A new study has identified mutations in a single gene as the cause of a previously unrecognized spectrum of severe neurological disorders ranging from fatal prenatal conditions to progressive neurodegenerative disease in childhood, according to a study published in the Journal of Clinical Investigation.
“Through genetic sequencing of multiple unrelated families whose children presented with severe, unexplained neurodevelopmental or neurodegenerative conditions, several teams across multiple countries, from the UK to Spain to Oman to Egypt, independently identified mutations in the same gene: BORCS5,” said Niccolo Mencacci, MD, PhD, assistant professor in the Ken and Ruth Davee Department of Neurology’s Division of Movement Disorders and first author of the study.
Within the cell, BORCS5 is known to regulate lysosomes: structures that break down and recycle waste. These organelles are particularly critical in neurons, which must maintain long-distance transport systems along axons.
In the study, investigators identified 16 patients from nine families with mutations affecting both copies of BORCS5. The severity of disease depended on the type of mutation, with mutations that completely eliminate the BORCS5 protein producing the most devastating outcomes.
“Patients with complete loss of the protein have a devastating prenatal syndrome — brain malformations, abnormal fetal movements and neuroaxonal dystrophy,” Mencacci said.
By contrast, patients with partially functioning mutations experienced a chronic but progressive neurological disorder, which featured epilepsy, movement problems, intellectual disability and loss of developmental milestones over time. While these individuals can survive into adulthood, their disabilities are profound.
Brain scans from these patients revealed widespread abnormalities, including hypomyelination, structural defects in the corpus callosum, and progressive brain atrophy — all hallmarks of ongoing neurodegeneration.
Next, the team engineered zebrafish lacking the BORCS5 gene. These animals developed smaller brains, motor impairments and increased seizure susceptibility, closely mirroring the human condition.
At the cellular level, experiments in human neurons derived from stem cells revealed deeper insights. Severe mutations caused lysosomes to cluster abnormally and fail to travel properly along axons.
However, milder mutations did not affect the distribution of lysosomes along axons but instead disrupted lysosomal function, Mencacci said.
Mencacci and his collaborators found that the gene helps maintain the activity of key enzymes that are essential for breaking down cellular waste. Reduced activity of these enzymes was seen in both severe and milder cases.
This dual role helps explain why the disease varies so widely.
“The protein has two separable functions, and mutations disrupt them in different ways, which explains why the clinical picture varies so dramatically between patients,” Mencacci said.
The enzymes involved have been previously implicated in Parkinson’s disease and other neurodegenerative disorders. Understanding how BORCS5 regulates these enzymes could provide new insights into more common conditions.
The findings of the study could also provide answers for parents of children with neurodegenerative disorders.
“Many children with unexplained epileptic encephalopathy or early-onset movement disorders may have BORCS5 mutations, simply because the gene wasn’t on anyone’s radar before this study,” Mencacci said.
Mencacci and his collaborators are now focusing on how BORCS5 controls lysosomal activity at a molecular level.
“It might seem like studying 16 patients with a condition almost no one has heard of is a narrow pursuit,” Mencacci said. “But again and again, deep investigation of rare monogenic disorders has illuminated mechanisms central to more common diseases.”
Dimitri Krainc, MD, PhD, the chair and Aaron Montgomery Ward Professor of Neurology and director of the Feinberg Neuroscience Institute, was senior author of the study.
The study was supported by National Institutes of Health grants 1K08NS131581, R37 NS096241 and R35 NS122257, as well as Parkinson’s Foundation grant PF-SPE-874858.
