A new neurological disorder that causes problems with speech and motor coordination has been identified in three children in the United States (USA).
Investigators from the National Institutes of Health’s National Human Genome Research Institute (NHGRI) and the Undiagnosed Diseases Program believe that disease is caused by a genetic mutation which affects the ability of neurons in the brain to correctly carry out a cellular recycling function called autophagy.
In addition to helping people affected by the disease, the scientists responsible for the discovery – whose results were recently published in npj genomic medicine – hope this discovery could help in other diseases in which autophagy is implicated, such as Alzheimer’s, reported the New Atlas.
The first child in the study showed symptoms at age three. He had an abnormal gait and reduced coordination. As he got older he started having seizures, diminished reflexes and speech patterns that were only 60-75% intelligible.
At the age of nine and a half, he was diagnosed with attention deficit hyperactivity disorder (ADHD), a slight cognitive impairment, and oppositional disorder, a condition marked by irritability and anger, as well as arguments with parents and other authority figures. The boy has a sister who, despite having developmental problems, grew up without symptoms of the disease.
The other two children are sisters. One of them started moving her hands abnormally, stumbling and having periods of staring, with a slight learning disability and speech difficulties. The other sister also had motor control problems which were eventually resolved, although she was left with problems relating to articulation of words.
By examining the children’s health records, the researchers found that they all had mutations in a gene known as ATG4D. Scientists knew, based on a study 2015 that a mutation in this gene caused problems with motor control and eye movement in Lagotto Romagnolo dogs, but they had not yet linked the mutation to humans.
The team found that affected cells could not perform autophagy, a process in which all cells break down old or damaged proteins for reuse when needed.
Enhanced autophagy has been linked to a narrowing of clogged arteries and longer lifespans in mice. Research published in 2022 shows that the process of autophagy can be manipulated to reduce the amount of plaque-causing proteins that build up in the brain, which ultimately cause Alzheimer’s disease.
Interestingly, the researchers found that the ATG4D mutation in the affected children’s skin cells did not interfere with autophagy. It was only in the brain that the mutation altered the cellular recycling system.
“The brain is so complex, and neurons have very specialized functions”, said May Christine Malicdan, NHGRI scientist and senior author of the study. “To fit these functions, different neurons use different genes, so changes in genes can have big impacts in the brain.”
Because autophagy is implicated in both Alzheimer’s and Parkinson’s disease, the researchers hope that their work will lead to breakthroughs in the investigation of these two conditions.
“That’s the million-dollar question in rare disease research. These can help us understand biological pathways, so that we can better understand how contribute to other rare and common conditions.”indicated the researcher.
ZAP // 
