Novel m.3764C>G variant in MT-ND1 linked to severe MELAS syndrome: A case report

Abstract

Background

MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) is a multisystem disorder with diverse clinical presentations. Approximately 80 % of MELAS cases are linked to the m.3243A>G pathogenic variant in the MT-TL1. Pathogenic variants in other mtDNA genes, including MT-ND1, can also cause MELAS. We report a case of MELAS in a 16-year-old boy with a novel m.3764C>G variant in the MT-ND1.

Case presentation

A 9 years old male patient developed bilateral sensorineural hearing loss followed by a generalized tonic-clonic seizure. At 15, he exhibited progressive fatigue, muscle weakness, and stroke-like episodes. MRI revealed stroke-like lesions in the brain. Over two years, he experienced multiple hospital admissions for severe symptoms including right-sided hemiparesis, hemianopia, seizures, and encephalopathy. Despite treatment, his condition deteriorated, leading to multi-organ failure and death at 16. Molecular genetic analysis identified a heteroplasmic m.3764C>G variant in MT-ND1.

Discussion/Conclusion

Presented case highlights the novel m.3764C>G variant in MT-ND1 associated with MELAS, emphasizing the variant's pathogenicity based on its absence in human mitochondrial databases, de novo occurrence, and predicted severe impact on ND1 protein function. The patient's rapidly progressive disease course contrasts with typical MELAS trajectories, underscoring the variant's severity. This report expands the clinical and mutational spectrum of MELAS and underscores the need for further research into MT-ND1 related MELAS.