̽��ֱ�� of Cambridge - MRC Mitochondrial Biology Unit

Throwing a ‘spanner in the works’ of our cells’ machinery could help fight cancer, fatty liver disease… and hair loss

cjb250 — Fri, 18 Apr 2025 18:00:53 +0000

Scientists at the Medical Research Council (MRC) Mitochondrial Biology Unit, ̽��ֱ�� of Cambridge, have worked out the structure of this machine and shown how it operates like the lock on a canal to transport pyruvate – a molecule generated in the body from the breakdown of sugars – into our mitochondria.

Known as the mitochondrial pyruvate carrier, this molecular machine was first proposed to exist in 1971, but it has taken until now for scientists to visualise its structure at the atomic scale using cryo-electron microscopy, a technique used to magnify an image of an object to around 165,000 times its real size. Details are published today in Science Advances.

Dr Sotiria Tavoulari, a Senior Research Associate from the ̽��ֱ�� of Cambridge, who first determined the composition of this molecular machine, said: “Sugars in our diet provide energy for our bodies to function. When they are broken down inside our cells they produce pyruvate, but to get the most out of this molecule it needs to be transferred inside the cell’s powerhouses, the mitochondria. There, it helps increase 15-fold the energy produced in the form of the cellular fuel ATP.”

Maximilian Sichrovsky, a PhD student at Hughes Hall and joint first author of the study, said: “Getting pyruvate into our mitochondria sounds straightforward, but until now we haven’t been able to understand the mechanism of how this process occurs. Using state-of-the-art cryo-electron microscopy, we’ve been able to show not only what this transporter looks like, but exactly how it works. It’s an extremely important process, and understanding it could lead to new treatments for a range of different conditions.”

Mitochondria are surrounded by two membranes. ̽��ֱ��outer one is porous, and pyruvate can easily pass through, but the inner membrane is impermeable to pyruvate. To transport pyruvate into the mitochondrion, first an outer ‘gate’ of the carrier opens, allowing pyruvate to enter the carrier. This gate then closes, and the inner gate opens, allowing the molecule to pass through into the mitochondrion.

“It works like the locks on a canal but on the molecular scale,” said Professor Edmund Kunji from the MRC Mitochondrial Biology Unit, and a Fellow at Trinity Hall, Cambridge. “There, a gate opens at one end, allowing the boat to enter. It then closes and the gate at the opposite end opens to allow the boat smooth transit through.”

Because of its central role in controlling the way mitochondria operate to produce energy, this carrier is now recognised as a promising drug target for a range of conditions, including diabetes, fatty liver disease, Parkinson’s disease, specific cancers, and even hair loss.

Pyruvate is not the only energy source available to us. Our cells can also take their energy from fats stored in the body or from amino acids in proteins. Blocking the pyruvate carrier would force the body to look elsewhere for its fuel – creating opportunities to treat a number of diseases. In fatty liver disease, for example, blocking access to pyruvate entry into mitochondria could encourage the body to use potentially dangerous fat that has been stored in liver cells.

Likewise, there are certain tumour cells that rely on pyruvate metabolism, such as in some types of prostate cancer. These cancers tend to be very ‘hungry’, producing excess pyruvate transport carriers to ensure they can feed more. Blocking the carrier could then starve these cancer cells of the energy they need to survive, killing them.

Previous studies have also suggested that inhibiting the mitochondrial pyruvate carrier may reverse hair loss. Activation of human follicle cells, which are responsible for hair growth, relies on metabolism and, in particular, the generation of lactate. When the mitochondrial pyruvate carrier is blocked from entering the mitochondria in these cells, it is instead converted to lactate.

Professor Kunji said: “Drugs inhibiting the function of the carrier can remodel how mitochondria work, which can be beneficial in certain conditions. Electron microscopy allows us to visualise exactly how these drugs bind inside the carrier to jam it – a spanner in the works, you could say. This creates new opportunities for structure-based drug design in order to develop better, more targeted drugs. This will be a real game changer.”

̽��ֱ��research was supported by the Medical Research Council and was a collaboration with the groups of Professors Vanessa Leone at the Medical College of Wisconsin, Lucy Forrest at the National Institutes of Health, and Jan Steyaert at the Free ̽��ֱ�� of Brussels.

Reference

Sichrovsky, M, Lacabanne, D, Ruprecht, JJ & Rana, JJ et al. Molecular basis of pyruvate transport and inhibition of the human mitochondrial pyruvate carrier. Sci Adv; 18 Apr 2025; DOI: 10.1126/sciadv.adw1489

Fifty years since its discovery, scientists have finally worked out how a molecular machine found in mitochondria, the ‘powerhouses’ of our cells, allows us to make the fuel we need from sugars, a process vital to all life on Earth.

Drugs inhibiting the function of the carrier can remodel how mitochondria work, which can be beneficial in certain conditions

Edmund Kunji

bob_bosewell (Getty Images)

Bald young man, front view

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Leading Cambridge neuroscientist appointed as Executive Chair of Medical Research Council

cjb250 — Tue, 22 Aug 2023 09:40:00 +0000

̽��ֱ��Secretary of State for Science, Innovation and Technology, Michelle Donelan, has appointed Professor Patrick Chinnery as the next Executive Chair of the MRC.

Michelle Donelan said: “Professor Chinnery brings a wealth of experience as a practicing clinician and an already established and valued member of the Medical Research Council.

“By heading up one of the UK’s key public funding bodies for medical research, he will spearhead delivery of high-quality training and fellowships for researchers and funding for life-changing discoveries that are so crucial to our country’s health and wellbeing.

“I also pay tribute to Professor John Iredale for his work as interim Executive Chair and thank him for his invaluable service.”

Professor Chinnery is currently the MRC’s Director of Clinical Sciences and Professor of Neurology at Cambridge. He is also an Honorary Consultant Neurologist at Cambridge ̽��ֱ�� Hospitals NHS Trust. Professor Chinnery’s key research interest concerns the role of mitochondria in human disease and investigating ways to develop new treatments for mitochondrial disorders.

UKRI Chief Executive Dame Ottoline Leyser said: "Professor Chinnery is an exceptional leader who will play a key role in the continued development of UKRI and the Medical Research Council, ensuring it maintains its pivotal role in driving excellence in the biomedical and health sciences.

"He brings a great breadth of experience from across the medical sciences combined with a deep knowledge of the organisation from his time as MRC’s Director of Clinical Sciences. I look forward to continuing to work with him in his new role.

"I would also like to take this opportunity to express my profound thanks to Professor John Iredale for his superb service and leadership as MRC's interim Executive Chair, on which Professor Chinnery will build."

Professor Chinnery said: “Opportunities to advance human health through research have never been greater, and the UK is in a very strong position globally. It will be a real privilege to lead the MRC at this exciting time, working with colleagues in UKRI and across the sector to deliver scientific and clinical impact.”

As MRC Executive Chair, Professor Chinnery will oversee the Council’s full range of funding programmes and be responsible for its annual core budget alongside infrastructure and other cross-cutting UKRI funding allocated to the MRC. He will be responsible for MRC’s portfolio of institutes as well as for the Council’s wider role in providing training and support for the UK medical research community.

Professor Chinnery will also join the other UKRI Executive Chairs as a member of the UKRI senior leadership team and will work closely with them, UKRI’s Chief Executive and the UKRI Board to collectively manage and oversee UKRI’s strategy, funding programmes and infrastructure. He will succeed the current interim Executive Chair of MRC, Professor John Iredale and is expected to start in October.

Professor Anne Ferguson-Smith, Pro-Vice Chancellor for Research at the ̽��ֱ�� of Cambridge, welcomed the appointment. She said: “Many congratulations to Patrick on his appointment as Executive Chair of the MRC. In addition to being a world-leading active researcher in mitochondrial disease genetics, Patrick brings a wealth of MRC experience to this role, most recently as its Clinical Director and I know he has a strong commitment to the development of our next generation of biomedical researchers.

“These are important times for the MRC as it continues to invest in fundamental discovery research in the life sciences, experimental medicine and the translation of both to the clinic. His is an excellent appointment and we wish Patrick all the very best as he takes the helm at the MRC.”

Professor Patrick Chinnery, Head of the Department of Clinical Neurosciences at the ̽��ֱ�� of Cambridge, has been appointed as the new Executive Chair of the Medical Research Council (MRC).

Opportunities to advance human health through research have never been greater, and the UK is in a very strong position globally. It will be a real privilege to lead the MRC at this exciting time

Patrick Chinnery

̽��ֱ�� of Cambridge

Professor Patrick Chinnery

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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New route to evolution: how DNA from our mitochondria gets into our genomes

cjb250 — Wed, 05 Oct 2022 15:00:50 +0000

In a study published today in Nature, researchers at the ̽��ֱ�� of Cambridge and Queen Mary ̽��ֱ�� of London show that mitochondrial DNA also appears in some cancer DNA, suggesting that it acts as a sticking plaster to try and repair damage to our genetic code.

Mitochondria are tiny ‘organelles’ that sit within our cells, where they act like batteries, providing energy in the form of the molecule ATP to power the cells. Each mitochondrion has its own DNA – mitochondrial DNA – that is distinct to the rest of the human genome, which is comprised of nuclear DNA.

Mitochondrial DNA is passed down the maternal line – that is, we inherit it from our mothers, not our fathers. However, a study published in PNAS in 2018 from researchers at the Cincinnati Children’s Hospital Medical Center in the USA reported evidence that suggested some mitochondrial DNA had been passed down the paternal line.

To investigate these claims, the Cambridge team looked at the DNA from over 11,000 families recruited to Genomics England’s 100,000 Genomes Project, searching for patterns that looked like paternal inheritance. ̽��ֱ��Cambridge team found mitochondrial DNA ‘inserts’ in the nuclear DNA of some children that were not present in that of their parents. This meant that the US team had probably reached the wrong conclusions: what they had observed were not paternally-inherited mitochondrial DNA, but rather these inserts.

Now, extending this work to over 66,000 people, the team showed that the new inserts are actually happening all the time, showing a new way our genome evolves.

Professor Patrick Chinnery, from the Medical Research Council Mitochondrial Biology Unit and Department of Clinical Neurosciences at the ̽��ֱ�� of Cambridge, explained: “Billions of years ago, a primitive animal cell took in a bacterium that became what we now call mitochondria. These supply energy to the cell to allow it to function normally, while removing oxygen, which is toxic at high levels. Over time, bits of these primitive mitochondria have passed into the cell nucleus, allowing their genomes to talk to each other.

“This was all thought to have happened a very long time ago, mostly before we had even formed as a species, but what we've discovered is that that’s not true. We can see this happening right now, with bits of our mitochondrial genetic code transferring into the nuclear genome in a measurable way.”

̽��ֱ��team estimate that mitochondrial DNA transfers to nuclear DNA in around one in every 4,000 births. If that individual has children of their own, they will pass these inserts on – the team found that most of us carry five of the new inserts, and one in seven of us (14%) carry very recent ones. Once in place, the inserts can occasionally lead to very rare diseases, including a rare genetic form of cancer.

It isn’t clear exactly how the mitochondrial DNA inserts itself – whether it does so directly or via an intermediary, such as RNA – but Professor Chinnery says it is likely to occur within the mother’s egg cells.

When the team looked at sequences taken from 12,500 tumour samples, they found that mitochondrial DNA was even more common in tumour DNA, arising in around one in 1,000 cancers, and in some cases, the mitochondrial DNA inserts actually causes the cancer.

“Our nuclear genetic code is breaking and being repaired all the time,” said Professor Chinnery. “Mitochondrial DNA appears to act almost like a Band-Aid, a sticking plaster to help the nuclear genetic code repair itself. And sometimes this works, but on rare occasions if might make things worse or even trigger the development of tumours.”

More than half (58%) of the insertions were in regions of the genome that code for proteins. In the majority of cases, the body recognises the invading mitochondrial DNA and silences it in a process known as methylation, whereby a molecule attaches itself to the insert and switches it off. A similar process occurs when viruses manage to insert themselves into our DNA. However, this method of silencing is not perfect, as some of the mitochondrial DNA inserts go on to be copied and move around the nucleus itself.

̽��ֱ��team looked for evidence that the reverse might happen – that mitochondrial DNA absorbs parts of our nuclear DNA – but found none. There are likely to be several reasons why this should be the case.

Firstly, cells only have two copies of nuclear DNA, but thousands of copies of mitochondrial DNA, so the chances of mitochondrial DNA being broken and passing into the nucleus are much greater than the other way around.

Secondly, the DNA in mitochondria is packaged inside two membranes and there are no holes in the membrane, so it would be difficult for nuclear DNA to get in. By contrast, if mitochondrial DNA manages to get out, holes in the membrane surrounding nuclear DNA would allow it pass through with relative ease.

Professor Sir Mark Caulfield, Vice Principal for Health at Queen Mary ̽��ֱ�� of London, said: “I am so delighted that the 100,000 Genomes Project has unlocked the dynamic interplay between mitochondrial DNA and our genome in the cell’s nucleus. This defines a new role in DNA repair, but also one that could occasionally trigger rare disease, or even malignancy.”

̽��ֱ��research was mainly funded by the Medical Research Council, Wellcome, and the National Institute for Health Research.

Reference
Wei, E et al. Nuclear-embedded mitochondrial DNA sequences in 66,083 human genomes. Nature; 5 Oct 2022; DOI: 10.1038/s41586-022-05288-7

Scientists have shown that in one in every 4,000 births, some of the genetic code from our mitochondria – the ‘batteries’ that power our cells – inserts itself into our DNA, revealing a surprising new insight into how humans evolve.

Mitochondrial DNA appears to act almost like a Band-Aid, a sticking plaster to help the nuclear genetic code repair itself. And sometimes this works, but on rare occasions if might make things worse or even trigger the development of tumours

Patrick Chinnery

Dr David Furness

Mitochondria surrounded by cytoplasm

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Live long and prosper

skbf2 — Thu, 14 Jul 2022 09:37:28 +0000

Meet Daniel Ives, co-founder of a Cambridge start-up with one big ambition: to put an end to ageing and the diseases that come with it.

Gene discovery indicates motor neurone diseases caused by abnormal lipid processing in cells

Anonymous — Mon, 20 Jun 2022 01:35:50 +0000

Motor neurone degenerative diseases (MNDs) are a large family of neurological disorders. Currently, there are no treatments available to prevent onset or progression of the condition. MNDs are caused by changes in one of numerous different genes. Despite the number of genes known to cause MNDs, many patients remain without a much-needed genetic diagnosis.

̽��ֱ��team behind the current work developed a hypothesis to explain a common cause of MNDs stemming from their discovery of 15 genes responsible for MNDs. ̽��ֱ��genes they identified are all involved in processing lipids - in particular cholesterol – inside brain cells. Their new hypothesis, published in the journal Brain, describes the specific lipid pathways that the team believe are important in the development of MNDs.

Now, the team has identified a further new gene – named TMEM63C – which causes a degenerative disease that affects the upper motor neurone cells in the nervous system. Also published in Brain, their latest discovery is important as the protein encoded by TMEM63C is located in the region of the cell where the lipid processing pathways they identified operate. This further bolsters the hypothesis that MNDs are caused by abnormal processing of lipids including cholesterol.

“This new gene finding is consistent with our hypothesis that the correct maintenance of specific lipid processing pathways is crucial for the way brain cells function, and that abnormalities in these pathways are a common linking theme in motor neurone degenerative diseases,” said study co-author Professor Andrew Crosby from the ̽��ֱ�� of Exeter. “It also enables new diagnoses and answers to be readily provided for families affected by some forms of MND”

MNDs affect the nerve cells that control voluntary muscle activity such as walking, speaking and swallowing. There are many different forms of MNDs that have different clinical features and severity. As the condition progresses, the motor neurone cells become damaged and may eventually die. This leads to the muscles, which rely on those nerve messages, gradually weakening and wasting away.

If confirmed, the theory could lead to scientists to use patient samples to predict the course and severity of the condition in an individual, and to monitor the effect of potential new drugs developed to treat these disorders.

In the latest research, the team used cutting-edge genetic sequencing techniques to investigate the genome of three families with individuals affected by hereditary spastic paraplegia – a large group of MNDs in which the motor neurons in the upper part of the spinal cord miscommunicate with muscle fibres, leading to symptoms including muscle stiffness, weakness and wasting. These investigations showed that changes in the TMEM63C gene were the cause of the disease. In collaboration with the group led by Dr Julien Prudent at the Medical Research Council Mitochondrial Biology Unit at the ̽��ֱ�� of Cambridge, the team also undertook studies to learn more about the functional relevance of the TMEM63C protein inside the cell.

Using state-of-the-art microscopy methods, the Cambridge team’s work showed that a subset of TMEM63C is localised at the interface between two critical cellular organelles, the endoplasmic reticulum and the mitochondria, a region of the cell required for lipid metabolism homeostasis and proposed by the Exeter team to be important for the development of MNDs.

In addition to this specific localisation, Dr Luis-Carlos Tabara Rodriguez, a Postdoctoral Fellow in Prudent’s lab, also uncovered that TMEM63C controls the morphology of both the endoplasmic reticulum and mitochondria, which may reflect its role in the regulation of the functions of these organelles, including lipid metabolism homeostasis.

“From a mitochondrial cell biologist point of view, identification of TMEM63C as a new motor neurone degenerative disease gene and its importance to different organelle functions reinforce the idea that the capacity of different cellular compartments to communicate together, by exchanging lipids for example, is critical to ensure cellular homeostasis required to prevent disease,” said Prudent.

“Understanding precisely how lipid processing is altered in motor neurone degenerative diseases is essential to be able to develop more effective diagnostic tools and treatments for a large group of diseases that have a huge impact on people’s lives,” said study co-author Dr Emma Baple from the ̽��ֱ�� of Exeter. “Finding this gene is another important step towards these important goals.”

̽��ֱ��Halpin Trust, a charity who support projects which deliver a powerful and lasting impact in healthcare, nature conservation and the environment, part-funded this research. Claire Halpin, who co-founded the charity with her husband Les, said “ ̽��ֱ��Halpin Trust are extremely proud of the work ongoing in Exeter, and the important findings of this highly collaborative international study. We’re delighted that the Trust has contributed to this work, which forms part of Les’s legacy. He would also have been pleased, I know.”

Reference:
Luis-Carlos Tábara et al. ‘TMEM63C mutations cause mitochondrial morphology defects and underlie hereditary spastic paraplegia.’ Brain (2022). DOI: 10.1093/brain/awac123

Adapted from a ̽��ֱ�� of Exeter press release.

A new genetic discovery adds weight to a theory that motor neurone degenerative diseases are caused by abnormal lipid (fat) processing pathways inside brain cells. This theory will help pave the way to new diagnostic approaches and treatments for this group of conditions. ̽��ֱ��discovery will provide answers for certain families who have previously had no diagnosis.

Andriy Onufriyenko via Getty Images

Neuron

Yes

Study in mice shows potential for gene-editing to tackle mitochondrial disorders

cjb250 — Tue, 08 Feb 2022 10:00:16 +0000

Our cells contain mitochondria, which provide the energy for our cells to function. Each of these mitochondria contains a tiny amount of mitochondrial DNA. Mitochondrial DNA makes up only 0.1% of the overall human genome and is passed down exclusively from mother to child.

Faults in our mitochondrial DNA can affect how well the mitochondria operate, leading to mitochondrial diseases, serious and often fatal conditions that affect around 1 in 5,000 people. ̽��ֱ��diseases are incurable and largely untreatable.

There are typically around 1,000 copies of mitochondrial DNA in each cell, and the percentage of these that are damaged, or mutated, will determine whether a person will suffer from mitochondrial disease or not. Usually, more than 60% of the mitochondria in a cell need to be faulty for the disease to emerge, and the more defective mitochondria a person has, the more severe their disease will be. If the percentage of defective DNA could be reduced, the disease could potentially be treated.

A cell that contains a mixture of healthy and faulty mitochondrial DNA is described as ‘heteroplasmic’. If a cell contains no healthy mitochondrial DNA, it is ‘homoplasmic’.

In 2018, a team from the MRC Mitochondrial Biology Unit at the ̽��ֱ�� of Cambridge applied an experimental gene therapy treatment in mice and were able to successfully target and eliminate the damaged mitochondrial DNA in heteroplasmic cells, allowing mitochondria with healthy DNA to take their place.

“Our earlier approach is very promising and was the first time that anyone had been able to alter mitochondrial DNA in a live animal,” explained Dr Michal Minczuk. “But it would only work in cells with enough healthy mitochondrial DNA to copy themselves and replace the faulty ones that had been removed. It would not work in cells whose entire mitochondria had faulty DNA.”

In their latest advance, published today in Nature Communications, Dr Minczuk and colleagues used a biological tool known as a mitochondrial base editor to edit the mitochondrial DNA of live mice. ̽��ֱ��treatment is delivered into the bloodstream of the mouse using a modified virus, which is then taken up by its cells. ̽��ֱ��tool looks for a unique sequence of base pairs – combinations of the A, C, G and T molecules that make up DNA. It then changes the DNA base – in this case, changing a C to a T. This would, in principle, enable the tool to correct certain ‘spelling mistakes’ that cause the mitochondria to malfunction.

There are currently no suitable mouse models of mitochondrial DNA diseases, so the researchers used healthy mice to test the mitochondrial base editors. However, it shows that it is possible to edit mitochondrial DNA genes in a live animal.

Pedro Silva-Pinheiro, a postdoctoral researcher in Dr Minczuk’s lab and first author of the study, said: “This is the first time that anyone has been able to change DNA base pairs in mitochondria in a live animal. It shows that, in principle, we can go in and correct spelling mistakes in defective mitochondrial DNA, producing healthy mitochondria that allow the cells to function properly.”

An approach pioneered in the UK known as mitochondrial replacement therapy – sometimes referred to as ‘three-person IVF’ – allows a mother’s defective mitochondria to be replaced with those from a healthy donor. However, this technique is complex, and even standard IVF is successful in fewer than one in three cycles.

Dr Minczuk added: “There’s clearly a long way to go before our work could lead to a treatment for mitochondrial diseases. But it shows that there is the potential for a future treatment that removes the complexity of mitochondrial replacement therapy and would allow for defective mitochondria to be repaired in children and adults.”

̽��ֱ��research was funded by the Medical Research Council UK, the Champ Foundation and the Lily Foundation.

Reference
Silva-Pinheiro, S et al. In vivo mitochondrial base editing via adenoassociated viral delivery to mouse post-mitotic tissue. Nature Comms; 8 Feb 2022; DOI: 10.1038/s41467-022-28358-w

Defective mitochondria – the ‘batteries’ that power the cells of our bodies – could in future be repaired using gene-editing techniques. Scientists at the ̽��ֱ�� of Cambridge have shown that it is possible to modify the mitochondrial genome in live mice, paving the way for new treatments for incurable mitochondrial disorders.

[This] shows that, in principle, we can go in and correct spelling mistakes in defective mitochondrial DNA, producing healthy mitochondria that allow the cells to function properly

Pedro Silva-Pinheiro

wir0man/Getty Images

Mitochondria - 3D illustration

Yes

Whole genome sequencing increases diagnosis of rare disorders by nearly a third

ta385 — Thu, 04 Nov 2021 06:00:00 +0000

Mitochondrial disorders affect around 1 in 4,300 people and cause progressive, incurable diseases. They are amongst the most common inherited diseases but are difficult for clinicians to diagnose, not least because they can affect many different organs and resemble many other conditions.

Current genetic testing regimes fail to diagnose around 40% of patients, with major implications for patients, their families and the health services they use.

A new study, published in the BMJ, offers hope to families with no diagnosis, and endorses plans for the UK to establish a national diagnostic programme based on whole genome sequencing (WGS) to make more diagnoses faster.

While previous studies based on small, highly selected cohorts have suggested that WGS can identify mitochondrial disorders, this is the first to examine its effectiveness in a national healthcare system – the NHS.

̽��ֱ��study, led by researchers from the MRC Mitochondrial Biology Unit and Departments of Clinical Neuroscience and Medical Genetics at the ̽��ֱ�� of Cambridge, involved 319 families with suspected mitochondrial disease recruited through the 100,000 Genomes Project which was set up to embed genomic testing in the NHS, discover new disease genes and make genetic diagnosis available for more patients.

In total, 345 participants – aged 0 to 92 with a median age of 25 years – had their whole genome sequenced. Through different analyses, the researchers found that they could make a definite or probable genetic diagnosis for 98 families (31%). Standard tests, which are often more invasive, failed to reach these diagnoses. Six possible diagnoses (2% of the 98 families) were made. A total of 95 different genes were implicated.

Surprisingly, 62.5% of the diagnoses were actually non-mitochondrial disorders, with some having specific treatments. This happened because so many different diseases resemble mitochondrial disorders, making it very difficult to know which are which.

Professor Patrick Chinnery from the MRC Mitochondrial Biology Unit and the Department of Clinical Neurosciences at the ̽��ֱ�� of Cambridge, said:

“We recommend that whole genome sequencing should be offered early and before invasive tests such as a muscle biopsy. All that patients would need to do is have a blood test, meaning that this could be offered across the whole country in an equitable way. People wouldn’t need to travel long distances to multiple appointments, and they would get their diagnosis much faster.”

Dr Katherine Schon from the MRC Mitochondrial Biology Unit and the Departments of Clinical Neuroscience and Medical Genetics, said:

“A definitive genetic diagnosis can really help patients and their families, giving them access to tailored information about prognosis and treatment, genetic counselling and reproductive options including preimplantation genetic diagnosis or prenatal diagnosis.”

̽��ֱ��researchers made 37.5% of their diagnoses in genes known to cause mitochondrial disease. These diagnoses were nearly all unique to a particular participant family, reflecting the genetic diversity found in these disorders. ̽��ֱ��impairment of mitochondrial function tends to affect tissues with high energy demand such as the brain, the peripheral nerves, the eye, the heart and the peripheral muscles. ̽��ֱ��study offers a valuable new resource for the discovery of future mitochondrial disease genes.

̽��ֱ��majority of the team’s diagnoses (62.5%) were, however, of non-mitochondrial disorders which had features resembling mitochondrial diseases. These disorders would have been missed if the participants had only been investigated for mitochondrial disorders through muscle biopsy and/or a specific mitochondrial gene panel. These participants were living with a range of conditions including developmental disorders with intellectual disability, severe epileptic conditions and metabolic disorders, as well as heart and neurological diseases.

Chinnery said: “These patients were referred because of a suspected mitochondrial disease and the conventional diagnostic tests are specifically for mitochondrial diseases. Unless you consider these other possibilities, you won't diagnose them. Whole genome sequencing isn’t restricted by that bias.”

A small number of newly diagnosed participants are already receiving treatments as a result. ̽��ֱ��team identified potentially treatable disorders in six participants with a mitochondrial disorder and nine with a non-mitochondrial disorder, but the impact of the treatments has yet to be determined.

Chinnery said: “Diagnostic services are fragmented and unevenly distributed across the UK, and that creates major challenges for people with rare diseases and their families. By delivering a national programme based on this genome-wide approach, you can offer the same level of service to everyone."

Schon said: “If we can create a national platform of families with rare diseases, we can give them the opportunity to engage in clinical trials so we can get definitive evidence that new treatments work.”

̽��ֱ��study points out that the relatively high number of patients with probable or possible diagnoses reflects the need for greater investment into the analysis of functional effects of new genetic variants which could be the cause of disease, but it is not certain at present.

It also argues that rapid trio whole genome sequencing should be offered to all acutely unwell individuals with suspected mitochondrial disorders, so that results can help guide clinical management. Currently in the UK, this is only available for acutely unwell children.

Dr Ellen Thomas, Clinical Director and Director of Quality at Genomics England, said:

“We are very pleased to see significant research like this being enabled by data generously donated by participants of the 100,000 Genomes Project. It is clear from these results how their contributions to a rich and, importantly, secure dataset is critical in facilitating the genomic research that leads to insights like these that then have the potential to return value to the NHS and their patients. We look forward to seeing how these findings could support future care for patients with suspected mitochondrial disorders.”

Reference

KR Schon et al., ‘Use of whole genome sequencing to determine the genetic basis of suspected mitochondrial disorders: a cohort study’, BMJ (2021). DOI: 10.1136/ bmj-2021-066288

Funding

National Institute for Health Research, NHS England, Wellcome, Cancer Research UK and the Medical Research Council within UK Research and Innovation

Whole genome sequencing from a single blood test picks up 31% more cases of rare genetic disorders than standard tests, shortening the ‘diagnostic odyssey’ that affected families experience, and providing huge opportunities for future research.

A definitive genetic diagnosis can really help patients and their families

Patrick Chinnery

Belova59 via Pixabay

Gloved hand holding two blood samples

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Heal thyself

skbf2 — Mon, 24 May 2021 13:28:20 +0000

Three companies, Astex Pharmaceuticals, Eisai Ltd and Eli Lilly and Company, are joining forces with research scientists across Cambridge to explore promising new approaches to the treatment of neurodegenerative disease.