National study seeks patients with ATP1A3 mutations to better understand these disorders and discover potential treatments

BUFFALO, N.Y. – Imagine waking up one day and finding that you are suddenly having difficulty swallowing, walking and talking. You start experiencing involuntary muscle contractions called dystonias. Then imagine that these symptoms do not go away.

That dramatic and often devastating experience is among the many ways that a group of disorders caused by a mutation in the ATP1A3 gene can affect patients. Originally called rapid onset dystonia Parkinsonism, they are now usually referred to as the ATP1A3 disorders, a reference to the mutated gene that causes them. Parkinsonism is an umbrella term that refers to brain disorders causing slowed movements, stiffness, rigidity and tremors.

These rare disorders, which may run in families, are the subject of a five-year, $3.3  million National Institutes of Health-funded clinical study on the Clinical Genetic and Cellular Consequences of Mutations in ATP1A3. More information is in this video.

The multidisciplinary, multi-institutional team is led by Allison Brashear, MD, vice president for health sciences at the University at Buffalo, dean of the Jacobs School of Medicine and Biomedical Sciences at UB and professor in the Department of Neurology. Brashear brought the grant with her in 2021 after moving across the country from the University of California, Davis to take the position at UB.

“We are actively recruiting patients with ATP1A3 disorders for our study,” says Brashear. “The goal is to generate a comprehensive natural history of the symptoms and progression of ATP1A3 disorders, which put such a heavy and sudden burden on patients. The immediate hope is to expand what we know about these disorders to begin working toward new treatments and ultimately improving the quality of patients’ lives.”

More information on the study and how to enroll is available at this web site.

The research is focused on what the ATP1A3 gene does and how and why this mutation causes these disorders.

“We will try to determine what does this gene do and why does it bring on these symptoms so quickly,” says Brashear. She adds that onset typically follows a trigger, such as fever, an infection, psychological stress, childbirth, an alcoholic binge or an intense physical workout, among others. While treatments can be prescribed to control seizures and dystonias, avoiding those triggers — difficult at best — is currently the most effective approach for many patients.

The research is also expected to result in new knowledge about other, more common brain diseases and how the brain functions in general.

“What do the variants that cause these disorders tell us about how the brain works and the pathways in the brain that are impacted by these mutations?” says Brashear. “If we have a better understanding of this rare disease, then we might be able to better understand more common diseases.”

She notes that this is the foundation on which NIH support for studying rare diseases is based.

“These patients have such a range of symptoms. They can have seizures, psychiatric and cognitive symptoms or dystonias or a combination,” she says. “They overlap with many other neurologic syndromes including autism, dystonia, Parkinsonism, epilepsy and psychiatric disease. We anticipate that the results of our work will also point to how this genetic dysfunction may contribute to these more common diseases, as well.”

Brashear describes one focus of the research as a “gene-first search for variants, phenotypes and risk factors in databases linked to clinical data” in order to accelerate discovery of new phenotypes.

The three most prevalent ATP1A3-related neurologic disorders that have been identified so far include:                

• Rapid-onset dystonia-parkinsonism (RDP), characterized by the abrupt onset of Parkinsonism and dystonia, which makes muscles contract involuntarily and can cause repetitive or twisting movements.
• Alternating hemiplegia of childhood (ACH), which affects infants and children, and is characterized by recurrent episodes of paralysis; symptoms disappear during sleep and return upon waking. Many affected children display some degree of developmental delay.
• Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS), which affects children up to age 4, and is characterized by episodes of ataxic encephalopathy where inflammation of the brain typically triggered by fever leads to ataxia, clumsiness and inability to control movement. These episodes often do resolve but can recur.

“I am confident that these disorders are underdiagnosed,” says Brashear, noting that many of these patients struggle for years with their symptoms before getting the correct diagnosis. In the 1960s, some of them were misdiagnosed as schizophrenic.

The goal of the study is to identify patients with these disorders throughout the United States, to learn how the disease affects them both clinically and genetically, and to use that knowledge to discover new or existing medications that could treat these disorders.

Patients who enroll will undergo extensive neurological and psychological assessment, and detailed medical histories will be taken, all done by telemedicine. Blood samples will also be collected so that more can be learned about the genetics and biochemistry of these disorders.

Brashear was part of the collaborative effort that identified the first family with these symptoms in 1991 when she was a neurology resident at Indiana University, where she would soon become a faculty member. After publishing about the family in 1993, Brashear and her co-authors began to hear from other neurologists in the U.S. and around the world who said they had patients with similar symptoms.

“We learned that there was a family in Poland. A few years later we found out about a family in Ireland, and then we found a family in Ohio,” says Brashear.

She began flying around the country to examine patients who had been identified with this disorder. She collected samples of their blood and spinal fluid, and sent them to Laurie Ozelius, PhD, then a fellow at Massachusetts General and now associate neuroscientist there and an associate professor of neurology at Harvard Medical School. Brashear and Ozelius have been working together ever since.

Ozelius used those samples to identify variants in the ATP1A3 gene. Then, Kathy Sweadner, PhD, also at Mass General at the time and an expert on the protein structure of this gene, helped show that this was, in fact, the disease-causing gene.

The team published the finding in 2004.  

“By 2008, we were funded by the National Institute of Neurological Disorders and Stroke to study this disease to find out what it looks like. We have been continuously funded ever since,” says Brashear. “We are investigating how this mutation impacts the brain. What does it tell us about more common brain diseases like Parkinson’s and cognitive problems?”

Since the transfer of Brashear’s grant to UB last summer, the research team has grown to include Daniel Sirica, MD, clinical assistant professor, and Ralph Benedict, PhD, professor, both of the Department of Neurology and UBMD Neurology; they will conduct the telemedicine interviews with patients. Kris Tjaden, PhD, professor in the Department of Communicative Disorders and Sciences in the College of Arts and Sciences, is also on the team; she will conduct voice and speech analysis of patients with communication disorders.

Brashear says UB has been a rich and welcoming environment for her research. She notes UB’s strong legacy in both the study of rare diseases and in neurological and neurosurgical research in general. (UB is hosting a virtual event marking Rare Disease Day on Feb. 28.)

“Between Larry Jacobs’ groundbreaking discovery about interferon that forever changed how MS was treated and our strengths in neurological, neurosurgical and neuroendovascular disease, including at the Gates Vascular Institute, UB’s academic health center is home to a well-recognized talent pool in neuroscience and related fields,” she says. “And it’s a pool we are eager to expand.”

With continuous funding by NIH since 2008 — the most recent renewal was awarded in 2021 — her commitment to the patients and families she has worked with has remained a constant throughout her career. As she moved among institutions to take positions with ever-increasing levels of administrative responsibility, she also continued to pursue this research.

When asked what motivates her to continue her research even as she has moved into leadership positions, she says, “Research allows you to bring creativity and innovation to the bedside.”

Initially funded while chair of the Department of Neurology at Wake Forest University, Brashear took her grant with her to the University of California, Davis in 2019 when she became dean of its School of Medicine, where her grant was renewed. She transferred the grant to UB when she became vice president for health sciences and dean of the Jacobs School in November 2021.

Brashear continues to partner on this work with her longtime collaborators: Beverly M. Snively, PhD, Wake Forest University School of Medicine; Ihtsham ul Haq, MD, University of Miami Miller School of Medicine; Laurie Jean Ozelius, PhD, Harvard Medical School; Kathleen J. Sweadner, PhD, Harvard Medical School; and Vicki L. Wheelock, MD, UC Davis.  

She also acknowledges the strong support of her mentors along the way, especially William B. Dobyns, MD.