Rare Disease Day warrants a closer look at neglected neurological disorders

Neurodegenerative disorders

By Mardi Chapman

1 Mar 2021

Associate Professor Bradley Turner

Rare disease or neglected disease? To recognise Rare Disease Day (Sunday, 28 February), the limbic spoke to Associate Professor Bradley Turner about the polyglutamine disorder Kennedy’s disease and the local research that hopes to make a difference.

Associate Professor Bradley Turner, head of the Motor Neurone Disease laboratory at the Florey Institute, described a fascinating but largely unknown disease which is difficult to classify, often associated with diagnostic delay, and has no effective treatment or cure.

However the opportunities are there for Kennedy’s disease or spinal bulbar muscular atrophy (SBMA) given another related disease, SMA in children, has had three FDA approved drugs in the last five years.

Associate Professor Turner said one of the fascinating aspects to the X-linked disease, which typically presents in men in their 30s-50s, is that it has both central and peripheral symptoms which span neurologic and endocrine disease.

“So it’s quite an unusual clinical entity. It affects the motor neurones in the brain stem and in the spinal cord and those motor neurones start to degenerate and die. Patients end up with a very slowly progressive muscle weakness, powerful muscle cramps, fatigue, muscle twitching and wasting. So most of these men use a cane or end up in a wheelchair or a scooter.”

“The other disabling aspects of the disease are the peripheral symptoms. The defective gene is an androgen receptor and that’s the gene you need to signal testosterone. These men end up with gynecomastia, fertility problems, testicular atrophy, impotence, reduced libido, and it’s all because of the gene.”

Associate Professor Turner said the defect is both a loss of function in the gene affecting secondary sex characteristics and a toxic overfunction in the CNS.

“The disease itself isn’t as fatal as MND. MND will kill you in 27 months from diagnosis on average. This disease is almost the opposite – it is slowly progressive, disabling and it will run over decades of your life.”

He estimates it probably affects a couple of hundred Australian men and there is push to work up a clinical registry.

Meanwhile, his preclinical research has taken the approach of working on a genetic treatment.

“We can try to do exactly what they did in SMA. We can correct the defective gene and my group at the Florey is working on a gene therapy approach that is completely new using synthetic DNA molecules injected into the body to suppress or turn off or disable the KD gene.”

The work involves using patient stem cells to create ‘Kennedy’s disease in a dish’ and then test in a mouse model.

“Gene correction therapy for SMA in children means hope for gene correction in adults. It should be feasible,” he said.

“There are therapeutic opportunities out there. There is a small drug development pipeline that is starting to emerge and patients want access to that pipeline.”

Associate Professor Turner said there was a case for better awareness and education about the disease.

He said it was unlikely that GPs and most neurologists – except movement specialists – would have come across it. As a consequence, it was often misdiagnosed for months or years as peripheral neuropathy, inflammatory conditions or MND.

He said a lot of patients feel despair and hopelessness because their disease doesn’t have an identity.

“The patients that I talk to feel like outliers. I thought MND was rare but at any one time you might find 100 drugs in the clinical trial pipeline. With Kennedy’s disease there is one or two.”

“Patients feel left out and we are trying to make a difference. To me they are not rare diseases, they are just neglected diseases.”

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