Mice homozygous for the megencephaly spontaneous mutation (Kcna1mceph) are characterized by a 25% increase in brain size in the first 8 months of life. This defect can be distinguished from macrocephaly, an enlarged head, which usually occurs as a consequence of congenital hydrocephalus. By 3-4 weeks of age, mice homozygous for the mceph mutation have a subtle shakiness in their gate and by 4-6 weeks are found to sit on their haunches using their tails as support with their forelimbs held loosely in front of them. They maintain this posture for a period ranging from 30 seconds to several minutes before returning to normal. They have lower overall body weights than their wildtype littermates and are hypersensitive to sharp sounds. Electroencephalogram readings for homozygotes are normal. Neither male nor female mutants breed, but ovarian transplant from homozygous donors is successful for colony maintenance. Homozygotes have an increased brain mass that is evident by one to two months of age and increases at least until 10 weeks of age, possibly longer. Hypertrophic astrocytes in the hippocampus were the only lesion detected by electron microscopy. This increase in brain mass does not appear to result from edema, hydrocephalus, or an increase in size restricted to any specific area of the brain. The ventricles were not found to be dilated, and no apparent increase in myelin was found. Two month old homozygotes did not show BrdU uptake in brain tissue, and the protein:DNA ration was normal. Thus, mceph appears to cause overall hypertrophy of cells in the brain rather than hyperplasia. Brains from homozygotes have only 13.8% fat while wild type have 15.6% fat.
In several evolutionarily associated regions of the brain, Petersson et al. found co-localized increases in mRNA levels for transforming growth factor beta 1, and insulin-like growth factor binding proteins 2, 4, 5, and 6 with decreases in mRNA levels for Insulin-like growth factor binding protein 5. These imbalances were found in the cerebral cortex, hippocampus, amygdala, and piriform/entorhinal cortex of homozygotes. They also reported a decreased transcript level in the corpus callosum for proteolipid protein of myelin. Immunohistochemistry and in situ hybridization also revealed changes in the expression levels of enkephalin, galanin, neuropeptide Y, and cholecystokinin in specific regions of the hippocampal formation and in ventral cortices. (Petersson et al., 1999; Peterson et al., 2000.)
Megencephaly occurs in several acquired and inherited human diseases including Sotos syndrome, Robinow syndrome, Canavan's disease, and Alexander disease.
