Leigh Syndrome
Leigh Syndrome
Leigh Syndrome, also known as Subacute Necrotizing Encephalomyelopathy, is a severe neurological disorder that typically presents in infancy or early childhood. It is characterized by progressive loss of mental and movement abilities (psychomotor regression) and typically results in early death.
Key Points:
- Incidence: Approximately 1 in 40,000 live births
- Age of onset: Typically infancy or early childhood, but can occur in adolescence or adulthood
- Inheritance: Can be inherited in multiple ways (mitochondrial, autosomal recessive, X-linked)
- Genes involved: Multiple genes affecting mitochondrial function
- Primary features: Progressive neurodegeneration with focal, bilateral lesions in the basal ganglia, thalamus, and brainstem
Clinical Features
Leigh Syndrome presents with a wide range of clinical features, which can vary in onset, severity, and progression:
Neurological Features:
- Psychomotor regression or developmental delay
- Hypotonia (low muscle tone)
- Ataxia (lack of voluntary coordination of muscle movements)
- Dystonia (abnormal muscle tone and postures)
- Seizures
- Respiratory abnormalities (e.g., hyperventilation, apnea)
- Nystagmus (involuntary eye movements)
- Optic atrophy
- Peripheral neuropathy
Non-neurological Features:
- Failure to thrive
- Feeding difficulties and dysphagia
- Vomiting
- Cardiomyopathy
- Renal tubular acidosis
- Endocrine dysfunction (e.g., diabetes mellitus, growth hormone deficiency)
Course of Disease:
- Early-onset form:
- Symptoms typically appear between 3 months and 2 years of age
- Rapid progression of symptoms
- Often fatal within a few years
- Late-onset form:
- Symptoms appear in late childhood, adolescence, or adulthood
- Generally slower progression
- Variable prognosis
Characteristic Progression:
- Initial period of normal development
- Onset of symptoms, often triggered by an infection or other stress
- Episodic exacerbations with periods of relative stability
- Progressive neurological deterioration
Diagnosis
Diagnosis of Leigh Syndrome is based on clinical features, neuroimaging, biochemical testing, and genetic analysis:
Clinical Diagnosis:
- Characteristic neurological symptoms
- Family history consistent with mitochondrial inheritance
Neuroimaging:
- MRI: Bilateral, symmetric focal lesions in the basal ganglia, thalamus, brainstem, and occasionally white matter
- CT: May show hypodense areas in the basal ganglia
- MR spectroscopy: Elevated lactate peak in affected brain regions
Biochemical Testing:
- Elevated lactate and pyruvate levels in blood and/or cerebrospinal fluid
- Abnormal respiratory chain enzyme activities in muscle biopsy
- Abnormal pyruvate dehydrogenase complex activity
Genetic Testing:
- Mitochondrial DNA sequencing
- Nuclear gene sequencing (panel testing or whole exome sequencing)
- Mitochondrial DNA deletion/duplication analysis
Diagnostic Criteria (Rahman et al., 1996):
Definitive diagnosis requires all of the following:
- Progressive neurological disease with motor and intellectual developmental delay
- Signs and symptoms of brainstem and/or basal ganglia disease
- Elevated lactate levels in blood and/or cerebrospinal fluid
- Characteristic symmetric necrotic lesions in the basal ganglia and/or brainstem
Differential Diagnosis:
Consider other mitochondrial disorders and conditions with similar presentations:
- Other mitochondrial encephalomyopathies
- Organic acidemias
- Biotinidase deficiency
- Wernicke encephalopathy
- Carbon monoxide poisoning
- Infantile bilateral striatal necrosis
Management
Management of Leigh Syndrome is primarily supportive and aimed at managing symptoms and preventing complications:
General Approach:
- Multidisciplinary team involvement (neurologist, geneticist, nutritionist, physical therapist, etc.)
- Regular monitoring of disease progression
- Avoidance of physiological stress (infections, dehydration, prolonged fasting)
Specific Interventions:
- Nutritional Support:
- High-fat, low-carbohydrate diet (in some cases)
- Vitamin and cofactor supplementation (e.g., thiamine, riboflavin, coenzyme Q10)
- Gastrostomy tube feeding if necessary
- Respiratory Support:
- Monitoring for central hypoventilation
- Oxygen therapy or mechanical ventilation as needed
- Neurological Management:
- Anticonvulsant medications for seizure control
- Management of dystonia and spasticity
- Physical therapy and occupational therapy
- Metabolic Management:
- Dichloroacetate (investigational) to reduce lactic acidosis
- Bicarbonate supplementation for acidosis
- Cardiac Management:
- Regular cardiac evaluations
- Management of cardiomyopathy if present
- Ophthalmological Care:
- Regular eye examinations
- Management of optic atrophy and visual impairment
Experimental Therapies:
- EPI-743 (investigational drug targeting oxidative stress)
- Stem cell transplantation (research stage)
- Gene therapy approaches (in development)
Genetic Counseling:
- Explanation of inheritance patterns and recurrence risks
- Discussion of reproductive options
- Prenatal testing when familial mutation is known
Palliative Care:
- Early involvement of palliative care team
- Focus on quality of life and symptom management
- Support for families in decision-making
Genetics
Leigh Syndrome is genetically heterogeneous, involving mutations in both mitochondrial and nuclear DNA:
Inheritance Patterns:
- Mitochondrial (maternal)
- Autosomal recessive
- X-linked
Genetic Causes:
- Mitochondrial DNA mutations:
- Most common: MT-ATP6 gene (ATPase 6 subunit)
- Others: MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND5, MT-ND6, MT-CO3, MT-TL1, MT-TK, MT-TV
- Nuclear DNA mutations:
- Genes encoding subunits of mitochondrial respiratory chain complexes
- Genes involved in assembly of respiratory chain complexes
- Genes involved in coenzyme Q10 biosynthesis
- Genes involved in pyruvate dehydrogenase complex
Common Nuclear Genes Associated with Leigh Syndrome:
- SURF1 (complex IV assembly)
- PDHA1 (pyruvate dehydrogenase E1-alpha subunit)
- NDUFS4 (complex I subunit)
- NDUFS7 (complex I subunit)
- NDUFS8 (complex I subunit)
- COX10 (complex IV assembly)
- COX15 (complex IV assembly)
Genetic Testing Strategies:
- Mitochondrial DNA sequencing and deletion/duplication analysis
- Nuclear gene panel testing for Leigh Syndrome and mitochondrial disorders
- Whole exome sequencing if targeted testing is negative
- Whole genome sequencing in select cases
Genotype-Phenotype Correlations:
- Generally poor correlation due to genetic heterogeneity
- Some trends observed:
- SURF1 mutations: Often associated with cytochrome c oxidase deficiency and early onset
- MT-ATP6 mutations: May have later onset and slower progression
- PDHA1 mutations: Often associated with corpus callosum abnormalities
Implications for Genetic Counseling:
- Complex inheritance patterns require careful genetic counseling
- Recurrence risk varies depending on the specific genetic cause
- Prenatal testing options depend on identified genetic cause
- Importance of identifying the genetic basis for accurate genetic counseling and family planning
