External ophthalmoplegia with severe progressive multiorgan involvement associated with the mtDNA A3243G mutation.
BACKGROUND
Chronic progressive external ophthalmoplegia (CPEO) may be related to primary nuclear DNA or mitochondrial (mt)DNA mutations. The A3243G mtDNA point mutation most frequently causes mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, but also has been associated with other phenotypes including CPEO, migraine, seizure, diabetes, and sensorineural hearing loss.


METHODS
We report a 38-year-old white man with seizures and progressive difficulties of infantile origin including CPEO, sensorineural hearing loss, cataracts, migraines, multiple endocrinopathy, myopathy, and cardiomyopathy. Moderate hearing loss in association with CPEO, diabetes mellitus, or migraines were noted in the proband's maternal grandmother, great aunt, mother, and three sisters, suggesting either an autosomal dominant or maternal inheritance. Detailed histological and biochemical analysis of the proband's biopsied muscle specimen revealed severe abnormalities compatible with a mitochondrial disease. MtDNA analysis excluded large-scale deletions, but revealed a heteroplasmic A to G transition at nt3243 in 56.4% and 27.4% of molecules in muscle and white blood cells, respectively.


CONCLUSIONS
We discuss possible causes of this intrafamilial heterogeneity of phenotypes associated with the A3243G mtDNA mutation.
Hansrote
Sun
S
Department of Neurology, MCP Hahnemann University, MS 423, 245 North 15th Street, Philadelphia, PA 19102, USA.
Croul
Sidney
S
Selak
Mary
M
Kalman
Bernadette
B
Schwartzman
Robert J
RJ
D000328:Adult; D001706:Biopsy; D004272:DNA, Mitochondrial / Q000235:genetics*; D005192:Family Health; D006801:Humans; D008297:Male; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000473:pathology; D018482:Muscle, Skeletal / Q000473:pathology; D017246:Ophthalmoplegia, Chronic Progressive External / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D017354:Point Mutation
D004272:DNA, Mitochondrial