[Monogenic diabetes: a useful dimension for diabetology practice]. / Les diabètes monogéniques: une dimension à intégrer dans la pratique clinique des diabétologues.

The number of identified monogenic diabetes progressively increases with time even if these forms of diabetes represent less than 5% of the cases. Every monogenic diabetes is characterized by an impairment of Beta cell at various levels. They are good models of diabetes-prone mechanisms. Diabetologists should recognize these forms because the management of the patients could be modified as a function of the genetic anomaly, in terms of either choice of hypoglycaemic agents, prognostic, management of associated manifestations or genetic counselling.

Gastrointestinal tract symptoms in Maternally Inherited Diabetes and Deafness (MIDD).

OBJECTIVE: To evaluate the prevalence and clinical consequences of gastro-intestinal manifestations in Maternally Inherited Diabetes and Deafness syndrome (MIDD). METHODS: We report the case of fatal intestinal pseudo-obstruction in a patient with severe MIDD. Using a standardized questionnaire, we evaluate the frequency of gastrointestinal tract (GIT) symptoms in 10 patients with MIDD (8 A3243G and 2 T14709C mutations of mitochondrial DNA). The reference population consisted of 50 patients with type 1 diabetes matched for disease duration. In 4 patients with digestive manifestations endoscopic examination of upper and lower GIT was performed allowing multiple biopsies for ultrastructural and molecular analysis. RESULTS: GIT symptoms were frequently reported in MIDD specially in patients bearing the mt 3243 mutation. The manifestations i.e. constipation, diarrhea or both, were more frequent in this subgroup than in type 1 diabetic population (88% vs 28%, p<0.05). Ileus is a rare and severe complication with a frequent fatal Issue. Ultrastructural analysis of the mucosa from oesophagus, stomach, duodenum, colon and rectum showed mild modifications such as accumulation of normal mitochondria and lipId droplets. Heteroplasmy levels were determined in 4 patients harboring the 3243 mutation. In three patients the percentage of mutated DNA increased from upper to lower GIT. CONCLUSIONS: Gastrointestinal symptoms are frequent in MIDD secondary to 3243 mutation. They might explain the lower body weight observed in these patients in comparison to reference diabetic populations. They can also lead to a severe complication namely the intestinal pseudo-obstruction.

Prevalence of macular pattern dystrophy in maternally inherited diabetes and deafness. GEDIAM Group.

OBJECTIVE: To evaluate the prevalence of macular pattern dystrophy (MPD) in maternally inherited diabetes and deafness (MIDD), a new subtype of diabetes mellitus that cosegregates with a mutation of mitochondrial DNA (i.e., the substitution of guanine for adenine at position 3243 of leucine transfer RNA) and to report the clinical characteristics of MPD. DESIGN: Prospective cohort study. PARTICIPANTS: Forty-six patients from 29 families with an adenine-to-guanine mutation of mitochondrial DNA were recruited from a French collaborative multicenter study. Thirty-five patients had MIDD, 8 were asymptomatic children of MIDD patients, and 3 had MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes). The 33 MIDD patients with diabetes were matched for diabetes duration and gender with 33 patients with "common" type-2 diabetes to compare the prevalence of diabetic retinopathy (DR) in both series. METHODS: All patients had a full ophthalmologic examination and fundus photographs. MAIN OUTCOME MEASURES: The presence and severity of MPD and DR were assessed in each patient. RESULTS: Thirty MIDD patients (85.7%) of 35 exhibited bilateral MPD characterized by linear pigmentation surrounding the macula and optic disc. In 24 of these 30 patients, visual acuity was 20/25 or more in both eyes. The prevalence of DR was 6% in MIDD patients with diabetes versus 15% for patients with common type-2 diabetes (a difference that was not significant, P = 0.23). The fundus of each of the eight asymptomatic children was normal. MPD was present in one of the three cases of MELAS. CONCLUSION: The prevalence of MPD in MIDD is high. Its detection may be helpful for the diagnosis of this new subtype of diabetes, for which specific treatments may be proposed.

Extra-pancreatic manifestations in diabetes secondary to mitochondrial DNA point mutation within the tRNALeu(UUR) gene.

OBJECTIVE: A point mutation in the mitochondrial genome has been identified as a cause of diabetes and deafness. We report two pedigrees with and A-to-G transition at nucleotide 3243 of mtDNA within the tRNALeu(UUR) gene and focus our investigations on other localizations of the anomaly, particularly muscle and retina. RESEARCH DESIGN AND METHODS: Muscular localization has been studied in probands by invasive and noninvasive methods, including muscle biopsy (evaluation of the proportion of mutated mtDNA in comparison to blood cells, measurement of respiratory chain complex activities and histological and histochemical aspects) and 31P-nuclear magnetic resonance (NMR) spectroscopy. Ophthalmic and angiographic examination of retina, electroretinography, and visual evoked potentials were performed in five subjects. RESULTS: This mutation, previously described in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), was expressed more abundantly in muscle than in nucleated blood cells. This low expression in blood cells could hamper the diagnosis for some patients. In addition, despite poor clinical expression, muscle was found to be highly affected. Ragged red fibers and dystrophic mitochondria were observed in muscle biopsy. Histochemical assays showed decreased activity of respiratory chain complexes, and 31P-NMR in vivo data further confirmed the defect of muscle oxidative processes. Exercise-induced lactate production was increased. Finally, in both families, an atypical "salt and pepper" pigmentary retinopathy was observed without consequences on visual acuity. CONCLUSIONS: In diabetes secondary to 3243 mtDNA mutation, infraclinical muscular and ocular lesions are frequent. These two locations of the disease, which are easily investigated by simple methods, can help in the diagnosis of this new type of diabetes.