Mitochondrial Diabetes in Children: Seek and You Will Find It

Abstract

Maternally Inherited Diabetes and Deafness (MIDD) is a rare form of diabetes due to defects in mitochondrial DNA (mtDNA). 3243 A>G is the mutation most frequently associated with this condition, but other mtDNA variants have been linked with a diabetic phenotype suggestive of MIDD. From 1989 to 2009, we clinically diagnosed mitochondrial diabetes in 11 diabetic children. Diagnosis was based on the presence of one or more of the following criteria: 1) maculopathy; 2) hearing impairment; 3) maternal heritability of diabetes/impaired fasting glucose and/or hearing impairment and/or maculopathy in three consecutive generations (or in two generations if 2 or 3 members of a family were affected). We sequenced the mtDNA in the 11 probands, in their mothers and in 80 controls. We identified 33 diabetes-suspected mutations, 1/33 was 3243A>G. Most patients (91%) and their mothers had mutations in complex I and/or IV of the respiratory chain. We measured the activity of these two enzymes and found that they were less active in mutated patients and their mothers than in the healthy control pool. The prevalence of hearing loss (36% vs 75–98%) and macular dystrophy (54% vs 86%) was lower in our mitochondrial diabetic adolescents than reported in adults. Moreover, we found a hitherto unknown association between mitochondrial diabetes and celiac disease. In conclusion, mitochondrial diabetes should be considered a complex syndrome with several phenotypic variants. Moreover, deafness is not an essential component of the disease in children. The whole mtDNA should be screened because the 3243A>G variant is not as frequent in children as in adults. In fact, 91% of our patients were mutated in the complex I and/or IV genes. The enzymatic assay may be a useful tool with which to confirm the pathogenic significance of detected variants.

Sideroblastic anaemia and primary adrenal insufficiency due to a mitochondrial respiratory chain disorder in the absence of mtDNA deletion

“…Diabetes mellitus is also a known complication of mitochondrial disease, often associated with sensorineural deafness due to a single point mutation in mtDNA (maternally inherited diabetes and deafness) 22. A number of cases have been described in association with other mtDNA deletions in the Pearson syndrome, KSS and Wolfram syndrome 10 23 24…”

The clinical utility of C‐peptide measurement in the care of patients with diabetes

“…There are limited data available on the utility of C‐peptide testing in identifying other forms of monogenic diabetes. Patients with mitochondrial diabetes may develop severe insulin deficiency and those with monogenic neonatal diabetes commonly have absolute insulin deficiency in the absence of sulphonylurea therapy . Patients with monogenic forms of diabetes associated with severe insulin resistance are likely to have raised C‐peptide.…”

Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society

“…16 Endocrinopathies can manifest during critical illness in mitochondrial patients. Diabetes mellitus due to insulin insufficiency secondary to islet cell dysfunction or insulin resistance [17][18][19] , primary adrenal insufficiency, thyroid dysfunction, hypoparathyroidism and hypogonadism are also seen. 20,21 Patients with mitochondrial diseases may be chronically malnourished with deficiencies of both macro and micronutrients.…”

“…Diabetes mellitus is one of the most common findings in patients with the m.3243A>G mutation, typically manifesting as maternally-inherited diabetes and deafness (MIDD). [17][18][19] Both hypothyroidism and, to a far lesser extent, hyperthyroidism have been reported in patients with primary mitochondrial diseases and may coexist with other endocrinopathies. 20,21 Short stature is common.…”