Novel Alanyl-tRNA Synthetase 2 Pathogenic Variants in Leukodystrophies

Abstract

The white matter disease spectrum is associated with many genetic diseases, including AARS2, CADASIL, ALD, and others. In this study, to determine the novel alanyl-tRNA synthetase 2 mutation implicated in white matter disease, several families with an autosomal recessive inheritance pattern of white matter disease were analyzed by whole-exome sequencing. Variants were prioritized according to their rarity and pathogenic variants in genes already known to be associated with leukodystrophies and were confirmed by Sanger sequencing using standard protocols. We identified 5 rare variants (c.452T>C chr6:44279256 p.M151T, c.1871G>A chr6:44272054 p.W624X, c.802A>G chr6:44278128 p.M268V, c.1703-1704del chr6:-44272430-44272431 p.Q568fs, and c.179C>A chr6-44280882 p.P60H) with varying expression in 4 independent Chinese families with leukodystrophy. These single nucleotide variants (SNVs), or deletion mutations, each induced a frameshift, causing a missense mutation in alanyl-tRNA synthetase 2. These findings suggested that all mutations might contribute to the development of leukodystrophy in the examined family members. Combined with previous findings, our data confirmed that the novel mutations are located in leukodystrophy-related risk genes. We also summarized all the alanyl-tRNA synthetase 2 mutations related to the onset of leukodystrophies in adults.

Case report: ‘AARS2 leukodystrophy’

“…Secondly, our patient presented with an abnormal gait, dysarthria, primitive reflexes and universal spasticity with a one-sided lower limb predominance, thus pyramidal signs were present as in many previous cases. Thus, our case conforms well to the predominant presentation of AARS2 leukodystrophy as reported in the literature [ 8 ]. Absent pharyngeal reflexes, involuntary hand tremor, ophthalmoplegia and psychiatric symptoms such as depression and psychosis were also described in earlier cases of AARS2 leukodystrophy [ 8 ], these were, however, not present in our patient.…”

“…With only 39 patients with the AARS2 leukodystrophic phenotype previously reported in the scientific literature and only three with homozygous genotype [ 8 , 28 , 29 ], it would be inaccurate to describe the present patient as a”classic” case of the disease. However, our case presents with several similarities compared to previous cases of AARS2 -L. Firstly, symptom-onset in our patient was cognitive decline in his 20's conforming with the mean age-of-onset in other cases [ 8 ]. Secondly, our patient presented with an abnormal gait, dysarthria, primitive reflexes and universal spasticity with a one-sided lower limb predominance, thus pyramidal signs were present as in many previous cases.…”

“…The slightly more prevalent adult phenotype, first described in 2014 [ 6 ], is characterized by adult-onset premature ovarian failure in females and progressive leukodystrophy [ 4 ]. Age at onset is typically around 25 years with patients displaying cognitive decline, neuropsychiatric symptoms along with pyramidal and extrapyramidal signs with rapid progression [ 4 , 7 , 8 ]. Some cases have been described with preexisting developmental delay or motor problems in childhood [ 8 ].…”

“…Age at onset is typically around 25 years with patients displaying cognitive decline, neuropsychiatric symptoms along with pyramidal and extrapyramidal signs with rapid progression [ 4 , 7 , 8 ]. Some cases have been described with preexisting developmental delay or motor problems in childhood [ 8 ]. However, the spectrum of AARS2 -related phenotypes has recently been widened.…”

New AARS2 Mutations in Two Siblings With Tremor, Downbeat Nystagmus, and Primary Amenorrhea: A Benign Phenotype Without Leukoencephalopathy

“…Alanyl-tRNA synthetase 2 (AARS2; MIM 612035) codes for the mitochondrial transfer RNA (tRNA) synthetase enzyme that charges tRNA Ala molecules with alanine. Mutations in the AARS2 gene have been associated with two main phenotypes: infantile/adult-onset leukoencephalopathy 1,2 and infantile lethal cardiomyopathy, 3 with or without leukoencephalopathy. Another presentation includes optic atrophy and retinopathy in late infancy.…”