THE EXPANDING CLINICAL PHENOTYPE OF THE TRNA(LEU(UUR)) A-]G MUTATION AT NP-3243 OF MITOCHONDRIAL-DNA - DIABETIC EMBRYOPATHY ASSOCIATED WITHMITOCHONDRIAL CYTOPATHY

We describe a family which demonstrates and expands the extreme clinic al variabilty now known to be associated with the A-->G transition at nucleotide position 3243 of the mitochondrial DNA. The propositus pres ented at birth with clinical manifestations consistent with diabetic e mbryopathy including anal atresia, caudal dysgenesis, and multicystic dysplastic kidneys. His co-twin was normal at birth, but at 3 months o f life, presented with intractable seizures later associated with deve lopmental delay. The twins' mother developed diabetes mellitus type I at the age of 20 years and gastrointestinal problems at 22 years. Sinc e age 19 years, the maternal aunt has had recurrent strokes, seizures, mental deterioration and deafness, later diagnosed as MELAS syndrome due to the tRNA(Leu(UUR)) A-->G mutation. A maternal uncle had diabete s mellitus type I, deafness, and normal intellect, and died at 35 year s after recurrent strokes. This pedigree expands the known clinical ph enotype associated with tRNA(Leu(UUR)) A-->G mutation and raises the p ossibility that, in some cases, diabetic embryopathy may be due to a m itochondrial cytopathy that affects both the mother's pancreas (and re sults in diabetes mellitus and the metabolic dysfunction associated wi th it) and the embryonic/fetal and placental tissues which make the em bryo more vulnerable to this insult. (C) 1996 Wiley-Liss, Inc.