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MitoSure | Screening

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Mitochondrial Diseases Mitochondrial Genetic Mutations
Advantages of NGS Process Flow


Mitochondrial Diseases

Mitochondrial diseases are a group of heterogeneous diseases caused by dysfunction due to genetic mutations in the mitochondrial genome or mutations in the nuclear genome which has an effect on the structure, function and integrity of the mitochondria. Mitochondrial diseases occur at an estimated frequency of 1:2000 to 1:5000 individuals, making it one of the most commonest  genetic  diseases. The mitochondria has a small genome, approximately over 16 kilo bases in length and encodes for a handful of genes. The mitochondrial genome is known to encode for 37 genes. 


  1. How does Mitochondrial Disease affect the body?

The parts of the body that need the most energy, such as the heart, brain, muscles and lungs, are the most affected by mitochondrial disease.  The affected individual may have strokes, seizures, gastro-intestinal problems, (reflux, severe vomiting, constipation, diarrhoea), swallowing difficulties, failure to thrive, blindness, deafness, heart and kidney problems, muscle failure, heat/cold intolerance, diabetes, lactic acidosis, immune system problems and liver disease.

  1. What symptoms could an undiagnosed individual exhibit?

The child or adult may have seizures, severe vomiting, failure to thrive, heat/cold intolerance, poor muscle tone, delayed achievement of milestones, severe diarrhoea/constipation, feeding problems, unable to fight typical childhood infections or repeated infections and fevers without a known origin.  A "red flag" for mitochondrial disease is when a child or adult has more than three organ systems with problems or when a "typical" disease exhibits atypical qualities. 

  1. Is Mitochondrial disease a childhood disease or it can affect adult also?

Although mitochondrial disorders are commonly seen in infants and children, they can occur at any  age. Some of these individuals have been ill through their whole lives but went undiagnosed.  Others have carried the genetic mutation that causes mitochondrial disease since birth but did not show any symptoms until a severe illness brought them on.  Adult mitochondrial disease patients are affected in a similar manner to the children who are affected.

  1. When is someone with Mitochondrial Disease at highest risk?

The child or adult with Mitochondrial Disease is at highest risk for neurological and organ damage during and for two weeks following an illness.  Therefore, even a simple flu or cold virus can have devastating effects on the patient. Any illness must be treated immediately with medical interventions.

  1. If parents don’t have any symptoms of a mitochondrial disease, is there any chance that their children can have a mitochondrial disease?

Parents can be ‘genetic carriers’ of a mitochondrial disease. This means that each parent has inherited a defective gene but do not show symptoms of the disease. However, ‘carriers’ are able to pass the defective gene onto their children.

Mitochondrial Genetic Mutations

  • Mitochondria has a high mutation rate, approximately 100 times that of the nuclear genome.  
  • Mutations which cause mitochondrial diseases are very well studied and catalogued. This encompass approx. 73 mtDNA functional loci and around 580 disease associations.
  • Mitochondria exhibit a unique property of hetroplasmy, which is defined as the existence of more than one type of organellar genetic material in a single mitochondria or in an individual. 
  • Approximately about 90% of the individuals carry at least one heteroplasmic site and ~20% of the individuals harbour heteroplasmies reported to be implicated in disease.

Diagnostic Workup of Mitochondrial Diseases

Molecular Genetics

Molecular genetics can confirm the genetic defect and therefore the diagnosis of disease. Understanding the molecular defect is also required for further counselling, carrier detection and pre-natal testing.

Biochemical Workup

Elevated Lactate and Pyruvate levels point to a defect in respiratory chain. The abnormal ratio will point to the type of defect. Serum Creatine Kinase might not be elevated in all cases, but high elevation would suggest to a mitochondrial depletion syndrome.

Family History and Inheritance

Mitochondrial diseases are typically maternally inherited.  A detailed family history would provide insights into the inheritance. Specifically ask for signs like deafness, opthalmoplegia, short stature, neurological/ muscular illnesses, sudden cardiac death.


Advantages of Next Generation Sequencing

Traditional capillary sequencing methods issued for the mitochondrial genome which is time-consuming, tedious and expensive. In a regular setting, this would involve amplification of 24 genomic loci independently followed by sequencing. Additionally, since capillary sequencing measures fluorescence of the pool of amplicons at each position, cannot accurately identify low frequency heteroplasmy.

Mitochondrial genome sequencing using Next Generation Sequencing (NGS) approaches can obviate low frequency hetroplasmy due to large number of reads to determine the mutation. At higher coverages, accurate estimation of even 10% heteroplasmy was possible using Next Generation Sequencing.

High throughput of mitochondrial genome using Next Generation Sequencing (NGS) enables to sequence hundreds of mitochondria for determination of most commonly occurring diseases. This reduces the cost of screening for individuals.

Manifestation of Mitochondrial Disease can be heterogeneous

  • Stroke, Ataxia, Epilepsy, Encephalopathy, Migraines
  • Deafness, Optic Neuropathy, Retinopathy,  External Opthalmoplegia
  • Cardiomyopathy, Conduction Defects
  • Liver Failure, Renal Failure, Anemai
  • Muscle Weakness, Cramps, Atrophy, Exercise Intolerance, Hypotonia
  • Diabetes Mellitus
  • Intestinal Pseudoobstruction, Diarrhea
  • Peripheral Neuropathy 


  • Mitochondrial Encephalomyopathy
  • Maternally Inherited Leigh Syndrome (MILS)
  • Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS)
  • Leber Hereditary Optic Neuropathy (LHON)
  • Maternally Inherited Diabetes and Deafness (MIDD)
  • Mitochondrial Cardiomypathy
  • Mitochondrial Myopathy
  • Chronic Progressive External Ophthalmoplegia (CPEO)

Process Flow

  1. Blood Collection
  2. Isolation of Mitochondrial Genome
  3. Sequencing of Mitochondrial Genome at 1000x coverage using NGS Platform-Illumina MiSeq/NextSeq.
  4. Automated Bioinformatic Analysis using MitoMatic pipeline.
  5. Report / counselling

How to collect and refer samples for

  1. Informed Consent and Documentation

Use the clinical scoring sheet to evaluate whether the patient has mitochondrial disease. Inform the patient about the test, its benefits and caveats. Get the informed consent and fill in the referral form.

  2. Sample collection

Collect whole blood by venepuncture. It is always best to use Acid Citrate Dextrose (ACD) vacutainers (Yellow cap) to collect blood. Please mark the tubes appropriately. Alternative body fluids/samples may alsobe collected, but first confirm with the laboratory.

  3. Transportation

Ship the tubes at room temperature to the Eurofins Clinical Genetics address. Please do not refrigerate.