Uncovering a 20 Year Old Family Murder Mystery With Genetics

In 1999, Kathleen Folbigg was convicted of murdering her four children over a ten year period. The first three children were all originally found to have died in their sleep, due to natural causes; however, the fourth death caused suspicion. Even though the fourth child, Sarah, had evidence of passing away from myocarditis (from a respiratory infection), the forensic pathologist stated that Sarah's death was undetermined after hearing about the three previous deaths. After misinterpreting her grieving diary entries, Kathleen's husband incriminated her and she was sentenced to 40 years of prison, four years later.

In 2018, Dr. Carola Vinuesa, immunologist/geneticist working at Australian National University, was contacted by a former student who wanted to discuss Kathleen. Immediately, Vinuesa was intrigued that all four children had evidence of epilepsy, myocarditis, and respiratory infections before their deaths and knew that murder may not have been the cause of their untimely death, but rather a rare genetic mutation. After taking a saliva sample from Kathleen, Vinuesa found a mutation in the CALM2 gene, which leads to heart arrhythmia and infant death. Two of the children were also found to have inherited the mutation from their mother. The other two children were found to have a rare pathogenic missense variant on a different gene (Bassoon), found to lead to cause early-onset lethal epilepsy in mice.  

In her time she spent in the courtroom, Vinuesa learned that many pieces of genetic evidence are ignored in our legal system, for they want to be entirely sure that a cause of death was from genetics alone. However, in a case where there was no actual evidence of foul play (only suspicion and strange circumstances), genetics must be taken higher into consideration. 

After five years and two legal inquiries from Vinuesa, Kathleen Folbigg was finally released from prison in June of 2023.

This discovery is incredibly fascinating and is a prime example of how important genetics is, in all areas in life. I also found this article intriguing because we have been discussing the discovery of DNA fingerprinting in the world of forensics in class the past couple weeks. There are many examples of genetics-solved-murders on television shows and movies, but to read about a real life example is truly breathtaking. 

 

SOURCES:

https://www.the-scientist.com/searching-for-the-rare-variants-in-a-genetic-haystack-72009

https://pubmed.ncbi.nlm.nih.gov/27100291/

https://www.science.org/content/article/how-geneticist-led-effort-free-mother-convicted-killing-her-kids

A Genetic Test May Reveal the Reason Behind Unexplained Epilepsy in Kids

A new study, led by Dr. Isabel Haviland, a postdoctoral research fellow in neurology/neurobiology at Boston Children's Hospital and Harvard Medical School, reveals that genetic testing may be the key to managing and treating unexplained epilepsy in children.  

The medical records of 152 children diagnosed with epilepsy were analyzed, all of which were from between 2012 and 2019. For 72% of the children who were diagnosed with epilepsy, management of their epilepsy was improved in one of four areas after genetic testing. These four areas were care coordination (48%); treatment (45%); prognosis (28%); and diagnosis (1%).

"Among the children whose treatment was affected by genetic testing: 36% had an impact on anti-seizure medication choice; 10% were eligible for gene-specific clinical trials or experimental drug use; 7% were started on a gene-specific vitamin or metabolic treatments, such as the ketogenic diet; and 3% were treated with a drug not yet approved for their type of epilepsy." (USNews)

How to Control Epilepsy

HOW TO CONTROL EPILEPSY

 

    Epilepsy is a medical condition where it affects the brain resulting in an individual having seizures. This is a long term condition to have to live with, there is not just one type of seizures; there are different types of seizures most of the time it is associated with epilepsy. For example, a person can be can be shaking and fall down, or some appears as "staring spells". 

    Some way people have manage their epilepsy are through medications, fixing their daily activities such as having a healthy diet, receiving regular amount of sleep, and lowering stress. A major necessity is to have a healthy support from family and friends. It is very important to find a specialist for this condition to continue with treatment. 

1. Epilepsy Fast Facts | CDC

2. Four Ways to Get Better Seizure Control | Features | Epilepsy | CDC

New Genetic Cause of Epilepsy Found

 

    Researchers have discovered two new gene mutations that cause epilepsy, more specifically the Familial adult myoclonic epilepsy (FAME). The two gene mutations are STARD7 and MARCH6 and they form the FAME2 and FAME3. These mutations form from repeat mutation which are mutations that are involved with neurological diseases. This explains why it is found in epilepsy. This new discovery proves to be extremely beneficial to families who have been affected with this disease because it allows a new treatment plan that could work out better for the patient themselves. With this knowledge testing is available to see the change thats able to be done for the patient which would include a more controlled form of the disease itself. Due to this form of mutation it can be very hard to find the mutation in the DNA sequence so special tools are used such as the expanded short tandem repeat algorithm. This tool can scan an entire genome to find the mutation and other tools aren't able to pick up repeat expansions. This discovery has relieved many families and patients that have had to deal with a disease that no one knew it was caused by. With this information we can begin to work on the important parts of the disease and maybe even find a cure.

https://medicalxpress.com/news/2019-12-genetic-epilepsy.html

https://www.aesnet.org/sites/default/files/file_attach/12.7%20-%20New%20Insight%20Into%20the%20Genetic%20Causes%20of%20Epilepsy_0.pdf

Epilepsy in Dogs

A few researchers from the University of Helsinki have identified the genetic cause of epilepsy in dogs. The gene associated with myoclonic epilepsy is DIRAS1 and still very little is known about it, so it is a little difficult to truly help with this condition until this is understood more. It is important to understand more so that a new treatment can be created from it.
This can help dog breeders so that they can test whether one of their dogs has the gene and refrain from passing the gene along to future puppies. It is theorized that 15% of all dogs within the Rhodesian Ridgeback breed carries the gene.
Also, there is no longer a need for dogs to be sedated in order to research epilepsy which is always a good thing. 

Link to Article
Info About Dog Seizures

Drug to Control Epilepsy

What is Epilepsy?

            Epilepsy is the fourth most common neurological disorder, which has an affect on people of all ages. This neurological disorder is characterized by unpredictable seizures and can cause other health problems such as schizophrenia and other severe mental illnesses. Epilepsy is a spectrum condition, which has a wide variety of seizure types varying from person to person. The seizures in epilepsy could relate to a brain injury or a family history of the disorder, but this cause has no cure and the treatment may work for some others can't be treated even with the most high dose medication.

Is Epilepsy Inherited?

           From the many types of epilepsy, not all of them are inherited, but in the case of generalized epilepsy it is inherited because it includes many genetic factors than partial factors. Overall, the risk of having or getting epilepsy is greater for a child whose father has the disorder, but not if the mother has it. And if both mother and father have the disorder the risk becomes much higher. For people who have epilepsy, they are allowed to have children without taking much consideration because most of the time these factors don't play a role in their children except in the worse case scenario where the child has brain damage such as a concussion.

What drug is able to control epilepsy successfully?

             A study has been done on two different drugs, one is Aptiom which is a one-a-day drug and the other is Tegretol and Carbatrol, which are twice-a-day drug. From the two type of drugs both have been successful. This is because the study was conducted on more than 800 patients who were diagnosed with partial epilepsy and as a result 71% taking the first drug and 76% taking the second drug were seizure-free. This test was conducted over the course of one year resulting 65% taking the first drug and 70% taking the second drug were still seizure-free. Overall, scientists and pharmaceutical companies recommend that the once-a-day drug is more helpful to the patients with memory problems and it has a more stronger impact on the disorder than the other drug.

*I believe that the drugs will help shape the future of these patients who have epilepsy. The drugs already developed are basically acting like DDT on pesticides. Based on this article I hope these medications don't ware of in the future. We have too many people getting this disorder but too few who can do anything about it. I have even saw many other drug alternatives that can be of treatment of epilepsy such as cannabis but I believe it can cause tolerance to the substance itself because of the high amounts of THC.   

Gene Mutations Found To Be Causing Pediatric Seizure Disorders

A new genetic mutation has been found that may be causing deadly seizure disorders in infants and young children. Epileptic seizures are caused by neurons firing, which create bursts of electrical activity in the brain. This study focused on developmental epilepsies, specifically early myoclonic encephalopathy, Ohtara syndrome, and infantile spasms. Developmental epilepsies occur after birth, in some cases only hours after, and can be fatal. Individuals who survive the seizures typically suffer from developmental disabilities, autism, and seizures for the remainder of their lives. 

The gene containing the mutation, salt-inducible kinase 1 (SIK1), has been found to play a role in gene and protein interactions in neurons that help to cause seizures. SIK1 regulates another gene, myocyte-specific enhancer factor 2C (MEF2C), which is known to be associated with severe seizures. Cellular machinery in neurons are interfered by mutated versions of these genes and hinder proper development.

          This study is vital to those who have children who suffer from developmental epilepsies. It can help to identify which patients may benefit from specific treatments and which will not. It is critical to identify which individuals will not benefit from treatment, as the drug used most often to treat development epilepsy is Adrenocorticotropic hormone (ACTH). ACTH is very expensive and can lead to severe side effects, and is only effective in about forty percent of cases. This study will improve treatment of patients suffering from developmental epilepsy and hopefully save those, who would otherwise not benefit from the treatment, from the drugs side effects.

Related Link

New 'master regulatory gene' identified as target to new epilepsy treatments

Researchers from Imperial College London, implementing a 'systems genetic' approach to study epilepsy, have discovered a gene that they consider to be a master regulatory gene for the disease. Epilepsy is a brain disorder marked by an abnormal pattern of neuron activity. Individuals who have epilepsy experience strange sensations, emotions, behavior and sometimes even convulsions, muscle spasms, and loss of consciousness. This disease, although very common, is very serious as it increases an individual’s mortality rate two to three times higher compared to the general population.

Epilepsy is known to have a strong genetic component; however, there a multiple factors involving hundreds of genes that have been related to the risks of epilepsy. Because multiple genes contribute to this disease, researchers have utilized 'systems genetics' to analyze several genes affiliated with the disease, rather than just analyzing one gene. This method has provided researchers with an insight on how these genes are coordinated in the brain and how they play a role with the disease.

More notably, found in the brain tissues of epileptic patients, researchers have identified a gene, known as Sestrin 3 (SESN3), that acts as a major regulator in the epileptic gene network. They have determined the gene to be a 'master regulatory gene' since it acts as a major control point in the epileptic gene network. Researchers are now targeting SESN3 to pave way a new method of treating epilepsy patients more effectively.

Given the discovery of this gene in relation to epilepsy, once targeted in the brain, it may be possible to control the entire epileptic gene network. This would be a remarkable method to develop medication that will work more effectively and give rise to new disease-modifying therapies that can help patients as well.

Epilepsy and Genes

Research teams at Scripps translational science institute has found a new genetic cause of a rare epilepsy that begins in early childhood. After sequencing an entire genome the researchers located a mutation in the KCNB1 gene after using a 10 year old girl from San Diego who has this rare form of epilepsy.

The KCNB1 regulates the flow of potassium ions through neurons, this affects how the cells communicate with one another. The finding of this has allowed new treatment options for children with a case of epilepsy encephalpathy. The research team allowed for this girl to improve drastically, from her almost seizing 25 times a day to less now. The scientists believe that with this finding she will only keep improving in time.

I think this finding is amazing. It could help childrens lives completely, from seizing many times a day and not being able to living their lives to being able to have an almost funtional normal life. If the treatments keep increasing because of the findings, I think that this could help the children that have this rare form of epilepsy.

Article Link: http://www.medicalnewstoday.com/articles/264705.php

Supporting link: http://neurology.stanford.edu/epilepsy/patientcare/videos/e_09.html

The Missing Link Between Fragile X Syndrome and Autism Spectrum Disorders

For a while, scientists have known that humans born with Fragile X Syndrome (FXS) have a high chance of being placed on the autism spectrum, but it was not known why this occurred. We knew that fragile X syndrome is characterized by an error in the production of the FMRP protein. We also knew that autism spectrum disorder (ASD) involves changes in normal brain development to effect social skills, empathy, learning ability, and speech. Therefore it was long theorized that the FRMP protein could be a factor in neurodevelopmental disorders, such as ASD.

Scientists have now obtained study results to support the idea that the FMRP protein does have an effect on embryonic development in the cortex of the brain. More specifically, FMRP is responsible for creating N-Cadherin. N-Cadherin helps neurons to reach their final positions in the cortex, and allow for the brain to be properly connected. Since this brain connectivity is lacking in someone with ASD, this may be a link to show the reasons why Fragile X Syndrome is highly associated with Autism Spectrum Disorder.

This study did not just give the reasoning for the link between FXS and ASD. The study also involved introducing the proper FMRP protein in mice embryos before birth to find out if it was possible to change the brain's wiring properly to potentially reduce or stop ASD from developing. It was shown that introducing the proper protein did have positive effects on the proper wiring of the cortex.

Those diagnosed with Fragile X Syndrome are highly affected by their disorder. With this, about 1/3 of those affected are also diagnosed with ASD. 15% are also affected by severe epilepsy. All three of these disorders are due to errors in development of the cortex. With this research, it could help treat or prevent Fragile X disorder in those with a genetic pre-disposition for it. Being able to help treat a disease with genetic factors is an important thing. It will allow for genetic reproduction without worry as to whether or not the offspring will inherit it.

Article: http://www.medicalnewstoday.com/releases/285578.php

New cause for Progressive Myoclonus Epilepsies (PME) has been identified.

     One of the most devastating forms of epilepsy is progressive myoclonus epilepsy. An team of researchers have discovered a new gene that causes this type of epilepsy. It was shown that a single mutation in a potassium ion channel is the main reason for this disease. Researches at University of Helsinki, Finland and Universities of Melbourne and South Australia have identified a new gene for a progressive form of epilepsy. 

     Progressive myoclonus epilepsies (PME) are rare and inherited. They are usually childhood-onset neurodegenerative diseases. The goal of the study was to identify underlying genetic causes in 84 PME patients. They did so using DNA sequencing targeting the protein coding elements of the human genome. A genetic diagnosis was found for 1/3 of the unsolved patients. The most successful finding from the study was that a single mutation in a potassium channel encoding gene (KCNC1) is the cause for a large number of unsolved PME patients. They found that there was a mutation was found in 13 patients that were not inherited from parents, as usual. It had emerged in a germ cell of one of the parents or in the fertilized egg. It was found that each of the 13 patient had dozens of these new mutations, however, they are rarely disease causing. The researchers estimate that this mutation occurs in roughly 1 out of every 5.7 million, being very rare. However, with such a large population on earth, t at least hundreds of people could have this mutation globally.

     "A fascinating aspect of this finding is that this single mutation can be found in several patients all over the world. The mutation site is an example of a 'mutation hotspot' of the genome - a DNA nucleotide which is more prone for alterations", says Professor Anna-Elina Lehesjoki, the corresponding principal investigator of the study in University of Helsinki and Folkhälsan Research Center, Finland. "The fact that the mutation occurs in a well-characterized ion channel gives hope to development of targeted therapy. There are anti-epileptic drugs in the market that target other similar ion channels and follow-up research aims to discover a way to rescue the function of the channel in PME patients."

     The mutation disrupts the function in a potassium channel, which has a central role in signal transmission in the brain. The mutation causes in inhibitory signals in certain parts of the brain to be reduced, which makes patients more susceptible to epileptic seizures and myoclonus in early childhood stages. The mutation also causes degeneration of the cerebellum and subtle cognitive decline.

     I think these findings really bring epileptic studies a long way. The knowledge they now have could potentially aid in diagnostics and potential therapeutic medications for the disease. The study also proved how significant DNA technologies are and how powerful they are in understanding the underlying genetic causes of severe diseases.

Article: http://www.medicalnewstoday.com/releases/285642.php

Scientists discover new Gene for Devasting form of Epilepsy

In the journal Nature Genetics, An international team with members from University of Finland and the Universities of Melbourne and South America reported their findings on a new genetic cause of progressive myoclonus epilepsy; it is one of the most devastating forms of epilepsy that emerges in early childhood and can result in early death. Progressive myoclonus epilepsy (PME) are very serve and rare form of epilepsy and can arise from hereditary metabolic disorders. The main symptoms that happen are epileptic seizures, debilitating involuntary muscle twitching, muscle rigidity, unsteadiness, and mental deterioration.

                                                 

For the research, the team accepted 84 patients with PME of unknown causes and sequenced their DNA's to pin point potential genetic causes of the disorder. The team found a unknown mutation in the potassium ion channel gene called KCNC1. It was present in 11 out of 84 patients and another two patients in a secondary cohort. It is said to be not inherited from the patients biological parents. The cells build-up concentration of ion inside which creates voltage difference. The researchers suggest the effect of the mutation is to reduce the inhibitory signals' making the people affected susceptible to epileptic seizures and myoclonus starting in childhood. Professor Lehesjoki says because the mutation occurs in will-known ion channel, there is hope of developing therapy that can target this. There are medications like anti-epileptic drugs in the market that target other similar ion channels. They are also planning on future research being done in this field. I think this is a great finding because it can lead to cures for PME.    

http://www.medicalnewstoday.com/articles/285582.php  
 

Neurons Derived from Human Stem Cells Reduce Seizures in Mice

Stem cell derived interneuons integrated into an epileptic mice's brain. 

Scientists at McLean Hospital and Harvard Stem Cell Institute have developed a new strategic approach in helping patients who suffer from epileptic seizures. Associate Neurobiologist Dr. Sangmi Chung successfully transplanted human neurons derived from embryonic stem cells into the brains of mice with epilepsy. The neurons had a special seizure-inhibiting factor. Once the neurons were transplanted into the mice, "The transplanted neurons begin to receive excitatory input from host neurons and in turn generate inhibitory responses that reverse the electrical hyperactivity that cause seizures;" explained Dr. Chung. Half of the mice in the study did not show any signs of seizure activity. The other half of the mice studied showed a diminished amount of seizure frequency.

Before testing on humans, further studies on primate must be conducted. However, the research done so far is very promising. Embryonic stem cells can be differentiated into many other cell types, even when they become neurons. For this reason, the neurons must first need to be purified before entering a human’s brain to ensure that only the interneurons (seizure-inhibiting) are transplanted. This is simply as a precaution to guarantee that cells transplanted into humans are safe without any risk of causing harm to the patient. The researchers are currently working on a method to extract only interneurons from their derived stem-cell neurons.

Approximately 65 million people suffer from epilepsy. Of those, many receive anti-seizure medication. However, approximately 33% of epileptic patients cannot reap the benefits from anti-seizure medication. The medication fails to decrease the seizure activity in their brain. Those who can’t take medication have the option of having the seizure-causing area of their brain removed. It is believed that people with epilepsy have minuscule amounts of interneurons in their brains. This new research takes a step forward for those patients who can’t take anti-seizure medication. It is definitely a new therapy that hopefully makes progress in the years to come.

Article: http://www.sciencedaily.com/releases/2014/11/141106132206.htm

Article Related: Interneurons - http://education-portal.com/academy/lesson/interneurons-definition-function-quiz.html

Ghost Illusion Created in the Lab

EPFL researchers in Switzerland have finally revealed how they recreated the illusion of a ghost in the laboratory. Olaf Blanke's research team demonstrated that an unusual "feeling of presence" actually occurs because of alterations in sensorimotor brain signals. Many of these "feelings of presence" occur in people with neurological or psychiatric conditions. 

The researchers did an experiment where they analyzed the brains of 12 patients with neurological disorders, most of them having epilepsy, that have experienced these "feelings of presence." They found that these patients had alterations in three areas of the brain: the insular cortex, parietal-frontal cortex, and temporo-parietal cortex. These three areas are involved in self awareness, movement and sense of position in space. They then took these patients and blindfolded them and had them perform movements with their hand in front of their body. 

The first half of this experiment consisted of them doing a movement while a robot behind them reproduced the same movement and touching them on the back. Since the first part of the experiment consisted of both of these happening at the same time the patients did not think anything of it, the brain was able to balance it out. The second half consisted of the patient doing a movement and the robot reproducing it but at a delayed time. This distorted the temporal and spatial perception in the brains of the patients. After a few minutes of the touch being delayed many patients said that they felt the "feeling of presence" and some of them actually felt it so strongly that they asked to stop the experiment. 

They used this experiment to prove that ghost illusions are actually caused by an alteration of perception due to an alteration of the sensorimotor brain signals. They also used this information to explain why people with schizophrenia often suffer from hallucinations and delusions. 

I found this article very interesting because I never thought that a "feeling of presence" could simply be from an alteration in sensorimotor cortex. Although I am a full believer of spirits and I do think that experiments and information like that can cause people to become more skeptical. 

http://www.sciencedaily.com/releases/2014/11/141106131849.htm

Discovery of Genetic Defect Which Triggers Epilepsy

In an investigation led Elisabeth Stogmann with Cairo's Ain Shams University and the Helmholtz Centre Munich, have identified a gene behind an epilepsy syndrome, which could also play an important role in other idiopathic (genetically caused) epilepsies. The research was focused on an Egyptian family in which 5 sick children resulted from a marriage from a first cousin to a second cousin.

They found that CNTN2 undertakes an important function in the attaching potassium channels to the synapses. Potassium channels are designed to allow the flow of potassium ions across the membrane, but to block the flow of other ions--in particular, sodium ions. This page goes more into depth about potassium channels.

The mutation they found makes it no longer possible to generate this protein and then, the potassium channels no longer remain attached to the synapses. The researchers believe that the epilepsy in this family is triggered by the altered function of the potassium channels.