And such is what happened to siblings in two families from Pakistan and Oman who have been diagnosed with an unnamed neurological disorder with symptoms that included below-normal postnatal brain growth, intellectual disability and progressively worsening motor problems.
Between the two families, there were 14 children, suffered from a condition known as spastic paraplegia. All children were able to walk by 3 years of age but lost that ability as motor control diminished in their legs a few years later.
The researchers, Qing Ouyan from Brown, Tojo Nakayama from Boston Children's Hospital and Ozan Baytas, a Ph.D. candidate in Brown's neuroscience graduate training program, collaborated with researchers from Pakistan and Oman and started investigating five years ago. They predicted a genetic mutation as spastic paraplegia is generally considered to involve a neurodegenerative cause.
Now the researchers have identified the genetic mutations involved and have been able to replicate them in mouse models and lab cultures to develop a better understanding of how the mutations cause the disease and look for possible treatments, highlighting new medical and scientific opportunities according to Dr. Eric Morrow, associate professor of biology and of psychiatry and human behavior in the Warren Alpert Medical School of Brown University.
Mutation lies on chromosome 16, gene GPT2
Two specific mutations on gene GPT2 located on chromosome 16 are to blame. Other research groups have also linked GPT2 mutations to neurological diseases in other families around the world. Collectively, the studies provide strong evidence that the gene is relevant to neurological disease, according to Morrow.
"This is a clear, new neurogenetic disorder due to mutations in GPT2," said Morrow, "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."
GPT2 is found to be expressed in the nucleus of cells and the enzyme generated, is vital at metabolic pathways in the mitochondria. Mutations of GPT2 curb the development of brains by handicapping off the biosynthetic abilities for it to grow properly and deficits the brain of metabolites that help prevent degeneration.
G in GPT2 abbreviates for glutamate, which is an important neurotransmitter that controls how neurons connect and interact.
"To find a glutamate metabolising enzyme that is associated with a brain disease is an opportunity to understand how that neurotransmitter might work or be modulated," Morrow said.
Abnormal metabolite levels, a threat to neuron health, causing degeneration
Through inducing mutations in mice and lab cultures of human cells as models, they were able to conclude that the mutations led to reduced enzyme activity and that the enzyme was located in the mitochondria. The mutant mice with a GPT2 enzyme deficiency also showed abnormal brain metabolism, which some of the differences undermined the TCA cycle - important for producing energy and generating building blocks for cells.
Plenty of studies on these metabolic pathways in cancer exist, however in the differentiation of neurons growing extensions and connections during early childhood has not been well studied.
The team sought help from Ralph DeBerardinis at the University of Texas Southwestern Medical Center and Shawn Davidson and David Housman at MIT, who are both cancer metabolism experts, to develop experiments pertinent to GPT2 and brain.
Investigating the neurons of developing mice, they found that ones with the GPT2 mutations produced fewer synapses due to abnormal metabolite levels which relate to amino acid metabolism, TCA and pathways required for protecting neuron health. The deficiencies in these neuroprotective metabolites, Morrow said, might explain why the disease appears to have a degenerative course.
Future steps to be taken
The team at Brown now aims to refine and deepen their understanding of how the metabolic pathways regulate brain disease and function, as well as test for potential ways to rescue development and prevent disease progression.
"I believe there is hope that if these children were identified early as having this genetic condition, there may be an intervention that could prevent the progression," Morrow said. MIMS
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