Phenotypic and Genotypic Peculiarities in Chinese Patients with Leigh Syndrome
Leigh syndrome (LS), a progressive neurodegenerative disorder characterized by bilateral symmetrical lesions in the brainstem, basal ganglia, and other regions of the central nervous system, presents with significant heterogeneity in clinical and genetic features. This study retrospectively analyzed 13 Chinese LS patients harboring mitochondrial DNA (mtDNA) mutations to delineate their phenotypic and genotypic peculiarities, offering insights into diagnosis, disease progression, and management within this population.
Patient Cohort and Diagnostic Criteria
The cohort comprised 13 patients (8 males, 5 females) diagnosed with LS based on clinical manifestations, neuroimaging findings, and genetic confirmation. Diagnostic adherence included criteria proposed by Baertling et al., emphasizing bilateral brainstem or basal ganglia lesions on magnetic resonance imaging (MRI), neurological regression, and elevated lactate levels in blood or cerebrospinal fluid (CSF). While 12 patients met criteria for Leigh-like syndrome, one patient was excluded due to a confirmed diagnosis of biotin-responsive basal ganglia disease.
Genetic Landscape and Mutation Spectrum
Mitochondrial genome sequencing revealed pathogenic mtDNA mutations in all patients, with no nuclear DNA (nDNA) mutations identified. The mutations spanned several mitochondrial genes:
- MT-ND3: m.10191T>C (3 patients) and m.10158T>C (1 patient)
- MT-ATP6: m.8993T>C (2 patients) and m.9176T>C (1 patient)
- MT-TL1: m.3243A>G (2 patients) and m.3271T>C (1 patient)
- MT-ND5: m.13513G>A (1 patient)
- MT-ND1: m.3697G>A (1 patient)
- MT-TV: m.1644G>A (1 patient)
Notably, the m.3243A>G mutation in MT-TL1, commonly associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), did not manifest stroke-like episodes (SLEs) or stroke-like lesions (SLLs) in the two affected patients, underscoring phenotypic variability. Maternal inheritance was confirmed in seven cases, while the m.13513G>A mutation in MT-ND5 arose de novo in one patient.
Clinical and Neuroimaging Features
All patients exhibited developmental delay or regression, with symptom onset ranging from infancy to adolescence (median age: 2 years). Motor dysfunction, including hypotonia, ataxia, and spasticity, was universal. Ocular abnormalities, such as nystagmus and optic atrophy, occurred in 84.6% (11/13). Remarkably, seizures were absent in all patients during the study period, though their potential emergence during disease progression could not be ruled out.
Neuroimaging consistently revealed symmetrical T2-weighted hyperintensities in the basal ganglia (100%), brainstem (76.9%), and thalamus (30.8%). Lesions in the cerebellum (15.4%) and cerebral white matter (7.7%) were less frequent. Magnetic resonance spectroscopy (MRS) detected elevated lactate peaks in three patients, corroborating mitochondrial dysfunction.
Laboratory and Cerebrospinal Fluid Findings
Blood lactate levels were elevated in 66.7% (6/9) of tested patients, while CSF lactate was elevated in all six patients undergoing lumbar puncture (median: 3.8 mmol/L, range: 2.6–5.4 mmol/L). CSF protein levels exceeded normal limits in four patients (median: 0.65 g/L, range: 0.4–1.2 g/L), a finding more consistent with Kearns-Sayre syndrome (KSS) but noted here as supportive of LS differentiation from non-mitochondrial disorders like neuromyelitis optica spectrum disorder (NMOSD).
Cardiac Involvement
Patient 7, harboring the de novo m.13513G>A mutation, presented with left ventricular noncompaction (LVNC) and preexcitation syndrome. Cardiac evaluation demonstrated sinus arrhythmia and intermittent preexcitation, though left ventricular ejection fraction remained normal. No cardiac-related therapies were initiated beyond standard mitochondrial cofactor supplementation (coenzyme Q10, L-carnitine, thiamine, riboflavin).
Heteroplasmy and Genetic Counseling
Heteroplasmy rates in maternal blood samples varied but were universally lower than in probands (range: 10–40% vs. 70–95% in patients). Despite maternal carriers remaining asymptomatic, incomplete family participation hindered comprehensive segregation analysis. This highlights challenges in genetic counseling, particularly regarding recurrence risk estimation for de novo or low-heteroplasmy mutations.
Disease Progression and Mortality
Three patients succumbed to respiratory failure at 3 months, 6 months, and 6 years post-diagnosis. Mortality correlated with early-onset disease (≤1 year), brainstem involvement, and high heteroplasmy loads (>90%). Survivors demonstrated relative stability under cofactor regimens, though longitudinal data were limited by loss to follow-up.
Absence of Stroke-Like Episodes
Despite the inclusion of two patients with the MELAS-associated m.3243A>G mutation, no cases exhibited SLEs or SLLs. This contrasts with classic MELAS presentations but aligns with reports of m.3243A>G phenotypic heterogeneity, where LS manifestations dominate without cortical involvement.
Limitations and Future Directions
The study’s cross-sectional design, small sample size, and absent nDNA analysis limit generalizability. Nine patients lacked identifiable pathogenic variants despite exome sequencing, suggesting undiscovered nDNA mutations or epigenetic factors. Prospective studies incorporating longitudinal follow-up, advanced functional assays, and multi-omics approaches are needed to unravel mechanisms underlying regional lesion susceptibility and phenotypic variability.
Therapeutic Implications
All patients received mitochondrial cofactors (coenzyme Q10, L-carnitine, thiamine, riboflavin), though regimens were not standardized. Dietary interventions, such as ketogenic or low-carbohydrate diets, were unexplored. The absence of targeted therapies underscores the need for genotype-specific management strategies and clinical trials evaluating redox-modulating agents, nucleoside bypass therapies, or gene-editing approaches.
Conclusion
This study delineates a distinct clinical and genetic profile of LS in Chinese patients, dominated by mtDNA mutations in complex I and V genes, frequent basal ganglia-brainstem pathology, and variable systemic involvement. Elevated CSF lactate emerged as a sensitive diagnostic biomarker, while the absence of seizures and SLEs contrasts with global cohorts. These findings enhance diagnostic precision, inform genetic counseling, and highlight unmet therapeutic needs in mitochondrial medicine.
doi.org/10.1097/CM9.0000000000000090
Was this helpful?
0 / 0