Overview

Mitochondria are known as our body's power plants. They burn the sugars, fats and proteins in our diet to generate the energy that our body needs to function normally. When our mitochondria don't function correctly this can impact our health.

The impact on health can present at birth or develop later in life and there is no cure.

What is this test?

Testing for mitochondrial disorders is performed using biochemical/enzymology methods and molecular DNA testing. The best method for testing depends on the age of onset, clinical symptoms, family history and results of screening tests (metabolic and imaging).

Testing is performed on blood, urine, skeletal muscle, liver, cardiac muscle, or cultured skin fibroblasts (see below for requirements).

What conditions does this test look for?

This test is looking for a number of different mitochondrial disorders, including Leigh syndrome, Alpers syndrome, Kearns Sayre syndrome, Pearson syndrome, MELAS, MERRF, Leber’s hereditary optic neuropathy, CPEO, mitochondrial hepatopathy, mitochondrial cardiomyopathy and other mitochondrial encephalopathies.

These disorders arise because the body is unable to generate energy properly. Every cell in the body needs functioning mitochondria and if they aren't working properly, it can lead to a range of symptoms. At one end, symptoms include an intolerance to exercise, through to more severe symptoms such as neurodegeneration, blindness, deafness, seizures, muscle weakness, heart, liver or kidney failure. In some patients, these symptoms can occur within the first few days of life, and for others, symptoms present in adulthood.

Mitochondrial

Disorders of mitochondrial energy generation can be caused by primary mutations in mitochondrial DNA (point mutations and single deletions) and secondary mutations in mitochondrial DNA (multiple deletions or depletion of mitochondrial DNA) caused by nuclear gene disorders. The range of testing offered by VCGS includes a panel of 22 of the most common mitochondrial DNA point mutations and tests for mitochondrial DNA deletions and depletion.

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Disorders of mitochondrial energy generation can be caused by mutations in approximately 200 different nuclear genes as well as in mitochondrial DNA. Mutations in some nuclear genes cause distinct genotype/phenotype correlations that may prompt candidate gene analysis. Autosomal recessive SURF1 mutations are a common cause of Leigh syndrome, particularly when there is relative cognitive sparing.

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Defects in the mitochondrial respiratory chain cause a diverse spectrum of conditions. Some enzyme defects affect one enzyme (e.g., isolated complex I) while others cause combined defects (e.g., combined complex I and IV). The pattern of enzyme deficiency can be useful in guiding and validating mutation analysis.

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How do I arrange a test?

Testing is performed when an individual is suspected of having a mitochondrial disorder. This can be at any age but often occurs in the newborn period or infancy. Testing can also be performed in early childhood, adolescence, in young adults or in middle age. This is a specialised test that is usually ordered by a paediatrician or other medical specialist.

Frequently asked questions

What are mitochondria?

Mitochondria are organelles in all our cells that take part in a wide range of metabolic pathways. They are the body's power plants that burn fuels (sugars, fats and proteins) to generate energy in the form of a small molecule called ATP.

The mitochondrial respiratory chain or oxidative phosphorylation system is the central energy generating pathway in cells. It comprises five enzyme complexes located in the mitochondrial inner membrane. More than 1000 genes are required for normal mitochondrial function. However, a unique feature of the mitochondrion is that it contains an additional genome (mitochondrial DNA), located within the mitochondrion itself.

What are the different testing methods for diagnosing mitochondrial disorders?

Due to their clinical and genetic complexity, there is no single method used as a gold standard front-line test, although the ultimate aim is to obtain a genetic diagnosis. The best approach for investigation depends on the age of onset, clinical symptoms, family history and results of screening tests. The latter typically include metabolic screening and imaging. Expert input is usually needed to determine which of the following forms of testing are most appropriate.

  1. Respiratory chain enzyme testing in biopsies or perimortem samples of muscle, liver or heart or in cultured skin fibroblasts. Enzyme testing has been the main diagnostic method for most children with suspected mitochondrial disease. An accurate enzyme diagnosis can be used to guide subsequent testing of single genes or to confirm that mutations in a candidate gene are truly causative.
  2. Mitochondrial DNA testing (VCGS Molecular Genetics Laboratory). A panel of 22 point mutations covers the most common mitochondrial DNA mutations associated with conditions such as MELAS, MERRF, Leber’s hereditary optic neuropathy and Leigh syndrome.
  3. Mitochondrial DNA deletion testing combines quantitative PCR and long range analyses to detect rearrangements found in conditions such as Chronic progressive external ophthalmoplegia (CPEO), Kearns Sayre syndrome and Pearson syndrome.
  4. Mitochondrial DNA depletion testing uses quantitative PCR to determine the amount of mitochondrial DNA in a tissue sample relative to the amount of nuclear DNA. Mitochondrial DNA depletion causes a range of conditions, most often affecting liver or muscle, and the testing typically needs to be performed on the affected tissue.
  5. DNA sequencing of specific nuclear genes is performed for some of the most common conditions, caused by mutations in genes such as POLG and SURF1. It can also usually be offered for confirmation, cascade testing or prenatal diagnosis of specific mutations in families where the genetic basis of a mitochondrial disorder has been identified.
  6. Clinical whole exome sequencing can be used to potentially identify mutations in any nuclear gene in a patient with a suspected mitochondrial disorder.

What are the symptoms of a mitochondrial disorder?

The symptoms of mitochondrial disorders vary widely. Some symptoms of inherited mitochondrial disorders include lethargy, failure to gain weight, developmental delay, seizures, diabetes, muscle weakness, deafness and loss of vision.

What treatments are available for a mitochondrial disorder?

Treatment focuses on management of specific symptoms, ensuring good nutrition, aggressive management of infections and identifying patients for whom specific treatment options are available. For some mitochondrial disorders, there are no effective treatments.

How much experience does the VCGS Mitochondrial laboratory have?

The laboratory has acted as the Australasian referral centre for diagnosis of mitochondrial disease in children for more than two decades. We have diagnosed more than 600 children. The laboratory is tightly integrated with the Murdoch Childrens Research Institute and has a high international profile in mitochondrial disease. Our achievements include translating knowledge of mitochondrial DNA genetics into reproductive options for families, defining the most widely used diagnostic criteria for mitochondrial disorders, defining the epidemiology of childhood mitochondrial diseases and improving diagnosis and discovery of new 'disease' genes through Next Generation DNA sequencing. Either in house or through collaboration with national and international colleagues, we have identified mutations in more than 60 different disease genes, 20 of which we were the first to identify.