Mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS) syndrome: Single centre experience 2001-2021

Objectives MELAS syndrome is a rare mitochondrial disorder with neurological manifestations. It is most commonly caused by m.3243A>G in MT-TL1. Patients typically present between two and 20 years-of-age with epilepsy, stroke-like episodes, recurrent headaches, vomiting and hearing/visual impairment. However, mitochondrial heteroplasmy creates notable phenotypic variation. We aim to ascertain the clinical heterogeneity among paediatric patients with MELAS syndrome at a UK tertiary paediatric neurology centre over the last 20 years.

Methods A retrospective analysis of paediatric MELAS syndrome patients was performed. Patients were identified by emailing all paediatric neurology and clinical genetics consultants. Their medical records were reviewed, and consent was sought from the parent(s).

Results Four children (6-15 years) were diagnosed with MELAS syndrome. Genomic diagnoses were achieved in all children: m.3243A>G in two, m.3252A>G in one, and the novel m.3955G>C, in one. All patients presented with seizures and had (sub/)cortical MRI changes that were not confined to a single vascular territory, consistent with a stroke-like episode. An additional child was identified as m.3243A>G carrier through cascade screening and reported episodic headaches with vomiting. Although not quantified in all cases, blood heteroplasmy varied considerably, and a muscle biopsy was required to reach the diagnosis in 2 cases.

Conclusion MELAS syndrome patients present with a recognisable, neurological phenotype. Careful phenotype-genotype correlation, awareness of the limitations of genomic investigations and judicious use of invasive tissue sampling is crucial to reach a diagnosis. Although precision therapy is lacking, a molecular diagnosis improves management, enables cascade screening, and informs family planning decisions.
Keywords: Mitochondrial disease, encephalopathy, stroke-like episodes, lactic acidosis, genetics