In a 5-year-old girl of Portuguese origin who presented with MELAS (540000) symptoms at age 3, Manfredi et al. (1996) identified a heteroplasmic 5814A-G transition in the MTTC gene within the D-stem. The mutation load in muscle and blood was high, above 90%, although analysis of individual muscle fibers showed a mutation load of 74 to 95%. The mutation was not found in 50 controls. The patient had episodic vomiting, lactic acidosis, seizures, and hemiparesis. Brain MRI showed diffuse white matter abnormalities in the frontal lobes and basal ganglia. However, ragged-red fibers were not noted on muscle biopsies, leading Manfredi et al. (1996) to use the term 'MELAS-like" to describe the phenotype.
The same group (Santorelli et al., 1997) identified the 5814A-G mutation in an Italian family with a maternally inherited encephalomyopathy including progressive external ophthalmoplegia, seizures, and neurophysiologic evidence of brainstem dysfunction. The proband was a 33-year-old woman who had normal development until adolescence, when she complained of easy fatigability and developed limitations of eye movements. By age 27, she also had hearing impairment, unsteady gait, hyporeflexia, nystagmus, and lactic acidosis. Brain MRI showed hyperintensities in the corpus callosum, posterior wall of the third ventricle, and brainstem. She later developed myoclonic jerks and generalized tonic-clonic seizures. Muscle biopsy showed ragged-red fibers and echocardiography showed abnormal repolarization and mild hypertrophy of the interventricular septum. She became ventilator-dependent and bedridden, and died at age 33. The mutation load was 96% in blood and 98% in muscle. Three maternal relatives also carried the mutation: the mother had moderate bradykinesia (mutation load of 88%), asymptomatic brother (74%), and teenage daughter (92%). All 3 relatives had abnormal neurophysiologic activity in the brainstem.
