Maternally inherited encephalopathy associated with a single-base insertion in the mitochondrial tRNATrp gene

We identified a single thymidine insertion at nucleotide position 5537 (T5537i) in the mitochondrial DNA transfer RNA gene for tryptophan in a family in which the proband had a progressive neurological disorder and his brother died in infancy of Leigh syndrome. Muscle biopsy from the proband showed subsarcolemmal proliferation of mitochondria and decreased activities of oxidative metabolism enzymes, in particular complex IV. Complex IV was also severely reduced in autopsy tissues, including heart and brain tissues, from the Leigh syndrome infant. The novel T5537i mutation was very abundant in tissues from the proband and the infant (>92%) and less abundant (range, 42-89%) in blood, hair follicles, and skin fibroblasts from 4 maternal relatives, 3 of whom showed a neuropsychiatric disturbance. The mutation was not found in more than 100 control subjects. The degree of heteroplasmy in blood correlated well with the severity of the clinical presentation, suggesting specific segregation with the disease.