Dr Shamima Rahman is pioneering a new means of diagnosis that is opening up astonishing prospects in understanding a devastating hereditary condition. Andrew Gimson finds out how the Masonic Samaritan Fund became involved
Aged just thirty-nine, Jason Brincle fell ill in March 2010. ‘He’d been perfectly healthy up to that point. He lived with his partner, and apparently had an epileptic fit in the middle of the night. It initially looked like a stroke. His speech and mobility were affected: the usual signs for a stroke,’ recalls his father Geoff. ‘A month after that, some tests gave us the devastating news that he had MELAS syndrome, which is one of the most severe variants of mitochondrial disease. You can imagine how difficult it is when you’re told there is no treatment and no cure.’
The mitochondrion is the part of a cell that converts food into energy. Its failure is like a power cut, with devastating effects for organs that need large supplies of energy, such as the brain, eyes, ears, kidneys, liver, heart and other muscles. The disease is hereditary.
Jason recovered enough to return to work as a manager with a charity in October of that year, but had a second attack in November. ‘The final blow was in early 2011: a particularly bad attack that took his sight. Obviously I was visiting every day,’ says Geoff. ‘He was in Salford Royal Hospital, about ten miles away. His sight came back to a degree, but was replaced by hallucinations and nightmares to the point where he had to be sectioned at one time.’
In April, Jason died. ‘As a parent, you feel guilty: could I have done more? This mitochondrial disease, we’d never heard of it. It’s horrendous. It’s so cruel. It affects about one in six thousand five hundred people. When we knew Jason had MELAS, it was obvious his mother had died from it twelve years before. On her death certificate it said “stroke”. She suffered for eight years – she couldn’t walk, talk, eat or hear.’
A life ebbing away
Like most people with first-hand experience of the disease, Geoff is a strong supporter of research: ‘When nature goes wrong, science has to correct it.’
Rachel Kean, who is twenty-four, has been diagnosed with MELAS, but has few symptoms. She inherited the disease from her mother, who has no symptoms. But her mother’s sister suffered and died from the condition, with ‘truly brutal’ effects including heart and kidney failure, severe hearing impairment and ‘very many miscarriages’. She too is an ardent supporter of research and says that UK charity the Muscular Dystrophy Campaign ‘are incredibly supportive of patients – truly wonderful’.
Val Wintle, who is fifty-three, began noticing the symptoms of mitochondrial disease when she was thirty-two and was diagnosed at the age of thirty-six. It affects her mobility and her eyesight, and she feels constantly tired: ‘I would say I haven’t got a life. I can’t travel – I’d get too tired. I don’t really feel that I’m part of this world. I had plans and hopes and aspirations. My husband took early retirement to look after me. I wouldn’t be able to cope on my own. I’ve just seen g my life ebb away from me, if you see what I mean. Slowly it gets worse and worse and worse.’
John McCrohan is Grants Director of the Masonic Samaritan Fund (MSF), which has given £30,000 to the Muscular Dystrophy Campaign to help fund research by Dr Shamima Rahman of University College London (UCL). For the past twenty-two years, the MSF has helped individuals with the cost of their medical treatment, but three years ago it decided to also support research into the conditions from which they suffer.
‘We have seen families struggling with the effects of muscular dystrophy and related neuromuscular conditions [such as mitochondrial disease], so we wanted to see if there was any good research out there. When Dr Rahman’s application came through, the research committee was very keen. Dr Rahman is herself a very talented researcher and is supported by a network at University College Hospital,’ says McCrohan.
‘We have seen families struggling with… muscular dystrophy and related neuromuscular conditions [such as mitochondrial disease], so we wanted to see if there was any good research out there.’ John McCrohan
‘Next generation’ technology
Dr Rahman is grateful for the support and hopes it will be possible to form a long-term relationship with the MSF. ‘This is an orphan group of disorders,’ she says. ‘It’s very difficult to get funding for rare diseases. These are devastating diseases, almost invariably life-threatening, very difficult to diagnose, and very, very difficult to treat.’
About one in five thousand babies is affected by mitochondrial disease. But the condition presents itself in many different ways, and has most often gone undiagnosed. ‘Next generation’ gene sequencing technology is changing that. It can identify the many different nuclear gene defects that underlie mitochondrial disease in childhood. But it is a very complex technology, requiring advanced computing, so Dr Rahman and her team have outsourced the actual sequence alignment to computer experts at UCL with whom they have a very close relationship.
In Dr Rahman’s experience, a different gene is responsible for mitochondrial disease in each family that she sees. It is likely that more than a thousand different genes cause the disease, so finding the exact causative gene in any family is akin to searching for a needle in a haystack. The ‘next generation’ sequencing, which g sequences all twenty thousand genes simultaneously in an individual, typically shows an average of twenty thousand changes in each person, and the real challenge is to determine which two of these changes are causing the disease in that person.
Having once been able to diagnose five per cent of cases of mitochondrial disease in babies and young children, Dr Rahman and her team can now detect fifty per cent. Because generating energy is so important, at least seven per cent of genetic function is devoted to supporting our mitochondrial function. She does not expect to be able to trace the myriad forms of mitochondrial disease back to only a few underlying causes, predicting that eventually more than a thousand genes will be linked to mitochondrial disease.
Timing is everything
After reading medicine at Oxford, Dr Rahman soon discovered the subject that has dominated her work: ‘My interest in mitochondrial disorders was kindled just over twenty years ago when I first joined the metabolic team at Great Ormond Street Hospital. The challenges both then and now are to provide accurate and prompt diagnoses, and to develop effective treatments.’
The past few years have witnessed great advances in genetic diagnosis for mitochondrial diseases, with the discovery of more than one hundred disease genes. ‘But it is likely that several hundred more genes will be linked to mitochondrial disease in the future,’ says Dr Rahman. ‘Our long-term goal is to translate this genetic knowledge into curative treatments for children with these challenging diseases.’
In one astonishing recent case, the detection by Dr Rahman and her colleagues of the rare mitochondrial disorder from which a fifteen-year-old girl was suffering enabled the patient to be treated with the B vitamins biotin and thiamine, with an immediate and dramatic improvement in symptoms. This early treatment was essential to avert permanent brain damage or death.
‘The challenges [of mitochondrial disorders] are to provide accurate and prompt diagnoses, and to develop effective treatments.’ Dr Shamima Rahman
The patient is currently doing well at school.
The more one learns about mitochondrial disease, the more worthwhile Dr Rahman’s research appears, and the more deserving of long-term support.
About the Muscular Dystrophy Campaign
The Muscular Dystrophy Campaign has pioneered the search for treatments and cures for fifty years, and is dedicated to improving the lives of children and adults affected by muscle-wasting conditions. Statutory income accounts for just five per cent of the charity’s funds, so its work relies on voluntary donations from individuals, groups and grant-making bodies. To find out more, visit www.muscular-dystrophy.org