Leigh encephalopathy (Leigh syndrome)

Key Points at a Glance

Key Points of This Disease

• Leigh syndrome is a subacute necrotizing encephalomyelopathy caused by mutations in nuclear or mitochondrial genes.
• Onset is most common in infancy, but adult-onset cases have also been reported.
• Ocular muscle palsy, nystagmus, optic atrophy, and ptosis are representative ocular symptoms.
• More than 110 causative genes have been identified, and inheritance patterns include maternal, autosomal recessive, and X-linked.
• There is no curative treatment; symptomatic therapy with coenzyme Q10, B vitamins, and anticonvulsants is the mainstay.
• Mortality by age 20 is about 80%, indicating a poor prognosis, but adult-onset cases may follow a relatively slow course.
• Use of sodium valproate is contraindicated in patients with POLG mutations.

1. What is Leigh encephalopathy?

Leigh syndrome (subacute necrotizing encephalomyelopathy) is a neurodegenerative disease caused by mutations in nuclear or mitochondrial genes that affect mitochondrial function. It was first described in 1951 by neuropsychiatrist Archibald Denis Leigh. ¹⁾

Epidemiology

The prevalence is reported to be approximately 1:40,000 live births in children. ¹⁾²⁾ A Swedish survey found a prevalence of 1 in 32,000 among preschool children. More than 110 causative genes have been identified, distributed in both the nuclear and mitochondrial genomes. ¹⁾ The overall birth prevalence of mitochondrial disease (PMD) is estimated at 1:5,000. ⁴⁾

Disease Classification

Based on age of onset and clinical features, it is classified into the following three subtypes. ²⁾

Disease type	Onset timing	Characteristics
Early-onset type	Under 2 years old	Most common; worst prognosis
Late-onset type	2 years or older	Rare; includes adult-onset cases
Leigh-like syndrome	Various	Related cases not meeting typical criteria

Prognosis Overview

The mortality rate by age 20 is approximately 80%, indicating a poor prognosis. ¹⁾ In a Japanese report of 166 cases, 40.3% of those with onset before 6 months died, while 14.3% of those with onset after 6 months died. ⁶⁾

Q Can Leigh syndrome develop in adulthood?

A

Onset is most common in infancy, but late-onset (adolescence to adulthood) is also rarely reported. Adult-onset cases often have a slower progression and relatively good prognosis. ⁶⁾

2. Main Symptoms and Clinical Findings

Subjective Symptoms

The following are initial symptoms noticed by caregivers.

• Developmental delay/psychomotor regression: Loss of motor skills such as sitting and walking
• Feeding difficulty/dysphagia: Due to damage to the swallowing center in the brainstem
• Convulsions: Experienced by approximately 40% of patients ⁶⁾
• Vomiting/diarrhea: May present as gastrointestinal symptoms
• Fatigue: Associated with impaired muscle energy metabolism ⁴⁾

Clinical Findings

Ocular Symptoms

Ophthalmoplegia: Weakness of the extraocular muscles. These muscles have high energy demands and are susceptible to mitochondrial dysfunction.

Nystagmus: Involuntary eye movements. Caused by impaired eye movement control due to cerebellar/brainstem lesions.

Optic atrophy: Degeneration and thinning of the optic nerve. In SURF1 mutation cases, MRI shows T2 hyperintensity and contrast enhancement of the optic nerve. ⁵⁾

Ptosis: Due to weakness of the levator palpebrae superioris muscle.

Neurological and systemic findings

Hypotonia: Frequently an initial finding in infancy.

Dystonia: Involuntary muscle contractions. Movement abnormalities account for 82.8% of initial symptoms. ³⁾

Ataxia: Balance disorder.

Lactic acidosis: Elevated lactate in blood, urine, and cerebrospinal fluid.

Cardiomyopathy and renal tubular dysfunction: Indicate multisystem involvement.

MRI findings: Bilateral symmetric T2/FLAIR hyperintense necrotic lesions in the basal ganglia, thalamus, and brainstem are characteristic. ³⁾⁶⁾ In SURF1 mutation cases, the putamen is spared with a brainstem-predominant lesion distribution, and may be accompanied by leukoencephalopathy, cerebellar atrophy, and contrast enhancement of cranial nerves and spinal nerve roots. ⁵⁾

Q What ocular symptoms appear in Leigh encephalopathy?

A

Ophthalmoplegia (weakness of extraocular muscles), nystagmus (involuntary eye movements), and optic atrophy are typical ocular symptoms. Ptosis may also occur. In cases with SURF1 mutations, MRI may show thinning and contrast enhancement of the optic nerve. ⁵⁾

3. Causes and Risk Factors

Molecular Genetic Causes

The pathogenesis of Leigh syndrome is mitochondrial dysfunction, involving the following mechanisms.

• Mitochondrial DNA (mtDNA) mutations: point mutations or heteroplasmic deletions (coexistence of wild-type and mutant mtDNA)
• Nuclear gene mutations: abnormalities in genes encoding respiratory chain enzyme complexes or accessory proteins

Main enzymes/complexes involved:

• Complex I (NADH-ubiquinone oxidoreductase): MT-ND5 mutation (m.13513G>A) and others³⁾
• Complex IV (cytochrome c oxidase/COX): SURF1, NDUFA4 mutations and others⁴⁾⁵⁾
• Pyruvate dehydrogenase complex
• Coenzyme Q10 metabolic pathway

Major causative genes include MT-ATP6 (T8993G, 9176T>C), MT-ND5 (m.13513G>A), SURF1, NDUFA4, and others.^2)3)4)5)6) To date, more than 110 causative genes have been identified.¹⁾

The proportion of heteroplasmy affects the severity of the phenotype, and symptoms may vary even within the same family.²⁾

Inheritance Pattern

• Maternal inheritance: due to mtDNA mutations
• Autosomal recessive inheritance: due to nuclear gene mutations (most common)
• X-linked inheritance: rare⁶⁾

Risk Factors and Triggers

• Consanguineous marriage: high risk due to autosomal recessive inheritance
• Infection, vaccination, anesthesia, surgery, dehydration: These stress conditions can trigger acute exacerbations⁵⁾⁶⁾

Q Is Leigh syndrome inherited?

A

It can be inherited via maternal, autosomal recessive, or X-linked patterns. Consanguineous marriage is a risk factor. Stress such as infection or surgery can trigger acute exacerbations.⁵⁾⁶⁾

4. Diagnosis and Testing Methods

Medical History and General Tests

It is important to obtain a detailed family history covering at least three generations (including history of early infant death or multisystem disease).

Blood tests: Complete blood count, serum CK, serum lactate and pyruvate measurement.

Cerebrospinal fluid analysis: Analysis of CSF pyruvate, amino acids, lactate, and 5-methyltetrahydrofolate.

Imaging studies

Brain MRI (T2/FLAIR): Characteristic abnormal white matter signals in the putamen, basal ganglia, and brainstem. MR spectroscopy shows a lactate peak. ⁶⁾ In SURF1 mutation cases, the putamen is spared with predominant brainstem involvement, and leukoencephalopathy, cerebellar atrophy, and cranial nerve enhancement are characteristic. ⁵⁾

Genetic testing and muscle biopsy

Next-generation sequencing (NGS) / whole exome sequencing (WES) / whole genome sequencing (WGS) to identify the causative gene is the mainstay of diagnosis. ³⁾⁴⁾

Muscle biopsy: In skeletal muscle biopsy, abnormalities in the activity of electron transport chain (respiratory chain) enzymes, ragged-red fibers on Gomori trichrome staining, and mitochondrial morphological abnormalities on electron microscopy may be observed. However, note that these findings are not specific to mitochondrial diseases including CPEO.

Computational diagnostic tool: The Leigh disease map on the MINERVA platform (which correctly identified the gene in 80% of cases in a blinded validation by two researchers) is publicly available.

Differential Diagnosis

The differential diagnosis from major mitochondrial diseases is shown below.

Disease	Main differences
MELAS	Stroke-like episodes, lactic acidosis predominant
MERRF	Myoclonus epilepsy, ragged-red fibers
NARP	Retinitis pigmentosa, onset after school age
LHON	Vision loss in young men; usually no myopathy
Barth syndrome	Dilated cardiomyopathy; neutropenia

5. Standard treatment

Currently, there is no curative treatment for most mutations associated with Leigh syndrome. Symptomatic treatment is the mainstay.

Replacement Therapy and Nutritional Therapy

The following administrations are attempted to compensate for mitochondrial dysfunction.

• Coenzyme Q10 (CoQ10): A coenzyme that supports the respiratory chain
• Thiamine (Vitamin B1): A coenzyme for the pyruvate dehydrogenase complex
• Biotin: May be effective for certain mutations
• Vitamin B complex and Vitamin C: Used to support mitochondrial function
• Vitamin cocktail (reported in pediatric cases): A combination of CoQ10 10 mg/kg/d, VitE 10 mg/kg/d, VitB1 5 mg/kg/d, VitB2 10 mg/kg/d, VitC 25 mg/kg/d, and levocarnitine 50 mg/kg/d has been reported to contribute to symptom improvement³⁾

Additionally, in childhood-onset mitochondrial encephalomyopathy, combination therapy with 5-aminolevulinic acid (5-ALA) and iron has been suggested to enhance ATP production, and clinical trials are underway.

Treatment of Seizures

Anticonvulsants are used in patients with epilepsy. ⁶⁾ The following points should be considered when selecting a treatment.

• Levetiracetam: Often recommended for myoclonic epilepsy
• Ketogenic diet: Reported to be effective for refractory mitochondrial epilepsy⁵⁾⁶⁾
• Lamotrigine: Generally safe, but may worsen myoclonus
• Sodium valproate: Contraindicated in patients with POLG mutations (mitochondrial toxicity) ⁶⁾

Management of psychiatric symptoms

There is a report of marked improvement with risperidone 3 mg/day in an adult LS patient presenting with schizophrenia-like symptoms. However, no consensus has been established for the treatment of psychosis in mitochondrial diseases. ²⁾

Precautions in treatment

Sodium valproate (e.g., Depakene®) should not be administered to patients with Leigh encephalopathy who have POLG gene mutations. There is a risk of causing liver failure or rapid worsening of neurological symptoms due to mitochondrial toxicity. ⁶⁾ It is advisable to confirm the genetic diagnosis before selecting an anticonvulsant.

Q Are there any drugs that should not be used in the treatment of Leigh syndrome?

A

If a POLG mutation has been confirmed, sodium valproate is contraindicated due to its mitochondrial toxicity. ⁶⁾ When using antipsychotics, atypical antipsychotics are considered to have less impact on mitochondrial function than typical antipsychotics, but no consensus has been established. ²⁾

6. Pathophysiology and Detailed Pathogenesis

Pathological Findings

Typical pathological findings are bilateral necrotic lesions with microcysts and spongiform changes in the thalamus, basal ganglia, brainstem, and spinal cord.

Molecular Mechanisms

Mutations in nuclear DNA and mtDNA at various sites of the electron transport chain disrupt mitochondrial metabolism.

• Oxidative phosphorylation (OXPHOS) impairment → decreased ATP production → brain and muscle tissues with high energy dependence become particularly vulnerable⁶⁾
• Free radical generation: oxidative stress from unused oxygen → cell damage¹⁾
• Immune-mediated inflammation: studies in Ndufs4 knockout mice have shown involvement of leukocyte-mediated inflammation in central nervous system lesions¹⁾

Complex IV consists of 14 subunits, including three mtDNA-derived catalytic core subunits and 11 nDNA-derived regulatory subunits. The NDUFA4 gene encodes an nDNA-derived complex IV subunit, and biallelic deletion of this gene results in a significant decrease in COX/CS activity.⁴⁾

Pathogenesis of ocular symptoms

Extraocular muscles have high energy demands per unit weight and are susceptible to mitochondrial dysfunction. Contrast enhancement of cranial nerves and spinal nerve roots is presumed to involve active demyelination, perivascular inflammation, and accumulation of cytotoxic metabolites. ⁵⁾

Heteroplasmy and Phenotype

Jaballah et al. (2023) reported that in an adult LS family with the MT-ATP6 T8993G mutation (heteroplasmy), the proportion of mutant mtDNA varied widely from 44% to 98% among family members and correlated with the severity of the phenotype. ²⁾

7. Latest Research and Future Perspectives (Research-Stage Reports)

For Patients: Please Read

The following content is currently at the research stage or under clinical trial and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Gene Therapy

AAV9-SURF1 gene replacement therapy: In Surf1 knockout mice, restoration of SURF1 expression and normalization of complex IV activity and lactate levels were confirmed. ¹⁾

Mitochondrial zinc finger nuclease: A method aimed at correcting heteroplasmy in vivo by cleaving specific mtDNA sequences. Improvement of mitochondrial function has been shown in mouse hearts. ¹⁾

Drug and Cell Therapy

Vatiquinone (EPI-743): A reactive oxygen species scavenger. Clinical improvement was reported in 11 of 14 patients with mitochondrial disease. ¹⁾

CSF-1R inhibitor (immunotherapy): Suppression of neuroinflammatory lesion progression has been confirmed in Ndufs4 knockout mice. ¹⁾

Hypoxia therapy: Improvement in motor and thermoregulatory dysfunction has been reported in Ndufs4 knockout mice. ¹⁾

Screening using iPSC-derived brain organoids: Large-scale drug screening using neural progenitor cells derived from SURF1 mutations is underway. ¹⁾

Patient registry: Over 200 patients have enrolled in the Cure Mito Foundation’s global LS patient registry, advancing research infrastructure. ¹⁾

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8. References

1. Moreira JD, Smith KK, Zilber S, et al. Teamwork makes the dream work: functional collaborations between families, scientists, and healthcare providers to drive progress in the treatment of Leigh Syndrome. Orphanet J Rare Dis. 2023;18(1):341.

2. Jaballah F, Ben Soussia Nouira R, Mallouli S, et al. Schizophrenia-Like Psychotic Symptoms Associated to Leigh Syndrome. Case Rep Psychiatry. 2023;2023:6690750.

3. Zhang J, Gan J, Wang J. A case of Leigh syndrome presented with paroxysmal body swing. Heliyon. 2024;10(2):e24356.

4. Misceo D, Strømme P, Bitarafan F, et al. Biallelic NDUFA4 Deletion Causes Mitochondrial Complex IV Deficiency in a Patient with Leigh Syndrome. Genes. 2024;15(3):380.

5. Dupré M, Warne R, Shipman P, et al. Cranial and spinal nerve enhancement in SURF1-associated Leigh syndrome. Pediatr Radiol. 2024;54(9):1547-1552.

6. Liao Y, Lai Y, Chen X, Zhao S. Adult-onset Leigh syndrome with recurrent seizures and peripheral neuropathy due to the 9176T>C mutation: a case report and literature review. BMC Neurol. 2025;25(1):78.