Saturday, October 6, 2018

Huntington's disease

Peta Brennan just turned 31 years of age, but she played down her birthday, as usual. It felt too much like part of a countdown.

The dread of another passing year is something Ms Brennan shares with her cousin Katie Young, 30.

Both women are from the NSW Hunter region and both have Huntington's disease.

Their fathers are among a generation of five Brennan men to have the disease.

Three of the brothers including Ms Brennan's father, Mark, are now dead.

The remaining two, including Ms Young's father Stephen, face shortened, diminished lives in aged care.

"There's only two left. They all pass away. Within a year or two we lost all of them around the same time," said Ms Brennan, whose father died at 60…

Dr David Williams, a neurologist at Newcastle's John Hunter Hospital, said the deadly genetic disease caused a person's movements to become "ballistic" and jerky, and took a severe toll on their cognitive ability.

"If I set out to tell a story, there's a trajectory and I might try to land a punchline," Dr Williams said.

"They go on tangents all the time. They have difficulty following a thought."

Perhaps most distressing for carers of people with Huntington's, Dr Williams said, was their loved ones' psychotic disturbance.

Sufferers are often anxious, depressed, easy to anger, prone to misreading social situations and quick to react.

Most die within 20 years of being diagnosed.

It is a cycle familiar to the next generation of Brennans…

If you are born to a parent with Huntington's your chances of acquiring it are 50-50.

That seems a cruel statistic to the Brennans, who count at least 20 of their family members with the illness, and four without.

The family's running joke is "that Brennan luck, again".

"It's supposed to be 50-50, but our family is ridiculous," Ms Young said.

Her sister Emma, about a year younger, has also been diagnosed with Huntington's and is already showing more obvious symptoms.

It means Katie and Emma's mother, Angela Hiscock, has seen her husband Stephen live in a nursing home since the age of 45, and two of her three daughters inherit the illness.

For a short time in his late 50s, Stephen lived in the same home as his brother Mark.

"[Stephen is now] the youngest one [in the nursing home] by far, and it's just sad to see him in there with all these old biddies," Ms Young said.

Ms Brennan said her father was often bad-tempered in the final years of his life…

The decision to have herself tested for Huntington's, Ms Young said, came with a recommended course of counselling sessions.

But being told of her sister Emma's diagnosis, she said, was worse than hearing her own.

Now Katie and Peta watch Emma, knowing her present struggles might await either of them on the other side of the next birthday, or even by Christmas.

"For Emma it's mainly the anger at the moment, clumsiness, not being able to remember anything," Ms Young said.

"One day being so sad you can't get out of bed. Can't even put your makeup on anymore."…

There is no a cure for Huntington's but there is promise, Dr Williams said, in research using antisense therapy — which tackles genetic disorders or infections.

Huntington's is caused by a mutation in a single gene that makes a protein called huntingtin.

A clumping effect and increased 'stickiness' causes the brain cells of Huntington's sufferers to die.

A treatment used in international trials, Dr Williams said, has excited Huntington's sufferers with its potential to stop the mutant protein by silencing the mutated gene.

Clinical trials by British and US researchers in 2014 tested the safety of a drug in people for the first time.

It resulted in decreases in the level of huntingtin in the cerebrospinal fluid of the trial's participants, who were people in the early stages of Huntington's disease.

Those trials did not demonstrate that Huntington's disease could be treated, but the pharmaceutical company Roche of Basel, Switzerland, planned to run expanded trials this year.

The Brennan women know a cure might never arrive, but they are determined to be the last in their family with Huntington's.

Medical science has already allowed Ms Young to have two children and Ms Brennan is expecting her second.

The options of IVF and testing for the disease at 11 weeks in utero mean that someone with Huntington's can be certain their child will not have it.

"A lot of people decide not to have kids, so that was the hardest part of it," Ms Brennan said.


  1. Scientists have for the first time corrected a protein defect that causes Huntington's disease, by injecting a drug into the spine, offering new hope for patients with the devastating genetic disease.

    Lead researcher Sarah Tabrizi, professor of clinical neurology at University College London, said the ability of the drug to tackle the underlying cause of Huntington's by lowering levels of a toxic protein was "ground-breaking".

    "The key now is to move quickly to a larger trial to test whether [it] … slows disease progression," she said in a statement.

    Senior vice-president of research Frank Bennett from Ionis Pharmaceuticals, which developed the drug, said the protein reductions observed in the study "substantially exceeded our expectations" and that the drug was also well tolerated.

    However, some experts cautioned the results were still early and the ability of the new medicine to improve clinical outcomes for patients had yet to be demonstrated.

    "The question is whether this is enough to make a difference to patients and their clinical course, and for that we will have to wait for bigger trials," said Roger Barker of the University of Cambridge, which was also involved in the research.

    The findings of the research have not yet been published in a journal or presented at a conference.

  2. Wild EJ, Tabrizi SJ. Therapies targeting DNA and RNA in Huntington's disease. Lancet Neurol. 2017 Oct;16(10):837-847. doi: 10.1016/S1474-4422(17)30280-6. Epub 2017 Sep 12. Review. Erratum in: Lancet Neurol. 2017 Dec;16(12 ):954.

    No disease-slowing treatment exists for Huntington's disease, but its monogenic inheritance makes it an appealing candidate for the development of therapies targeting processes close to its genetic cause. Huntington's disease is caused by CAG repeat expansions in the HTT gene, which encodes the huntingtin protein; development of therapies to target HTT transcription and the translation of its mRNA is therefore an area of intense investigation. Huntingtin-lowering strategies include antisense oligonucleotides and RNA interference targeting mRNA, and zinc finger transcriptional repressors and CRISPR-Cas9 methods aiming to reduce transcription by targeting DNA. An intrathecally delivered antisense oligonucleotide that aims to lower huntingtin is now well into its first human clinical trial, with other antisense oligonucleotides expected to enter trials in the next 1-2 years and virally delivered RNA interference and zinc finger transcriptional repressors in advanced testing in animal models. Recent advances in the design and delivery of therapies to target HTT RNA and DNA are expected to improve their efficacy, safety, tolerability, and duration of effect in future studies.