Ashkenazim are ten times more likely to have the LRRK2 gene mutation which can result in Parkinson’s. A London-based study is increasing knowledge
May 10, 2018 10:25
ByBen Weich, Ben Weich
Carole Pearl was 55 when she was diagnosed with Parkinson’s 17 years ago. Overcome with dread, the North Londoner’s first thoughts were of her mother, whom she had cared for as the same disease decimated her physical and mental capabilities.
Soon afterwards, Mrs Pearl learned that she had inherited a specific gene mutation, LRRK2 (pronounced “lark two”), from her mother that can lead to the neuro-degenerative disorder.
What she did not realise is that Ashkenazim are around ten times more likely to have LRRK2 than those in the general population.
The family connection was one of the reasons she signed up to a major new study by researchers at University College London (UCL), with the eventual aim of finding a cure for the disease. Led by professors Nick Wood and Huw Morris and funded by the National Institute of Health Research, it is investigating the function of the LRRK2 gene in Parkinson’s.
“I was very upset when I found out [the diagnosis],” Mrs Pearl recalled. “I was particularly upset because I was the one who looked after my mother.
“When I looked after her it was like a punishment. It was really, really hard. She was overdosed on drugs and she began to hallucinate. And she had this fear, this terrible, terrible fear.
“I know we won’t find a cure in my lifetime. But it’s a terrible disease and many people suffer. I thought it [taking part in the study] was the right thing to do.”
In her own case, Mrs Pearl suffered tremors so debilitating that she elected to undergo deep-brain stimulation surgery.
The pioneering procedure, performed with the patient awake, involved stimulating the part of her brain which controls movement. Cruelly, it is also located next to the brain’s language centre, resulting in her being left with a very weak voice.
“The minute they touch the part of the brain that’s affected, your hand stops shaking. It was like a miracle. I was absolutely dumbfounded,” she said.
A decade on from the surgery, she can drive, as well as cycle and walk, albeit carefully, and with the aid of support equipment.
Mutations in the LRRK2 gene are the most common genetic cause of “typical Parkinson’s disease”, according to the Michael J Fox Foundation.
One mutation, G2019S, is particularly frequent in Ashkenazim (about 14 per cent) and North African Berbers (between 30 and 40 per cent) — although these are ever-shifting figures.
Not all LRRK2 carriers develop Parkinson’s symptoms — the figure for Ashkenazi carriers is estimated at between 25 to 35 per cent.
Environmental factors also come into play, the biggest being longevity. But for patients such as Mrs Pearl, there are also family considerations.
Given her own story and her mother’s plight, “it worries me about my children. And not just my children, but I worry about my seven grandchildren, too. But I don’t want them to be tested because I don’t see the point. Why would you want to know? Besides, they could have this LRRK2 mutation and never develop the symptoms.”
The UCL study has already attracted 300 participants from various ethnic backgrounds — 70 were found to have LRRK2.
It is hoped another 150 will sign up and project leaders are keen to involve more Ashkenazim who either have Parkinson’s, or are closely related to someone who does.
The first objective, Prof Wood explained, is to better understand the disease and its triggers. But he also wants to recruit participants for a clinical trial for whenever a pioneering drug is ready.
“They will have been studied, received counselling, had scans, and they’ll be ready to go. That’s the real value in this. Think of true disease-modifying and, hopefully in time, curative treatments. That’s the ultimate goal.
“Rather than relying on serendipity, we want to actually design therapies.”
Denali Therapeutics, a San Francisco pharmaceutical company, announced in December that two distinct small molecules targeting LRRK2 inhibition have passed pre-clinical trials. They are currently are being tested on healthy volunteers.
Other companies including Genentech, Merck, Pfizer and GlaxoSmithKline are also working to develop safe LRRK2 inhibitors.
Dr Mie Rizig, one of the study’s clinical research fellows, added that it was equally important to appreciate why the LRRK2 mutation often does not lead to Parkinson’s.
“Understanding what protects them will hopefully answer a lot of questions,” she said. “Understanding these differences is crucial to identify protective factors which could be used to prevent or modify the course of the disease in affected individuals.
“This is why it is crucial for relatives of Parkinson’s patients to take part in research, even if they do not have any symptoms themselves.”
Dr Rizig and Prof Wood stressed that participants can opt not to be told whether they carry the LRRK2 mutation. If they do want to know, there is a three-month “cooling off period” between their agreeing to the test and taking it. A full complement of genetic counselling services is also available.
Another volunteer, who preferred to remain anonymous, explained that it took “months and years” to become comfortable with the idea of finding out whether she was a carrier of the mutation.
The volunteer, a 71-year-old North London woman, said: “As the months and years have gone on, I suppose I am more concerned about it. But then it’s an age-related thing. So the longer I live, the more likely I am to get the symptoms.
“Most of the time I don’t think about it but there are times when I do. But I don’t dwell on it.”
Parkinson’s, described by Prof Wood as a “numerically important disease”, will only become more prevalent as people live longer.
Its treatment has not progressed dramatically since the 1960s.
“If we could move that bar along a few years so you lived better for longer, you’d have a huge impact on patients’ quality of life — and that of their carers,” Prof Wood concluded.
“It becomes a burden to their carers. Even modest gains could have a huge impact on the prevalence, and the impact on society.
“To do nothing is not really an option.”
For more information email mie.rizig@nhs.net
