Phenotypic heterogeneity within twins with MELAS with epilepsy: Case report

Mitochondrial encephalomyopathy with lactic acidemia and stroke-like episodes (MELAS) syndrome is a maternally inherited mitochondrial disorder caused by mutations in mitochondrial DNA, most commonly the m.3243A>G variant. This mutation impairs oxidative phosphorylation, leading to inadequate cellular energy production, particularly in high-demand tissues such as the brain and muscles. The resultant energy deficit manifests as neurological and muscular dysfunction, including stroke-like episodes, seizures, and lactic acidosis.

Twin brothers presented with heterogeneous clinical characteristics. The elder twin experienced seizures, blurred vision, hypertrichosis, exercise intolerance, and had learning difficulties since age 10. The younger twin developed hearing loss at age 12, followed by persistent epileptic seizures 3 months later. Both had a history of progressive neurological and multisystemic symptoms suggestive of a metabolic disorder.

Diagnostic evaluations included electroencephalography (EEG), which showed widespread mixed high-amplitude slow waves, and cranial magnetic resonance imaging, which revealed migratory lesions that changed with recurrent episodes. Genetic testing confirmed the m.3243A>G mutation in both twins. Their mother was identified as an asymptomatic carrier with an estimated heteroplasmy level of 30.79%.

The elder twin was initially treated with acyclovir (antiviral) and methylprednisolone (anti-inflammatory) for suspected viral encephalitis, with symptomatic support. After genetic confirmation of MELAS, supportive therapies included coenzyme Q10, adenosine triphosphate disodium, levocarnitine, and arginine. During recurrent admissions for status epilepticus, antiepileptic regimens were maintained or adjusted, and imaging (magnetic resonance imaging/electroencephalogram) was repeatedly used for monitoring. His brother received similar interventions - levetiracetam, coenzyme Q10, and adenosine triphosphate disodium - upon diagnosis, with additional management for seizures, headaches, and gastrointestinal symptoms.

Both twins were definitively diagnosed with MELAS syndrome. The elder twin was diagnosed first based on clinical and genetic findings, while the younger twin was diagnosed after the emergence of hearing loss and seizures. The condition highlights the progressive and variable nature of MELAS.

The case underscores the significant phenotypic heterogeneity of MELAS, which often leads to misdiagnosis or delayed diagnosis. Early genetic testing is critical for accurate identification and prompt intervention. Family screening is recommended due to the maternal inheritance pattern, and tailored management should address the multifaceted clinical manifestations.