Clinical features, pathogenesis, and management of stroke-like episodes due to MELAS

Abstract

Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is a disease that should be considered as a differential diagnosis to acute ischemic stroke taking into account its onset pattern and neurological symptoms, which are similar to those of an ischemic stroke. Technological advancements in neuroimaging modalities have greatly facilitated differential diagnosis between stroke and MELAS on diagnostic imaging. Stroke-like episodes in MELAS have the following features: (1) symptoms are neurolocalized according to lesion site; (2) epileptic seizures are often present; (3) lesion distribution is inconsistent with vascular territory; (4) lesions are common in the posterior brain regions; (5) lesions continuously develop in adjacent sites over several weeks or months; (6) neurological symptoms and stroke-like lesions tend to be reversible, as presented on magnetic resonance imaging; (7) the rate of recurrence is high; and; (8) brain dysfunction and atrophy are slowly progressive. The m.3243ANG mutation in the MT-TL1 gene encoding the mitochondrial tRNALeu(UUR) is most commonly associated with MELAS. Although the precise pathophysiology is still unclear, one possible hypothesis for these episodes is a neuronal hyperexcitability theory, including neuron–astrocyte uncoupling. Supplementation, such as with L-arginine or taurine, has been proposed as preventive treatments for stroke-like episodes. As this disease is still untreatable and devastating, numerous drugs are being tested, and new gene therapies hold great promise for the future. This article contributes to the understanding of MELAS and its implications for clinical practice, by deepening their insight into the latest pathophysiological hypotheses and therapeutic developments.

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Data availability

The authors declare that data supporting the findings of this study are available within the article. The datasets are available from the corresponding author upon reasonable request.

Code availability

Not applicable.

Abbreviations

CT:

Computed tomography

MRI:

Magnetic resonance imaging

MELAS:

Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes

LHON:

Leber’s hereditary optic neuropathy

mtDNA:

Mitochondrial DNA

ATP:

Adenosine triphosphate

FLAIR:

Fluid-attenuated inversion recovery

DWI:

Diffusion-weighted image

SPECT:

Single-photon emission CT

ASL-MRI:

Arterial spin labeling MRI

MRA:

Magnetic resonance angiography

ANLS:

Astrocyteneuron lactate shuttle

NO:

Nitric oxide

NOS:

Nitric oxide synthase

ROS:

Reactive oxygen species

iPSCs:

Induced pluripotent stem cells

GC:

Guanylate cyclase

GTP:

Converts guanosine triphosphate

GMP:

Guanosine monophosphate

Cyt c:

Cytochrome c

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Acknowledgements

The authors would like to thank Enago (www.enago.jp) for the English language review.

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The concept and idea of the study was designed by ST. The manuscript was written by ST and TO. ST, RH and HK revised the manuscript and edited English. RH and HK critically revised the important content of the revision. RH and HK contributed immensely to the amendments. All authors have approved final article version.

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Correspondence to Syuichi Tetsuka.

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Highlights

• Lesion distribution is inconsistent with vascular territory.

• MELAS tends to present spontaneous reversibility of both neurological symptoms and stroke-like lesions, but both of those are prone to relapse later.

• The m.3243ANG mutation in the MT-TL1 gene encoding the mitochondrial tRNALeu(UUR) is commonly associated with MELAS.

• The mutation affects the taurine modification of tRNA and impairs protein synthesis.

• Neuronal hyperexcitability is a hypothesized cause of these episodes.

• Taurine administration is a new, practical, and therapeutic approach for MELAS.

• New gene therapies hold great promise for the future.

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Cite this article

Tetsuka, S., Ogawa, T., Hashimoto, R. et al. Clinical features, pathogenesis, and management of stroke-like episodes due to MELAS. Metab Brain Dis (2021). https://doi.org/10.1007/s11011-021-00772-x

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Keywords

  • Mitochondrial disease
  • MELAS
  • Stroke-like episodes
  • tRNA modification disorder
  • Neuronal hyperexcitability
  • Taurine supplementation