It’s mitochondrial disorder awareness week which means it’s an opportunity to increase education and awareness about this complex group of conditions. Many people have heard about mitochondrial disorders but don’t understand what they are. Mitochondria are important structures within most cells of the human body that allow us to make and use energy. While there has been significant advancement in understanding the role of mitochondria in human disease, the road to better treatment and diagnosis is still being paved.
What are mitochondrial disorders?
Mitochondrial disorders are a complex group of conditions that affect how the body makes and uses energy. Some cells need more energy (like muscle cells) and therefore, have more mitochondria. While other cells need less energy (like skin cells) and therefore, have fewer mitochondria. However, mitochondria have additional roles that vary depending on cell function. These cell-specific roles are just now being identified and studied, and while we have much more to learn, we do know these specialized roles are critical for normal cellular function.
Mitochondrial disorders occur when mitochondria cannot make or use the energy needed by the cell and/or perform the specialized roles specific to each cell. Over 3000 genes help mitochondria function. The vast majority of these genes are located in the nucleus of a cell (which are packaged within our 23 chromosomes) with only 37 genes located in the mitochondria.
If a genetic change occurs in any of these 3000+ genes, symptoms of a mitochondrial disorder can occur. It is estimated 80-90% of individuals with a mitochondrial disorder have genetic changes in the genes located in the nucleus of a cell, and 10-20% have genetic changes in 37 genes located in the mitochondria1. Sometimes these genetic changes occur brand new in a person and other times they are inherited from a parent(s).
This image was created by the NHS HEE Genomics Education Programme.
What are the symptoms of mitochondrial disorder?
There are many types of mitochondrial diseases. Symptoms vary from person to person and may become apparent at different ages between individuals (some onset in childhood and others adulthood). However, when symptoms are reviewed for a single person or family, they often include multiple organ systems, and typically the organ systems are those with high energy demands. This includes muscle, heart, brain, eye/ear, and endocrine system. Mitochondrial disorder symptoms typically worsen with time and may include 1,2:
Muscle: muscle weakness (myopathy), easy fatigue with exercise, cramping, low muscle tone (hypotonia), and gastrointestinal problems like chronic diarrhea, constipation or dysmotility
Heart: heart disease affecting the heart muscles (cardiomyopathy) or heart conduction defects (arrhythmia)
Eyes and Ears: worsening vision loss, droopy eye lid (ptosis), difficulty moving eyes (ophthalmoplegia), retinitis pigmentosa (a type of progressive blindness), and hearing loss
Endocrine: diabetes, parathyroid dysfunction, pancreas dysfunction, poor weight gain, and short stature
Some mitochondrial symptoms occur more often together than others and consequently, can be clearly identified as a well characterized mitochondrial disorder. Examples of these disorders include Pearson syndrome, Leber’s Hereditary Optic Neuropathy (LHON), MECR-related neurologic disorder, Mitochondrial Encephalopathy Lactic Acidosis and Stroke-like Episodes (MELAS), Chronic Progressive External Ophthalmoplegia (CPEO), Alpers Disease, or Complex II deficiency. Other times, symptoms are less defined or do not fit a well characterized mitochondrial disorder. For individuals with less defined symptoms, confirming a diagnosis of a mitochondrial disorder is difficult and many individuals are never diagnosed.
How are mitochondrial disorders diagnosed?
Symptoms of mitochondrial disorders are often vague or can be attributed to many other conditions, making it difficult to identify a mitochondrial disorder. Diagnosing mitochondrial disease in children is particularly challenging and typically only occurs when symptoms are severe, and results from other tests are normal or not diagnostic. Diagnoses are typically made after careful review of a person’s symptoms and their family history. It is like putting puzzles pieces together to find the bigger picture.
Genetic testing is available and recommended for anyone suspected of having a mitochondrial disease3. In general, sequencing all of a person’s genes (or DNA) in both the nucleus and mitochondria (called whole exome sequencing with mitochondrial DNA sequencing or whole genome sequencing) is recommended for any person suspected of having a mitochondrial disorder. Gene sequencing means doing a “spell check” of the genes to look for any misspellings that may affect how a gene functions. Sometimes, results may be normal or yield genetic changes that have unknown significance. Follow up testing in muscle tissue, blood, urine, and/or spinal fluid may be needed for further evaluation.
Negative or normal genetic test results in a person with a suspected mitochondrial disorder can be frustrating and disappointing. It does not mean the person does not have a mitochondrial disorder necessarily. In genetics, it is important to know we are limited by our understanding of how genetic changes impact the role of genes and what the role of those genes may play in human disease. As we learn more, our interpretation of results can change4. This means genetic changes with unknown significance may be re-interpreted and determined to be either not concerning (benign) or may indeed explain a person’s symptoms. Alternatively, previously “normal” results may be re-interpreted, and a cause may be later found as our understanding of genes improves.
Is there treatment available for mitochondrial disorders?
Currently, there is no cure for individuals with a mitochondrial disorder. However, several clinical trials have investigated treatment options, including mitochondrial transplantation5. Although the outcome of these trials is still unknown, they may eventually provide effective options for people with mitochondrial disorders. At this time, mitochondrial disease treatment is typically focused on easing symptoms or slowing the course of the condition6.
For example, anti-seizure medications are used to treat individuals with seizures, while others may modify their diet to improve the gastrointestinal symptoms or take a “cocktail” of vitamins and supplements to improve energy. Importantly, not everyone may benefit from specific options, which can be costly. For these reasons, close monitoring by a medical provider familiar with mitochondrial disorders is important to weigh the risks and benefits.
Mitochondrial disorders are complex and caused by genetic changes in thousands of genes.
Mitochondrial disorders often impact multiple body systems and organs, and sometimes symptoms can be vague or nonspecific making the diagnosis more challenging to identify.
Genetic testing can be helpful in identifying a mitochondrial disorder, which can lead to treatment options that may ease symptoms and slow down the progression of the disorder.