Leigh syndrome represents a severe mitochondrial disorder characterized by progressive neurodegeneration, typically manifesting in infancy with devastating outcomes. We present a 30-day-old male infant who presented with acute neurological deterioration, including seizures, dystonia, and respiratory failure. Laboratory evaluation revealed elevated levels of lactate and pyruvate. Brain magnetic resonance imaging (MRI) demonstrated characteristic bilateral symmetric T2 hyperintensity with restricted diffusion involving the basal ganglia, thalami, brainstem structures, and multiple other regions. Single-voxel spectroscopy confirmed an elevated lactate peak in the basal ganglia. Genetic testing identified a 95% heteroplasmic pathogenic variant in MT-ND5, confirming mitochondrial DNA-associated Leigh syndrome. Despite intensive supportive care including mechanical ventilation and anticonvulsant therapy, the patient's condition progressively deteriorated, resulting in death 16 days after admission. This case highlights the fulminant presentation of neonatal Leigh syndrome and emphasizes the critical role of neuroimaging in establishing this diagnosis, particularly when combined with biochemical and genetic findings. Mitochondrial DNA-associated Leigh syndrome spectrum (mtDNA-LSS) is part of a continuum of progressive neurodegenerative disorders caused by abnormalities of mitochondrial energy generation, which includes the overlapping phenotypes mtDNA-associated Leigh syndrome and mtDNA-associated Leigh-like syndrome. Mitochondrial DNA-LSS is characterized by onset of manifestations typically between ages three and 12 months, often following an intercurrent illness (usually viral) or metabolic challenge (vaccinations, surgery, prolonged fasting). Decompensation (often with elevated lactate levels in blood and/or cerebrospinal fluid) is typically associated with developmental delay and/or regression. Neurologic features include hypotonia, spasticity, seizures, movement disorders, cerebellar ataxia, and peripheral neuropathy. Brain stem dysfunction may manifest with respiratory symptoms, swallowing difficulties, ophthalmoparesis, and abnormalities in thermoregulation. Extraneurologic manifestations may include poor weight gain, cardiomyopathy, and conduction defects. Up to 50% of individuals die by age three years, most often from respiratory or cardiac failure. The diagnosis of mtDNA-LSS is established in a proband fulfilling clinical diagnostic criteria for LSS by identification of a heteroplasmic or homoplasmic pathogenic variant in one of the 15 mtDNA genes known to be involved in mtDNA-LSS. Treatment of manifestations: Treatment is supportive. Sodium bicarbonate or sodium citrate for significant acidosis (THAM may be used if there is hypernatraemia); anti-seizure medication for seizures; dystonia therapy with benzhexol, baclofen, tetrabenazine, or gabapentin alone or in combination, or by botulinum toxin injection; treatment of respiratory compromise per pulmonologist; caloric and nutritional supplementation and feeding therapy as needed; developmental and educational support; physical therapy and occupational therapy; standard treatment of eye movement disorders; medical management of cardiomyopathy; treatment of constipation as needed; treatment of liver failure per hepatologist; treatment of electrolyte abnormalities per nephrologist; hearing aids or cochlear implants for sensorineural hearing loss; speech therapy and hearing support services as needed; management of diabetes mellitus and adrenal insufficiency per endocrinologist; standard treatments for anxiety and/or depression; psychological support and care coordination for the affected individual and family. Surveillance: Affected individuals should be followed at regular intervals to monitor for progression of disease and associated complications. Neurologic assessment for ataxia and seizures at each visit along with an assessment of pulmonary issues, growth, nutrition, and gastrointestinal manifestations. Development, educational, and cognitive assessment and assessment of mobility and self-help skills at least annually. Ophthalmology assessment every six to 12 months or as advised by ophthalmologist. Annual blood pressure, EKG, and echocardiogram or as advised by cardiologist. Liver function tests, urinalysis, urine albumin-to-creatinine ratio, urine amino acids, serum electrolytes, blood urea nitrogen, creatinine, complete blood count, and fasting glucose annually. Annual audiology assessment. Assessment of care coordination and family psychosocial needs at each visit. Agents/circumstances to avoid: Sodium valproate, medications that cause acidosis, and dichloroacetate should be avoided or used with caution; administration of anesthesia requires careful consideration to avoid aggravation of respiratory symptoms and precipitation of respiratory failure. Mitochondrial DNA-LSS is transmitted by maternal inheritance. The mother of a proband may have the mtDNA pathogenic variant and may exhibit mild clinical manifestations of mtDNA-LSS. Many affected individuals have no known family history of mtDNA-LSS or other mitochondrial disorder. The explanation for apparently simplex cases may be absence of a comprehensive and/or reliable family history, a maternal heteroplasmy level below the disease threshold (i.e., the minimum level of heteroplasmy expected to result in mitochondrial disease), or a de novo mtDNA pathogenic variant in the proband. If the mother of the proband has the mtDNA pathogenic variant identified in the proband, all sibs of the proband are at risk of inheriting the pathogenic variant. Sibs may inherit the pathogenic variant at varying heteroplasmy levels due to the bottleneck effect and variant-specific segregation patterns. The risk to a sib of developing clinical manifestations is difficult to determine and depends on heteroplasmy level, the variation in heteroplasmy levels among different tissues, and the disease threshold for the specific variant. Recurrence risk assessment and prenatal testing for disorders caused by pathogenic variants in mtDNA is challenging due to the intricacies of mtDNA transmission and the inherent challenge in using prenatal genetic test results to predict clinical outcome. Reproductive options for the family members of a proband with an mtDNA pathogenic variant may include prenatal testing, preimplantation genetic testing, and oocyte donation.

Mitochondrial DNA (mtDNA)-associated Leigh syndrome is influenced by mutant pathogenicity and corresponding heteroplasmic loads; however, the manner in which heteroplasmic mutant load affects patient phenotypes and the relationship between mutant types and heteroplasmic mutant loads remain unknown. We aimed to investigate the distribution of the mutant load of different mtDNA mutations in a single-center cohort. We used next-generation sequencing to confirm mtDNA mutations in 31 patients with Leigh syndrome. Subsequently, we counted the number of mtDNA reads to quantitatively analyze the heteroplasmic mutant load and categorize the patients according to the mtDNA mutations they harbored. Confirmed cases of mtDNA-associated Leigh syndrome were classified according to the mutations observed in six genes and 10 nucleotides. Of the 31 patients with Leigh syndrome, 27 harbored known pathogenic mutations. We discovered that MT-ATP6 was the most commonly mutated gene (n = 13 patients), followed by MT-ND3 (n = 7) and MT-ND5 (n = 4). MT-ATP6 had a significantly higher mutant load than MT-ND3 and MT-ND5 (P < 0.001, each). By contrast, MT-ND5 had a significantly lower mutant load than MT-ND3 (P = 0.007). Notably, the mutation loads varied significantly among patients carrying the MT-ATP6, MT-ND3, and MT-ND5 mutations. Our study illustrated the heteroplasmic diversity and phenotypic expression threshold of mutated mitochondrial genes in mtDNA-associated Leigh syndrome. The results provide promising insights into the genotype-phenotype correlation in mtDNA-associated Leigh syndrome that are expected to guide the development of tailored treatments for Leigh syndrome.

Background and Purpose: Recent advances in molecular genetic testing have led to a rapid increase in the understanding of the genetics of Leigh syndrome. Several studies have suggested that Leigh syndrome with MT-ND3 mutation is strongly associated with epilepsy. This study focused on the epilepsy-related characteristics of Leigh syndrome with MT-ND3 mutation identified in a single tertiary hospital in South Korea. Methods: We selected 31 patients with mitochondrial DNA (mtDNA) mutations who were genetically diagnosed with mtDNA-associated Leigh syndrome. Among them, seven patients with MT-ND3 mutations were detected. We reviewed various clinical findings such as laboratory findings, brain images, electroencephalography data, seizure types, seizure frequency, antiepileptic drug use history, and current seizure status. Results: The nucleotide changes in the seven patients with the Leigh syndrome with MT-ND3 mutation were divided into two groups: m.10191T>C and m.10158T>C. Six of the seven patients were found to have the m.10191T>C mutations. The median value of the mutant load was 82.5%, ranging from 57.9 to 93.6%. No particular tendency was observed for the first symptom or seizure onset or mutant load. The six patients with the m.10191T>C mutation were diagnosed with epilepsy. Three of these patients were diagnosed with Lennox-Gastaut syndrome (LGS). Conclusion: We reported a very strong association between epilepsy and MT-ND3 mutation in Leigh syndrome, particularly the m.10191T>C mutation. The possibility of an association between the epilepsy phenotype of the m.10191T>C mutation and LGS was noted. The purpose of this overview is to: 1.. Describe the clinical characteristics of primary mitochondrial disorders. 2.. Provide evaluation strategies to identify the genetic cause of a primary mitochondrial disorder in a proband. 3.. Identify patient care guidelines for primary mitochondrial disorders. 4.. Inform genetic counseling of family members of an individual with a primary mitochondrial disorder.

Background: Leigh syndrome is a mitochondrial cytopathy that presents as a neurodegenerative disease with apparent manifestation in the central nervous system. The aim of the present study was to describe its dominant neurological clinical features and analyze data related to epilepsy in Leigh syndrome accompanied by a mitochondrial DNA mutation. Methods: Whole mitochondrial sequencing was performed on 125 patients clinically suspected of Leigh syndrome. Among them, 25 patients were identified to have mitochondrial DNA associated Leigh syndrome. Electroencephalography (EEG) findings, semiology, brain imaging findings, and biochemical results, were evaluated. We also compared brain magnetic resonance imaging findings and biochemical features in patients with Leigh syndrome based on the presence of epilepsy. Results: Clinical seizures were observed in 14 out of 25 enrolled patients (56%), with focal seizures being the most common type (6/14, 42.8%). All patients were found to have slow and disorganized background neural activity while eight exhibited epileptic discharges on EEG. Mutations at base pairs 10,191 and 8,993 were revealed in a relatively larger number of patients of Leigh syndrome with epilepsy. The presence of gastrointestinal symptoms was significantly more frequent in the epilepsy group (P = 0.042). Diffuse cerebral atrophy was significantly increased (P = 0.042) and cortex signal abnormalities were also increased (P = 0.033) in the epilepsy group. Conclusions: Patients with Leigh syndrome and mitochondrial DNA mutations had a high proportion of central nervous system comorbidities, though the prevalence of epilepsy in this population was not particularly high. Various types of seizure and EEG findings are common in those with Leigh syndrome. Future imaging studies involving more patients and proper mitochondrial DNA mutation analyses are needed to further evaluate the natural course of Leigh syndrome with epilepsy.