A Series of Unfortunate Events

Edward and his parents on his 18th birthday

After losing 6 children to the same disease, Sharon and Neil Bernardi never wanted to lose yet another hope. They did all that they could just to keep their son alive. However, they still lost their fighter to the disease on 1st March 2011. Edward Bernardi, aged 21, was the oldest surviving patient of the deadly mitochondrial disorder known as Leigh's Disease. He was diagnosed with the disease when he was four and a half year old and things were predicted to be gloomy. However, something was different about Edward. He was a miracle who pushed through the predicament and survived way longer than any person could expect. He lost a sister when he was 11, who was not as fortunate as he was, as she died from a condition hours after birth.

Sharon and a 1-year-old Edward

'When you've lost six children, you want to give him everything you can and that's what we did with Edward.'--Sharon Bernardi

Just when it seemed like things were looking better for Edward, after surviving through many years past the expected lifespan of 5 years, his condition started to worsen and he was admitted to the hospital in December 2010. According to his parents, he seemingly lost all hope and determination after being discharged from the hospital in January 2011. Despite the lack of willpower observed in Edward, nobody expected his sudden departure just months later, especially his parents. It had been extremely tough on the parents to have lost their seventh hope, the last that they thought could have lasted longer than it did. Sharon, who was a full time carer to Edward, expressed that she still could not accept the fact that Edward is no longer around. 

Sharon and Edward Bernardi

"I keep thinking he should be awake now, i don't think it's hit me yet. It's hard"

Edward was the eighteenth child in the family to have lost a battle with Leigh's disease. Sharon's mother had experienced a loss of 3 children and her extended family lost 8. Incurable as it seems right now, the Bernardi family hope to see more advancement in the medical field to help save lives from the disease, and to prevent more devastation that future generation parents might experience, the same way they did. 

Sharon and the 11-year-old Edward

'It will be too late for me but it would be an amazing thing if scientists and doctors can prevent this in the future.'

 Interview with Sharon Bernardi about Edward

Leigh's Disease - The Killer

What caused such devastation in the Bernadis and many other families is a deadly disease known as the Leigh's disease. 

 

Isaac Farooq Malik, Jacob Wright,Isabella Carreiro, and many more who died from this deadly disease are deeply missed by all of their families.

Leigh's Disease--What is it?

• A neurometabolic disorder that degenerates the nervous system
• Cause seizures and premature death. 
• Affecting 1 in 40,000 newborns
• Rare genetic disease
• Usually occurs in the early years of life

• Primarily caused by a defect in the mitochondria, which serves as a power house to supply energy required for the proper functioning of the body as well as survival.
•  Deficiency in one or many enzymes that are play a role in important metabolic pathways, that is involved in the generation of energy 
• Deficiency of enzyme is due to defective genes. A single mutation in one of 30 genes results in the disease. 
• Genes involved can be nuclear DNA or mitochondrial DNA.

Biochemistry behind the Cause

Leigh's disease is caused by the lack of enzymes in the mitochondria. The mitochondria act as a power house for the body to produce energy from the metabolism of carbohydrates. These enzymes accelerate the rate of biochemical reactions and facilitates pathways involved in the production of energy in the body for survival. However, in Leigh's disease, due to the lack of  functional enzymes, they result in the decrease in energy production in the body, which can be highly detrimental and fatal.

Examples of these enzymes are cytochrome C oxidase and pyruvate dehydrogenase.

 

 At cellular level, the biochemistry behind the lack of energy by the mitochondria is due to the deficiency in  enzymes that are involved in metabolic pathways occurring in the mitochondria. Examples of such metabolic pathways are oxidative decarboxylation and electron transport chain.

1. Oxidative Decarboxylation and Pyruvate Dehydrogenase 

Pyruvate dehydrogenase is an enzyme that is involved in oxidative decarboxylation. In a Leigh's Disease patient who is deficient in this enzyme, his/her gene that codes for this enzyme is defective. 

What the defective gene results in is the disruption in the production of a metabolite necessary for the downstream production of energy. In order to produce energy, Acetyl-CoA is required to be produced from pryruvate (a metabolite from the process of glucose catabolism) so that it can continue into the Krebs cycle to produce more direct energy and alternative forms of indirect energy (FADH2 and NADH) which can be converted into direct energy for use. The progression into other metabolic pathways is necessary to extract the complete amount of energy from each glucose molecule, which would then be sufficient for sustaining life. Without progression into Krebs Cycle and Electron Transport Chain, there would be insufficient energy for the body.

2. Electron Transport Chain and Cytochrome C oxidase 

Cytochrome C oxidase, also known as Complex IV is highly essential in the metabolic pathway occurring in the mitochondria. In patients diagnosed with Leigh's disease, SURF1 in their nuclear DNA is impaired.This gene codes for information and protein required to assemble a functional Cytochrome C oxidase. With it being defective, it results in a non-functional or absence of this enzyme, this affecting energy production

   

A defective or missing Cytchrome C oxidase results in the decrement in energy production via the following biochemistry. This enzyme is involved in a process called Electron transport chain, that helps to produce majority of the energy required by the body. In a normal person with functional enzyme, this is done by establishing a Proton Gradient as protons are pumped out when they transfer electrons from one to another. When a gradient is formed, the protons would diffuse back to where it was originally from through ATP Synthase, resulting in the generation of energy. The amount of protons being pumped out thus determines the amount of energy produced. Given that there are no deficiencies in the enzymes and each enzyme pumps out the correct amount of electrons, there would be a lot of energy produced, which is sufficient for life. However, the deficiency of Cytochrome C oxidase causes a decrease in the amount of protons that are pumped out. This results in a decrement in the energy produced. With lesser energy produced, there would be an adverse effect on tissues and cells, as all of these require energy to work.

Inheritance and Adverse Effects

Depending on the different ways Leigh's disease is inherited from the parents, different enzymes may be defective in the patient as different defective genes are passed on.

• Can be inherited in the form of autosomal recessive, X-linked recessive, autosomal dominant or mitochondrial inheritance pattern. 

Symptoms and Effects

• Result in:

1. Developmental delays

2. Hypertonia 

3. Lactic acidosis.

• Individuals may also experience: 

1. Respiratory discomforts

2. Neurological dysfunction

3. Abnormalities of the eye and heart.

A Glimmer of Hope

Leigh's Disease is caused by various deficiencies in one or more types of enzymes and can result in more than one consequence. Depending on the type of enzyme deficiency and resultant effects, there are a number of treatments that can be administered. However, there is currently no specific permanent cure for such a mitochondrial disorder.

 

What Can Be Done Now -- Common Prescriptions

•  Thiamine and vitamin B1

Help to temporarily slow down the progress of the disease and relive the uncomfortable symptoms experienced.

• High fat, low carbohydrate diet.

 For patients who are diagnosed to be deficient in pyruvate dehydrogenase.

• Oral sodium bicarbonate or sodium citrate.

 In cases of patients who experience lactic acidosis.

•   Tris-hydroxy-methyl-aminomethane  

In other severe cases. Aim to lower the high acid levels in the blood and the brain.

•  Reference to an ophthalmologist 

In events of eye problems. Seeking professional assistance to get more help to ease the condition.
 

A Glimmer of Hope - Too Far Away

To prevent similar occurrences of such unfortunate events in future families with parents whom have been genetically identified to bear the possibility of giving birth to a baby with such disorders, the medical field have made certain breakthroughs in their experiments and research to help benefit more people. One of such treatment is known as the Three-Parent-In-Vitro-Fertilization (IVF).

British's take on 3-Parent IVF treatment.

UK's take on 3-Parent IVF treatment

Under this treatment, the genes that are responsible for the defective mitochondrial enzymes are replaced with functional ones, thus resulting in a healthy baby. As much as this treatment provides great promise in creating a future void of all mitochondrial diseases, this treatment has yet to receive the green light in the world because of various ethical issues and safety concerns. Since the resultant baby would have 3 genetic parents and it involves the manipulation of the original DNA that the baby was supposed to inherit, some of the people stated that this treatment was ‘meddling around with the delicate building blocks of life'. In addition, this technique also has its limitations in safety. Under the current law, only after the embryo have been placed in the mother's womb and left to develop for 14 days, then will they be allowed to screen the embryo for any long-term health implications. Hence, this technique is not exactly the best alternative to guarantee that the baby is healthy. There is always a possibility of producing a baby that is inflicted with long-term health implications in the process due to unforeseen circumstances, which may result in the endangered lives of the baby and the mother. Nonetheless, Britain and United Kingdom are intending to go ahead with this treatment because they see a great potential in it to successfully prevent such inherited diseases that affect many families in their country.

A Glimmer of Hope - A Step Away

The above mentioned treatment mainly targets mothers who have been diagnosed with the possibility of passing her defective mitochondrial genes to the children, thus resulting in the disease. However, there are currently children who are born with the disease and they are struggling to survive. Their parents would not have known that their child would suffer under the fate of Leigh's Disease until they are born. This would only mean that the parents would have to inevitably undergo the fear and pain of losing their child to such a genetic disease any moment, just like the Bernadis. For now, there are no approved drugs in the market that are able to treat Leigh's Disease in the children who have received confirmed diagnosis. For parents like Lori Martin who has a child with Leigh's Disease, a glimmer of hope was seen when the scientists have successfully created an experimental drug that provides some promise in reversing the effects of the disease. It allows the syndrome to be considered as curable in the near future. This drug is known as the EPI-743, developed by Edison Pharmaceuticals. It is currently in the clinical trials phases and one of the subjects in the trial is Will Martin. Will Martin was diagnosed with Leigh's Disease and is predicted to not survive past his seventh birthday. His mitochondria are producing energy that are barely enough to keep him alive. Currently, he is under the treatment of EPI-743 and is producing results which reflect progress in his condition. His mother, Lori Martin, is keeping her hopes high as she commented that Will has been taking EPI-743 for over a year, and she thinks it's helping. He has fewer falls, better bowel movements and has started to talk in sentences.

A Hope or A Disappointment ?

As much as this drug shows great promise, it is still not approved by the FDA and is in the midst of clinical trials. The only way for parents to get their hands on the drug and grab onto that glimmer of hope in curing their beloved ones, is to send their children as subjects of the clinical trials. However, there are specific criteria that are required in order for them to qualify for the trials. Hence, the drug still remains unreachable for many children out there in the world, who may lose their life any moment. They might be unable to live long enough to witness the approval of an official cure that they have been waiting all their life. So far, the clinical trials are going smoothly and it is highly possible that in the future, it is able to help cure thousands of children inflicted with the disease.It is unapproved but currently, it is the only hope that people can pray for and hold on to.