Scientists from the National Human Genome Research Institute (NHGRI) and the Undiagnosed Diseases Program at the National Institutes of Health have identified a neurological disorder that causes problems with speech and motor coordination in three children. Researchers believe the condition is caused by genetic mutations that affect the ability of neurons in the brain to properly perform a cell-recycling function called autophagy. In addition to helping people suffering from this condition, scientists hope the findings will help evaluate other diseases in which autophagy is implicated, such as Alzheimer’s disease.
The first subject in this study presented symptoms at the age of 3 years. He had an abnormal gait, had decreased coordination in his movements, and was lost in episodes of staring. As the boy grew older, he experienced seizures, decreased reflexes, and speech patterns that only 60-75% understood. At the age of nine and a half, the boy was diagnosed with ADHD, mild cognitive impairment, and oppositional defiant disorder. This condition is characterized by irritability and anger, as well as quarreling with his parents and other authority figures. The boy has a sister who grew up without any symptoms of the disease despite his early developmental problems.
Two other subjects are affected sisters. One experienced abnormal hand movements, stumbling episodes, and staring periods in childhood, and was left with mild learning and speech impairments. Another sister also had motor control problems, which were eventually resolved, but still have issues related to verbal clarity.
After examining the children’s health records, NIH researchers found that all had mutations in a gene known as ATG4D. Scientists knew from her 2015 study that mutations in this gene cause problems with motor control and eye movements in Lagotto Romagnolo dogs, but compared the mutations to problems in human subjects. I hadn’t gotten around to making the connection yet.
To find out if ATG4D mutations are causing problems in children, the researchers inserted the child mutations into cells in experimental dishes. They found that the affected cells were unable to carry out autophagy. This is the process by which all cells break down old or damaged proteins for reuse as needed. Enhanced autophagy has been associated with reducing arterial clogging and extending lifespan in mice, but a study published last year showed that the process of autophagy could be manipulated to accumulate in the brain and eventually It has been shown to be able to reduce the amount of proteins that cause plaques leading to Alzheimer’s disease.
Interestingly, the researchers found that ATG4D mutations in skin cells from affected children did not interfere with autophagy. It was only in the brain that mutations altered the cellular recycling system.
“The brain is very complex and the neurons have very specific functions,” said NHGRI staff scientist May Christine Malicdan, senior author of the study. “To accommodate these functions, different neurons use different genes, so redundant gene changes can have profound effects on the brain.” Therefore, researchers hope their work will lead to breakthroughs in related research.
“This is a million-dollar problem in rare disease research,” said Malicdan. “Rare diseases help us understand biological pathways, so we can better understand how those pathways contribute to other rare and common conditions.”
Moving forward, researchers will continue to work with the three children participating in the study to find other children who suffer from the disorder.
The study was published in a journal npj genomic medicine.
Source: National Human Genome Research Institute
