Atypical Brain Disorder: Much More Common Than Supposed

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Currently, different brain diseases are burdening our society. More than the danger they bring to the life of the patient, they also precipitate emotional and financial loads. Researchers have conducted several studies about other brain diseases, which can help shed light and pave the way to treatment development. The scientists from Mayo, led a global group of neuroscientists, in a pivotal study about a brain disorder which may be more common than it was once thought to be.

The researchers articulated that 14 different mutations were found in the gene CSF1R, which can result to the development of hereditary diffuse leukoencephalopathy with spheroids (HDLS).  This can be found in the Dec. 25th online issue of Nature Genetics. Moreover, HDLS is a distressing pathology involving the brain’s white matter which can result to death of people aging 40-60. This gene can be inherited which can predispose the person to HDLS. A brain examination through a biopsy or autopsy was a must for an exact diagnosis of HDLS, until now.

This finding is essential since it is suspected that HDLS is more usual than once believed; moreover, there is already a possibility of a genetic diagnosis even without a brain biopsy or autopsy. Zbigniew K. Wszolk, MD, the study’s senior researcher, said that a notable number of people who were screened positive for the abnormal gene in this investigation were diagnosed with a broad scale of other conditions. Since these people were connected to patients with HDLS, their genes were also tested.

According to Dr. Wszolek, the patients were misdiagnosed to have schizophrenia, epilepsy, multiple sclerosis, stroke, Parkinson’s disease, frontotemporal dementia or other diseases because the manifestations of HDLS are diverse (all from behavior and personality changes to movement problems to seizures). He elaborated that with this finding, there may be a blood test soon that can aid the physicians in diagnosing HDLS. They could find further if this exists in more people than anyone once thought.

Dr. Wszolek is famous globally for his efforts in gathering researchers across the globe to assist in case-finding for hereditary brain disorders and find out their genetic origins. A seriously disabled woman approached him in 2003 and told him that her other family members were affected. It was then that he gained interest in HDLS. Furthermore, Dr. Dennis W. Dickson, a Mayo Clinic colleague, diagnosed HDLS by studying the autopsy results of the patient’s uncle (once diagnosed to have multiple sclerosis). HDLS was found in all the members of the family.

Dr. Dickson found other cases of HDLS from Florida, New York, Oregon and Kansas in the Mayo Clinic Florida brain bank. Dr. Wszolek and those from University of Virginia also obtained DNA sample from the Virginia kindred, through concentrated efforts. Additionally, Dr. Wszolek obtained samples from Norway, UK, Germany, Canada and other parts of US and examined other neuropathology literature. Studies about the clinical, pathologic and imaging features of this brain disorder were published by their team, and they initiated 5 HDLS international meetings.

In this research performed by 38 researchers from 12 institutions in 5 countries, Rosa Rademakers, Ph.D. was the leader in finding the gene linked to HDLS. They examined the DNA samples from 14 families, wherein at least 1 member was HDLS-diagnosed. Then, they made a comparison of these sample from more than 2, 000 healthy participants. The gene was detected utilizing traditional genetic linkage studies and modern, reliable sequencing methodologies. Many family members examined (tested positive for HDLS gene mutations) had not been diagnosed with the disorder, but with another pathology that clearly shows that HDLS may truly be an underdiagnosed disease.

Furthermore, the CSF1R protein is an essential brain receptor that is mainly found in microglia (brain immune cells). Dr. Rademakers explained that they recognized a different CSF1R mutation in each HDLS family they examined. All mutations are found in the kinase domain of CSF1R (crucial for its activity), that implies that the mutations may result to deficient microglia activity. An imperative foundation of the study has already been revealed although the process of involving the white matter pathology in HDLS patients is still unclear.

Dr. Wszolek said that this disorder may truly be quite usual, not atypical. He further added that it is remarkable that you can begin the study with just one case and end up in this breakthrough—discovering this gene—with the contribution of many. This research was funded by a Mayo benefactor and Mayo Foundation.




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