Leigh Syndrome: Symptoms, Types, Causes and Treatment

Leigh syndrome is a rare but devastating neurological disorder, mostly affecting children, but with cases reported in adults as well. It is known for its rapid progression, severe neurologic symptoms, and complex genetic underpinnings. Despite being the most common pediatric presentation of mitochondrial disease, Leigh syndrome remains a challenging diagnosis for families and clinicians alike. This article presents a detailed overview of Leigh syndrome, focusing on its symptoms, types, underlying causes, and current approaches to treatment.

Symptoms of Leigh Syndrome

Leigh syndrome presents with a broad range of symptoms, reflecting its impact on multiple systems—most notably the central nervous system. Symptoms often emerge in infancy or early childhood, although later onset can occur. Understanding these symptoms is crucial for early detection and management.

Symptom	Frequency/Features	System Affected	Source(s)
Developmental delay	Common, often initial sign	Neurological	2 3 6
Hypotonia	Frequently observed	Muscular	2 3
Seizures	Regular occurrence	Neurological	2 3
Respiratory failure	Leading cause of mortality	Respiratory	1 4
Elevated lactate	72% in blood/CSF	Metabolic	2 13
Poor feeding	Especially in infants	Gastrointestinal	2 3
Nystagmus, ataxia	Eye movement, coordination issues	Neurological	1 7
Cardiomyopathy	Possible complication	Cardiac	3 8
Psychiatric symptoms	Rare, e.g., psychosis	Neuropsychiatric	5

Table 1: Key Symptoms

Overview of Core Symptoms

Leigh syndrome typically begins with subtle symptoms—such as developmental delay or failure to thrive—before progressing rapidly to severe neurological deficits. Most patients develop symptoms before the age of two, with about 80% showing signs in infancy 3 6. However, late-onset cases are increasingly recognized 6 7.

Neurological Manifestations

• Developmental Delay: This is often the first noticeable symptom, manifesting as delayed milestones or regression of previously acquired skills 2 3 6.
• Seizures: Occur in about one-third to three-quarters of patients, sometimes accompanying or following developmental regression 2 3.
• Ophthalmologic Symptoms: Nystagmus (involuntary eye movement), ophthalmoparesis (eye muscle weakness), and optic atrophy are frequently described 1.
• Movement Disorders: Ataxia (poor coordination), dystonia (involuntary muscle contractions), and motor weakness are common, particularly in late-onset cases 6 7.
• Altered Consciousness: Episodes of stupor or coma can occur during disease progression 3.

Systemic and Metabolic Symptoms

• Respiratory Dysfunction: Respiratory failure is the most serious and common cause of death, often due to brainstem involvement 1 4.
• Elevated Lactate: Blood and/or cerebrospinal fluid (CSF) lactate is increased in more than 70% of cases, reflecting underlying mitochondrial dysfunction 2 13.
• Poor Feeding and Failure to Thrive: These issues are particularly prominent in infants 2 3.
• Cardiac and Liver Involvement: Cardiomyopathy and liver dysfunction can be present, especially in Leigh-like or variant syndromes 3 8.

Additional and Rare Features

• Peripheral Neuropathy and Myopathy: Some patients show muscle weakness or nerve involvement 1.
• Psychiatric Symptoms: Rarely, psychiatric manifestations such as psychosis have been reported, particularly in long-term survivors 5.
• Other Non-Neurologic Symptoms: These can include diabetes, anemia, renal failure, vomiting, and diarrhea 1.

Types of Leigh Syndrome

Leigh syndrome is not a single disease but a spectrum of related disorders, each with unique features depending on the underlying genetic and biochemical defect. These types can be classified based on age of onset, genetic causes, or specific clinical presentations.

Type	Distinguishing Features	Typical Onset	Source(s)
Classic Leigh syndrome	Symmetrical CNS lesions, rapid progression	Infancy/childhood	3 4 6
Late-onset Leigh syndrome	Atypical symptoms, slower progression	>2 years/adulthood	6 7
Leigh-like syndrome	Includes non-neurological symptoms	Variable	1 9
LSFC (French-Canadian)	LRPPRC mutations, metabolic crises	Infancy/childhood	8
Pyruvate dehydrogenase (PDH) deficiency	Thiamine-responsive, variable severity	Infancy/childhood	5 12

Table 2: Types of Leigh Syndrome

Classic Leigh Syndrome

This is the most frequently encountered form, marked by:

• Early onset (typically between 3–12 months)
• Rapid neurological decline
• Symmetrical lesions in the basal ganglia and/or brainstem visible on MRI
• Life expectancy of only a few years after symptom onset 3 4 6

Late-Onset Leigh Syndrome

Although rare, some individuals develop symptoms after the age of two or even in adulthood. These cases often present with:

• Ataxia, bulbar palsy, and pyramidal tract signs
• Slower progression and more variable symptoms
• Less frequent cognitive impairment
• Mutations commonly found in mitochondrial DNA, especially those affecting complex I 6 7

Leigh-Like Syndrome

This term refers to patients with clinical and radiological features similar to Leigh syndrome but with:

• More prominent non-neurological symptoms (e.g., polyneuropathy, myopathy, renal failure)
• Broader involvement of peripheral organs 1 9

LSFC (Leigh Syndrome, French-Canadian Type)

A variant caused by mutations in the LRPPRC gene, LSFC is characterized by:

• Higher prevalence in certain Canadian populations due to a founder effect
• Episodes of severe metabolic crisis
• Early childhood onset 8

Pyruvate Dehydrogenase (PDH) Deficiency-Related Leigh Syndrome

Some cases are due to PDH complex deficiency, which may be:

• Thiamine-responsive
• Associated with variable neurological symptoms and sometimes psychiatric features 5 12

Causes of Leigh Syndrome

Leigh syndrome is highly heterogeneous in its genetic and biochemical origins. It is primarily a disorder of mitochondrial energy metabolism—either due to defects in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) that encode mitochondrial proteins.

Cause	Mechanism	Genetic Inheritance	Source(s)
mtDNA mutations	Respiratory chain protein defects	Maternal (mitochondrial)	2 4 7 12
nDNA mutations	Respiratory chain, PDH, CoQ, etc.	Autosomal recessive	2 4 10 12
PDH complex deficiency	Impaired pyruvate metabolism	X-linked/Autosomal	1 5 12
Coenzyme Q10 deficiency	Electron transport chain failure	Autosomal recessive	1 19
LRPPRC gene mutation (LSFC)	Impaired mitochondrial translation	Autosomal recessive	8

Table 3: Causes of Leigh Syndrome

Genetic Heterogeneity

• Mitochondrial DNA Mutations: These account for about one-third of cases and are inherited maternally. Commonly affected genes include MT-ND3, ND5, ND6, ND1, and MT-ATP6, most of which encode subunits of the mitochondrial respiratory chain complexes 2 7 12.
• Nuclear DNA Mutations: Responsible for a large proportion of cases, these often affect genes encoding components of mitochondrial respiratory chain complexes I, II, IV, or V, or their assembly factors. Over 75 genes have been implicated, including SURF1, NDUFS4, NDUFAF6, and others 4 10 12.

Biochemical Defects

Most cases involve a defect in:

• Mitochondrial Respiratory Chain (Complexes I, II, IV, V): Disruption leads to impaired ATP production, increased lactate, and neuronal degeneration 1 2 13.
• Pyruvate Dehydrogenase (PDH) Complex: Impaired conversion of pyruvate to acetyl-CoA leads to lactic acidosis and energy deficiency 1 5 12.
• Coenzyme Q10 (CoQ) Deficiency: Results in failure of electron transport and energy production 1 19.

Special Genetic Subtypes

• Leigh Syndrome, French-Canadian Type (LSFC): Caused by mutations in the nuclear LRPPRC gene, affecting mitochondrial translation and energy production 8.
• Aminoacyl-tRNA Synthetase Mutations: Variants in genes like NARS2 and IARS2 can cause Leigh syndrome with or without additional features such as hearing loss 11 12.

Pathophysiology

The core problem in Leigh syndrome is an energy deficit in neurons, leading to cell death in areas of high metabolic demand—particularly the basal ganglia, brainstem, and thalamus. Accumulated lactate, oxidative stress, and excitotoxicity further contribute to the disease process 13 14.

Treatment of Leigh Syndrome

Currently, there is no cure for Leigh syndrome, and treatment remains largely supportive. However, several promising experimental therapies and targeted interventions are emerging based on the underlying genetic or metabolic defect.

Treatment Approach	Description & Effectiveness	Notes/Status	Source(s)
Supportive care	Symptomatic management	Mainstay of therapy	19 4
Thiamine/Biotin	For PDH or SLC19A3 mutations	Effective in some cases	5 12
Coenzyme Q10	For CoQ deficiency	Can stabilize symptoms	1 19
EPI-743	Antioxidant, improves function	Clinical trial positive	15
mTOR inhibitors (Rapamycin)	Delays neurodegeneration (mice)	Preclinical	16
Hypoxia therapy	Reverses lesions (mice)	Preclinical	17
NAD+ precursors (NMN)	Extends lifespan (mice)	Preclinical	18
Gene-based therapies	Personalized, gene-specific	Emerging, experimental	4 14 12

Table 4: Treatment Approaches

Supportive and Symptomatic Care

• Multidisciplinary Approach: Includes nutrition management, physiotherapy, respiratory support, and seizure control 19 4.
• Monitoring and Early Intervention: Regular follow-up is crucial due to the risk of rapid deterioration, especially in early-onset cases 6 19.

Targeted Treatments

• Thiamine (Vitamin B1) and Biotin: High-dose thiamine can be life-saving in specific PDH complex or SLC19A3 gene defects. Biotin may also be effective in biotin-thiamine–responsive basal ganglia disease 5 12.
• Coenzyme Q10 Supplementation: Beneficial for patients with primary or secondary CoQ10 deficiency 1 19.

Emerging and Experimental Therapies

• EPI-743: An antioxidant that has shown reversal of disease progression and improved quality of life in children with genetically confirmed Leigh syndrome in clinical trials 15.
• mTOR Inhibitors (Rapamycin): Shown to delay neurological symptoms and extend survival in mouse models by modifying metabolic pathways 16.
• Hypoxia Therapy: Continuous low-oxygen exposure prevented and even reversed neurodegeneration in Leigh syndrome mouse models, suggesting possible future human application 17.
• NAD+ Precursors (NMN): Supplementation improved lifespan and metabolic balance in animal models, highlighting NAD+ metabolism as a therapeutic target 18.
• Gene-Based Personalized Therapies: Advances in genetic diagnosis now allow for the identification of treatable subtypes and the potential for future gene therapies 4 14 12.

The Importance of Early Diagnosis

Early genetic and metabolic testing is vital, as certain forms of Leigh syndrome are treatable if identified before irreversible damage occurs. Personalized therapies based on the underlying mutation are a growing area of research 4 12 19.

Conclusion

Leigh syndrome is a complex and devastating disorder, but recent advances in genetics, diagnostics, and experimental therapeutics offer new hope for affected individuals and families. Ongoing research is crucial to turn these breakthroughs into effective, widely available treatments.

Key Points Covered:

• Symptoms: Leigh syndrome presents with a broad array of neurological, metabolic, and systemic symptoms, with rapid progression and high mortality in early-onset cases.
• Types: Various subtypes exist, classified by age of onset, genetic cause, and clinical features.
• Causes: Genetic heterogeneity is a hallmark, with mutations in both mitochondrial and nuclear DNA affecting mitochondrial energy metabolism.
• Treatment: While supportive care remains the mainstay, emerging therapies—including antioxidants, metabolic modulators, and gene-based approaches—are showing promise, especially when tailored to the underlying genetic defect.

Prompt diagnosis, multidisciplinary management, and continued research into targeted therapies are the best strategies for improving the outlook for individuals with Leigh syndrome.