Mitochondrial aminoacyl-tRNA synthetase disorders: an emerging group of developmental disorders of myelination

Abstract

Background: The mitochondrial aminoacyl-tRNA synthetase proteins (mt-aaRSs) are a group of nuclear-encoded enzymes that facilitate conjugation of each of the 20 amino acids to its cognate tRNA molecule. Mitochondrial diseases are a large, clinically heterogeneous group of disorders with diverse etiologies, ages of onset, and involved organ systems. Diseases related to mt-aaRS mutations are associated with specific syndromes that affect the central nervous system and produce highly characteristic MRI patterns, prototypically the DARS2, EARS, and AARS2 leukodystrophies, which are caused by mutations in mitochondrial aspartyl-tRNA synthetase, mitochondria glutamate tRNA synthetase, and mitochondrial alanyl-tRNA synthetase, respectively. Body: The disease patterns emerging for these leukodystrophies are distinct in terms of the age of onset, nature of disease progression, and predominance of involved white matter tracts. In DARS2 and EARS2 disorders, earlier disease onset is typically correlated with more significant brain abnormalities, rapid neurological decline, and greater disability. In AARS2 leukodystrophy cases reported thus far, there is nearly invariable progression to severe disability and atrophy of involved brain regions, often within a decade. Although most mutations are compound heterozygous inherited in an autosomal recessive fashion, homozygous variants are found in each disorder and demonstrate high phenotypic variability. Affected siblings manifest disease on a wide spectrum. Conclusion: The syndromic nature and selective vulnerability of white matter tracts in these disorders suggests there may be a shared mechanism of mitochondrial dysfunction to target for study. There is evidence that the clinical variability and white matter tract specificity of each mt-aaRS leukodystrophy depend on both canonical and non-canonical effects of the mutations on the process of mitochondrial translation. Furthermore, different sensitivities to the mt-aaRS mutations have been observed based on cell type. Most mutations result in at least partial retention of mt-aaRS enzyme function with varied effects on the mitochondrial respiratory chain complexes. In EARS2 and AARS2 cells, this appears to result in cumulative impairment of respiration. Mt-aaRS mutations may also affect alternative biochemical pathways such as the integrated stress response, a homeostatic program in eukaryotic cells that typically confers cytoprotection, but can lead to cell death when abnormally activated in response to pathologic states. Systematic review of this group of disorders and further exploration of disease mechanisms in disease models and neural cells are warranted.

Neurological involvement in patients with pulmonary alveolar proteinosis related to MARS mutations

“…Finally, brain MRI abnormalities isolated in our patients are distinct from those identi ed in patients harboring mutations in genes encoding mitochondrial ARS. Indeed, those mutations are responsible for deep developmental disorders of myelination leading to often severe leukodystrophies (17).…”

Mitochondrial disease in children

“…basal ganglia) as well as white matter lesions. Leukoencephalopathy was initially reported in deficiencies of complexes I, II and IV but is now recognized to be a feature of many of the mitochondrial translation disorders, particularly the aminoacyl‐tRNA synthetase deficiencies [125]. Some mitochondrial disease genes appear to be associated with very specific neuroimaging appearances (Table 5), which can be used to direct genetic investigations and expedite genetic diagnoses of these cases.…”

Mitochondrial translation defects and human disease

“…In addition to mt-ARS genes functioning in mitochondrial translation, there is growing evidence that mt-ARS proteins have potential non-canonical roles in immune regulation, inflammation, and neuronal differentiation [34] . Further work is in progress to further explore the many roles of mt-ARS genes.…”