IDENTIFICATION OF A LARGE-SCALE MITOCHONDRIAL DEOXYRIBONUCLEIC-ACID DELETION IN ENDOCRINOPATHIES AND DEAFNESS - REPORT OF 2 UNRELATED CASESWITH DIABETES-MELLITUS AND ADRENAL INSUFFICIENCY, RESPECTIVELY

In recent years, a broad variety of chronic diseases have been related to different mitochondrial DNA (mtDNA) rearrangements. We have invest igated two 16-yr-old unrelated girls with unexplained endocrine disord ers for a mtDNA mutation. One initially presented with an adrenal cris is at the age of 4 yr. Complete adrenal insufficiency for nearly 15 yr was the main clinical manifestation, along with insiduous growth reta rdation and sensorineural hearing loss since age 6. The other girl pre sented with ketoacidosis at the age of 15 yr. She exhibited incomplete deafness since age 6 and poor growth. In both patients, brain magneti c resonance imaging abnormalities and raised cerebrospinal fluid prote in concentration indicated mild leucodystrophy. Biopsy of skeletal mus cle showed a mitochondrial dysfunction; molecular analysis using a PCR screening procedure revealed a 7.4 kb deletion of the mtDNA in skelet al muscle but not in leucocytes. Direct sequence analysis of the junct ional regions showed that the deletion spanned 7.436 kb (nucleotide 86 49 to nucleotide 16084). The relative amount of deleted mtDNA estimate d 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 endoc rine conditions supports the view that the 7.4 kb mtDNA deletion shoul d be considered as one of the candidate causes for phenotypically unco mmon cases of endocrinopathies, specially in children with deafness. T his is the first report of a mitochondrial disease with primary adreno cortical insufficiency as the clinical onset.