Maternally inherited diabetes and deafness (MIDD) results from a variant in mitochondrial DNA and causes maternally inherited diabetes with bilateral sensorineural deafness that may be accompanied by a wide range of other features. It affects up to 1% of those with diabetes, but is frequently misdiagnosed.

Pathogenesis and inheritance

The vast majority of mitochondrial diabetes results from the m.3243A>G point variant in mitochondrial DNA and other mitochondrial DNA variants are rare. The m.3243A>G variant affects the mitochondrial respiratory chain and therefore results in cellular energy deficiency. Organs with high metabolic activity including the endocrine pancreas and cochlea are most affected. Mitochondrial dysfunction in pancreatic islets results in abnormal β- cell function, loss of β- cell mass, and insulin deficiency. As mitochondria are inherited from the mother, only the maternal line in a family is affected, and children of an affected father are not at risk. All children of an affected woman will inherit the variant; however, phenotype varies widely within a family due to heteroplasmy. Offspring inherit a mix of variant and wild- type mitochondrial DNA and the proportion of mitochondria carrying the variant will vary, as will segregation of variant and wild- type mitochondria to different tissues.

Clinical features

The characteristic clinical features of MIDD are summarized in Figure 1. The majority of variant carriers develop diabetes (over 85%) and sensorineural hearing loss (over 75%). Diabetes is progressive but may present acutely, with ketoacidosis occurring in ~8% of cases. Mean age at diagnosis of diabetes is 37 years, but age of diagnosis can range from 11 years to 68 years.

Fig1. Phenotypes of (a) renal cysts and diabetes syndrome due to HNF1B variant or deletion; and (b) maternally inherited diabetes and deafness caused by mitochondrial m.3243A>G variant. LFTs, liver function tests. Source: Adapted from Murphy et al. and Clissold et al.

Hearing loss typically develops in early adulthood and is more common in men than women. Those with the m.3243A>G variant have a high prevalence of renal failure, with focal segmental glomerular sclerosis found frequently on biopsy. Macular retinal dystrophy is a frequent finding, but rarely causes visual symptoms. Cardiac abnormalities include left ventricular hypertrophy, heart failure, and cardiac arrhythmias. Other clinical manifestations of the m.3243A>G variant include short stature, MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke- like episodes), psychiatric disorders, proximal myopathy, and gastrointestinal symptoms, particularly constipation.

Differentiating from type 1 diabetes and type 2 diabetes

 Diabetes caused by the m.3243A>G variant is difficult to differentiate from type 1 diabetes or type 2 diabetes. The presence of deafness in the individual or clustering of diabetes and/or sensorineural deafness in maternal relatives should prompt investigation for the m.3243A>G variant. The diagnosis can be confirmed by testing for the m.3243A>G variant in blood leucocytes or urine. In rare cases the result may be negative on blood- derived DNA because of heteroplasmy loads in leucocytes. Urine or buccal samples may therefore be preferable.

Management

 Insulin treatment is usually required within two years of diabetes diagnosis. There is a theoretical basis for avoiding metformin in view of the risk of lactic acidosis. Whether there is benefit for the diabetes from use of coenzyme Q10 supplementation is currently unclear. Monitoring for cardiac manifestations should be considered from a young age. Aggressive blood pressure management and early angiotensin- converting enzyme (ACE) inhibitor treatment may be appropriate in view of the high risk of renal complications. Management of hearing loss involves avoidance of exacerbating factors, prompt treatment of ear infections, hearing aids if necessary, and consideration of cochlear implants where there is profound hearing loss.

Maternal relatives of affected individuals and children of a woman with the disease should be assumed to carry the m.3243A>G variant. Therefore, annual HbA1c after 30 years and prompt referral to audiology if suspicion of hearing loss and complications of MIDD may be advisable.

اخر الاخبار

اخبار العتبة العباسية المقدسة

قسم التطوير يقيم دورة عن أخلاقيات المهنة للمنتسبين الجدد

تتضمن زيارة المراقد المقدسة في كربلاء.. معهد القرآن الكريم النسوي ينظم سفرة دينية لطالباته

المجمع العلمي يحتفي بذكرى ولادة الإمامين الباقر والهادي (عليهما السلام)

قسم الشؤون الفكرية يطلق فعاليات الأسبوع الثالث من برنامج البذرة الصالحة

المزيد

الآخبار الصحية

ثورة طبية.. الذكاء الاصطناعي يكشف سرطان الكلى في وقت قياسي

لتعزيز الطاقة والتغلب على التعب.. عليك بـ7 طرق بسيطة

لتحسين الهضم والتحكم في الشهية.. ما أفضل وقت لتناول التمر؟

خبراء يكشفون تأثير الاستحمام في الظلام على جودة النوم !

المزيد

الآخبار التكنلوجية

إزالة ثاني أكسيد الكربون من الغلاف الجوي.. ما دور المحيطات والبحار؟

نظائر الهيليوم مقياس لاكتشاف رواسب الذهب.. كيف ذلك؟

الصين تطلق أول ناقلة نفط خام ذكية في العالم تعمل بالميثانول

الزمن على المريخ أسرع من الأرض.. دراسة علمية تكشف الفوارق

المزيد

مواضيع ذات صلة

Renal cysts and diabetes (HNF1B MODY)

Genetic testing in neonatal diabetes

Human Hemoglobin and Associated Diseases

The Relationship Between Genotype and Phenotype in Genetic Disease

Effect of Pathogenic Variants on Protein Function

HNF1A and HNF4A (Transcription factor MODY)

Categories of Epigenetic disorders

Epigenetics in Development

Mosaicism

Pseudoautosomal inheritance

Characteristics of autosomal recessive inheritance

Patterns of Inheritance