Neuromuscular and Systemic Presentations in Adults: diagnoses beyond MERRF and MELAS

Abstract

Mitochondrial diseases are a diverse group of inherited and acquired disorders that result in inadequate energy production. They can be caused by inheritable genetic mutations, acquired somatic mutations, and exposure to toxins (including some prescription medications). Normal mitochondrial physiology is responsible, in part, for the aging process itself, as free radical production within the mitochondria results in a lifetime burden of oxidative damage to DNA, especially the mitochondrial DNA that, in turn, replicate the mutational burden in future copies of itself, and lipid membranes. Primary mitochondrial diseases are those caused by mutations in genes that encode for mitochondrial structural and enzymatic proteins, and those proteins required for mitochondrial assembly and maintenance. A number of common adult maladies are associated with defective mitochondrial energy production and function, including diabetes, obesity, hyperthyroidism, hypothyroidism, and hyperlipidemia. Mitochondrial dysfunction has been demonstrated in many neurodegenerative disorders, including Alzheimer's disease, Parkinson disease, amyotrophic lateral sclerosis, and some cancers. Polymorphisms in mitochondrial DNA have been linked to disease susceptibility, including death from sepsis and survival after head injury. There is considerable overlap in symptoms caused by primary mitochondrial diseases and those illnesses that affect mitochondrial function, but are not caused by primary mutations, as well as disorders that mimic mitochondrial diseases, but are caused by other identified mutations. Evaluation of these disorders is complex, expensive, and not without false-negative and false-positive results that can mislead the physician. Most of the common heritable mitochondrial disorders have been well-described in the literature, but can be overlooked by many clinicians if they are uneducated about these disorders. In general, the evaluation of the classic mitochondrial disorders has become straightforward if the clinician recognized the phenotype and orders appropriate confirmatory testing. However, the majority of patients referred for a mitochondrial evaluation do not have a clear presentation that allows for rapid identification and testing. This article provides introductory comments on mitochondrial structure, physiology, and genetics, but will focus on the presentation and evaluation of adults with mitochondrial symptoms, but who may not have a primary mitochondrial disease.

Modification of the wobble uridine in bacterial and mitochondrial tRNAs reading NNA/NNG triplets of 2-codon boxes

“…6,42,79,80 Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) and myoclonus epilepsy associated with ragged-red fibers (MERRF) are mostly due to mutations in genes mt-tRNA Leu(UUR) and mt-tRNA Lys , respectively, with A3243G in mt-tRNA Leu(UUR) , and A8343G in mt-tRNA Lys , being the most frequent. 81 Patient cells exhibit mitochondrial translation defects, oxidative stress, and diminished respiratory enzyme activity and oxygen consumption. [82][83][84][85] mt-tRNAs carrying MERRF and MELAS mutations lack the U34 modifications that are normally present in nonmutated tRNAs.…”

Myositis Mimics

“…For example, patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like syndrome (MELAS) and myoclonic epilepsy with ragged red fibers (MERRF) syndrome present with varying degrees of cognitive impairment, hearing loss, seizures, and neuropathy [58,59].…”

Systemic Diseases Associated with Retinal Dystrophies

“…A higher proportion of mutant 8993 mtDNA is associated with more severe disease: Leigh syndrome with 490% mutant mtDNA, NARP with 75-90% mutant mtDNA, asymptomatic patients, or patients with pigmentary retinopathy or migraines 575% mutant mtDNA. 78,[80][81][82] It is important to note that Leigh syndrome is also associated with mutations in other mtDNA genes as well as nuclear genes; e.g., SURF1 and POLG. 70 Syndromic Retinal Dystrophies 325 !…”