A new genetic disease was first described in three children with shared neurodevelopmental issues.
Researchers have identified a gene that is primarily responsible for the rare speech and movement disorder, although more research is needed to understand its role in clearing up dead proteins in the brain.
Building on this knowledge could contribute to understanding more common brain diseases such as Alzheimer’s disease, which is also believed to arise from a failure in brain maintenance.
One of the children identified in the present study was brought to the physician at the age of three with abnormal gait, poor coordination and episodes of staring. A second individual showed abnormal hand movements and episodes of staring at just nine months of age.
His younger sister was born prematurely. As she grew older, her sister also experienced soft speech and gross motor delays. Around age three, her development began to pick up, although she was still a little behind compared to others her age.
In all three cases, the researchers identified mutations in both copies of a gene linked to the recycling of damaged or defective cells in the brain, called ATG4D.
This cleaning process is called autophagy, and malfunctions in its operation have been linked to other neurological disorders in the past. When autophagy is disrupted in Alzheimer’s disease, for example, proteins seem to clog brain cells and prevent them from working properly.
In 2015, ATG4D mutations were associated with neurodegenerative diseases in canines and zebrafish, while in 2021 mice with the mutation showed signs of neurodegeneration. But this is the first time the gene has been linked to neurological disorders in humans, with researchers revealing Mutations in the ATG4D gene can also lead to developmental disorders in speech and movement in children.
How this plays out in practice in various neurodevelopmental diseases will need to be further explored using human neurons.
The three children examined in the present study showed similar symptoms, although with small variations. They also had almond-shaped eyes, a depressed bridge of the nose, and a prominent Cupid’s bow on their upper lip.
These physical characteristics could be a sign of your shared genetic mutation, or they could simply be a coincidence. With such a small number of patients identified, it’s hard to say for sure.
“We only have a bird’s-eye view of many important cellular processes, such as autophagy,” admits genomics researcher May Christine Malicdan of the National Institutes of Health (NIH).
The current study was limited to the three patients, and when their shared gene mutations were replicated in a human cell line, there were no apparent defects in autophagy observed, despite models predicting otherwise.
This discrepancy could be due to other genes that also play a role in autophagy. In other words, ATG4D is not the only gene that instructs protein release.
Unlike other cells in the body, however, neurons are particularly dependent on autophagy. Here, there is a chance that the function of the ATG4D is irreplaceable.
“The brain is very complex and neurons have very specialized functions”, explains Malicdan.
“To adjust these functions, different neurons use different genes, so changes in redundant genes can have big impacts in the brain.”
How exactly ATG4D contributes to cellular waste recycling in the brain is not well understood. Bearing in mind the challenges they can pose to individuals and their families, rare diseases like this yet-to-be-named new condition present avenues for scientists to learn more about the many ways the human body works (and fails).
“That’s the million dollar question in rare disease research,” says Malicdan. “Rare diseases can help us understand biological pathways so that we can better understand how these pathways contribute to other rare and common conditions.”
The study was published in npj genomic medicine.