Breakthrough shines light on a rare brain disease

A new study has “flipped the narrative” on a rare brain disease, says Dr Malvindar Singh-Bains.

Lead author of a recently published paper Dr Adelie Tan and senior author Singh-Bains spent four years carrying out the largest-ever study of brain tissue from people with X-linked Dystonia Parkinsonism (XDP).

The scientists from the University of Auckland Centre for Brain Research examined donated brain tissue from 18 men who died with the disease and 10 healthy people.

XDP is a severe movement disorder caused by a mutation of the TAF1 gene.

It typically affects men of Filipino descent, often striking when they are in their twenties or thirties, says Singh-Bains.

XDP symptoms are a mixture of parkinsonian symptoms and dystonia. The parkinsonian symptoms include tremors, unusually slow movement, rigidity, inability to hold the body upright, and a shuffling gait that can lead to frequent falls.

In many patients, the more concerning symptoms are dystonia, characterised by involuntary muscle spasms that often begin in the eyes, jaw, or neck, before spreading to other parts of the body.

The degenerative brain disease can cause difficulty with speaking, swallowing and coordination, and leaves many unable to walk.

The study is groundbreaking in providing the first clear evidence of a signature of XDP in the brain, offering insights that will be vital for developing treatments in the future, says Singh-Bains.

Traditionally, XDP was thought to be largely driven by degeneration of the striosomes, which are clusters of neurons in a brain region called the striatum. Striosomes govern the interface between emotions and physical actions.

The Auckland team discovered the disease affects the matrix of the striatum far more than was previously thought.

The matrix makes up more than 80 percent of the striatum. It surrounds an anthill-like maze of tunnels containing striosomes.

“The matrix regulates movement, so our findings make sense of the movement symptoms of XDP,” says Singh-Bains.

The team also discovered distinct brain-chemical patterns in people who died at a young age from the disease, compared with those who had XDP for decades before their death.

“This is the first study that gives a detailed view of what happens as patients live longer with the disease – no one else in the world has done that.

“Different treatments might be needed at the start of the disease than in the late stages.”

While XDP is a unique disease, aspects resemble Huntington’s, Parkinson’s and motor neuron diseases, says Singh-Bains.

“That means research on XDP helps shine a light on all these disorders.”

The discovery of a clear signature in the XDP brain will aid scientists trying to replicate the disease in lab-grown brain cells and animal models.

The Auckland team’s ultimate goal is to establish a foundation of anatomical knowledge that might one day help scientists develop drugs that can relieve the symptoms of XDP, prevent its onset, or delay its impacts, says Singh-Bains.

Existing treatments have limited success for some patients, but don’t help others, she says.

About eight years ago, Singh-Bains, Distinguished Professor Sir Richard Faull, and Associate Professor Henry Waldvogel from the Centre for Brain Research and colleagues at Massachusetts General Hospital helped set up the XDP Brain Bank in the Philippines, which provided tissue for the study. The Neurological Foundation Human Brain Bank at the University of Auckland provided healthy brain tissue for comparison.

While sharing her knowledge in the Philippines, Singh-Bains witnessed the devastating impacts of XDP.

The island of Panay in the Philippines has a population of approximately 4.5 million and about six out of every 100,000 people there suffer from XDP.

Mothers who carry the gene that causes the disease have no symptoms, but many carry a burden of blame and guilt for passing the gene to their sons, she says.

The livelihoods of many families are shattered when young men are struck down by XDP and can no longer work and provide for their partners, children and older generations, says Singh-Bains.

“My main motivation is the families who have to watch their loved one’s health decline and can’t do anything about it.

“I went through a similar journey when my mum was diagnosed with cancer and I was helpless to stop it.

“The people struggling with XDP look to us for answers and we want to be able to give them some,” she says.