offsprings and he can be reassured. However, the children of a female carrier almost always inherit the mutations and should be monitored for the different features of MIDD including diabetes and deafness. It has been observed that women with the m.3243A>G mutation have a higher risk of miscarriage compared to women with other diabetes types, despite similar or better glycaemic control. It is suggested that the presence of high mitochondrial mutation load in the foetus maybe the underlying cause [^1].
^ Murphy, R., et al., Clinical features, diagnosis and management of maternally inherited diabetes and deafness (MIDD) associated with the 3243A>G mitochondrial point mutation. Diabet Med, 2008. 25(4): p. 383-99.
^ van den Ouweland, J.M., et al., Mutation in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nat Genet, 1992. 1(5): p. 368-71.
^ Reardon, W., et al., Diabetes mellitus associated with a pathogenic point mutation in mitochondrial DNA. Lancet, 1992. 340(8832): p. 1376-9.
^ Maassen, J.A., et al., Mitochondrial diabetes: molecular mechanisms and clinical presentation. Diabetes, 2004. 53 Suppl 1: p. S103-9.
^ Heteroplasmy is the percentage of normal and mutated mitochondrial DNA in each cell.