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The Clinical Variability of Maternally Inherited Diabetes and Deafness Is Associated with the Degree of Heteroplasmy in Blood Leukocytes

Assistance Publique-Hôpitaux de Paris (APHP) (M.L.-M., T.M., C.A., M.V., P.J.G.), Department of Medicine B, Lariboisiere Hospital, University Paris 7 Denis-Diderot, 75010 Paris, France; APHP (C.B.-C., S.B.), Department of Genetics, Pitie-Salpetriere Hospital, 75013 Paris, France; APHP (P.M., A.L.-C.), Service of Ophthalmology, Lariboisiere Hospital, University Paris 7 Denis-Diderot, 75010 Paris, France; Department of Endocrinology (B.V.), La Timone Hospital, 13274 Marseilles, France; University Hospital (H.G.), 33064 Pessac, France; APHP (J.T., D.D.-L.), Department of Immunology and Diabetology, Cochin Hospital, Université René-Descartes, 75014 Paris, France; Begin Hospital (B.Ba.), 94160 Saint-Mandé, France; General Hospital (L.B.), 28000 Chartres, France; Robert Debre Hospital (E.B.), 51100 Reims, France; Department of Internal Medicine B (J.-F.B., D.P.-B.), University Hospital, 67091 Strasbourg, France; Department of Endocrinology and Diabetology (J.C.-V., P.C.), General Hospital, 95107 Argenteuil, France; Department of Diabetology (A.C.), General Hospital, 64109 Bayonne, France; North Cardiology Center (S.C.), 93207 Saint-Denis, France; Department of Endocrinology (P.C.), University Hospital, 42000 Saint-Etienne, France; Department of Diabetology (G.C., J.P.R.), Gilles-de-Corbeil Hospital, 91106 Corbeil, France; Department of Diabetology (T.C.), General Hospital, 57126 Thionville, France; Department of Diabetology and Endocrinology (B.D.), Robert Debré Hospital, 51092 Reims Cédex, France; Department of Medicine (F.D.), General Hospital, 80100 Abbeville, France; Department of Endocrinology (P.H.D.), University Hospital, 49933 Angers, France; Department of Internal Medicine and Hypertension (B.Bo.), Rangueil Hospital, 31059 Toulouse, France; Sainte-Blandine Hospital (L.D., J.L.), 57046 Metz, France; General Hospital (T.G.), 89011 Auxerre, France; APHP (A.G.), Department of Diabetology, Pitie-Salpetriere Hospital, 75013 Paris, France; Department of Diabetology (B.G.), Jeanne-d’Arc Hospital, 54201 Dommartin-les-Toul, France; Department of Diabetology (V.J.), General Hospital, 44600 Saint-Nazaire, France; Department of Endocrinology (E.K.), General Hospital, 60324 Compiègne, France; Department of Diabetology (E.L., A.S.-G.), Hôtel Dieu Hospital, 75004 Paris, France; Department of Diabetology (F.L.), Rangueil Hospital, 31043 Toulouse, France; Department of Endocrinology and Diabetology (J.M.), Dupuytren Hospital, 87042 Limoges, France; Department of Endocrinology and Metabolism Diseases (A.M.), Hotel-Dieu, 44093 Nantes, France; Department of Diabetology (S.N.-F.), Saint-Joseph Hospital, 75014 Paris, France; Department of Endocrinology (F.O.), General Hospital, 46005 Cahors, France; Unit of Genetics (V.P.-F.), L’Archet Hospital, 06202 Nice, France; Medical Center (I.R.), 37000 Tours, France; Department of Endocrinology (Y.R.), University Hospital, 14033 Caen, France; Department of Diabetology (S.S.), Bretagne Sud Hospital, 56322 Lorient, France; Department of Endocrinology (E.S.), La Cavale Blanche University Hospital, 29200 Brest, France; APHP (J.L.T.), Department of Internal Medecine, Henri-Mondor Hospital, 94010 Créteil, France; and Department of Diabetology (B.T.), Y. Le Foll Hospital, 22027 Saint-Brieuc, France

Address all correspondence and requests for reprints to: P. J. Guillausseau, Department of Internal Medicine B, Hôpital Lariboisière, 2 Rue Ambroise Paré, F 75475 Paris Cedex 10, France. E-mail: pierre-jean.guillausseau{at}lrb.aphp.fr.

Context: Maternally inherited diabetes and deafness (MIDD) is a rare form of diabetes with a matrilineal transmission, sensorineural hearing loss, and macular pattern dystrophy due to an A to G transition at position 3243 of mitochondrial DNA (mtDNA) (m.3243A>G). The phenotypic heterogeneity of MIDD may be the consequence of different levels of mutated mtDNA among mitochondria in a given tissue.

Objective: The aim of the present study was thus to ascertain the correlation between the severity of the phenotype in patients with MIDD and the level of heteroplasmy in the blood leukocytes.

Participants: The GEDIAM prospective multicenter register was initiated in 1995. Eighty-nine Europid patients from this register, with MIDD and the mtDNA 3243A>G mutation, were included. Patients with MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) or with mitochondrial diabetes related to other mutations or to deletions of mtDNA were excluded.

Results: A significant negative correlation was found between levels of heteroplasmy and age of the patients at the time of sampling for molecular analysis, age at the diagnosis of diabetes, and body mass index. After adjustment for age at sampling for molecular study and gender, the correlation between heteroplasmy levels and age at the diagnosis of diabetes was no more significant. The two other correlations remained significant. A significant positive correlation between levels of heteroplasmy and HbA_1c was also found and remained significant after adjustment for age at molecular sampling and gender.

Conclusions: These results support the hypothesis that heteroplasmy levels are at least one of the determinants of the severity of the phenotype in MIDD.

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