Molecular and neurological features of MELAS syndrome in paediatric patients: A case series and review of the literature

Abstract

Background: Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome is one of the most well-known mitochondrial diseases, with most cases attributed to m.3243A>G. MELAS syndrome patients typically present in the first two decades of life with a broad, multi-systemic phenotype that predominantly features neurological manifestations--stroke-like episodes. However, marked phenotypic variability has been observed among paediatric patients, creating a clinical challenge and delaying diagnoses.

Methods: A literature review of paediatric MELAS syndrome patients and a retrospective analysis in a UK tertiary paediatric neurology centre were performed.

Results: Three children were included in this case series. All patients presented with seizures and had MRI changes not confined to a single vascular territory. Blood heteroplasmy varied considerably, and one patient required a muscle biopsy. Based on a literature review of 114 patients, the mean age of presentation is 8.1 years and seizures are the most prevalent manifestation of stroke-like episodes. Heteroplasmy is higher in a tissue other than blood in most cases.

Conclusion: The threshold for investigating MELAS syndrome in children with suspicious neurological symptoms should be low. If blood m.3243A>G analysis is negative, yet clinical suspicion remains high, invasive testing or further interrogation of the mitochondrial genome should be considered.

Keywords: MELAS syndrome; encephalopathy; genetics; lactic acidosis; m.3243A>G; mitochondrial disease; paediatric neurology; stroke-like episodes.

FIGURE 1

PRISMA flow diagrams showing the selection of paediatric MELAS syndrome cases from (a) Cambridge University Hospital NHS Foundation Trust included in the case series, and (b) the PubMed search included in the literature review

FIGURE 2

Brain MRIs, axial view T2‐weighted (first row) and DWI (second row), showing development and resolution of signal abnormalities within the (i) right medial temporal lobe upon initial presentation, (ii) right lateral temporal lobe 4 months after initial presentation, and (iii) left lateral temporal lobe 5 months after initial presentation

FIGURE 3

(a) Brain MRI axial FLAIR sequences showing development signal abnormalities within (i) right occipital lobe on admission, (ii) that progressed to the left occipital lobe 5 months later, and (iii) further progressed to the right temporal, insula and frontal lobes a further 6 months later. (b) Histology slides of biopsy from left quadriceps demonstrating subsarcolemmal accentuation upon (i) SDH and (ii) NADH staining (×40 magnification), and (iii) no obvious COX‐negative‐SDH‐positive muscle fibres upon sequential COX‐SDH staining

FIGURE 4

(a) Brain MRI T2‐weighted sequences showing progressive generalised atrophy and reciprocal dilatation of the ventricular system over 5 years: (i) 4 years after initial presentation; (ii) 9 years after initial presentation, following second emergency surgery. Multiple old signal abnormalities are present in bilateral basal ganglia, bilateral occipital lobes and right insula. (b) Histology slides of a muscle biopsy: (i) subsarcolemmal Gomori positivity forming the RRFs characteristic of mitochondrial cytopathy (×60 magnification); (ii) H&E staining showing muscle fibres, with a clear surrounding rim, that vary in size, as well as basophilic stippling (×40 magnification). (c) Electron microscopy at (i) ×15,000 magnification and (ii) ×40,000 magnification, both showing subsarcolemmal mitochondria with abnormal forms