MELAS and l‐arginine therapy: pathophysiology of stroke‐like episodes

Abstract

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a maternally inherited multisystem mitochondrial disorder. Although many molecular and cellular mechanisms have been discovered leading to mitochondrial cytopathy, the pathogenic mechanism of stroke-like episodes seen in MELAS has not been clarified yet. According to the muscle and brain pathology and vascular physiology, mitochondrial angiopathy, or endothelial dysfunction, were proposed to play an important role for developing stroke-like episodes. Based on a hypothesis of mitochondrial angiopathy theory, we use L-arginine in MELAS patients and report its usefulness. This review aims to give a general idea on the actual knowledge about the possible pathogenic mechanism of stroke-like episodes, including clinical symptoms that lead to stroke-like episodes, muscle, or brain pathology, molecular cellular functions, neuroimagings including MRI, MRS, and SPECT, and the proposed site of action of L-arginine therapy on MELAS patients. Currently, L-arginine therapy may be the most promising for the treatment of stroke-like episodes in MELAS.

Review of Clinical Trials for Mitochondrial Disorders: 1997–2012

“…MELAS is associated with recurrent "metabolic strokes", attributed to possible vasoconstriction. This concept has been supported by a series of uncontrolled, open-label, chronic clinical trials of oral arginine administration, and also short-term controlled trials of acute administration of arginine-hydrogen chloride (HCl) during clinical exacerbations, originating from Karume University in collaboration with other medical centers in Japan [12][13][14][15][16]. Although arginine has been used widely for clinical purposes, including treatment of urea cycle disorders, it may be associated with adverse effects, particularly in the soluble arginineHCl form, which is administered parenterally [17].…”

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS): diagnostic criteria, features of epileptic seizures, and treatment approaches by the example of a clinical case

“…Переход в дальнейшем на перораль-ный прием препарата в дозе 0,15-0,3 г/кг/сут уменьшает ча-стоту и тяжесть инсультоподобных эпизодов [11,12]. Одна-ко нужно учитывать, что передозировка L-аргинина может вызвать гипотензию и тяжелую гипонатриемию (возможно, вследствие натрийуреза, обусловленного повышением про-дукции оксида азота), а также развитие центрального пон-тинного/экстрапонтинного миелинолиза при быстрой кор- [13]. В последние годы появились данные о применении L-цитруллина у больных MELAS.…”

Clinical Reasoning: A complicated case of MELAS

“…It is thought to reduce the severity and frequency of stroke-like episodes through its action as a potent donor of NO, thereby reducing the amount of lactate accumulation in the brain, leading to improved microcirculation and preservation of vascular tone. 4,5 The patient continues to be on this medication without adverse side effects.…”

“…DISCUSSION MELAS is a multisystem, maternally inherited mitochondrial disorder with a relapsing and remitting type course which can present with a wide spectrum of manifestations ranging from seizures and stroke-like episodes 5,6 to maternally inherited diabetes with or without deafness. Over 40 causative mitochondrial DNA mutations have been documented, with 80% of cases carrying the m.3243A.G mutation, affecting the respiratory transport chain, and 10% the m.3271T.C transfer RNA mutation.…”