Leigh Syndrome

What Causes Leigh Syndrome?

LS is caused by abnormal changes in genes (mutations) that cause some of the body’s cells to decline and die. Scientists have identified mutations in more than 75 different genes that appear to cause LS. Most of those mutations interfere with the chemical process through which cells produce energy. Without their usual energy sources, cells fail to function and eventually die. As more and more cells die, especially in the brain and the central nervous system, the resulting symptoms worsen.

Is Leigh Syndrome Hereditary?

LS is an inherited disorder. The pattern of inheritance varies depending on the specific gene mutation involved. Most cases are inherited in an autosomal recessive pattern. This means a child must inherit two copies of the mutated gene, one from each parent. The parents in these cases carry just one copy of the mutation, so they typically do not show any symptoms of the disorder.

In about 20 percent of cases, LS is inherited in a mitochondrial pattern. In this case, the disorder-causing mutation is in mitochondrial DNA, which is inherited only from the mother. Both males and females can be affected by the disorder.

In rare cases, LS is inherited in an X-linked recessive pattern. In these cases, the disorder-causing mutation is on the X chromosome. Females have two copies of the X chromosome in their cells. One copy is inherited from the mother and the other from the father. Males have only one copy of the X chromosome, inherited either from the mother or father. Males develop this type of LS if they have the gene mutation on their only X chromosome. Females only develop the disorder if they have the mutation on both of their X chromosomes. Consequently, this form of the disorder is more common in males than females.

How Is Leigh Syndrome Detected?

The earliest symptoms of LS may be vague and resemble those of other disorders, leading to delayed diagnosis. However, many of these symptoms can manifest in feeding difficulties, including:

• Difficulty sucking or swallowing
• Vomiting
• Diarrhea
• Poor appetite
• Irritability
• Loss of head control

As a result of feeding difficulties, babies may experience weight loss and slowing development.

How Is Leigh Syndrome Diagnosed?

When a baby’s observed symptoms make a doctor suspect LS, the diagnosis can be confirmed using imaging scans such as magnetic resonance imaging (MRI) or computerized tomography (CT). These scans can detect abnormal areas in the brain where cell death has caused distinct lesions.

Laboratory tests may be used to detect other characteristic signs of the disorder, including elevated lactate levels or lower than normal blood sugar levels.

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Leigh Syndrome Treated?

LS has no cure. Standard treatments focus on managing the symptoms and lessening the severity of complications. Of particular concern are high lactate levels in the bloodstream, a condition called lactic acidosis, which can impair respiratory and kidney function. Medications used to managed lactic acidosis include:

• Sodium bicarbonate
• Sodium citrate
• Dichloroacetate

Certain types of LS respond well to treatment with thiamine (vitamin B1) or biotin (vitamin B7).

A high-fat, low-carbohydrate ketogenic diet has also shown effectiveness at treating some forms of the disorder.

How Does Leigh Syndrome Progress?

The symptoms of LS worsen over time, and life expectancy in most cases is only a few years. The prognosis varies according to the form of the disorder. Children with a form of LS producing only a partial deficiency of critical metabolic chemicals may survive into early childhood. Cases with later onset are also more likely to have a slower rate of progression and a longer life expectancy. In rare cases, survival to the teenage years has occurred.

How Is Leigh Syndrome Prevented?

There is no known way to prevent LS. Parents with a family history of epilepsy, or who have had another child with LS, may consult a genetic counselor to assess their risk if they plan to have another child.

Leigh Syndrome Caregiver Tips

LS puts extraordinary physical and emotional demands on everyone living with the disorder. However, the burden can be a little easier for parents to bear if they keep some essential tips in mind.

• Take time to cope with your diagnosis. It’s normal for the parent of a child with LS to move through a range of emotions, including grief, sadness, and anger. Dealing with the process takes time, and it’s essential that you give yourself the space you need to process your feelings.
• Learn as much as you can about the disorder, and be active in your child’s treatment. You will feel better when you know you’re doing all you can to help your child.
• Get help from people who know what you’re going through. People Against Leigh Syndrome (PALS) maintains a directory of resources to help parents and families living with LS.
• Even after an LS diagnosis, you will have moments of pure bliss with your child. Be sure to relish every one of them.

Leigh Syndrome Brain Science

LS causes damage to several different parts of the brain:

• The basal ganglia – helps control motor functions and movement.
• The cerebellum – responsible for balance and coordination.
• The brainstem – connects the brain to the rest of the body through the spinal cord. It also is responsible for certain automatic functions such as swallowing and breathing.

The overall effect of LS is cellular mortality resulting from their inability to produce the energy needed to survive. Scientists believe the brain is particularly vulnerable to the effects of LS because brain cells require more energy than other cells typically do. As more and more cells die, they create areas of dead tissue called lesions. When the lesions are in critical areas of the brain, the symptoms of the disorder develop.

Leigh Syndrome Research

Title:  The NIH MINI Study: Metabolism, Infection, and Immunity in Inborn Errors of Metabolism

Stage: Recruiting

Principal Investigator: Peter J. McGuire, MD

National Institutes of Health Clinical Center

Bethesda, MD

The Metabolism, Infection, and Immunity (MINI) Study is a longitudinal natural history study at the National Institutes of Health (NIH) that will define the relationship between infection, immunity, and clinical decline in individuals with mitochondrial disease. Mitochondrial diseases are a group of disorders caused by problems with the cell s ability to produce energy. Infection in individuals with mitochondrial disease can lead to worsening clinical symptoms, particularly neurologic symptoms.

Goals:

The main goal of our study is to understand the relationship between infection and clinical decline in patients with mitochondrial disease. Mitochondrial diseases can affect many different parts of the body, including the immune system and its ability to respond to infection. Therefore, a comprehensive evaluation of participants is performed, including a detailed immunologic assessment.

“We are not testing any new medicine or procedure to treat or cure IEM or mitochondrial diseases. However, by understanding the relationship between infection and mitochondrial disease, we hope to develop treatments in the future. At the NIH, we are interested in research. Although we do provide advice and care for people enrolled in our study, we are not able to take over the long-term care of participants. To enroll in our study, you (your child) must already have a confirmed diagnosis of a mitochondrial disease. We are not able to provide a “first-time” diagnosis or regular metabolic care.”

Title: A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy (MIT-E)

Stage: Recruiting

Principal investigator:  Vikas Bhambhani, Dr.

Children’s of Minnesota

Minneapolis, MN

This is a parallel-arm, double-blind, placebo-controlled study with a screening phase that includes a 28-day run-in phase to establish baseline seizure frequency, followed by a 24-week, randomized, placebo-controlled phase. After completing the randomized, placebo-controlled phase, participants may enter a 48-week, long-term extension phase during which they will receive open-label treatment with vatiquinone.

Title: The Leigh Syndrome Registry

Stage: Recruiting

Principal Investigator: Mary Kay Koenig, MD

The University of Texas Health Science Center at Houston

Houston, TX

Leigh syndrome, also known as juvenile sub-acute necrotizing encephalopathy, is a progressive neurodegenerative disorder associated with dysfunction of mitochondrial oxidative phosphorylation (OXPHOS). First described in 1951 by British neuropsychiatrist Archibald Denis Leigh, the condition has evolved from a post mortem diagnosis to a clinical entity with characteristic radiologic and laboratory findings.

Leigh syndrome is a rare and heterogeneous disease; finding a substantial number of patients to study is difficult. The lack of natural history data in Leigh syndrome and the small number of patients included in clinical reports thus far has limited the ability to fully comprehend the progression of this disease and assess prognostic factors. A Leigh syndrome database will help improve our understanding of this rare disease leading to an improved ability to predict outcomes and/or improve treatment paradigms. Collecting natural history data on Leigh syndrome and integrating this information into a database will be useful in understanding the course of the disease and identifying trends.