A Pediatric Case of Homocystinuria Due to MTHFR Deficiency with Early Clinical Features Resembling Leigh Encephalopathy

Background: Leigh encephalopathy is one of the most common phenotypes of mitochondrial diseases. It is characterized by progressive psychomotor regression, accompanied by elevated lactate/pyruvate ratios in blood and cerebrospinal fluid (CSF) and lactate on MRS, and symmetric lesions in the bilateral basal ganglia on brain MRI. A clinical diagnosis is made based on these findings and is confirmed by demonstrating mitochondrial dysfunction through genetic or enzymatic testing. However, some patients who present with clinical features of Leigh encephalopathy actually develop secondary mitochondrial dysfunction due to inborn errors of metabolism, thereby exhibiting a Leigh syndrome phenotype. Case Presentation: The patient was born at term without perinatal complications. Poor feeding was noted from two months of age, and microcephaly and hypotonia were identified at the 4-month health checkup. At 5 months, the patient was admitted for further evaluation. CSF analysis revealed an elevated lactate-to-pyruvate ratio of 21. Brain MRI demonstrated symmetrical T2-weighted hyperintensities in the bilateral basal ganglia, and MR spectroscopy detected a lactate peak in the same region. Based on clinical findings, CSF results, and MRI features, Leigh encephalopathy was suspected. At 9 months, mitochondrial DNA sequencing of skeletal muscle showed no significant mutations, and skeletal muscle biopsy revealed no findings suggestive of neuromuscular disease. At 7 years of age, two weeks after contracting COVID-19, the patient was admitted to the hospital with acute metabolic decompensation characterized by acidosis and complicated by a small intraventricular hemorrhage. Tandem mass spectrometry performed during the episode suggested homocystinuria due to MTHFR deficiency. Subsequent trio-based genetic testing revealed compound heterozygous variants in MTHFR. Measurement of MTHFR enzyme activity revealed a profound reduction, confirming the diagnosis of homocystinuria due to MTHFR deficiency. After initiation of specific metabolic therapy, including betaine, both urinary and plasma homocysteine levels decreased, and clinical symptoms improved. Conclusions: Homocystinuria due to MTHFR deficiency may cause secondary mitochondrial dysfunction, leading to a Leigh syndrome phenotype. When Leigh encephalopathy is suspected, metabolic screening should be performed to avoid missing potentially treatable diseases.