Rett Syndrome and Mitochondrial Disease: Is There a Link?

Long before researchers identified the gene mutation most often linked to Rett syndrome, some believed Rett syndrome might be a mitochondrial disease. This type of disorder affects how cells produce energy. Newer research has led health experts to revisit the idea that Rett syndrome and mitochondrial disease may be linked.

In this article, we explain what mitochondrial diseases are and explore possible connections with Rett syndrome.

Understanding Rett Syndrome

Rett syndrome is a genetic neurodevelopmental disorder (a condition that affects brain development) linked to the MECP2 gene, which is on the X chromosome. For this reason, Rett syndrome mainly affects girls, according to Cleveland Clinic. Typically, females have two X chromosomes, while males have one X and one Y chromosome. In rare cases, males can also develop Rett syndrome, and their symptoms may be different.

Most children with Rett syndrome reach typical developmental milestones on time until about 6 months of age. After that, family members, caregivers, and healthcare providers may notice developmental delays. As a child continues getting older, they might begin to lose skills they had learned, such as speaking and using their hands. Symptoms can look similar to those of autism spectrum disorder, including reduced interest in social interaction.

In the next stage of Rett syndrome, development plateaus and symptoms stabilize. The child stops losing skills, and some abilities may even improve. This stage can last for years. Eventually, many people enter a final stage called late motor deterioration, when muscle strength declines and some remaining abilities, like walking, may be lost.

Understanding Mitochondrial Disease

Mitochondria are small structures found in nearly every cell in the body. They produce energy, creating about 90 percent of the energy the body needs to function. This energy is called adenosine triphosphate (ATP).

Like Rett syndrome, mitochondrial diseases are genetic. However, instead of being caused by changes in the MECP2 gene, many mitochondrial diseases result from changes in mitochondrial DNA. This genetic material is passed down from the mother. In some cases, mitochondrial dysfunction can also occur in other conditions, such as Alzheimer’s disease or muscular dystrophy.

Mitochondrial diseases affect how well the mitochondria work and how much energy they produce. When mitochondria don’t function properly, organs may not work as well as they should because they don’t get enough energy. This can affect almost any organ, including the brain, nerves, and muscles.

There are many types of mitochondrial disease, and each can affect different parts of the body. Symptoms vary depending on the type and which cells are affected. Some symptoms appear at birth, while others aren’t noticeable until later in life.

Overlapping Signs and Symptoms

Researchers have noticed some similarities between common symptoms of Rett syndrome and mitochondrial disease. The two conditions share several features, including the following.

Developmental Delays

Developmental delays are often the first sign of Rett syndrome. Although mitochondrial diseases can begin at any age, children who develop them early may also show signs of developmental delays. Delays in cognitive development (thinking and learning skills) are especially common.

Developmental delays mean a child doesn’t reach developmental milestones within the expected time range. Examples of milestones include sitting up without help, rolling over, taking first steps, and saying first words.

Motor and Mental Regression

Motor and mental regression means a person goes “backward,” losing skills they once had. Motor regression might mean a child stops walking after they’ve already taken their first steps. Mental regression might show up as losing interest in learning, playing, or interacting with others.

Ataxia

Both mitochondrial diseases and Rett syndrome may involve ataxia, which means a person has trouble controlling their muscles. This can result in balance and coordination problems, trouble with speech and swallowing, and unusual or uncontrolled eye movements. Muscle weakness is also common in both conditions.

Seizures

People with both conditions may have seizures, which occur when there’s a sudden burst of electrical activity in the brain. Seizures look different from person to person but may cause a person to lose consciousness, lose muscle control, or stare into space.

In Rett syndrome, seizures often begin during the plateau stage. In mitochondrial diseases, seizures might happen when brain cells are affected.

Gastrointestinal Reflux

Gastrointestinal reflux — also called acid reflux — can occur along with swallowing difficulties in people with mitochondrial diseases. This is a common condition in people with Rett syndrome, who may also experience constipation.

Acid reflux happens when stomach acids back up into the esophagus (the tube connecting the mouth to the stomach). This can irritate the lining of the esophagus and cause a burning feeling in the chest or throat or a sour taste in the mouth.

High Levels of Lactate and Pyruvate

Both Rett syndrome and mitochondrial disease can raise levels of lactate and pyruvate (molecules involved in ATP production) in the blood or cerebrospinal fluid (the fluid surrounding the brain and spinal cord). Doctors can detect these levels through lab tests.

What the Research Says

Research has found several possible connections between Rett syndrome and mitochondrial diseases. Some studies show that the mitochondria in people with Rett syndrome may have an altered structure, suggesting that these structures could play a role in the condition. For example, biopsies (tests that examine tissue samples) have found mitochondria that are oversized or misshapen compared with typical mitochondria, particularly in brain and nerve cells.

Another possible link involves the MECP2 gene, the gene most often associated with Rett syndrome. Some studies in mice have shown that changes in this gene can affect mitochondrial function, which may lead to lower ATP production and reduced energy levels in the brain and nerves.

More research is needed to understand how MECP2 gene changes — or the absence of this gene — affect ATP energy production, especially in people. However, researchers think that mitochondrial diseases may contribute to or worsen brain and nerve dysfunction in people with Rett syndrome.

Mitochondrial Disease Testing

Diagnosing mitochondrial diseases can be challenging because symptoms vary widely from person to person. No single test can confirm a mitochondrial disease.

When To Request Testing for Mitochondrial Disease

People with Rett syndrome and their caregivers may want to ask about testing for mitochondrial disease in certain situations. Some researchers believe mitochondrial problems may affect how severe Rett symptoms are. Healthcare providers may consider testing for mitochondrial disease if a person with Rett syndrome has:

• Multiple organs involved in their condition
• Severe fatigue
• Unexplained metabolic problems (issues with how the body processes energy), such as high blood sugar
• Unusual results on routine lab tests

What Testing for Mitochondrial Disease Looks Like

Doctors use several examinations and tests to rule out other causes of symptoms and look for signs of mitochondrial dysfunction. The diagnostic process may include:

• A physical exam
• A review of family medical history
• Blood tests
• Urinalysis (urine tests)
• Spinal tap (testing cerebrospinal fluid)
• A neurological exam (tests of brain and nerve function)
• Genetic or DNA testing

Depending on a person’s symptoms, doctors might also use imaging tests, an electrocardiogram (a test that measures heart rhythm), or other tests to check organs and systems that could be affected by mitochondrial disease.

Talk to Your Doctor

If you notice possible signs of mitochondrial disease in someone with Rett syndrome, tell their doctor or healthcare team. A team of specialists may evaluate these symptoms, including experts in neurology (brain and nervous system health), endocrinology (hormones and metabolism), psychology, and other fields. They can review test results and adjust the care plan if needed.

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