Clinical Characteristics of Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes

Abstract

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, a maternally inherited mitochondrial disorder, is characterized by its genetic, biochemical and clinical complexity. The most common mutation associated with MELAS syndrome is the mtDNA A3243G mutation in the MT-TL1 gene encoding the mitochondrial tRNA-leu(UUR), which results in impaired mitochondrial translation and protein synthesis involving the mitochondrial electron transport chain complex subunits, leading to impaired mitochondrial energy production. Angiopathy, either alone or in combination with nitric oxide (NO) deficiency, further contributes to multi-organ involvement in MELAS syndrome. Management for MELAS syndrome is amostly symptomatic multidisciplinary approach. In this article, we review the clinical presentations, pathogenic mechanisms and options for management of MELAS syndrome.

Keywords: MELAS; genetics; mitochondrial DNA.

Figure 1

Structure and metabolic pathways in mitochondria. (A) Ultra-structure of normal mitochondria (original magnification 34,000×). (B) Schematic representation of oxidative phosphorylation. The TCA cycle, which is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins, produces the reducing equivalents NADH and FADH2, which can transport e⁻ to the mitochondrial respiratory chain (or electron transport chain, ETC). When e⁻ are passing through the complexes in the inner membrane of mitochondria, a mitochondrial membrane potential is formed and generates ATP. These reactions, known as oxidative phosphorylation (OXPHOS), require oxygen. The mitochondrial ETC contain five enzymatic complexes (I–V), ubiquinone (or coenzyme Q10, CoQ), and cytochrome c (Cytc).Complexes I, III, and IV pump protons out from the mitochondrial matrix to IMS. Complex II connects the TCA cycle to ETC. Complex IV (cytochromec oxidase; COX) receives an electron from each of four cytochrome c molecules and transfers these electrons to one dioxygen molecule, converting the molecular oxygen into two molecules of water. During this process, Complex IV binds four protons from the inner aqueous phase to form two water molecules and translocates four additional protons across the membrane, increasing the difference in the transmembrane electrochemical potential. Complex V synthesizes ATP from ADP and phosphates utilizing the energy provided by the proton electrochemical gradient. ADP: adenosine diphosphate; ATP:adenosine triphosphate; CoQ:coenzyme Q; Cytc:cytochromec; e⁻: electrons; FAD:flavin adenine dinucleotide; α-KG:α-ketoglutarate; mtDNA: mitochondrial deoxyribonucleic acid; NADH:nicotinamide adenine dinucleotide; OAA:oxaloacetate; PC:pyruvate carboxylase; PDHC: pyruvate dehydrogenase complex; TCA: tricarboxylic acid.

Figure 2

MELAS syndrome manifestations. The clinical features of MD are not specific and are variable between patients, including neurological and non-neurological presentations. MELAS, a common MD, is a progressive syndrome where patients can recover from one phenotype and develop others later. Subjects with mtDNA mutations can be asymptomatic or have multi-organ involvement.

Figure 3

Characteristic findings of MELAS. (A) Axial T1-weighted imaging shows focal hypointensity involving the right temporal lobe cortex and subcortical white matter; Gyral swelling is noted. (B) Axial FLAIR imaging reveals focal hyperintensity in the same area of the right temporal lobe, and abnormal thickening of the cerebral cortex. (C,D) Diffusion weighted imaging (DWI) shows restricted diffusion as bright signal intensity along the right temporal lobe cortex; the corresponding area appears as dark signal intensity on the ADC map, compatible with an infarction area. The findings that the area of restricted diffusion in DWI commonly appears with a high signal on the ADC map may be used to distinguish stroke-like episodes from hemodynamic infarctions.(E) Proton MR spectroscopy localized to the right temporal lobe of the same patient confirms elevation of lactate doublet at 1.3 ppm (arrow). (F) Hematoxylin and eosin staining of muscle histology show focal scattered fibers with clear rim (200×).(G) Gomori trichrome staining of ragged red fibers (200×). (H) Electron micrographs show focal disruption of myofilaments with accumulated elongated, bizarrely-shaped mitochondria(arrow) in the subsarcolemmal and in the interfibrillar space (3000×). (I) Disruption of myofilaments and bizarrely-shaped mitochondria (12,000×).

Figure 4

Schematic representation of arginine metabolism. Carbamoyl phosphate interacts with ornithine and releases a phosphate group converted to citrulline through ornithine transcarbamoylase. The TCA cycle begins with condensation of acetyl-CoA and oxaloacetate (OAA) to produce citrate. Aspartate and citrulline form argininosuccinate via argininosuccinate synthetase. Argininosuccinate is cleaved by argininosuccinase to generate fumarate and arginine. Fumarate produced in the cytosol can translocate into the mitochondria, where it can serve as a substrate for the mitochondrial fumarase, which catalyzes its hydration into malate. Arginine undergoes cleavage by arginase to produce ornithine and urea. Ornithine is shuttled back to the mitochondria to roll the urea cycle. Nitric oxide synthases (NOSs) hydroxylate arginine to generate N-hydroxy-l-arginine (NOHA), which is oxidized by the enzyme to generate citrulline and NO, with NADPH and O₂ serving as co-substrates.

Figure 5

A patient with MELAS syndrome with his family members carrying the heteroplasmic mtDNA A3243G mutation. (A) The pedigree of the family. Arrow indicates the proband, who had typical features of MELAS syndrome including seizures, lactic acidemia, headache, hemiparesis, hemianopsia, stroke-like episodes, hearing impairment, and mental deficits. His family members (3, 7) are asymptomatic. Levels of mutant mtDNA in the (B) blood and (C) hair follicle. (D) Quantification the ratio of mutation mtDNA A3243G of the B and C. M: 100–1000 bp DNA marker. Our results show that ratio of mutation is higher in the proband than in his family, and the ratio of mutation is higher in subjects with symptomatic presentations than asymptomatic carriers.