Leigh Syndrome is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Leigh syndrome (LS), also known as subacute necrotizing encephalomyelopathy, is the most common pediatric presentation of [[mitochondria[/mechanisms/[mitochondrial-dysfunction-ad[/mechanisms/[mitochondrial-dysfunction-ad[/mechanisms/[mitochondrial-dysfunction-ad--TEMP--/mechanisms)--FIX-- disease[/diseases/[[mitochondria[/mechanisms/[mitochondrial-dysfunction-ad[/diseases/[[mitochondria--TEMP--/mechanisms/mitochondrial-dysfunction-ad//mechanisms//mechanisms/[mitochondrial-dysfunction-ad--TEMP--//diseases//diseases//diseases/[mitochondria[//mechanisms//mechanisms//mechanisms//mechanisms/[mitochondrial-dysfunction-ad--TEMP--//mechanisms//mechanisms/mitochondrial-dysfunction-ad[//diseases//diseases//diseases/[[mitochondria](//mechanisms//mechanisms/](//mechanisms//mechanisms//mechanisms//mechanisms/mitochondrial-dysfunction-ad](//mechanisms//mechanisms/mitochondrial-dysfunction-ad](//diseases/](//diseases//diseases//diseases/[mitochondria](//mechanisms//mechanisms/](//mechanisms//mechanisms//mechanisms//mechanisms/mitochondrial-dysfunction-ad](//mechanisms//mechanisms/mitochondrial-dysfunction-ad--FIX----FIX-- (/diseases/[mitochondria) (/mechanisms/mitochondrial-dysfunction-ad) (/mechanisms)--FIX---diseases). First described by British neuropathologist Denis Leigh in 1951, it is a severe progressive [[neurodegenerative disease[/diseases/[neurodegeneration[/diseases/[neurodegeneration[/diseases/[neurodegeneration--TEMP--/diseases)--FIX--[/[diseases[/[diseases[/[diseases[/[diseases[/[diseases[/diseases characterized by bilateral symmetric necrotizing lesions in the [basal ganglia[/brain-regions/[basal-ganglia[/brain-regions/[basal-ganglia[/brain-regions/[basal-ganglia--TEMP--/brain-regions)--FIX--, [brainstem[/brain-regions/[brainstem[/brain-regions/[brainstem[/brain-regions/[brainstem--TEMP--/brain-regions)--FIX--, [thalamus[/brain-regions/[thalamus[/brain-regions/[thalamus[/brain-regions/[thalamus--TEMP--/brain-regions)--FIX--, and [cerebellum[/brain-regions/[cerebellum[/brain-regions/[cerebellum[/brain-regions/[cerebellum--TEMP--/brain-regions)--FIX--. The disease typically presents in infancy or early childhood, though late-onset forms can occur in adolescents and adults 1(https://pmc.ncbi.nlm.nih.gov/articles/PMC11940177/).
Leigh syndrome affects approximately 1 in 40,000 live births, with higher incidence in certain populations, including the Saguenay-Lac-Saint-Jean region of Quebec (1 in 2,000) and the Faroe Islands 2(https://www.ncbi.nlm.nih.gov/books/NBK320989/). Prognosis is generally poor, with a median survival of approximately 2 years from symptom onset in the classic infantile form, though significant variability exists depending on the underlying genetic cause.
¶ Genetics and Molecular Basis
Leigh syndrome is genetically heterogeneous, with more than 120 causative genes identified across both the nuclear and [mitochondria[/mechanisms/[mitochondrial-dysfunction-ad[/mechanisms/[mitochondrial-dysfunction-ad[/mechanisms/[mitochondrial-dysfunction-ad--TEMP--/mechanisms)--FIX-- genomes. Approximately 80% of cases are caused by [genetic mutations[/mechanisms/[genetic-mutations[/mechanisms/[genetic-mutations[/mechanisms/[genetic-mutations--TEMP--/mechanisms)--FIX--s in nuclear DNA, while about 20% result from [genetic mutations[/mechanisms/[genetic-mutations[/mechanisms/[genetic-mutations[/mechanisms/[genetic-mutations--TEMP--/mechanisms)--FIX--s in [mitochondria[/mechanisms/[mitochondrial-dysfunction-ad[/mechanisms/[mitochondrial-dysfunction-ad[/mechanisms/[mitochondrial-dysfunction-ad--TEMP--/mechanisms)--FIX-- DNA (mtDNA) 3(https://medlineplus.gov/genetics/condition/leigh-syndrome/).
Nuclear gene [genetic mutations[/mechanisms/[genetic-mutations[/mechanisms/[genetic-mutations[/mechanisms/[genetic-mutations--TEMP--/mechanisms)--FIX--s affect various components of [mitochondria[/mechanisms/[mitochondrial-dysfunction-ad[/mechanisms/[mitochondrial-dysfunction-ad[/mechanisms/[mitochondrial-dysfunction-ad--TEMP--/mechanisms)--FIX-- energy metabolism:
- Complex I (NADH:ubiquinone oxidoreductase) deficiency: The most common cause, accounting for approximately one-third of all Leigh syndrome cases. Key genes include [NDUFS1[/genes/[ndufs1[/genes/[ndufs1[/genes/[ndufs1--TEMP--/genes)--FIX--, NDUFS2, NDUFS3, [NDUFS4[/genes/[ndufs4[/genes/[ndufs4[/genes/[ndufs4--TEMP--/genes)--FIX--, NDUFS7, NDUFS8, NDUFV1, and NDUFA10 1(https://pmc.ncbi.nlm.nih.gov/articles/PMC11940177/).
- Complex IV (cytochrome c oxidase/COX) deficiency: Accounts for approximately 15% of cases. The most frequently mutated gene is [SURF1[/genes/[surf1[/genes/[surf1[/genes/[surf1--TEMP--/genes)--FIX--, which encodes a Complex IV assembly factor 3(https://medlineplus.gov/genetics/condition/leigh-syndrome/).
- Complex V ([ATP[/mechanisms/[energy-metabolism[/mechanisms/[energy-metabolism[/mechanisms/[energy-metabolism--TEMP--/mechanisms)--FIX-- synthase) deficiency: Mutations in [ATP[/mechanisms/[energy-metabolism[/mechanisms/[energy-metabolism[/mechanisms/[energy-metabolism--TEMP--/mechanisms)--FIX--5F1E and other subunit genes.
- Pyruvate dehydrogenase complex (PDHc) deficiency: Mutations in PDHA1 (X-linked), PDHB, DLAT, and DLD genes impair the conversion of pyruvate to acetyl-CoA 4(https://pmc.ncbi.nlm.nih.gov/articles/PMC4235479/).
- Coenzyme Q10 biosynthesis defects: Mutations in COQ2, COQ9, and related genes.
- Complex II deficiency: Mutations in SDHA (succinate dehydrogenase subunit A).
mtDNA [genetic mutations[/mechanisms/[genetic-mutations[/mechanisms/[genetic-mutations[/mechanisms/[genetic-mutations--TEMP--/mechanisms)--FIX--s causing Leigh syndrome include:
- MT-[ATP[/mechanisms/[energy-metabolism[/mechanisms/[energy-metabolism[/mechanisms/[energy-metabolism--TEMP--/mechanisms)--FIX--6 (m.8993T>G/C): Most common mtDNA cause, affecting [ATP[/mechanisms/[energy-metabolism[/mechanisms/[energy-metabolism[/mechanisms/[energy-metabolism--TEMP--/mechanisms)--FIX-- synthase subunit 6. The m.8993T>G [genetic mutations[/mechanisms/[genetic-mutations[/mechanisms/[genetic-mutations[/mechanisms/[genetic-mutations--TEMP--/mechanisms)--FIX-- causes Leigh syndrome at high heteroplasmy (>90%), while lower levels cause the milder NARP syndrome (neuropathy, [ataxia[/mechanisms/[ataxia-cerebellar[/mechanisms/[ataxia-cerebellar[/mechanisms/[ataxia-cerebellar--TEMP--/mechanisms)--FIX--, retinitis pigmentosa).
- MT-ND1, MT-ND3, MT-ND5, MT-ND6: Mutations in Complex I subunits.
- MT-CO3: Mutations in Complex IV subunit III.
- MT-TW, MT-TV, MT-TL1: Mutations in [mitochondria[/mechanisms/[mitochondrial-dysfunction-ad[/mechanisms/[mitochondrial-dysfunction-ad[/mechanisms/[mitochondrial-dysfunction-ad--TEMP--/mechanisms)--FIX-- tRNA genes 1(https://pmc.ncbi.nlm.nih.gov/articles/PMC11940177/).
Depending on the causative gene, Leigh syndrome can follow:
- Autosomal recessive inheritance (most nuclear gene [genetic mutations[/mechanisms/[genetic-mutations[/mechanisms/[genetic-mutations[/mechanisms/[genetic-mutations--TEMP--/mechanisms)--FIX--s)
- X-linked inheritance (PDHA1 [genetic mutations[/mechanisms/[genetic-mutations[/mechanisms/[genetic-mutations[/mechanisms/[genetic-mutations--TEMP--/mechanisms)--FIX--s)
- Maternal inheritance (mtDNA [genetic mutations[/mechanisms/[genetic-mutations[/mechanisms/[genetic-mutations[/mechanisms/[genetic-mutations--TEMP--/mechanisms)--FIX--s)
The pathophysiology of Leigh syndrome centers on defective [mitochondria[/mechanisms/[mitochondrial-dysfunction-ad[/mechanisms/[mitochondrial-dysfunction-ad[/mechanisms/[mitochondrial-dysfunction-ad--TEMP--/mechanisms)--FIX-- [oxidative phosphorylation[/mechanisms/[oxidative-phosphorylation[/mechanisms/[oxidative-phosphorylation[/mechanisms/[oxidative-phosphorylation--TEMP--/mechanisms)--FIX-- (OXPHOS), leading to impaired [ATP[/mechanisms/[energy-metabolism[/mechanisms/[energy-metabolism[/mechanisms/[energy-metabolism--TEMP--/mechanisms)--FIX-- production. The brain is particularly vulnerable due to its high metabolic demands, accounting for approximately 20% of total body oxygen consumption despite representing only 2% of body weight.
Defective OXPHOS complexes reduce [ATP[/mechanisms/[energy-metabolism[/mechanisms/[energy-metabolism[/mechanisms/[energy-metabolism--TEMP--/mechanisms)--FIX-- generation, leading to:
- Cellular energy failure in metabolically active brain regions
- Shift toward anaerobic glycolysis with [lactic acid] accumulation
- Failure of energy-dependent ion pumps, causing cellular swelling
- Impaired neurotransmitter synthesis and release 5(https://pubmed.ncbi.nlm.nih.gov/25978847/)
Dysfunctional electron transport chain complexes leak electrons, generating excessive [reactive oxygen species ([ROS[/mechanisms/[oxidative-stress[/mechanisms/[oxidative-stress[/mechanisms/[oxidative-stress--TEMP--/mechanisms)--FIX--:
- Superoxide anion (O₂⁻) production at Complex I and Complex III
- Secondary damage to [mitochondria[/mechanisms/[mitochondrial-dysfunction-ad[/mechanisms/[mitochondrial-dysfunction-ad[/mechanisms/[mitochondrial-dysfunction-ad--TEMP--/mechanisms)--FIX-- DNA, proteins, and lipids
- Activation of [apoptotic] and [necroptotic] cell death pathways
- Amplification of [neuroinflammation[/mechanisms/[neuroinflammation[/mechanisms/[neuroinflammation[/mechanisms/[neuroinflammation--TEMP--/mechanisms)--FIX-- through microglial activation
The characteristic bilateral symmetric lesions reflect the selective vulnerability of specific brain regions:
- [basal ganglia[/brain-regions/[basal-ganglia[/brain-regions/[basal-ganglia[/brain-regions/[basal-ganglia--TEMP--/brain-regions)--FIX-- (putamen, caudate, globus pallidus) — affected in ~90% of patients
- Brainstem nuclei (periaqueductal gray, inferior olivary nuclei)
- [thalamus[/brain-regions/[thalamus[/brain-regions/[thalamus[/brain-regions/[thalamus--TEMP--/brain-regions)--FIX-- and subthalamic nuclei — affected in ~42% of patients
- [cerebellum[/brain-regions/[cerebellum[/brain-regions/[cerebellum[/brain-regions/[cerebellum--TEMP--/brain-regions)--FIX-- (dentate nuclei)
- Spinal cord (posterior columns) 7(https://link.springer.com/article/10.1186/s13023-021-02029-3)
These regions have the highest metabolic rates and are most dependent on [oxidative phosphorylation[/mechanisms/[oxidative-phosphorylation[/mechanisms/[oxidative-phosphorylation[/mechanisms/[oxidative-phosphorylation--TEMP--/mechanisms)--FIX-- for energy production.
The most common presentation, accounting for approximately 50–75% of cases:
- Psychomotor regression: Loss of previously acquired developmental milestones (sitting, walking, speech)
- Hypotonia: Generalized muscle weakness and reduced tone
- Feeding difficulties: Dysphagia, vomiting, failure to thrive
- Movement disorders: Dystonia, choreoathetosis, tremor
- Respiratory abnormalities: Central hypoventilation, episodic hyperventilation, apnea
- Ophthalmological signs: Nystagmus, ophthalmoplegia, optic atrophy, strabismus
- Seizures: Present in 30–40% of patients
- Lactic acidosis: Elevated lactate in blood and/or cerebrospinal fluid 1(https://pmc.ncbi.nlm.nih.gov/articles/PMC11940177/)
A smaller proportion of patients present later in childhood, adolescence, or rarely in adulthood:
- Ataxia and progressive gait disturbance
- Cognitive decline
- Dystonia and spasticity
- Exercise intolerance
- Generally slower progression than the infantile form
Some patients present with systemic involvement beyond the CNS:
- Cardiomyopathy (hypertrophic or dilated)
- Hepatic dysfunction
- Renal tubular acidosis
- Endocrine abnormalities (diabetes mellitus, short stature)
- Peripheral neuropathy or myopathy 2(https://www.ncbi.nlm.nih.gov/books/NBK320989/)
Metabolic crises are often precipitated by:
- Intercurrent febrile illness
- Fasting or metabolic stress
- Surgical procedures under general anesthesia
- Vaccination (rare)
MRI is the primary diagnostic tool, revealing characteristic bilateral symmetric lesions:
- T2-weighted/FLAIR: Hyperintense lesions in the [basal ganglia[/brain-regions/[basal-ganglia[/brain-regions/[basal-ganglia[/brain-regions/[basal-ganglia--TEMP--/brain-regions)--FIX--, [brainstem[/brain-regions/[brainstem[/brain-regions/[brainstem[/brain-regions/[brainstem--TEMP--/brain-regions)--FIX--, and [thalamus[/brain-regions/[thalamus[/brain-regions/[thalamus[/brain-regions/[thalamus--TEMP--/brain-regions)--FIX--
- Diffusion-weighted imaging (DWI): Restricted diffusion during acute episodes
- MR spectroscopy: Elevated lactate peak, reduced N-acetylaspartate (NAA)
- CT: Hypodense lesions in the same distribution (less sensitive than MRI) 8(https://radiopaedia.org/articles/leigh-syndrome-3)
- Plasma lactate and pyruvate: Elevated lactate with increased lactate:pyruvate ratio
- CSF lactate: Often elevated, even when plasma lactate is normal
- Organic acid analysis: May show elevated Krebs cycle intermediates
- Acylcarnitine profile: Can suggest specific fatty acid oxidation defects
- Muscle biopsy: Enzyme analysis of OXPHOS complexes I–V, though increasingly replaced by genetic testing
- Whole exome sequencing (WES): First-line genetic diagnostic approach, identifying causative [genetic mutations[/mechanisms/[genetic-mutations[/mechanisms/[genetic-mutations[/mechanisms/[genetic-mutations--TEMP--/mechanisms)--FIX--s in ~60–70% of cases
- Whole genome sequencing (WGS): Can detect deep intronic variants and structural variants missed by WES
- Mitochondrial genome sequencing: Complete mtDNA analysis for maternal inheritance
- Long-read sequencing: Emerging technology for detecting complex structural variants 9(https://www.imrpress.com/journal/FBS/17/4/10.31083/FBS45427)
The classic diagnostic criteria for Leigh syndrome require:
- Progressive neurological disease with motor and intellectual developmental delay
- Signs and symptoms of [brainstem[/brain-regions/[brainstem[/brain-regions/[brainstem[/brain-regions/[brainstem--TEMP--/brain-regions)--FIX-- and/or [basal ganglia[/brain-regions/[basal-ganglia[/brain-regions/[basal-ganglia[/brain-regions/[basal-ganglia--TEMP--/brain-regions)--FIX-- disease
- Raised lactate levels in blood and/or CSF
- Characteristic neuropathological changes or bilateral symmetric signal abnormalities on MRI
The hallmark neuropathological findings include 5(https://pubmed.ncbi.nlm.nih.gov/25978847/):
- Focal bilateral symmetric necrotic lesions: Spongy degeneration with vacuolation of the neuropil
- Capillary proliferation: Striking vascular proliferation within and around lesions
- Gliosis: Reactive astrocytic response surrounding necrotic areas
- Relative neuronal preservation: [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX-- at the periphery of lesions may be relatively spared initially
- Demyelination: Loss of myelin sheaths within affected white matter tracts
¶ Treatment and Management
No curative treatment exists for Leigh syndrome. Current management is largely supportive and symptom-based:
Metabolic Supplements:
- Coenzyme Q10 (ubiquinone): 5–15 mg/kg/day, may benefit Complex III deficiency and CoQ10 biosynthesis defects
- Riboflavin (vitamin B2): 100–300 mg/day, cofactor for Complex I and Complex II
- Thiamine (vitamin B1): 100–300 mg/day, cofactor for PDHc; particularly beneficial in PDHc deficiency
- L-carnitine: 50–100 mg/kg/day, supports fatty acid transport
- Idebenone: Synthetic CoQ10 analog with improved bioavailability
- Creatine monohydrate: Enhances cellular energy stores 1(https://pmc.ncbi.nlm.nih.gov/articles/PMC11940177/)
Dietary Management:
- Ketogenic diet for PDHc deficiency (bypasses the pyruvate dehydrogenase block)
- Avoidance of prolonged fasting
- Emergency protocols during illness to prevent metabolic crises
Symptomatic Treatment:
- Antiepileptic drugs for [seizures[/mechanisms/[epilepsy-seizures[/mechanisms/[epilepsy-seizures[/mechanisms/[epilepsy-seizures--TEMP--/mechanisms)--FIX-- (avoiding valproate in POLG [genetic mutations[/mechanisms/[genetic-mutations[/mechanisms/[genetic-mutations[/mechanisms/[genetic-mutations--TEMP--/mechanisms)--FIX--s)
- Botulinum toxin for dystonia
- Respiratory support (non-invasive ventilation, tracheostomy in severe cases)
- Gastrostomy feeding for dysphagia
Several promising therapeutic approaches are under investigation:
The prognosis for Leigh syndrome varies considerably depending on the underlying genetic defect:
- Classic infantile form: Median survival approximately 2–3 years from diagnosis. Many patients die from respiratory failure during metabolic crises.
- Late-onset forms: May survive into adolescence or adulthood, particularly with milder genetic variants.
- [SURF1[/genes/[surf1[/genes/[surf1[/genes/[surf1--TEMP--/genes)--FIX-- [genetic mutations[/mechanisms/[genetic-mutations[/mechanisms/[genetic-mutations[/mechanisms/[genetic-mutations--TEMP--/mechanisms)--FIX--s: Paradoxically associated with longer survival despite severe clinical presentation, with some patients surviving beyond the second decade.
- mtDNA [genetic mutations[/mechanisms/[genetic-mutations[/mechanisms/[genetic-mutations[/mechanisms/[genetic-mutations--TEMP--/mechanisms)--FIX--s (MT-[ATP[/mechanisms/[energy-metabolism[/mechanisms/[energy-metabolism[/mechanisms/[energy-metabolism--TEMP--/mechanisms)--FIX--6): Prognosis correlates with heteroplasmy level; lower mutant load associated with milder disease (NARP syndrome) 7(https://link.springer.com/article/10.1186/s13023-021-02029-3).
Disease progression is often stepwise, with relatively stable periods interrupted by acute deterioration triggered by intercurrent illness.
- [All Diseases[/[diseases[/[diseases[/[diseases[/[diseases[/[diseases[/diseases
The study of Leigh Syndrome has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
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- [Barkovich R, et al. Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview. GeneReviews. NCBI Bookshelf)
- [MedlinePlus. Leigh syndrome. MedlinePlus Genetics. Link)
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- [Lake NJ, et al. (2015]. Leigh syndrome: neuropathology and pathogenesis. J Neuropathol Exp Neurol. 74(6):482-92. PMID 25978847)
- [Picca A, et al. (2020]. Mitochondrial Dysfunction, Oxidative Stress, and neuroinflammation: Intertwined Roads to Neurodegeneration. Antioxidants. 9(8):647. PMC7466131)
- [Ardissone A, et al. (2021]. Clinical, imaging, biochemical and molecular features in Leigh syndrome: a study from the Italian network of [[mitochondria[/mechanisms/[mitochondrial-dysfunction-ad[/mechanisms/[mitochondrial-dysfunction-ad[/mechanisms/[mitochondrial-dysfunction-ad--TEMP--/mechanisms)--FIX-- disease[/diseases/[[mitochondria[/mechanisms/[mitochondrial-dysfunction-ad[/diseases/[[mitochondria--TEMP--/mechanisms/mitochondrial-dysfunction-ad//mechanisms//mechanisms/[mitochondrial-dysfunction-ad--TEMP--//diseases//diseases//diseases/[mitochondria[//mechanisms//mechanisms//mechanisms//mechanisms/[mitochondrial-dysfunction-ad--TEMP--//mechanisms//mechanisms/mitochondrial-dysfunction-ad[//diseases//diseases//diseases/[[mitochondria](//mechanisms//mechanisms/](//mechanisms//mechanisms//mechanisms//mechanisms/mitochondrial-dysfunction-ad](//mechanisms//mechanisms/mitochondrial-dysfunction-ad](//diseases/](//diseases//diseases//diseases/[mitochondria](//mechanisms//mechanisms/](//mechanisms//mechanisms//mechanisms//mechanisms/mitochondrial-dysfunction-ad](//mechanisms//mechanisms/mitochondrial-dysfunction-ad--FIX----FIX-- (/diseases/[mitochondria) (/mechanisms/mitochondrial-dysfunction-ad) (/mechanisms)--FIX---diseases)s. Orphanet J Rare Dis. 16(1):413. [DOI)(https://link.springer.com/article/10.1186/s13023-021-02029-3)
- [Radiopaedia. Leigh syndrome. [Link)(https://radiopaedia.org/articles/leigh-syndrome-3)
- [Pagliano E, et al. (2025]. The Path to Precision Medicine in Leigh Syndrome Spectrum. Front Biosci. DOI)
- [Rahman S, et al. (2025]. Two tales of therapeutic innovations for Leigh syndrome spectrum. PubMed. PMID 40050739)
- [Leigh Syndrome Foundation. (2025]. Expanding research and care for Leigh syndrome. Res Involv Engagem. DOI)
- [Sofou K, et al. (2023]. Leigh syndrome. Handb Clin Neurol. PMID 36813320)