Mitochondrial myopathy is a group of muscle disorders that arise when the tiny energy factories inside our cells cannot produce enough power to keep the body running smoothly. These conditions affect people differently, causing a range of symptoms from mild muscle weakness to serious complications that impact multiple body systems.

Understanding Mitochondrial Myopathy

To understand mitochondrial myopathy, it helps to first know what mitochondria do. Often called the powerhouse of the cell, mitochondria are tiny compartments found inside nearly every cell in your body. Their main job is to take the food you eat and the oxygen you breathe and convert them into a usable form of energy called ATP (adenosine triphosphate). This energy keeps your heart beating, your lungs breathing, your brain thinking, and your muscles moving. In fact, mitochondria produce about 90 percent of all the energy your body needs to function.^[1][4]

When mitochondria don’t work properly, they cannot produce enough energy. This creates problems throughout the body, but especially in parts that need a lot of power to function. Muscles and nerves require particularly high amounts of energy, which is why muscular and neurological problems are common features of mitochondrial disorders.^[3]

Mitochondrial myopathies are forms of mitochondrial disease that cause prominent muscle problems. The term myopathy comes from “myo,” meaning muscle, and “pathos,” meaning disease. Three types of muscles can be affected: skeletal muscles around the bones and eyes, cardiac muscles of the heart, and smooth muscles lining the intestines, gastrointestinal tract, bladder, and blood vessels.^[2]

When mitochondrial disease causes both prominent muscle problems and neurological issues, it is called a mitochondrial encephalomyopathy, with “encephalo” referring to the brain.^[1][3]

How Common Is Mitochondrial Myopathy?

Mitochondrial diseases are rare but more common than many people realize. An estimated 1 in 5,000 people has a genetic mitochondrial disease, though this number may be underestimated because these conditions are often misdiagnosed due to the variety of symptoms and organ systems involved.^[4]

The exact prevalence of primary mitochondrial myopathies specifically is currently unknown. These disorders can affect males, females, and individuals from any ethnic or racial group.^[6][10]

Mitochondrial myopathies can present at any age. In general, more severe forms of the disease appear earlier in life. Most mitochondrial myopathies occur before the age of 20, and often begin with exercise intolerance or muscle weakness.^[6][13]

What Causes Mitochondrial Myopathy?

Mitochondrial myopathies are genetic conditions. They are caused by inherited gene mutations in either mitochondrial DNA or nuclear DNA. More than 350 genes have been linked to primary mitochondrial myopathies.^[6][10]

To understand how these genetic changes lead to disease, it’s important to know that about 2,000 different proteins are required to make a mitochondrion work properly. A genetic defect could theoretically affect any of these building blocks, which is why there are so many different types of mitochondrial diseases.^[15]

When these genetic mutations occur, they lead to defects in normal mitochondrial function. The mitochondria cannot carry out the metabolic process that controls the majority of energy generation in the cell. When your mitochondria don’t receive the instructions they need from your body’s DNA to make energy, it can damage your cells or cause them to die early. This affects how your organs and organ systems function, leading to the symptoms of the condition.^[4][6]

Because mitochondria cannot produce sufficient energy through a process called oxidative phosphorylation, there is an over-reliance on a less efficient energy-producing process called anaerobic glycolysis. This leads to lactic acidosis, which means a buildup of lactic acid in the body, either at rest or during exercise.^[5]

Primary mitochondrial myopathies are inherited conditions. Secondary mitochondrial myopathies may also be inherited or can result from environmental factors.^[5]

Risk Factors

Because mitochondrial myopathies are genetic conditions, the main risk factor is having a family history of the disease. Given the genetic involvement of mitochondrial disorders, family members are commonly affected.^[16]

The inheritance patterns can be complex. Inheritance was once believed to be exclusively maternal, meaning passed down only through the mother’s side. However, it is now known that certain nuclear DNA deletions can also cause mitochondrial myopathy.^[5]

Since mitochondrial myopathies can affect individuals from any ethnic or racial group and can affect both males and females equally, there are no specific demographic groups at higher risk based on sex or ethnicity.^[6][10]

Symptoms of Mitochondrial Myopathy

Symptoms of mitochondrial myopathies vary widely because a person can have a unique mixture of healthy and defective mitochondria, with a unique distribution of each throughout the body. Symptoms can range from mild to severe and can be present at birth or arise at any age.^[3][4]

The main symptoms of mitochondrial myopathy include muscle fatigue, weakness, and exercise intolerance. Exercise intolerance, also called exertional fatigue, refers to unusual feelings of exhaustion brought on by physical activity. The severity varies greatly among individuals. Some people might have trouble only with athletic activities like jogging, while others might feel exhausted after minimal exertion.^[3][6]

Chronic Progressive External Ophthalmoplegia, often abbreviated as CPEO, is the most common feature of primary mitochondrial myopathies. This condition affects the muscles that control eye and eyelid movements. Symptoms include drooping eyelids, a condition called ptosis, and paralysis of the muscles that control eye movement. In some cases, there may also be weakness of the limbs.^[6][10]

When someone develops progressive external ophthalmoplegia, the muscles controlling the eyes can eventually become paralyzed. This leads to difficulty moving the eyes up and down as well as side to side. Often, people automatically compensate by moving their necks to look in different directions and might not notice any visual problems. However, ptosis can impair vision and cause a listless facial expression.^[3]

Other common symptoms include:^[6][10]

• Fatigue that can be severe
• Difficulty swallowing, known as dysphagia
• Slow or slurred speech, called dysarthria
• Muscle wasting
• Shortness of breath

Early onset forms of primary mitochondrial myopathy may also include diminished muscle tone, called hypotonia, failure to thrive, breathing difficulty, and reduced or absent tendon reflexes.^[6][10]

During physical activity, muscles may become easily fatigued or weak. Muscle cramping is rare but may occur. Nausea, headache, and breathlessness are also associated with these disorders.^[13]

Mitochondrial myopathies can cause weakness and wasting in other muscles of the face and neck, leading to difficulty with swallowing and, more rarely, slurred speech. People with these conditions may also experience muscle weakness in their arms and legs.^[3]

Because mitochondrial diseases can affect multiple organ systems, symptoms are not always limited to muscles. The nervous system, heart, liver, kidneys, eyes, ears, pancreas, and digestive system can all be affected.^[1][4]

Potential symptoms affecting other body systems include:^[1][4]

• Seizures and developmental delays
• Hearing loss and deafness
• Visual system defects and blindness
• Poor balance and problems with peripheral nerves
• Heart muscle weakness and conduction problems
• Liver and kidney problems
• Digestive issues including vomiting, diarrhea, constipation, and swallowing difficulties
• Diabetes

A healthcare provider usually detects symptoms affecting more than one organ or organ system at the same time. Importantly, symptoms of the same disease can vary significantly from person to person, even among family members.^[4]

Prevention

Because mitochondrial myopathies are genetic conditions, there is no way to prevent them from developing in someone who has inherited the genetic mutations. However, there are important steps that can be taken by families affected by or at risk for these conditions.

Genetic counseling is recommended for families since primary mitochondrial myopathies are inherited and the pattern of inheritance varies depending on the causative gene. Genetic counselors can help families understand their risks and make informed decisions about family planning.^[6][10]

For some families, recent developments in reproductive options mean that the possibility of preventing transmission of the mutation to the next generation is now available. These options should be discussed with healthcare providers and genetic counselors.^[8]

While the disease itself cannot be prevented, people with mitochondrial myopathies can take steps to prevent complications and manage their symptoms better. Regular medical monitoring is crucial. People affected by mitochondrial diseases can do a great deal to take care of themselves by monitoring their health and scheduling regular medical exams.^[9][18]

Those with mitochondrial disorders should watch for signs of problems that may require immediate attention. For example, they should watch for signs of respiratory insufficiency, such as shortness of breath or morning headaches, and have their breathing checked regularly by a specialist.^[9][18]

How the Disease Affects the Body

Understanding how mitochondrial myopathy affects the body requires looking at what happens at the cellular level and how those changes impact overall body function. The fundamental problem is energy production. When mitochondria are damaged or missing necessary components, they cannot produce sufficient energy through the normal process of oxidative phosphorylation.^[5][8]

With ATP production deficient in mitochondria, cells must rely more heavily on anaerobic glycolysis to produce energy. This alternative pathway is much less efficient and produces lactic acid as a byproduct. The accumulation of lactic acid leads to lactic acidosis, which can occur either at rest or be triggered by exercise.^[5]

Because different cells and tissues have different energy requirements, the impact of mitochondrial dysfunction varies throughout the body. Organs and body parts that require more energy, such as the heart, muscles, and brain, are often the most severely affected. This is why muscle weakness and neurological problems are so common in mitochondrial myopathies.^[2]

When cells cannot produce enough energy, they may become damaged or die prematurely. This cellular damage and death affects how organs and organ systems function, leading to the wide range of symptoms seen in mitochondrial myopathies.^[4]

In muscle tissue from patients with these diseases, special staining techniques often reveal what are called “ragged-red fibers.” These fibers get their name from their appearance under the microscope when stained with a specific dye called Gomori trichrome stain. The ragged-red appearance is due to a buildup of abnormal mitochondria underneath the muscle cell membrane. These ragged-red fibers are a hallmark finding in mitochondrial myopathies.^[5]

The ragged-red fibers may contain normal or abnormally increased accumulations of glycogen and neutral lipids. Histochemical staining shows abnormal function of the respiratory chain, the system of proteins within mitochondria responsible for energy production. There may be decreased activity of specific enzymes like succinate dehydrogenase or cytochrome c oxidase.^[5]

The degree of mitochondrial dysfunction can vary not just between different people but also between different cells in the same person. This is because individuals can have a mixture of normal and mutated mitochondrial DNA within their cells, a phenomenon called heteroplasmy. The proportion of mutated to normal mitochondrial DNA can differ from tissue to tissue and even from cell to cell, which helps explain why symptoms can be so variable.^[8]

In more severe cases, multiple organ systems become involved. The heart may develop cardiomyopathy, meaning weakness of the heart muscle, or conduction blocks that affect the heart’s rhythm. The nervous system may experience seizures, strokes before age 40, developmental delays, or peripheral nerve problems. The digestive system may develop swallowing difficulties, chronic vomiting, or diarrhea. The pancreas may be affected, leading to diabetes.^[1]

The progressive nature of many mitochondrial myopathies means that symptoms may worsen over time as more cells accumulate damage or as the energy deficit becomes more pronounced. This progressive weakness can significantly impact quality of life and, in severe cases, can be life-threatening.^[13]