The biology underpinning a rare genetic mutation that allows its carrier to feel almost no pain, heal faster and had reduced anxiety and fear, has been uncovered in a new study published in Brain.
Though it may sound like the stuff of superheroes, the carrier of the genetic mutation is an ordinary Scottish woman named Jo Cameron, who was first referred to pain geneticists at University College London in 2013, after her doctor noticed that she experienced no pain after major surgeries on her hip and hand. In 2019, they identified a new gene that they appropriately named FAAH-OUT, which had a rare genetic mutation. In combination with another, more common mutation in FAAH, it was found to be the cause of Jo’s unique characteristics.
The new research describes how the mutation in FAAH-OUT ‘turns down’ FAAH gene expression, as well as the knock-on effects on other molecular pathways linked to wound healing and mood. It is hoped the findings will lead to new drug targets and open up new avenues of research in these areas.
The area of the genome containing FAAH-OUT had previously been assumed to be ‘junk’ DNA that had no function, but it was found to mediate the expression of FAAH, a gene that is part of the endocannabinoid system and that is well-known for its involvement in pain, mood and memory.
In this study, the team from UCL sought to understand how FAAH-OUT works at a molecular level, the first step towards being able to take advantage of this unique biology for applications like drug discovery.
This included a range of approaches, such as CRISPR-Cas9 experiments on cell lines to mimic the effect of the mutation on other genes, as well as analysing the expression of genes to see which were active in molecular pathways involved with pain, mood and healing.
The team observed that FAAH-OUT regulates the expression of FAAH. When it is significantly turned down as a result of the mutation carried by Jo Cameron, FAAHenzyme activity levels are significantly reduced.
Dr Andrei Okorokov (UCL Medicine), a senior author of the study, said: “The FAAH-OUT gene is just one small corner of a vast continent, which this study has begun to map. As well as the molecular basis for painlessness, these explorations have identified molecular pathways affecting wound healing and mood, all influenced by the FAAH-OUT mutation. As scientists it is our duty to explore and I think these findings will have important implications for areas of research such as wound healing, depression and more.”
The authors looked at fibroblasts taken from patients to study the effects of the FAAH-OUT-FAAH axis on other molecular pathways. While the mutations that Jo Cameron carries turn down FAAH, they also found a further 797 genes that were turned up and 348 that were turned down. This included alterations to the WNT pathway that is associated with wound healing, with increased activity in the WNT16 gene that has been previously linked to bone regeneration.
Two other key genes that were altered were BDNF, which has previously been linked to mood regulation and ACKR3, which helps to regulate opioid levels. These gene changes may contribute to Jo Cameron’s low anxiety, fear and painlessness.
Senior study author Professor James Cox said: “The initial discovery of the genetic root of Jo Cameron’s unique phenotype was a eureka moment and hugely exciting, but these current findings are where things really start to get interesting. By understanding precisely what is happening at a molecular level, we can start to understand the biology involved and that opens up possibilities for drug discovery that could one day have far-reaching positive impacts for patients.”
UCT Lab technician Fadheela Patel, pictured here preparing mastermix in the clean room
In a first for the African continent, researchers at the University of Cape Town are using a cutting-edge technique to fast-track the diagnosis of disease, ensuring patients receive the correct treatment sooner.
Clinical microbiologists Professor Adrian Brink and Dr Gert Marais at UCT’s Faculty of Health Sciences have operationalised clinical metagenomics in South Africa, transforming the procedure from a complex logistical procedure to a routine test.
Clinical metagenomics fast tracks the medical diagnostic process, cutting turnover time down – from sample to result – from weeks or even months to just a few days. It can also be used as a ‘sentinel surveillance tool’ to spot new infectious diseases and sound an early warning alarm for future pandemics.
“This kind of technology has never been used in South Africa and as far as we know, the African continent. “Certainly there’s no diagnostic lab in South Africa that does it,” says Brink. He and Marais believe they are the first to develop a clinical metagenomics service in Africa.
The genetic sequences appearing in a sample are compared to a database of all known organisms, allowing any and every pathogen present within the patient to be detected at the same time from just one sample. This metagenomic approach is sometimes referred to as “agnostic sequencing”.
Key steps in Brink and Marais’ clinical metagenomics study on the brain 1) A medical sample is obtained (from cerebral spinal fluid in their study) and treated to extract and purify all the nucleic acids (genetic material) it contains. These DNA fragments are then made into a ‘library’ by attaching short molecules called adaptors to the ends. This prepares the sample to be run through a sequencing machine. 2) The genetic code of the library is read in real-time by running it through a sequencing machine. This generates a series of ‘reads’ (DNA sequences). 3) The reads are compared to an online database of all known organisms’ genetic codes, allowing any and every pathogen present within the patient’s brain to be detected at the same time from just one sample. 4) The results are examined for matches with infections organisms and used to determine appropriate patient treatment.
By contrast, conventional diagnostic testing requires testing individually for a specific suspected disease. If the result comes back negative, a new sample will need to be taken and sent for a different test – a lengthy process when lives are at stake.
“In some cases we investigated, patients had a disease that could have been treated if it had been identified initially. But because the diagnosis could only be made months later, it was too late [to save them]. That’s where the idea for our study originated,” says Marais.
Brink recounts the case of a cancer patient who developed neurological symptoms. “Because he was highly immunocompromised, the list of potential causes for these symptoms was a page long,” says Brink.
The patient passed away, and clinical metagenomics testing of a sample taken at the autopsy revealed he was suffering from Aspergillus, an aggressive fungal infection that requires specific treatment.
Although he was already very sick due to cancer, Brink says the untreated central nervous system aspergillosis may have led to the patient’s death. “If clinical metagenomics methods had been available at the time, the right therapy could have been started weeks earlier, potentially changing the outcome for this patient,” he says.
Brink and Marias used clinical metagenomics to diagnose neurological disorders and study the effects of COVID-19 on the brain. It’s an area of health care where a timely diagnosis is particularly important. “Once the brain is damaged, there’s no going back,” says Marais. This research is currently under review for publication and expected to be released shortly.
While metagenomics has been applied in research settings in Africa before, this is the first time the method has been fully operationalised for clinical applications on the continent – meaning that all sample processing and analysis can now be done in the same laboratory in real time.
Previously, researchers in Africa have had to send samples overseas to Europe or the United States for processing. The reason: the chemical reagents required to run clinical metagenomic tests, despite in some instances being as easy to access in Europe as a DHL order, were not readily available in Africa.
Supported by funding from Oppenheimer Generations Research and Conservation, Brink and Marias remedied this by establishing a reagent supplier pipeline for South Africa, a tricky task when the pandemic had interrupted global supply chains. With a reliable source of reagents, samples can now be processed in labs in South Africa, opening the door for advances in medicine and research on the continent.
Building capacity instead of ‘helicopter research’
Marais emphasised their focus on upskilling and building capacity for Africa, in contrast to the ‘helicopter research’ that has defined clinical metagenomic work on the continent up to this point. “Our goal was to increase the capacity for infectious disease diagnostics going forward, rather than just coming in, testing a few samples, publishing a paper and leaving,” he says.
According to Marias, most prior metagenomics work in Africa has been in the form of discreet research projects with an international collaborator or as field work for an international lab, with little investment in local medical infrastructure and capabilities.
Their initial work so far has already created opportunities for skills transfer in genetic sequencing and bioinformatics at UCT medical school and medical research departments, and at institutes in Johannesburg.
Although the high cost of reagents and lack of standardised protocols remain challenges for a clinical metagenomics rollout in Africa, Brink and Marais are confident that the technology can become a cost-effective tool to improve patient individual care and to identify novel pathogens in low- and middle-income countries (LMICs).
A vast range of applications
Their new paper, co-authored with Associate Professor Diana Hardie and published in The Lancet Microbe in December 2022, calls for the expanded infrastructure developed in LMICs for COVID-19 monitoring to be leveraged to improve infectious disease diagnostics through clinical metagenomics.
“We applied clinical metagenomics to the COVID-19 brain, but the picture is bigger than that,” says Brink. Clinical metagenomics can be used for diagnosing an array of diseases across many health disciplines. In collaboration with colleagues at Cape Town’s Groote Schuur Hospital, Brink and Marias are now exploring the application of the technology in orthopaedics, neurosurgery, haematology-oncology and cardiothoracic surgery.
Specifically, they’re looking at patients with prosthetic joint infections, heart valve infections, brain tumours and leukaemia. The team welcomes collaborators and asks researchers and health care professionals across the continent interested in utilising clinical metagenomics to reach out to them.
Brink and Marias are also examining patients suffering from severe respiratory tract infections without a diagnosis, another area where clinical metagenomics is particularly revolutionary.
Because the genetic sequences found in patient samples are compared to a database of all known organisms, if a sequence yields no match to the database, there’s a chance it could be a novel pathogen.
This application is particularly relevant in LMICs where novel pathogens pose a higher risk due to socioeconomic factors and a lack of infrastructure to deal with local outbreaks. However, despite this, infectious disease surveillance infrastructure is more developed and readily available in high income nations.
While hurdles remain to be navigated before clinical metagenomics can be widely accessible across Africa, the team is confident that technology holds real promise for advancing the continent’s capabilities for medical research and diagnosis. “There aren’t a lot of people doing this kind of thing [in Africa], but this is the future,” says Brink.
Researchers report in Nature Ecology and Evolution that human DNA traces can be found nearly everywhere, short of isolated islands and remote mountaintops. That ubiquity is both a scientific boon and an ethical dilemma, say the University of Florida researchers who sequenced this ‘errant’ DNA. The DNA was of such high quality that the scientists could identify mutations associated with disease and determine the genetic ancestry of nearby populations. They could even match genetic information to individual participants who had volunteered to have their errant DNA recovered.
David Duffy, the UF professor of wildlife disease genomics who led the project, says that ethically handled environmental DNA samples could benefit fields from medicine and environmental science to archaeology and criminal forensics. For example, researchers could track cancer mutations from wastewater or spot undiscovered archaeological sites by checking for hidden human DNA. Or detectives could identify suspects from the DNA floating in the air of a crime scene.
But this level of personal information must be handled extremely carefully. Now, scientists and regulators must grapple with the ethical dilemmas inherent in accidentally — or intentionally — sweeping up human genetic information, not from blood samples but from a scoop of sand, a vial of water or a person’s breath.
The paper by Duffy’s group outlines the relative ease of collecting human DNA nearly everywhere they looked.
“We’ve been consistently surprised throughout this project at how much human DNA we find and the quality of that DNA,” Duffy said. “In most cases the quality is almost equivalent to if you took a sample from a person.”
Because of the ability to potentially identify individuals, the researchers say that ethical guardrails are necessary for this kind of research. The study was conducted with approval from the institutional review board of UF, which ensures that ethical guidelines are adhered to during research studies.
“It’s standard in science to make these sequences publicly available. But that also means if you don’t screen out human information, anyone can come along and harvest this information,” Duffy said. “That raises issues around consent. Do you need to get consent to take those samples? Or institute some controls to remove human information?”
Duffy’s team at UF’s Whitney Laboratory for Marine Bioscience and Sea Turtle Hospital has successfully used environmental DNA, or eDNA, to study endangered sea turtles and the viral cancers they are susceptible to. They’ve plucked useful DNA out of turtle tracks in the sand, greatly accelerating their research program.
The scientists knew that human eDNA would end up in their turtle samples and probably many other places they looked. With modern genetic sequencing technology, it’s now straightforward to sequence the DNA of every organism in an environmental sample. The questions were how much human DNA there would be and whether it was intact enough to harbor useful information.
The team found quality human DNA in the ocean and rivers surrounding the Whitney Lab, both near town and far from human settlement, as well as in sand from isolated beaches. In a test facilitated by the National Park Service, the researchers traveled to part of a remote island never visited by people. It was free of human DNA, as expected. But they were able to retrieve DNA from voluntary participants’ footprints in the sand and could sequence parts of their genomes, with permission from the anonymous participants.
Duffy also tested the technique in his native Ireland. Tracing along a river that winds through town on its way to the ocean, Duffy found human DNA everywhere but the remote mountain stream where the river starts, far from civilization.
The scientists also collected room air samples from a veterinary hospital. They recovered DNA matching the staff, the animal patient and common animal viruses.
Now that it’s clear human eDNA can be readily sampled, Duffy says it’s time for policymakers and scientific communities to take issues around consent and privacy seriously and balance them against the possible benefits of studying this errant DNA.
“Any time we make a technological advance, there are beneficial things that the technology can be used for and concerning things that the technology can be used for. It’s no different here,” Duffy said. “These are issues we are trying to raise early so policy makers and society have time to develop regulations.”
Diagram comparing the nose shape of a Neanderthal with that of a modern human by Dr Macarena Fuentes-Guajardo.
Humans inherited genetic material from Neanderthals that affects the shape of noses of many populations, finds a new study published in Communications Biology. The new study finds that a particular gene, which leads to a taller nose (from top to bottom), may have been the product of natural selection as ancient humans adapted to colder climates after leaving Africa, and is even found in native populations of the Americas.
Co-corresponding author Dr Kaustubh Adhikari (UCL Genetics, Evolution & Environment and The Open University) said: “In the last 15 years, since the Neanderthal genome has been sequenced, we have been able to learn that our own ancestors apparently interbred with Neanderthals, leaving us with little bits of their DNA.
“Here, we find that some DNA inherited from Neanderthals influences the shape of our faces. This could have been helpful to our ancestors, as it has been passed down for thousands of generations.”
The study used data from more than 6000 volunteers across Latin America, of mixed European, Native American and African ancestry, who are part of the UCL-led CANDELA study, which recruited from Brazil, Colombia, Chile, Mexico and Peru. The researchers compared genetic information from the participants to photographs of their faces, specifically looking at distances between points on their faces, such as the tip of the nose or the edge of the lips, to link different facial traits to different genetic markers.
The researchers newly identified 33 genome regions associated with face shape, 26 of which they were able to replicate in comparisons with data from other ethnicities using participants in east Asia, Europe, or Africa.
In one genome region in particular, called ATF3, the researchers found that many people in their study with Native American ancestry (as well as others with east Asian ancestry from another cohort) had genetic material in this gene that was inherited from the Neanderthals, contributing to increased nasal height. They also found that this gene region has signs of natural selection, suggesting that it conferred an advantage for those carrying the genetic material.
First author Dr Qing Li (Fudan University) said: “It has long been speculated that the shape of our noses is determined by natural selection; as our noses can help us to regulate the temperature and humidity of the air we breathe in, different shaped noses may be better suited to different climates that our ancestors lived in. The gene we have identified here may have been inherited from Neanderthals to help humans adapt to colder climates as our ancestors moved out of Africa.”
Co-corresponding author Professor Andres Ruiz-Linares (Fudan University, UCL Genetics, Evolution & Environment, and Aix-Marseille University) added: “Most genetic studies of human diversity have investigated the genes of Europeans; our study’s diverse sample of Latin American participants broadens the reach of genetic study findings, helping us to better understand the genetics of all humans.”
The finding is the second discovery of DNA from archaic humans, distinct from Homo sapiens, affecting our face shape. The same team discovered in a 2021 paper that a gene influencing lip shape was inherited from the ancient Denisovans.*
The study involved researchers based in the UK, China, France, Argentina, Chile, Peru, Colombia, Mexico, Germany, and Brazil.
Gene editing therapy aimed at two targets – HIV-1 and CCR5, the co-receptor that helps the virus get into cells – can effectively eliminate HIV infection, report scientists in PNAS. This is the first to combine a dual gene-editing strategy with antiretroviral drugs to cure animals of HIV-1.
“The idea to bring together the excision of HIV-1 DNA with inactivation of CCR5 using gene-editing technology builds on observations from reported cures in human HIV patients,” said Kamel Khalili, PhD, professor at the Lewis Katz School of Medicine. “In the few instances of HIV cures in humans, the patients underwent bone marrow transplantation for leukaemia, and the donor cells that were used carried inactivating CCR5 mutations.”
Dr Khalili and Howard E. Gendelman, MD, professor at UNMC, were senior investigators on the new study from the Lewis Katz School of Medicine at Temple University and the University of Nebraska Medical Center (UNMC). The two researchers have been long-time collaborators and have strategically combined their research strengths to find a cure for HIV.
“We are true partners, and what we achieved here is really spectacular,” Dr Gendelman said. “Dr Khalili’s team generated the essential gene-editing constructs, and we then applied those constructs in our LASER-ART mouse model at Nebraska, figuring out when to administer gene-editing therapy and carrying out analyses to maximise HIV-1 excision, CCR5 inactivation, and suppression of viral growth.”
In previous work, Drs Khalili and Gendelman and their respective teams showed that HIV can be edited out from the genomes of live, humanised HIV-infected mice, leading to a cure in some animals. For that research, CRISPR gene-editing technology for targeting HIV-1 was combined with a therapeutic strategy known as long-acting slow-effective release (LASER) antiretroviral therapy (ART). LASER ART holds HIV replication at low levels for long periods of time, decreasing the frequency of ART administration.
Despite being able to eliminate HIV in LASER-ART mice, the researchers found that HIV could eventually re-emerge from tissue reservoirs and cause rebound infection. This effect is similar to rebound infection in human patients who have been taking ART but suddenly stop or experience a disruption in treatment. HIV integrates its DNA into the genome of host cells, it can lie dormant in tissue reservoirs for long periods of time, out of reach of antiretroviral drugs. As a consequence, when ART is stopped, HIV replication renews, giving rise to AIDS.
To prevent rebound infection, Dr Khalili and colleagues began work on next-generation CRISPR technology for HIV excision, developing a new, dual system aimed at permanently eliminating HIV from the animal model. “From success stories of human HIV patients who have undergone bone marrow transplantation for leukaemia and been cured of HIV, our hypothesis was that the loss of the virus’s receptor, CCR5, is important to permanently eliminating HIV infection,” he explained. They developed a simple and more practical procedure for the inactivation of CCR5 that includes an IV inoculation of the CRISPR gene editing molecule.
Experiments in humanized LASER-ART mice carried out by Dr Gendelman’s team showed that the constructs developed at Temple, when administered together, resulted in viral suppression, restoration of human T-cells, and elimination of replicating HIV-1 in 58% of infected animals. The findings support the idea that CCR5 has a key role in facilitating HIV infection.
The Temple team also anticipates soon testing the dual gene-editing strategy in non-human primates.
The new dual CRISPR gene-editing strategy holds exceptional promise for treating HIV in humans. “It is a simple and relatively inexpensive approach,” Dr Khalili noted. “The type of bone marrow transplant that has brought about cures in humans is reserved for patients who also have leukaemia. It requires multiple rounds of radiation and is not applicable in resource-limited regions, where HIV infection tends to be most common.”
Human height is dictated by the sealing of the growth plates at the ends of bones that harden as a child develops. Along with diet and disease, heritability has long been known to be a factor determining height. Now, researchers report in Cell Genomics that cells in these plates determine the length and shape of bones and may partly predict final stature. The study identified potential “height genes” and found that genetic changes affecting cartilage cell maturation may strongly influence adult height.
“The study is really understanding the genetics of skeleton,” says paediatric endocrinologist and senior author Nora Renthal of Boston Children’s Hospital and Harvard University. “Height is a good starting point to understand the relationship between genes, growth plates, and skeletal growth because we can measure the height of every human being.”
To pinpoint height-associated genes, the team screened 600 million mouse cartilage cells to identify genes that, when deleted, can alter cell growth and maturation. These types of cellular changes in the growth plate are known to lead to variations in human height. The search turned up 145 genes mostly linked to skeletal disorders and are crucial for growth plate maturation and bone formation.
The team then compared these genes with data from genome-wide association studies (GWAS) of human height, which located “hotspots” along the entire human genome where “height genes” are located. But these regions can contain multiple genes, making it hard for researchers to track down and study an individual target.
“That’s kind of like looking for your friend’s house, but you only know the zip code,” says Renthal. “It’s difficult.”
The comparison revealed that genes affecting cartilage cells overlap with hotspots from human height GWAS, precisely locating genes in our DNA that likely play a role in determining our stature. Renthal and her team also discovered that many of the GWAS suggested height genes led to early maturation in cartilage cells. These findings suggest that genetic changes affecting cartilage cell maturation may influence height more.
Renthal notes that studies in mouse cells may not fully translate to humans, and GWAS are observational studies that cannot fully illustrate the cause and effects of height. But her study provides a novel method to bridge the two methods and provide new insights into human genetics.
Next, the team plans to use the method to understand hormones’ effect on cartilage cells. They will also look into some of the 145 genes that have no known connection to skeletal growth. The investigation may reveal new genes and pathways that play a role in the bones.
“I see patients with skeletal dysplasia, where there isn’t any treatment because genetics made their bones grow this way,” says Renthal. “It’s my hope that the more we can understand about the biology of the growth plate, the more we would be able to intervene at earlier times in growing skeletons and the life of a kid.”
Pompe disease (PD) is an autosomal-recessively inherited neuromuscular disease that can be fatal if it is not diagnosed and treated early.1 Due to lack of acid alpha-glucosidase (GAA), there is progressive intracellular accumulation of glycogen, which can severely damage the muscles and heart.1
PD can present from early infancy into adulthood, with variable rates of disease progression.1 Severity is determined by age of onset, organ involvement, including the degree of muscle involvement (skeletal, respiratory, and cardiac), and rate of progression.1
Classification1
PD is classified into two groups: infantile and late-onset.
Infantile form:
• Classic infantile PD is most severe and rapidly progressive, and is characterised by prominent cardiomegaly, hepatomegaly, muscular weakness and hypotonia. Death results from cardiorespiratory failure in <1 year, if not treated.
• Infantile variant form (non-classic, in the <1-year group that has slower progression and less severe or absent cardiomyopathy).
Late-onset form:
• Childhood/juvenile or muscular variant (heterogeneous group) presenting later than infancy and typically excluding cardiomyopathy.
• Adult-onset form characterised by slowly progressive myopathy predominantly involving skeletal muscle and presenting as late as the 2nd – 6th decade of life.
Signs and symptoms
In infants, symptoms begin in the first months of life, with feeding problems, poor weight gain, breathing difficulties, profound hypotonia, and cardiomegaly.2 Many infants with PD also present with macroglossia.2
Kelly du Plessis, CEO and Founder of non-profit organisation, Rare Diseases SA (RDSA), says that the difficulty for both parents and healthcare professionals is that PD shows itself in many ways. “There is not one specific thing that you can pinpoint. My child, who is a PD sufferer, took longer to reach his milestones, and got slower as time progressed. It is better to be overcautious than under-cautious because early identification is critical to a positive outcome, and the damage done up until diagnosis cannot be undone.”
Du Plessis says that RDSA is also seeing many more adults being diagnosed with PD lately, and describes a few of the signs and symptoms: “In adults these include difficulty walking, particularly up stairs or inclines, recurring chest infections, being very fatigued, finding that their arms are getting weaker when they try to reach something on a top shelf, and falling over quite often owing to lower muscle tone and foot drop. Healthcare professionals need to be aware of this link with PD – because early intervention is critical to outcomes.”
Diagnosis
While making an early diagnosis is imperative to optimise disease management and outcomes,1 many patients experience a diagnostic odyssey.3
Monique Nel, Medical Advisor – Rare Diseases at Sanofi, says: “The diagnostic odyssey for PD can be quite long and complicated, as the symptoms can be similar to those of other conditions, and the disease is quite rare. The journey to diagnosis can take years, and many patients go through a battery of tests and specialists before finally receiving a correct diagnosis.”
In the United States it was reported that before implementation of newborn screening, there was, on average, a 3-month delay in diagnosing infantile-onset PD after the onset of symptoms.3 In late-onset PD, symptoms may begin any time from infancy to adulthood.3 In paediatric onset cases, on average: symptom onset occurs at approximately 6 years of age, yet diagnosis is generally made around 18 years of age, with a potential 12-year delay in diagnosis.3 The average age of symptom onset in adult-onset PD is 35 years, with a 7-year delay in diagnosis after symptom onset.3
Adds Nel: “In South Africa, we do enzyme activity testing via a dried blood spot test to measure the activity of the alpha-glucosidase enzyme. If the enzyme activity is low, it suggests that the individual may have PD. Genetic testing is currently performed abroad. This involves analysing a person’s DNA to look for mutations in the GAA gene. If two mutated copies of the GAA gene are found, it confirms a diagnosis of PD.”
Treatment
Enzyme replacement therapy (ERT) is available for all forms of PD, and has dramatically changed patient outcomes.3 This life-changing therapy is more effective when started before the onset of symptoms.3
Since the end of 2012, ERT (as alglucosidase alfa) has been registered with the South African Health Products Regulatory Authority (SAHPRA) for use in PD patients.1 Patients with infantile-onset PD who receive ERT have significantly prolonged survival, decreased cardiomegaly, and improved cardiac and skeletal muscle function.1 Cardiac response appears to be good, irrespective of the stage of disease at initiation of ERT, while the skeletal muscle response appears more variable.1 The best skeletal muscle response occurs when ERT is administered prior to skeletal muscle damage.1
Says Nel: “Early screening for PD and prompt treatment is crucial to prevent or delay the onset of disease complications. Therefore, healthcare providers must consider PD as a potential differential diagnosis when evaluating patients with muscle weakness, respiratory difficulties, and other related symptoms.”
Says du Plessis: “With medication, you see a difference in the patients within weeks, and they have a lot more energy. RDSA advocates as much as is necessary to get patients approved for medication, since this treatment changes their lives and quality of life – and in fact saves their lives. We need to do everything we can now, with the treatments we have today, to keep these patients as healthy as possible, so that they can benefit from the treatments that come tomorrow.”
Studies have shown that hypnosis is an effective treatment for pain for many individuals – but it depends on the patient’s susceptibility to hypnosis. Testing for hypnotisability requires special training and in-person evaluation rarely available in the clinical setting. Now, investigators have developed a fast, point-of-care molecular diagnostic test that identifies a subset of individuals. Their study, published in The Journal of Molecular Diagnostics, also found that a subset of highly hypnotisable individuals may be more likely to experience high levels of postoperative pain.
“Since hypnotisability is a stable cognitive trait with a genetic basis, our goal was to create a molecular diagnostic tool for objectively identifying individuals who would benefit from hypnosis by determining ‘treatability’ at the point-of-care,” explained co-lead investigator Dana L. Cortade, a recently graduated PhD at Stanford University. “The advancement of nonpharmacological adjuvant treatments for pain is of the utmost importance in light of the opioid epidemic.”
Prior research established that the genetic basis for hypnotisability includes four specific single-nucleotide polymorphisms (SNPs), or genetic variations, found in the catechol-o-methyltransferase (COMT) gene for a brain enzyme responsible for dopamine metabolism in the prefrontal cortex. Although SNPs can contain valuable information on disease risk and treatment response, cost, complexity and time prevent widespread use.
The investigators developed a SNP genotyping assay on a giant magnetoresistive (GMR) biosensor array to detect the optimal combination of the COMT SNPs in patient DNA samples. GMR biosensor arrays are reliable, cheaper, sensitive, and can be easily deployed in point-of-care settings using saliva or blood samples.
The study investigated the association between COMT diplotypes and hypnotisability using a clinical hypnotisability scale called the Hypnotic Induction Profile (HIP) in individuals who had participated in one of the three previous clinical trials in which an HIP was administered. An additional exploratory study of the association between perioperative pain, COMT genotypes, and HIP scores was conducted with the patients in the third cohort, who had undergone total knee arthroplasty (TKA). DNA was extracted from blood samples previously collected in the first cohort, and saliva samples were collected by mail from participants in the other two trials. Participants were considered treatable by hypnosis if they had HIP scores of 3 or higher on a scale of zero to 10.
For participants identified with the optimal COMT diplotypes by the GMR biosensor array, 89.5% scored highly on the HIP, which identified 40.5% of the treatable population. The optimal COMT group mean HIP score was significantly higher than that in the suboptimal COMT group. Interestingly, further analysis revealed that the difference was observed only in women.
“Although we had expected some difference in effect between females and males, the association between hypnotisability and COMT genotypes was strongest in the females in the cohort,” said co-lead investigator Jessie Markovits, MD, Department of Internal Medicine, Stanford School of Medicine, Stanford, CA, USA. “The difference may be due to lower numbers of males in the cohort, or because COMT is known to have interactions with oestrogen and to differ in activity by sex. Additional gene targets including COMT, with stratification by sex, could be the focus of future study.”
In the exploratory analysis of the relationship between COMT genotypes and pain after TKA surgery, the same optimal COMT individuals had significantly higher postoperative pain scores than the suboptimal group, indicating a greater need for treatment. “This supports the body of evidence that COMT genotypes impact pain, and it is also known that COMT genotypes affect opioid use after surgery. Pain researchers can use this technology to correlate genetic predisposition to pain sensitivity and opioid use with response to an evidence-based, alternative remedy: hypnosis,” Dr Cortade said.
COMT SNPs alone are not a complete biomarker for identifying all individuals who will score highly on a hypnotisability scale and experience high pain sensitivity. The GMR sensor nanoarray can accommodate up to 80 SNPs, and it is possible that other SNPs, such as those for dopamine receptors, are needed to further stratify individuals.
The investigators observe that this study highlights the utility and potential of the evolving applications of precision medicine. “It is a step towards enabling researchers and healthcare professionals to identify a subset of patients who are most likely to benefit from hypnotic analgesia,” Dr Markovits said. “Precision medicine has made great strides in identifying differences in drug metabolism that can impact medication decisions for perioperative pain. We hope to provide similar precision in offering hypnosis as an effective, non-pharmacological treatment that can improve patient comfort while reducing opioid use.”
A twin study of the relatively newly described eating disorder ARFID has found that it is strongly influenced by genetic factors. The study, perfomed by researchers at Karolinska Institutet, has been published in the journal JAMA Psychiatry.
An estimated 1 to 5% of people suffer from an eating disorder that few are even aware exists. Avoidant/restrictive food intake disorder (ARFID) is a serious eating disorder that leads to malnutrition and nutritional deficiencies, and is a relatively new diagnosis only introduced to the World Health Organization’s ICD-11 this year.
Unlike anorexia, ARFID is not about the patient’s experience of their own body and fear of gaining weight. Instead, the disease is characterised by the avoidance of certain types of food due to a sensory discomfort because of the characteristics or appearance of food, or for example, the fear of choking, a food poisoning phobia or lack of appetite.
17 000 twin pairs involved in the study
Researchers at Karolinska Institutet have now investigated the importance of genetic factors for developing ARFID. A cohort of almost 17 000 pairs of twins in Sweden born between 1992 and 2010 participated in the study. A total of 682 children with ARFID between the ages of six and 12 years could be identified.
The researchers used the twin method to determine the influence of genes and the environment on the onset of the disease.
“We know that identical twins share all genes and that fraternal twins share about half of their genes that make people different. When we then see that a certain trait is more common in both members of identical twin pairs than in fraternal twin pairs, it is an indication that there is a genetic influence. We can then estimate the degree to which a trait is influenced by genetic factors,” says Lisa Dinkler, a postdoctoral researcher at the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet.
The genetic component for developing ARFID was high, 79%.
“This study suggests that ARFID is highly heritable. The genetic component is higher than that of other eating disorders and on par with that of neuropsychiatric disorders such as autism and ADHD,” says Lisa Dinkler.
The findings are important, says Lisa Dinkler, because an increased understanding of what causes the disease can make it easier for those affected and their relatives.
“I hope that the results can reduce stigma and guilt, which is a big problem with eating disorders. A child does not choose to develop ARFID, nor can a parent cause it in a child. That is important to remember.”, says Lisa Dinkler.
Possible connections with other conditions
The next step in Lisa Dinkler’s research is to study the extent to which ARFID is associated with other psychiatric diagnoses, such as anxiety and depression, neurodevelopmental disorders, and gastrointestinal problems.
“We will use twin studies to test the extent to which ARFID shares underlying genetic and environmental factors with these conditions,” says Lisa Dinkler.
ARFID is a relatively new diagnosis. In 2013, the disorder was included in the Diagnostic and Statistical Manual of Mental Disorders, DSM-5, and this year it was included in the World Health Organization’s diagnostic manual ICD. The latest edition, ICD-11, will be introduced to the Swedish healthcare system in a couple of years, consequently, the diagnosis is not an official part of Swedish health and medical care yet.
Patients can experience 30% fewer serious adverse reactions if their drugs are tailored to their genes, reports a study published in The Lancet. A European collaboration involving researchers from Karolinska Institutet suggests that a genetic analysis prior to drug therapy could significantly reduce suffering and healthcare costs.
A significant proportion of patients experience adverse reactions to their medication. Since we each carry a unique set of genes, we react differently to the same drugs. For example, some people break them down faster, meaning that they require a higher dose to obtain the desired effect.
DNA pass that fits in the wallet
To overcome this problem, researchers from Leiden University Medical Center in the Netherlands, Karolinska Institutet and other collaborating institutions have developed the principle for a “DNA pass” that has been clinically validated in the recently published study.
“It’s basically a credit card-sized card with a magnetic strip containing all the important genetic data on a particular patient,” explains one of the study’s co-authors Magnus Ingelman-Sundberg, professor of molecular toxicology at the Department of Physiology and Pharmacology at Karolinska Institutet.
“When a patient’s card is scanned, doctors and pharmacists can work out the optimal dose of a drug for that particular individual.”
The study included almost 7 000 patients from seven European countries between March 2017 and June 2020 all of whom were genotyped with respect to variations in twelve specific genes of significance to drug metabolism, transport and side-effects. All participants then received their drugs either conventionally or with a genotype-based modification.
Twelve weeks after their drug regimen began, the patients were contacted by a specialist nurse about any adverse reactions, such as diarrhoea, pain or loss of taste. The study concluded that such adverse reactions to drugs can be greatly reduced by analysing the genes that code for enzymes that metabolise them.
“The patients who’d received genotype-driven treatment had, on average, 30 per cent fewer adverse reactions than the controls,” says Professor Ingelman-Sundberg.
Now sufficiently compelling data
Professor Ingelman-Sundberg, a long-standing expert at the European Medical Agency on the development of this method, believes that there is now sufficiently compelling data to warrant the widespread use of the DNA pass.
“I think we’ve come to the point where a genetic pass like this will be useful,” he says.
Globally, the problem of adverse reactions is considerable. In the EU, they cause up to 128 000 fatalities a year and up to 9% of all hospital admissions, a figure that more than doubles to 20% in over 70s.
“Our results strongly suggest that an initial genotyping of the patients will deliver significant savings to society,” says Professor Ingelman-Sundberg. “The genotyping itself need only be done once per patient at a maximum cost of 6,000 SEK. The general introduction of this predictive system could therefore go a long way towards reducing public healthcare costs.”
