Mitochondrial Encephalopathy, Lactic Acidosis, and Strokelike Episodes

Abstract

Since the initial description almost 25 years ago, the syndrome of mitochondrial encephalopathy, lactic acidosis, and strokelike episodes (MELAS) has been a useful model to study the complex interplay of factors that define mitochondrial disease. This syndrome, most commonly caused by an A-to-G transition mutation at position 3243 of the mitochondrial genome, is typified by characteristic neurological manifestations including seizures, encephalopathy, and strokelike episodes, as well as other frequent secondary manifestations including short stature, cognitive impairment, migraines, depression, cardiomyopathy, cardiac conduction defects, and diabetes mellitus. In this review, we discuss the history, pathogenesis, clinical features, and diagnostic and management strategies of mitochondrial disease in general and of MELAS in particular. We explore features of mitochondrial genetics, including the concepts of heteroplasmy, mitotic segregation, and threshold effect, as a basis for understanding the variability and complicated inheritance patterns seen with this group of diseases. We also describe systemic manifestations of MELAS-associated mutations, including cardiac, renal, endocrine, gastrointestinal, and endothelial abnormalities and pathology, as well as the hypothetical role of derangements to COX enzymatic function in driving the unique pathology and clinical manifestations of MELAS. Although therapeutic options for MELAS and other mitochondrial diseases remain limited, and recent trials have been disappointing, we also consider current and potential therapeutic modalities.

Glucose metabolism derangements in adults with the MELAS m.3243A>G mutation

“…After its initial clinical description, MELAS was found to be associated with a mutation in the MT-TL1 gene encoding tRNA LEU(UUR) , changing adenine to guanine at position 3243 of mtDNA (m.3243A>G) (Goto et al 1990; Kobayashi et al 1990). Other mutations have subsequently been found to be associated with MELAS; however, the m.3243A>G remains the most common and is known as the MELAS mutation (Sproule and Kaufmann 2008). The m.3243A>G mutation was also found to be associated with other phenotypes that collectively constitute a wide spectrum, ranging from MELAS at the severe end to asymptomatic carrier status.…”

“…In pancreatic β-cells, an ATP-sensitive potassium channel is required for insulin release. Decreased ATP synthesis as a result of mitochondrial dysfunction can result in impaired insulin secretion (Maassen et al 2004; Sproule and Kaufmann 2008). Impaired glucose utilization by muscle can occur due to insulin resistance.…”

“…Finally, lactic acidemia in mitochondrial diseases can result in increasing hepatic glucose production because lactate is a major substrate for gluconeogenesis. Lactic acidemia results from an inability of dysfunctional mitochondria to oxidize NADH to generate sufficient ATP, leading to a shift to anaerobic glycolysis (Maassen et al 2004; Sproule and Kaufmann 2008). …”

Pseudo‐obstruction, stroke, and mitochondrial dysfunction: A lethal combination

“…Symptoms arising from gastrointestinal dysmotility in patients with mitochondrial disease are increasingly recognized and often include dysphagia, abdominal pain, abdominal distention, and constipation 6, 7, 8. Although gastrointestinal involvement, manifesting as intestinal pseudo‐obstruction (IPO), has been reported previously 9, 10, 11, 12, 13 and indeed is a recognized feature of the rare neurogastrointestinal encephalopathy (MNGIE) syndrome,14, 15 there remains a limited awareness of the severity of IPO in m.3243A>G‐related mitochondrial disease 16, 17…”

The Importance of the Ionic Product for Water to Understand the Physiology of the Acid-Base Balance in Humans

“…L-lactic acidosis may be secondary to congenital or acquired mitochondrial respiratory chain dysfunction, including tissue hypoxia [59], carbon monoxide poisoning [60], cyanide poisoning [61] and drugs such as linezolid, phenformin, and stavudine [62–64]. In addition, pyruvate dehydrogenase deficiency [65], defective gluconeogenesis pathway [66], thiamine (vitamin B1) deficiency [67], malignancy [68], liver disease [69], sepsis [70], asthma [71], fructose infusion [72], and ingestion of ethanol [73] may produce L-lactic acidosis.…”