A brain disorder once thought to be fairly rare may in fact be more common than was previously thought, a new study into the disorder’s genetic basis by a global team of neuroscientists led by researchers at Mayo Clinic in Florida have found.
HDLS, or hereditary diffuse leukoencephalopathy with spheroids, is a devastating brain disorder that impacts the brain’s white matter and leads to early death, usually between 40 and 50 years of age. Until now the disorder’s prevalence has been thought to be relatively limited.
However new research published in the Dec. 25 online issue of Nature Genetics, tells how researchers have identified 14 different mutations of the gene CSF1R that leads to the development of HDLS. The study’s senior investigator, neurologist Zbigniew Wszolek, M.D., also found that a significant number of people who had these mutations of the gene have not been diagnosed with HDLS but rather misdiagnosed with a wide range of other conditions.
“Because the symptoms of HDLS vary so widely — everything from behavior and personality changes to seizures and movement problems — these patients were misdiagnosed as having either schizophrenia, epilepsy, frontotemporal dementia, Parkinson’s disease, multiple sclerosis, stroke, or other disorders,” says Dr. Wszolek. “Many of these patients were therefore treated with drugs that offered only toxic side effects.
In this study, which included 38 researchers from 12 institutions in five countries, the study’s first author, Rosa Rademakers, Ph.D., led the effort to find the gene responsible for HDLS. Her laboratory studied DNA samples from 14 families in which at least one member was diagnosed with HDLS and compared these with samples from more than 2,000 disease-free participants. The gene was ultimately found using a combination of traditional genetic linkage studies and recently developed state-of-the art sequencing methods. Most family members studied — who were found to have HDLS gene mutations — were not diagnosed with the disease, but with something else, thus emphasizing the notion that HDLS is an underdiagnosed disorder.
The CSF1R protein is an important receptor in the brain that is primarily present in microglia, the immune cells of the brain. “We identified a different CSF1R mutation in every HDLS family that we studied,” says Dr. Rademakers. “All mutations are located in the kinase domain of CSF1R, which is critical for its activity, suggesting that these mutations may lead to deficient microglia activity. How this leads to white matter pathology in HDLS patients is not yet understood, but we now have an important lead to study.”
“With no other disease have we found so many affected families so quickly,” says Dr. Wszolek. “That tells me this disease is not rare, but quite common.”
Researchers hope that, in order to guard against misdiagnosis, they will soon be able to offer a blood test to detect HDLS, however there is as yet no cure for HDLS.