Researchers have managed to identify and describe a rare new brain disease, which is characterized by reduced brain growth in affected children and can eventually lead to paralysis of the legs. The previously unknown neurodegenerative condition was identified in two separate families living more than 1,600 kilometers (1,000 miles) apart, and shows a strong genetic component as multiple siblings in each family are affected.
After five years of studying the two families and the 14 children who have the condition, the scientists were able to pinpoint exactly which mutated gene was responsible for the neurological disorder, narrowing it down to GPT2. The condition affects brain development in children, who show intellectual disability and a degeneration in motor skills. For example, up until the age of three, the children will typically be able to walk normally, but then they will steadily lose function of their legs as a condition known as spastic paraplegia develops.
While the gene GPT2 is expressed in the nucleus of the cell, the enzyme it codes for actually gets to work in the mitochondria – the powerhouse of the cell. The result is that the enzyme cannot function correctly, leaving the developing brains of young children without the biosynthetic abilities they need to grow properly. It may also lead to reduced levels of other substances necessary in preventing neurological degeneration.
The researchers were able to identify two specific mutations within the GPT2 gene, with their findings backed up by other research groups linking mutations in the same gene to a neurological disease found in other families. To establish how the altered GTP2 gives rise to the disease, the researchers then created both human cells and mouse models where they introduced the mutations, and found that developing mice showed reduced neural and brain growth. When they looked in closer detail, they found that the neurons in affected mice had fewer synapses, which are the connections between brain cells that make up brain circuits.
“This is a clear, new neurogenetic disorder due to mutations in GPT2,” explains Dr Eric Morrow, co-author of the paper describing the as yet unnamed disease in the Proceedings of the National Academy of Sciences, in a statement. “In addition to the relevance this has to the diagnosis of developmental disorders, and potentially therapeutics, it is also a window into how the brain develops and how the brain functions.”
Not only that, but the enzyme GPT2 is also related to the amino acid glutamate, a neurotransmitter that regulates how brain cells interact. “To find a glutamate metabolizing enzyme that is associated with a brain disease is an opportunity to understand how that neurotransmitter might work or be modulated,” says Morrow. It is hoped that if the condition is diagnosed in children early enough, there could be some way to prevent its progression. Researchers are now trying to learn as much as they can about the disease and how it can be prevented.
