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Identification of a Large-Scale Mitochondrial Deoxyribonucleic Acid Deletion in Endocrinopathies and Deafness: Report of Two Unrelated Cases with Diabetes Mellitus and Adrenal Insufficiency, Respectively¹

Service d’Endocrinologie Pédiatrique (M.N., M.D., P.C.), Laboratoire de Biochimie Pédiatrique (T.F., B.M.), and INSERM U 329 (M.F.) Hôpital Debrousse, 69322 Lyon, France; INSERM CRI 9401 (H.C.), Faculté de Médecine Alexis Carrel, 69372 Lyon, France; and CNRS UMR 5534 (C. G.), Université Claude Bernard Lyon I, 69622 Villeurbanne, France

Address all correspondence and requests for reprints to: Marc Nicolino, M.D., Service d’Endocrinologie Pédiatrique, Hôpital Debrousse, 29, rue Soeur Bouvier, 69322 Lyon Cedex 05, France.

In recent years, a broad variety of chronic diseases have been related to different mitochondrial DNA (mtDNA) rearrangements. We have investigated two 16-yr-old unrelated girls with unexplained endocrine disorders for a mtDNA mutation. One initially presented with an adrenal crisis at the age of 4 yr. Complete adrenal insufficiency for nearly 15 yr was the main clinical manifestation, along with insiduous growth retardation and sensorineural hearing loss since age 6. The other girl presented with ketoacidosis at the age of 15 yr. She exhibited incomplete deafness since age 6 and poor growth. In both patients, brain magnetic resonance imaging abnormalities and raised cerebrospinal fluid protein concentration indicated mild leucodystrophy. Biopsy of skeletal muscle showed a mitochondrial dysfunction; molecular analysis using a PCR screening procedure revealed a 7.4 kb deletion of the mtDNA in skeletal muscle but not in leucocytes. Direct sequence analysis of the junctional regions showed that the deletion spanned 7.436 kb (nucleotide 8649 to nucleotide 16084). The relative amount of deleted mtDNA estimated by Southern blot analysis was 25 and 15%, respectively. No deletion was present in leukocytes obtained from the asymptomatic mothers.

The presence of the same mutation in different patients with various endocrine conditions supports the view that the 7.4 kb mtDNA deletion should be considered as one of the candidate causes for phenotypically uncommon cases of endocrinopathies, specially in children with deafness. This is the first report of a mitochondrial disease with primary adrenocortical insufficiency as the clinical onset.

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