Category: Genetics

Categories : Diseases, Syndromes and Conditions GeneticsTags :

Pompe Disease – Early Diagnosis and Treatment are Crucial

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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.”

For more information, visit: www.rarediseases.co.za

References

1. Bhengu, L, et al. Diagnosis and management of Pompe disease. South African Medical Journal 2014;104(4):273-274.

2. National Institute of Neurological Disorders and Stroke. Pompe disease. N.d. Available at: https://www.ninds.nih.gov/health-information/disorders/pompe-disease#, accessed 7 April 2023.

3. Ficicioglu, C, et al. Newborn screening for Pompe disease: Pennsylvania experience. Int J Neonatal Screen 2020;6(4):89.

Categories : Genetics Pain ManagementTags :

Whether Hypnosis for Pain is Effective Depends on a Patient’s Genetics

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Photo by Bruce Christianson on Unsplash

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.”

Source: Elsevier

Categories : Genetics Mental HealthTags :

Serious Eating Disorder ARFID is Highly Heritable

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Photo by KoolShooters

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.

Source: Karolinska Institutet

Categories : GeneticsTags :

DNA Analysis can Cut Adverse Drug Reactions by 30%

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Genetics
Image source: Pixabay

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.”

Source: Karolinska Institutet

Categories : GeneticsTags :

Genetic Variations Influence Drug Metabolism in Patients of African Descent

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Photo by Agung Pandit Wiguna

Investigators have identified new genetic variations that affect gene expression in the liver cells of patients of African ancestry, findings that provide insight into how drugs are metabolised differently in different populations, according to a study published in The American Journal of Human Genetics.

Expression quantitative locus (eQTL) studies use an individual’s genomic and transcriptomic data to uncover unique genetic variants that regulate gene expression. However, people of African descent have not been well represented in these databases.

Having this comprehensive, multiomic data is key to uncovering the mechanisms that regulate an individual’s genome and understanding how different groups of people respond to drugs differently, which can improve treatment strategies, according to Minoli Perera, PharmD, PhD, associate professor of Pharmacology and senior author of the study.

“We don’t have data from any historically excluded populations to run these analyses, so a big motivation of my lab is to create data in African ancestry populations so that they are represented in multiomics,” said Perera.

In the current study, the investigators treated hepatocytes from liver tissue samples from African American patients with six FDA approved drugs: Rifampin, Phenytoin, Carbamazepine, Dexamethasone, Phenobarbital and Omeprazole.

The investigators then performed whole-genome genotyping and RNA sequencing on primary hepatocytes treated both with and without the drugs. They also mapped eQTLs, or single-nucleotide polymorphisms (SNPs) affecting gene expression, in the liver cells.

From this comprehensive analysis, they uncovered varying transcriptional changes in the cell lines across the different drug treatments and identified NRF2 as a potential gene transcription regulator.

“NRF2 has been already identified as a very important transcription factor for drug metabolism, but this is a much more comprehensive way to look at it,” Perera said.

The investigators also discovered nearly 3000 genetic variants that affect how well hepatocytes respond to external stimuli, including drugs, which the investigators called drug response eQTLs, or reQTLs. Notably, they discovered reQTLs for drug-metabolising genes such as CYP3A5.

Most individuals of European ancestry carry a specific genetic variant in CYP3A5 which results in no/low CYP3A5 enzyme, whereas individuals of African ancestry carry that variant at a lower frequency. According to Perera, this is a problem because most participants that are recruited for clinical trials are of European ancestry, and the findings from these trials directly inform how often and how much of a drug should be prescribed to all patients, regardless of their ancestry.

“When you test drugs in a group of people with limited diversity, and then say this is the dose, this is how fast it’s metabolised, this is how often you dose the drug and then you give this medication to the entire U.S. population, we don’t know for sure how accurate those measures are, and that’s just with one variant. Other variants that may influence how much or how little we up-regulate these important enzymes,” Perera said.

Perera said her team is now expanding their work by increasing the number of hepatocytes from African American participants they’re studying and incorporating other types of omics techniques, such as epigenetic profiling.

“Almost exclusively we’ve done epigenetic screenings in European populations, so what can we find in the epigenome that’s important for African Americans. Also, because there’s more genetic variation in individuals of African descent, would that change the epigenome in ways that we aren’t able to see in Europeans,” Perera said. “We hope that what we’re doing can help annotate new studies coming along for African ancestry populations.”

Source: Northwestern University

Categories : GeneticsTags :

Why do Older Fathers Pass on More Mutations?

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Photo by Muhammad Daudy on Unsplash

It is not known exactly why older fathers pass on more mutations than younger ones do, even though the male reproductive system is a hotpot for evolution. The mechanisms that might underlie these well-documented trends have long remained a mystery. Now, a new study in the journal Nature Ecology & Evolution describes why older male fruit flies are more likely to pass mutations onto their offspring, which may hold clues for inherited-disease risk in humans.

Researchers in Li Zhao’s lab at Rockefeller University studied mutations that occur during the production of sperm from germline cells, known as spermatogenesis. They found that mutations are common in the testes of both young and old fruit flies, but more abundant in older flies from the outset. Moreover, many of these mutations seem to be removed in younger fruit flies during spermatogenesis by the body’s genomic repair mechanisms – but they fail to be fixed in the testes of older flies.

“We were trying to test whether the older germline is less efficient at mutation repair, or whether the older germline just starts out more mutated,” says first author Evan Witt. “Our results indicate that it’s actually both. At every stage of spermatogenesis, there are more mutations per RNA molecule in older flies than in younger flies.”

Genetic self-repair

Genomes have a few repair mechanisms. When it comes to testes, they have to work overtime; testes have the highest rate of gene expression of any organ. Moreover, genes that are highly expressed in spermatogenesis tend to have fewer mutations than those that are not. This sounds counterintuitive, but it makes sense: One theory to explain why the testes express so many genes holds that it might be a sort of genomic surveillance mechanism – a way to reveal, and then weed out, problematic mutations.

But when it comes to older sperm, the researchers found, the weed-whacker apparently sputters out. Previous research suggests that a faulty transcription-coupled repair mechanism, which only fixes transcribed genes, could be to blame.

Inherited or new mutations?

To get these results, scientists in the Laboratory of Evolutionary Genetics and Genomics did single-cell sequencing on the RNA from the testes of about 300 fruit flies, roughly half of them young (48 hours old) and half old (25 days old), advancing a line of inquiry they began in 2019. In order to understand whether the mutations they detected were somatic, or inherited from the flies’ parents, or de novo they then sequenced the genome of each fly. They were able to document that each mutation was a true original. “We can directly say this mutation was not present in the DNA of that same fly in its somatic cells,” says Witt. “We know that it’s a de novo mutation.”

This unconventional approach – inferring genomic mutations from single-cell RNA sequencing and then comparing them to the genomic data – allowed the researchers to match mutations to the cell type in which they occurred. “It’s a good way to compare mutational load between cell types, because you can follow them throughout spermatogenesis,” Witt says.

Applicability to humans

The next step is to expand the analysis to more age groups of flies and test whether or not this transcription repair mechanism can occur – and if it does, identify the pathways responsible, Witt says. “What genes,” he wonders, “are really driving the difference between old and young flies in terms of mutation repair?”

Because fruit flies have a high reproductive rate, investigating their mutation patterns can offer new insights into the effect of new mutations in human health and evolution, says Zhao.

Witt adds, “It’s largely unknown whether a more mutated male germline is more or less fertile than a less mutated one. There’s not been very much research on it except for at a population level. And if people inherit more mutations from ageing fathers, that increases the odds of de novo genetic disorders or certain types of cancers.”

Source:

Categories : GeneticsTags :

Genetic Radiation Damage Passed down Through Fathers

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Chromosomes. Source: NIH

Whether radiation exposure of fathers can have consequences on their children is one of the most long-standing questions in radiation biology. Using the nematode Caenorhabditis elegans as a model, University of Cologne researchers reported in the journal Nature that radiation damage to mature sperm cannot be repaired but is instead passed on to the offspring.

Female eggs with radiation damage either accurately repair it or, if the damage is too severe, are eliminated and no damage is passed on. However, when the egg is fertilised with a radiation-damaged sperm, the maternal repair proteins that are provided by the egg try to repair the paternal DNA.

For this purpose, a highly error-prone repair mechanism is used and fuses the broken DNA pieces randomly. These random fusions of the breaks then lead to structural changes in the paternal chromosomes. The resulting offspring now carry the chromosome damage and in turn their offspring show severe developmental defects. The work done on C. elegans lays the foundation for a better understanding of the mechanisms for the heritable effects of paternal radiation exposure.

This work has now been published under the title ‘Inheritance of paternal DNA damage by histone-mediated repair restriction’ in 

The offspring that results from male animals that have been exposed to radiation and healthy female worms carry on the so-called structural variations – random connections of chromosome parts. In the offspring, these aberrations lead to recurrent breaks but this damage can no longer be repaired. Instead, the damaged chromosomes are shielded from accurate repair by proteins, so-called histones, that densely pack the long strands of DNA. In the densely packed DNA, the breaks can no longer be reached by the repair proteins. The packed DNA structures are held tightly together by the specific histone proteins, HIS-24 and HPL-1. When those histone proteins are removed, the paternally inherited damage is completely eliminated and viable offspring can be produced. The finding that histone proteins govern the accessibility of DNA for repairs could provide effective therapeutic targets for treating radiation damage.

Adding to the work on nematodes, the team detected the same structural variants, or randomly assembled chromosomes, in humans. Also here, the chromosome aberrations were specifically passed on from the fathers but not the mothers. For this, the scientists analysed various data sets from the 1000 Genome Project that contains genetic data from more than a thousand people and the Islandic deCODE project with genetic data from the respective mothers, fathers and children.

“Genome aberrations, especially structural variations in chromosomes, which develop in the paternal germline, are thought to increase the risk of disorders like autism and schizophrenia,” study leader Professor Dr Björn Schumacher said. This means that also in humans, mature sperm needs to be especially protected from radiation damage, and damaged mature sperm should not be used for conception. He added, “Such damage could potentially be inflicted during radiotherapy or chemotherapy and thus pose a risk in the two months that it takes to generate new sperm to replace the damaged one.” This is because in contrast to mature sperm, newly generated sperm have the capacity to accurately repair the damage.

Interestingly, the scientists found those structural variations in the chromosomes also in nematodes in the wild and in the human population. These results suggest that damage to mature sperm and the inaccurate repair of paternal DNA in the zygote could be major drivers for genetic diversity during evolution and might be responsible for genetic diseases in humans.

Source: University of Cologne

Categories : Diseases, Syndromes and Conditions GeneticsTags :

Scientists Uncover Three Genes Linked to Multiple Sclerosis

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Genetics
Image source: Pixabay

New research published in the Annals of Clinical and Translational Neurology has identified three genes and their expressed proteins that may be involved in the pathogenesis of multiple sclerosis.

By comparing information on the genes and proteins expressed in the brains of thousands of individuals with and without multiple sclerosis, investigators discovered different expression levels of the SHMT1, FAM120B, and ICA1L genes (and their proteins) in brain tissues of patients versus controls.

Protein abundance alteration in human brain has linked to MS. For instance, protein abundance of glial fibrillary acidic protein (GFAP), myelin basic protein (MBP)3 and thymosin β-46 was dysregulated in lesions from MS patients’ brain, and these proteins have been used for disease severity prediction and targeted therapy lately. In addition, compared to bodily fluid samples like cerebrospinal fluid and plasma, human brain tissue directly reflects the pathophysiology changes of MS and has become increasingly important in disease biomarker identification. However, few studies focused on specific subregions of the brain, ignoring the possible differences in protein types and abundance between subregions with distinct functions.

Studying the functions of these genes may uncover new information on the mechanisms involved in the development and progression of multiple sclerosis. “Our findings shed new light on the pathogenesis of MS and prioritised promising targets for future therapy research,” the authors wrote.

Source: Wiley

Categories : GeneticsTags :

Down Syndrome Research Should Expand Focus to the Whole Cell

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Human chorosomes. Source: NIH

Researchers propose in The American Journal of Human Genetics a new way of looking at Down syndrome, suggesting that when an extra chromosome is present, the impact on the cell depends less on which chromosome is duplicated and more on the presence of extra DNA.

“Understanding the complexity and general nature of disease phenotypes allows us to see a bigger picture and not get stuck focusing on a single gene, due to its presence on the extra chromosome,” says lead author Maria Krivega, developmental biologist at Heidelberg University.

Every cell starts out with extra chromosomes during early embryogenesis; however, this DNA gets sorted into pairs after about a week of growth. When this process goes awry, it often leads to death of the embryo, with only a few being able to survive with the extra DNA, like in the case of Down syndrome.

By taking a step back and looking at the entire cell, researchers were able to create a new understanding of these syndromes. Krivega and her collaborators took a critical look at recent evidence suggesting that Down syndrome phenotypes arise not only because of increased dosage of genes on chromosome 21 but also because of global effects of chromosome gain.

The researchers sifted through published datasets of proteins and RNA of individuals with Down syndrome and compared these to laboratory made cells with trisomies of chromosomes 3, 5, 12, and 21. What they found from this comparison was that it didn’t matter which chromosome was in excess, the cells all had decreased ability to replicate, survive, and maintain their DNA.

“We were interested to find out why cells with imbalanced chromosomal content – in other words, aneuploid – are capable of surviving,” says Krivega. “It was particularly exciting to me to learn if viable aneuploid embryonic cells have similarities with aneuploid cancer cells or cell lines, derived in the laboratory.”

Additionally, they found that the adaptive T cell immune system was underdeveloped in all cells, while the innate immune system seemed to be overactive. The authors suggest that this is a consequence of general chromosome gain. This research can be expanded into autoimmune diseases, such as Alzheimer disease or acute leukemias in trisomy chr. 8 or 21, that also exist without any connection to aneuploidy.

“We hope that our work elucidating a complex trisomy phenotype should help to improve such kids’ development,” says Krivega.

Source: Cell Press

Categories : Cancer GeneticsTags :

Chemo Drug Ifosfamide could Increase Disease Risk for Survivors’ Descendants

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The common chemotherapy drug ifosfamide could leave a lasting toxic legacy for children and grandchildren of adolescent cancer survivors, suggests a study published online in iScience.

Researchers from Washington State University found that male rats given ifosfamide during adolescence had offspring and grand-offspring with increased incidence of disease. Other studies have shown that cancer treatments can increase patients’ chance of developing disease later in life, this is one of the first-known studies showing that susceptibility can be passed down to a third generation of unexposed offspring.

“The findings suggest that if a patient receives chemotherapy, and then later has children, that their grandchildren, and even great-grandchildren, may have an increased disease susceptibility due to their ancestors’ chemotherapy exposure,” said corresponding author Michael Skinner, a WSU biologist and corresponding author on the study.

Skinner emphasised that the findings should not dissuade cancer patients from undertaking chemotherapy since it can be a very effective treatment. Chemotherapy drugs kill cancerous cells and stop multiplication, but have many side effects, including on reproductive systems.

The researchers therefore recommend that cancer patients who plan to have children later take precautions, such as using cryopreservation to freeze sperm or ova before having chemotherapy.

In the study, researchers exposed a set of young male rats to ifosfamide over three days, mimicking a course of treatment an adolescent human cancer patient might receive. Those rats were later bred with unexposed female rats. The resulting offspring were bred again with another set of unexposed rats.

The first-generation offspring had some exposure to the chemotherapy drug since their fathers’ sperm was exposed, but researchers found greater incidence of disease in not only the first- but also the second-generation, who had no direct exposure to the drug. While there were some differences by generation and sex, the associated problems included greater incidence of kidney and testis diseases as well as delayed onset of puberty and abnormally low anxiety, indicating a lowered ability to assess risk.

The researchers also looked for epigenetic changes. Previous research has shown that exposure to toxicants, particularly during development, can create epigenetic changes that can be passed down through sperm and ova.

The results of the researchers’ analysis showed epigenetic changes in two generations linked to the chemotherapy exposure of the originally exposed rats. The fact that these changes could be seen in the grand-offspring, who had no direct exposure to the chemotherapy drug, indicates that the negative effects were passed down through epigenetic inheritance.

Skinner and colleagues at Seattle Children’s Research Institute are currently working on a human study with former adolescent cancer patients to learn more about the effects chemotherapy exposure has on fertility and disease susceptibility later in life.

A better knowledge of chemotherapy’s epigenetic shifts could also help inform patients of their likelihood of developing certain diseases, creating the possibility of earlier prevention and treatment strategies, Skinner said.

“We could potentially determine if a person’s exposure had these epigenetic shifts that could direct what diseases they’re going to develop, and what they’re going to potentially pass on to their grandchildren,” he said. “We could use epigenetics to help diagnose whether they’re going to have a susceptibility to disease.”

Source: Washington State University