Involvement of nervous system in maternally inherited diabetes and deafness (MIDD) with the A3243G mutation of mitochondrial DNA.

Abstract

The A3243G mutation of mitochondrial DNA (mtDNA) has been associated with maternally inherited diabetes and deafness (MIDD) in a number of reports; however, the involvement of the nervous system has rarely been mentioned, prompting this exploration of the manifestation of neurological disorders in MIDD cases. We investigated four generations of a large Taiwanese family in which MIDD is manifest. We conducted a series of clinical examinations, including computed tomography (CT) and magnetic resonance imaging (MRI) of the head, brain 99mTc-HMPAO single photon emission computed tomography (SPECT), cognitive function tests, and nerve conduction velocity (NCV) studies. Blood levels of creatine kinase (CK) and lactate, pathology of muscle biopsy samples and proportions of mutant mtDNA in blood cells, hair follicles, muscle and skin were also analyzed. Mean follow-up period was 4 years. The patients exhibited the clinical features of diabetes mellitus including sensorineural hearing loss, short stature, and/or histories of spontaneous abortion. No stroke-like episodes were reported. Analysis for mtDNA revealed that the A3243G mutation existed in 11 members (6 symptomatic and 5 asymptomatic members) of this MIDD-prone family, with the proportion of mutant mtDNA ranging from 21% to 47% in leukocytes. Head CT revealed diffuse brain atrophy for all 6 (100%) patients examined and bilateral basal ganglia calcification in 4 of 6 (67%) patients. Brain 99mTc-HMPAO SPECT revealed diminished uptake in the bilateral parieto-occipital or occipital regions for all 6 tested patients, cognitive function for these patients was normal. Results of head CT and SPECT were normal in one asymptomatic member of the family. One muscle biopsy revealed abundant ragged-red fibers with modified Gomori-trichrome stain. Muscle-enzyme activity and serum-lactate levels were normal. We have demonstrated that a wide spectrum of sub clinical pathologies of the central nervous system and muscle are present for this MIDD-prone family, none of whom developed typical MELAS during the 4-year period of follow-up study.