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PubMed This is a summary of 19 peer-reviewed journal articles Updated
Neurology

Symptoms, Triggers, and the Journey Ahead

At a Glance

Leigh syndrome causes a stepwise loss of mental and motor skills, known as psychomotor regression. Symptoms can suddenly worsen into a metabolic crisis triggered by fever, illness, or fasting. Immediate emergency care is required for high fevers, vomiting, or sudden skill loss.

Leigh syndrome is often described as a “relapsing-remitting” or “stepwise” condition. This means that while symptoms may remain stable for a time, they can suddenly worsen during periods of physical stress [1]. Understanding these patterns can help you anticipate your or your child’s needs and respond quickly to changes.

Common Symptoms and “Regression”

The hallmark of Leigh syndrome is psychomotor regression, which is the loss of previously acquired mental and motor skills [2][3]. For example, a child who has learned to roll over or an adult who had normal coordination may suddenly lose those abilities.

Common symptoms across all age groups include:

  • Dystonia: Involuntary muscle contractions that cause repetitive or twisting movements [2][4].
  • Ataxia: A lack of muscle coordination during voluntary movements, such as walking or picking up objects [2][5].
  • Chorea: Brief, semi-directed, irregular movements that are not rhythmic [2].
  • Epilepsy: Seizures are common and can vary in type and frequency [5].
  • Muscle Weakness: A general lack of muscle tone (hypotonia) or strength [2].

The Role of Triggers and When to Go to the ER

The “power plants” (mitochondria) in a person with Leigh syndrome are already working at maximum capacity just to keep the body running. When the body faces extra stress, the demand for energy increases beyond what the mitochondria can provide, leading to a metabolic crisis [6][7].

Common triggers for these crises include:

  • Viral illnesses (like the flu or a common cold) [8][6].
  • Fevers [9][5].
  • Metabolic stress (such as long periods of fasting, dehydration, or intense physical exertion) [10][11].

During a crisis, laboratory tests at the hospital may reveal a sudden spike in lactate levels in the blood or brain [3][5]. Therefore, it is critical to seek immediate medical care if you or your child exhibits crisis symptoms. Go to the ER immediately if there is a high fever, inability to keep fluids down, persistent vomiting, severe lethargy, or a sudden loss of motor skills. Do not wait out a fever at home. Read more about preparing for emergencies in Management and Therapies.

Onset and Prognosis Reality

Having an honest understanding of the disease’s trajectory is crucial for making informed medical and life decisions. The age at which symptoms first appear often provides a guide for what to expect, though every journey is unique [12].

Onset Type Typical Age of Onset Characteristics & Trajectory
Infantile-Onset Before age 2 [1] Generally follows a rapid and severe course. It often starts with feeding difficulties, vomiting, and irritability, followed by a loss of motor milestones [1][13]. Sadly, this early-onset form is typically terminal, often resulting in death within a few years of diagnosis, most frequently due to respiratory failure [1][14].
Late-Onset After age 2 (childhood to adulthood) [1] Symptoms may be milder or progress more slowly over years or decades [15]. It may present with non-specific signs like headaches, stomach issues, or coordination problems before progressing [15][16].

The Influence of Genetics

The specific “glitch” in the DNA significantly influences how the disease progresses. For instance, mutations in the NDUFS4 gene typically cause a very early and severe onset [13][17]. Conversely, those with mitochondrial DNA mutations (like MT-ATP6) may have symptoms that fluctuate depending on their heteroplasmy level [18][19]. Knowing the specific mutation allows the care team to monitor for complications and provide targeted supportive care.

Common questions in this guide

What are the first signs of infantile-onset Leigh syndrome?
In infantile-onset Leigh syndrome, early signs typically include feeding difficulties, vomiting, and irritability. This is often followed by a noticeable loss of motor milestones and developmental skills.
What triggers a metabolic crisis in Leigh syndrome?
A metabolic crisis is usually triggered by physical stress that increases the body's energy demands beyond what the cells can handle. Common triggers include viral illnesses, fevers, dehydration, fasting, or intense physical exertion.
When should someone with Leigh syndrome go to the ER?
You should go to the emergency room immediately if the patient has a high fever, cannot keep fluids down, has persistent vomiting, experiences severe lethargy, or shows a sudden loss of motor skills. You should never try to wait out a fever at home.
What does psychomotor regression mean?
Psychomotor regression is the loss of previously acquired mental and motor skills. For example, a child may lose the ability to roll over or sit up, while an adult may suddenly lose physical coordination or balance.
Does the age when Leigh syndrome starts affect the prognosis?
Yes, the age when symptoms start strongly influences the disease trajectory. Infantile-onset typically follows a rapid, severe course. In contrast, late-onset Leigh syndrome often progresses more slowly over years or decades and may present with milder symptoms.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Does this case represent infantile-onset or late-onset Leigh syndrome, and how does this classification affect the prognosis?
  2. 2.Could you provide an 'Emergency Protocol' letter for us to give to ER doctors if a fever or infection develops?
  3. 3.What specific movement disorders (like dystonia or ataxia) are present, and what therapies are available to manage them?
  4. 4.Is there a risk of developing epilepsy, and what specific signs should I watch for?

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 (19)
  1. 1

    Clinical Characteristics of Early-Onset and Late-Onset Leigh Syndrome.

    Hong CM, Na JH, Park S, Lee YM

    Frontiers in neurology 2020; (11()):267 doi:10.3389/fneur.2020.00267.

    PMID: 32351444
  2. 2

    Deep Brain Stimulation in Leigh-Like Syndrome Due to DNM1 Pathogenic Variant.

    Villa-Villegas L, Lira-Jaime LG, Farías-Moreno KC, et al.

    Tremor and other hyperkinetic movements (New York, N.Y.) 2025; (15()):32 doi:10.5334/tohm.1017.

    PMID: 40717768
  3. 3

    A meta-analysis and systematic review of Leigh syndrome: clinical manifestations, respiratory chain enzyme complex deficiency, and gene mutations.

    Chang X, Wu Y, Zhou J, et al.

    Medicine 2020; (99(5)):e18634 doi:10.1097/MD.0000000000018634.

    PMID: 32000367
  4. 4

    Biallelic NDUFA9 variants cause a progressive neurodevelopmental disorder with prominent dystonia and mitochondrial complex I deficiency.

    Magrinelli F, Taylor LS, Sedighzadeh S, et al.

    Brain communications 2025; (7(5)):fcaf369 doi:10.1093/braincomms/fcaf369.

    PMID: 41069424
  5. 5

    Leigh syndrome in an infant: autopsy and histopathology findings.

    Saini AG, Chatterjee D, Bhagwat C, et al.

    Autopsy & case reports 2021; (11()):e2021334 doi:10.4322/acr.2021.334.

    PMID: 34805005
  6. 6

    Leigh Syndrome and SURF1 Gene Presenting with Febrile Seizure.

    Panda PK, Sharawat IK, Sharma V, Sherwani P

    Annals of Indian Academy of Neurology 2021; (24(2)):251-252 doi:10.4103/aian.AIAN_567_20.

    PMID: 34220073
  7. 7

    Exclusion of sulfide:quinone oxidoreductase from mitochondria causes Leigh-like disease in mice by impairing sulfide metabolism.

    Kanemaru E, Shimoda K, Marutani E, et al.

    The Journal of clinical investigation 2024; (134(15)).

    PMID: 38870029
  8. 8

    Complex I deficiency and Leigh syndrome through the eyes of a clinician.

    Reinson K, Õunap K

    EMBO molecular medicine 2020; (12(11)):e13187 doi:10.15252/emmm.202013187.

    PMID: 33124751
  9. 9

    Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease.

    Friederich MW, Elias AF, Kuster A, et al.

    Journal of inherited metabolic disease 2020; (43(5)):1024-1036 doi:10.1002/jimd.12232.

    PMID: 32160317
  10. 10

    Management considerations for stroke-like episodes in MELAS with concurrent COVID-19 infection.

    Sen K, Harrar D, Hahn A, et al.

    Journal of neurology 2021; (268(11)):3988-3991 doi:10.1007/s00415-021-10538-1.

    PMID: 33796896
  11. 11

    Anesthetic Management in Mitochondrial Encephalomyopathy: A Case Report.

    Yamamoto T, Miyazawa N, Yamamoto S, Kawahara H

    Anesthesia progress 2017; (64(4)):235-239 doi:10.2344/anpr-64-03-06.

    PMID: 29200367
  12. 12

    Clinical spectrum, treatment and outcomes of the m.10197G>A mutation in MT-ND3: a case report, systematic review and meta-analysis.

    Shi Y, Chen B, Niu S, et al.

    Orphanet journal of rare diseases 2025; (20(1)):59 doi:10.1186/s13023-025-03588-5.

    PMID: 39923090
  13. 13

    Ndufs4 related Leigh syndrome: A case report and review of the literature.

    Ortigoza-Escobar JD, Oyarzabal A, Montero R, et al.

    Mitochondrion 2016; (28()):73-8.

    PMID: 27079373
  14. 14

    Mortality of Japanese patients with Leigh syndrome: Effects of age at onset and genetic diagnosis.

    Ogawa E, Fushimi T, Ogawa-Tominaga M, et al.

    Journal of inherited metabolic disease 2020; (43(4)):819-826 doi:10.1002/jimd.12218.

    PMID: 31967322
  15. 15

    Late-Onset Leigh Syndrome With Protracted Gastrointestinal Manifestations: A Rare Case Report.

    Amar Z, Hussaini H, Kachhadia MP, et al.

    Cureus 2024; (16(5)):e59669 doi:10.7759/cureus.59669.

    PMID: 38836159
  16. 16

    Fatal cerebellar oedema in adult Leigh syndrome.

    Edwards LS, Halmagyi GM, Mallawaarachchi A, et al.

    Practical neurology 2020; (20(4)):336-337 doi:10.1136/practneurol-2019-002409.

    PMID: 32680832
  17. 17

    A Novel NDUFS3 mutation in a Chinese patient with severe Leigh syndrome.

    Lou X, Shi H, Wen S, et al.

    Journal of human genetics 2018; (63(12)):1269-1272 doi:10.1038/s10038-018-0505-0.

    PMID: 30140060
  18. 18

    Heteroplasmic Mutant Load Differences in Mitochondrial DNA-Associated Leigh Syndrome.

    Na JH, Lee YM

    Pediatric neurology 2023; (138()):27-32 doi:10.1016/j.pediatrneurol.2022.09.006.

    PMID: 36335839
  19. 19

    Leigh syndrome T8993C mitochondrial DNA mutation: Heteroplasmy and the first clinical presentation in a Vietnamese family.

    Weerasinghe CAL, Bui BT, Vu TT, et al.

    Molecular medicine reports 2018; (17(5)):6919-6925 doi:10.3892/mmr.2018.8670.

    PMID: 29512743

This page provides educational information about Leigh syndrome symptoms and metabolic crises. Always seek immediate emergency medical care if you or your child experience signs of a metabolic crisis, and consult your neurologist for specific medical advice.

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