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Page 74 Webb et al. J Transl Genet Genom 2020;4:71-80 I https://doi.org/10.20517/jtgg.2020.11

can result in the phenotype of maternally inherited diabetes and deafness, whereas the point mutations
m.14674T>G or m.14674T>C in MTTE can result in infantile transient mitochondrial myopathy.

Nearly all mitochondrial disease resulting from mt-tRNA mutations display maternal inheritance as
mitochondrial DNA is inherited from the mother. However, few instances of paternal inheritance have been
reported as well [13,14] . Cells that carry a homogeneous population of the mitochondrial genome, either wild-
type or mutant, are termed homoplasmic. Cells that carry two or more populations of the mitochondrial
genome are termed heteroplasmic. With mitochondrial disease due to maternal inheritance, clinical disease
severity often correlates with mutation load in affected tissues.

The two most well-known mitochondrial diseases associated with mt-tRNA mutations are MELAS and
myoclonic epilepsy with ragged red fibers (MERRF). In approximately 80% of MELAS patients, the causative
Leu
mutation is the m.3243A>G pathogenic variant in MTTL1 (mt-tRNA ). Most patients with MELAS
develop symptoms between ages 2 and 40 years old, and these symptoms include stroke-like episodes,
encephalopathy with seizures and/or dementia, muscle weakness, exercise intolerance, headaches, vomiting,
hearing impairment, peripheral neuropathy, learning disability, and short stature. Treatment for MELAS
is supportive and includes treatment with a mitochondrial cocktail. Intravenous arginine is recommended
during acute stroke-like episodes, and arginine should be given orally for prophylaxis after a patient has had
[15]
a first stroke-like episode .
The most common mutation causing MERRF in more than 80% of affected patients is the m.8344A>G
Lys
mutation in MTTK (mt-tRNA ). Onset of MERRF is usually in childhood and the first symptom is often
myoclonus. Other common symptoms and findings are epilepsy, ataxia, weakness, dementia, hearing loss,
short stature, optic atrophy, and cardiomyopathy with Wolff-Parkinson-White syndrome. Treatment is also
[16]
supportive with antiepileptic medications to treat seizures, mitochondrial cocktail, and physical therapy .

MITOCHONDRIAL AMINOACYL-tRNA SYNTHETASE DISORDERS
Mitochondrial aminoacyl-tRNA synthetases (mt-ARSs) are essential for protein synthesis in the
mitochondria and generation of oxidative phosphorylation (OXPHOS) system components. mt-ARS
proteins are nuclear-encoded and function to charge mitochondrial tRNA molecules, which are
mitochondrial-encoded, with their cognate amino acids. While mt-ARS proteins vary in size and oligomeric
[17]
state (from monomer to tetramer), all contain a catalytic domain and a tRNA anticodon-binding domain .
mt-ARS genes are named with an ARS2 nomenclature (for example, MARS2 for methionine tRNA
synthetase, mitochondrial). For the amino acids glycine and lysine, a separate mt-ARS gene does not exist,
and GARS and KARS, respectively, function as the aminoacyl-tRNA synthetase in both the cytosol and the
mitochondria. Additionally, an mt-ARS has not been identified for glutamine (Q), and Q-tRNA is believed
[18]
to be formed by postconjugation modification of glutamate .
The first Mendelian disease reported to be caused by mt-ARS mutations was leukoencephalopathy with
brain stem and spinal cord involvement and lactate elevation (MIM #611105) due to autosomal recessive
[19]
pathogenic variants in DARS2, which was reported in 2007 . Since then, pathogenic variants in all known
mt-ARSs have been identified with the majority being identified by whole exome sequencing studies, and the
associated conditions represent a new class of Mendelian disorders [Table 2]. All mt-ARS disorders exhibit
[17]
autosomal recessive inheritance and most often patients are compound heterozygotes . These Mendelian
disorders are extremely rare as deleterious mutations in mt-ARS genes leading to absent mt-ARS function
are expected to be lethal. Therefore, patients most often have at least one allele with a mild mutation leading
to some residual mt-ARS gene function.

Interestingly, although pathogenic variants in all mt-ARSs are expected to result in disruption of protein
synthesis of OXPHOS system components via impairment of mitochondrial translation, the identified