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Page 6 of 11 Agresti et al. J Transl Genet Genom 2018;2:9 I http://dx.doi.org/10.20517/jtgg.2018.05

spectrum of disease characteristics . This begs the question that given the possible prevalence of mtDNA
[30]
mutations, what differentiates an asymptomatic carrier, oligosymptomatic patient, and an individual
presenting a phenotypic clinical manifestation of the disease? As mutant and wild-type mtDNA can exist in
tandem, the clinical observance of an mtDNA pathogenic mutation is largely determined by the proportion
of mutant to wild-type genomes in varying tissues . Typically, greater percentages of mutant heteroplasmy
[25]
are linked with a severe clinical presentation and an earlier disease onset . The variability of mitochondrial
[4]
heteroplasmy can impact the clinical phenotypic manifestations of disease. Generally, the mtDNA deletion
phenotypic threshold value is approximately 60%, and for other mtDNA mutations is close to 90% [31,32] . The
critical threshold level seems to vary within different tissues and organs, which is directly due to their energy
demand . The causal relationship between heteroplasmy and the threshold effect can explain clinical
[33]
phenotype variations in one individual, or the same family of individuals, via their percentage of mutated
mtDNA . Moreover, on a global cellular level, mitotic segregation can further explain how some patients
[27]
can possess a clinical phenotype in childhood and alternative phenotype in adulthood .
[25]
Mitochondrial diseases have been divided into the following categories: mtDNA mutations, nuclear DNA
mutations, and intergenomic signaling defects . The first category, diseases attributed to mtDNA, involves
[25]
the identification and characterization of pathogenic mutations with a larger number of mtDNA deletions and
duplications . Conversely, the second category, nuclear DNA mutations, focuses on how the defects of the
[25]
respiratory chain due to mendelian genetics comprises a considerable portion of mitochondrial diseases .
[25]
Lastly, the third category, intergenomic signaling defects, are mutations that arise from the nuclear genome
that directly affect the mtDNA copy number and its stability . Mitochondrial disease can present itself as
[25]
either a distinct clinical syndrome or an myriad of disease phenotypes .
[27]
Diagnosing a disease of this variety can remain challenging as its fundamental roots may point to either
mitochondrial or nuclear DNA, which can be determined using a two-tiered approach that includes both
non-molecular (neuroimaging, muscle biopsy, cardiac and lactate concentration evaluation) and molecular
(sequencing either nuclear or mitochondrial DNA for pathogenic mutations from isolated tissue) genetic
testing methods . The vast diversity of causes leading to mitochondrial encephalomyopathies correlates to a
[34]
diverse patient treatment plan that relies on: physiological, biochemical, and genetic approaches . Medicine,
[25]
surgery, prosthetics, and perhaps dialysis or transfusions are at the forefront of physiological treatment
options . Whereas biochemical treatments rely on the supplementation of oxidative phosphorylation
[25]
components, and the reduction of accompanying toxicity . As a complement to the physiological and
[25]
biochemical approaches, genetic treatments may depend on either genetic counseling, the alteration of
heteroplasmy, and the cellular import of exogenous biological material (i.e. nucleic acids/proteins) .
[25]

MERRF and MELAS
Of particular interest, MERRF and MELAS are debilitating diseases that are among the multisystemic
mitochondrial diseases/syndromes that are clinically defined, alongside Kearns-Sayre syndrome (KSS) .
[35]
MERRF and MELAS, both classified as orphan diseases, are caused by a mtDNA point mutation that is
responsible for disrupting the pairing of the codon-anticodon that is necessary for protein synthesis by
disturbing the tRNAs tri-dimensional structure, as well as any associated post-transcriptional modifications .
[2]

MERRF syndrome, commonly associated with an origination in childhood is described as a multisystem
disease that is characterized by spontaneous muscle contractions, generalized epilepsy, loss of control
regarding bodily movements, dementia and weakness . Uncommon pathogenic variants within mtDNA
[36]
encoded tRNA genes (defined as MT-TX) correlated with MERRF are: MT-TF, MT-TL1, MT-TI, and MT-
TP . However, the most prominent pathogenic variant (present in approximately 80% patients or greater)
[36]
is MT-TK (encodes for tRNALys), which can be observed by an A-to-G nucleotide switch at position 8344
(m.8344A>G) [Figure 1] . While the clinically detectable pathogenic variants associated with MERRF can
[36]