International team identifies new neurodegenerative disease
Dr. Sami Harik
“The more we learn, the more we realize how little we know.” — R. Buckminster Fuller
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Susan J. Hayflick, MD, chair of the Department of Molecular and Medical Genetics at Oregon Health & Science University, has focused much of her career on iron deposition in the brain. She spearheaded the BPAN research and was lead author on a scholarly paper that appeared in the Dec. 7, 2012 edition (vol. 91, issue 6, pp. 1144-1149) of the American Journal of Human Genetics. Sami I. Harik, MD, who recently retired from the University of Arkansas for Medical Sciences, was a contributing author on “Exome Sequencing Reveals De Novo WDR45 Mutations Causing a Phenotypically Distinct, X-Linked Dominant Form of NBIA.” www.sciencedirect.com/science/article/pii/S0002929712005782
While that particular version of the quote is attributed to American architect, systems engineer and poet Bucky Fuller, the sentiment behind it is one that has been expressed by men and women of discovery for centuries. Certainly that holds true for an international team that has identified a new neurodegenerative disease associated with iron accumulation in the basal ganglia located deep in the brain’s cerebral hemispheres.
“We are just scratching the surface here … we have a new disease,” said Sami I. Harik, MD, who was one of the researchers involved in identifying BPAN (beta-propeller protein associated neurodegeneration).
Neurodegeneration with brain iron accumulation (NBIA) has been recognized since the 1920s. Originally called Hallervorden-Spatz disease, it was later tied to a gene mutation affecting the protein pantothenate kinase 2 (PANK2). Other mutated genes were subsequently identified, most notably C19orf12 and PLA2G6. The common tie among the three is the accumulation of iron in the brain, hence NBIA, which results in developmental delays and neurological deterioration in movement and cognitive functions.
Now a newly-discovered mutation in the WDR45 gene, located on the X chromosome, has been identified as a distinct entity of NBIA. Harik, who served as chairman of the Department of Neurology at the University of Arkansas for Medical Sciences from 1994-2010 and continued on as a professor until his retirement at the end of 2012, said the discovery came from studying MRI scans of patients, particularly pediatric patients, who were not achieving normal developmental milestones.
“Iron happens to give a characteristic appearance to the head MR,” explained Harik. “You look and you see dark areas in the basal ganglia.” With PKAN (pantothenate kinase-associated degeneration), he continued, “You get the so-called ‘eye of the tiger’ sign on the MRI … the dark area and in the center there’s a white area that is compatible with tissue necrosis.” In other entities of NBIA, he noted, “There is tissue iron accumulation but without necrosis.”
Harik and other physician-scientists in Europe and America who were studying NBIA under the leadership of Susan J. Hayflick, MD, chair of the Department of Molecular and Medical Genetics at Oregon Health & Science University, would send blood samples from patients with NBIA to Hayflick. She performed genetic and other biochemical studies on the samples and found a considerable fraction … 30 to 40 patients … did not fit the known diagnostic gene abnormalities.
“In collaboration with the Institute of Human Genetics at the University of Munich in Germany, who performed exome sequencing on samples from these patients, in 20 of them, they described a definite gene mutation in the WDR45 gene located on the X chromosome,” said Harik.
Interestingly, of the 20 patients, 18 were women and two were men. Harik said there are various explanations as to why there is a female predominance in this form of NBIA. One reason might be that more pregnancies carrying a male fetus with the XY chromosome spontaneously abort if the WDR45 gene is defective. In the XX female fetus, it’s possible the healthy X chromosome provides some protection against fetal loss.
In those born with BPAN, Harik explained, “This gene that is defective — WDR45 — encodes for the beta propeller protein.” However, he continued, at this time researchers do not know of a link between this protein deficiency and brain iron accumulation. “So there’s a lot we don’t know,” he said. What is known so far is that the mutation doesn’t seem to be hereditary. Blood studies were run on siblings and parents without finding evidence of WDR45 gene mutations.
Those who present with BPAN have a number of neurological symptoms, often from very early childhood. “Many believe this abnormality has a high penetrance, which means it is unlikely it will go unnoticed by an astute clinician,” Harik said. However, he noted, there may be a major selection bias in those identified with BPAN by the researchers. All of them exhibited clear signs of developmental delay in childhood, with progression in adulthood with parkinsonism, dystonia and dementia.
“These patients have hallmarks of neurodegeneration,” said Harik. “They don’t attain developmental milestones.” He added, “Some of them did relatively well until they were older and then because the basal ganglia is involved, they had basal ganglia dysfunction which manifests as a movement disorder.”
What isn’t known is whether or not there might be those with a mutated WDR45 gene who have a milder form of the disease or even no visible symptoms. “The next step is to catalogue the clinical manifestations of the disease. There seems to be considerable variations amongst patients.” Particularly with women who have two X chromosomes, he continued, “There is a process in the body where one X chromosome is activated and the other is suppressed. There may be variations in how much the diseased X is expressed.”
Ultimately, of course, researchers will hope to one day understand the mutation and find a way to reverse its effects. Echoing Fuller, Harik concluded, “There’s a lot of work to be done. Every time you discover a new thing, you discover just how much you didn’t know.”