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.