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PubMed This is a summary of 75 peer-reviewed journal articles Updated
Neurology

Understanding Leigh Syndrome: An Orientation

At a Glance

Leigh syndrome is a rare genetic disorder where cellular power plants, called mitochondria, fail to produce enough energy for the brain and muscles. It is caused by inherited genetic mutations. While there is no cure yet, emerging research is exploring gene therapy and metabolic support.

Receiving a diagnosis of Leigh syndrome can feel overwhelming and isolating. It is a rare neurological disorder, affecting approximately 1 in 40,000 live births globally [1][2]. However, in certain areas like the Saguenay-Lac-Saint-Jean region of Quebec, a specific version known as Leigh syndrome French-Canadian type (LSFC) is much more common, occurring in about 1 in 2,063 births due to a “founder effect” where a specific genetic mutation is passed down through generations in a specific population [3][4].

While the news is difficult, you are not alone. Understanding the biological “why” behind the syndrome can be a first step in navigating the road ahead for you or your child.

The Power Plant Analogy

To understand Leigh syndrome, it helps to think of the body’s cells as a city. Every city needs a power plant to function. In your or your child’s cells, tiny structures called mitochondria act as these power plants [5]. They take in nutrients and oxygen to create ATP (adenosine triphosphate), the fuel that powers everything from breathing to thinking [6][7].

In Leigh syndrome, a genetic “glitch” prevents these power plants from working correctly. This leads to energy failure, where the cells—especially those in the brain and muscles that require the most energy—cannot get the fuel they need to function [8][9]. When the brain’s energy supply drops, it can lead to the characteristic “lesions” (areas of cellular stress or damage) often seen on an MRI [8][10]. For more on what these MRIs look like, see Mapping the Diagnosis.

Two Sets of Blueprints: nDNA vs. mtDNA

The instructions for building and running these “power plants” come from two different sets of genetic blueprints. Knowing which blueprint is affected helps doctors understand how the condition may progress and the risks for future family members.

  • Nuclear DNA (nDNA): These are the primary blueprints located in the center (nucleus) of almost every cell. Most cases of Leigh syndrome involve mutations here, such as in the SURF1 gene [11][12]. These are typically inherited in an autosomal recessive pattern, meaning a person must inherit one mutated gene from each parent [13][14]. However, some forms are X-linked (such as mutations in the PDHA1 gene), meaning they are passed down on the X chromosome.
  • Mitochondrial DNA (mtDNA): Mitochondria actually have their own small set of unique blueprints. Mutations here, like in the MT-ATP6 gene, are passed down only from the mother [15][16]. A unique feature here is heteroplasmy, which means a cell can have a mix of healthy and mutated mitochondria [17][18]. The severity of symptoms often depends on what percentage of the mitochondria are mutated [17][19].

Specific Genetic Drivers

Researchers have identified many specific genes that can cause this energy failure. Two of the most well-studied include:

  • SURF1: This gene helps assemble a specific part of the energy-making chain (Complex IV). When it is mutated, the power plant cannot finish the assembly, leading to a significant energy shortage [12][20].
  • MT-ATP6: This mutation affects the final step of energy production (Complex V). It’s like having a turbine that won’t spin, resulting in a chronic “energy crisis” [21][6].

Looking Forward

While there is currently no universal cure, the landscape of Leigh syndrome research is changing rapidly. Scientists are actively investigating several promising areas:

  • Gene Therapy: Using modified, harmless viruses to deliver healthy copies of genes directly to cells [22][12].
  • Small Molecule Interventions: Testing drugs that might help the body bypass the broken part of the power plant or reduce the inflammation caused by energy failure [23][24].
  • Metabolic Support: Researching ways to optimize how cells use fuel to minimize “metabolic crises,” such as the buildup of lactate [25][26].

Finding support through patient advocacy groups (such as the United Mitochondrial Disease Foundation or MitoAction) is crucial for managing the emotional and logistical challenges of this diagnosis. Read more about managing daily life and emergencies in Symptoms, Triggers, and the Journey Ahead.

In this guide

4 chapters

01

Symptoms, Triggers, and the Journey Ahead

Learn about Leigh syndrome symptoms, including psychomotor regression. Understand what triggers a metabolic crisis and how the age of onset affects prognosis.

02

Mapping the Diagnosis: Imaging, Labs, and Genetics

Learn how Leigh syndrome is diagnosed through MRI imaging, metabolic markers like lactate and pyruvate, and genetic testing to find the exact mutation.

03

Management and Therapies: The Mitochondrial Cocktail and Beyond

Learn how Leigh syndrome is managed with the mitochondrial cocktail, targeted gene treatments, and critical emergency protocols for medical crises.

04

Building Your Team: Specialists and Long-Term Care

Learn how to build a Leigh syndrome care team. Understand which specialists you need, ER protocols for metabolic crisis, and how to focus on quality of life.

Common questions in this guide

What causes Leigh syndrome?
Leigh syndrome is caused by genetic mutations that affect the mitochondria, which act as the power plants of your cells. This genetic glitch prevents the cells, particularly in the brain and muscles, from generating the energy they need to function.
What is the difference between nDNA and mtDNA mutations in Leigh syndrome?
Nuclear DNA (nDNA) mutations are usually inherited from both parents, such as changes in the SURF1 gene. Mitochondrial DNA (mtDNA) mutations, like MT-ATP6, are inherited only from the mother and can result in varying levels of healthy and mutated mitochondria within the cells.
What does heteroplasmy mean for a Leigh syndrome diagnosis?
Heteroplasmy means that a single cell contains a mixture of both healthy and mutated mitochondria. The severity of a person's symptoms often depends on the specific percentage of mitochondria that carry the genetic mutation.
Are there treatments available for Leigh syndrome?
While there is currently no universal cure, researchers are actively studying new treatments. These include gene therapies to deliver healthy genes, small molecule drugs to bypass cellular damage, and metabolic support to help cells use fuel more efficiently.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Which specific gene is affected, and is it located in the nuclear (nDNA) or mitochondrial (mtDNA) genome?
  2. 2.If the mutation is in the mitochondrial DNA (like MT-ATP6), what is the heteroplasmy level, and how does that influence symptoms?
  3. 3.Is this condition a variant with a known 'founder effect,' such as the French-Canadian type?
  4. 4.What clinical trials or research studies are currently enrolling patients with this specific genetic mutation?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (26)
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    Schizophrenia-Like Psychotic Symptoms Associated to Leigh Syndrome.

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    Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention.

    van de Wal MAE, Adjobo-Hermans MJW, Keijer J, et al.

    Brain : a journal of neurology 2022; (145(1)):45-63 doi:10.1093/brain/awab426.

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    Novel LRPPRC compound heterozygous mutation in a child with early-onset Leigh syndrome French-Canadian type: case report of an Italian patient.

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    Expression signature of the Leigh syndrome French-Canadian type.

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    Cytochrome C oxydase deficiency: SURF1 gene investigation in patients with Leigh syndrome.

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    Homoplasmy of the m. 8993 T>G variant in a patient without MRI findings of Leigh syndrome, ataxia or retinal abnormalities.

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This page provides educational information about the genetics and biology of Leigh syndrome. It is not a substitute for professional medical advice, so please consult your neurologist or geneticist regarding your specific diagnosis and care plan.

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