Case report: ‘AARS2 leukodystrophy’

Abstract

Background Mitochondrial alanyl-tRNA synthetase 2 gene ( AARS2 ) related disease is a rare genetic disorder affecting mitochondrial metabolism, leading to severe cardiac disease in infants or progressive leukodystrophy in young adults. The disease is considered ultra-rare with only 39 cases of AARS2-leukodystrophy previously reported. Case presentation We present the case of a young man of consanguineous heritage suffering from cognitive decline and progressive spasticity as well as weakness of the proximal musculature. Utilizing MRI and whole genome sequencing, the patient was diagnosed with a homozygous AARS2 missense variant (NM_020745.3:c.650C > T; p.(Pro217Leu)) and a homozygous CAPN3 variant (NM_000070.2: c.1469G > A; p.(Arg490Gln)), both variants have previously been identified in patients suffering from AARS2 related leukodystrophy and limb-girdle muscular dystrophy, respectively. Conclusions This case report presents a case of homozygous AARS2 leukodystrophy and serves to highlight the importance of whole genome sequencing in diagnosing rare neurological diseases as well as to add to the awareness of adult onset leukodystrophies.

Pearls & Oy-sters: AARS2 Leukodystrophy—Tremor and Tribulations

“…The 63 cases reported to date involved a constellation of symptoms including tremor, personality change, dementia, reduced mobility, and leukodystrophy, with progressive symptomatic worsening and reduced functional capacity. 9 The typical phenotype described is consistent with the case reported here and includes a mean age at presentation of 29 years, initial psychiatric symptoms coupled with cognitive decline, parkinsonism, ataxia, tremor, pyramidal signs, and seizures, followed by severe and rapid motor decline. Nystagmus has been reported in other forms of leukodystrophy, diagnosed in both childhood 10 and adult life 11 ; however, unlike the case reported here, leukodystrophy-associated childhood-onset nystagmus is typically observed in the context of a wider clinical phenotype including global developmental delay and central hypotonia.…”

Novel mitochondrial alanyl-tRNA synthetase 2 (AARS2) heterozygous mutations in a Chinese patient with adult-onset leukoencephalopathy

“…AARS2 -related leukoencephalopathy is reportedly less common than CSF1R -related leukoencephalopathy. With approximately 40 cases caused by AARS2 gene mutations have been reported in the literature [ 20 ], we have just begun to recognize the wide genetic and phenotypic spectrum related to AARS2 gene mutations. The whole-exome sequencing has emerged as a powerful approach in the diagnosis of adult-onset leukoencephalopathies, and more collaborative efforts are needed in order to improve better therapeutic management.…”

Insights Into the Role of CSF1R in the Central Nervous System and Neurological Disorders

“…Emerging studies have also identified recessive mutations in alanyl-transfer (t)RNA synthetase 2 (AARS2) gene, which encodes a tRNA synthetase responsible for correctly loading alanine onto tRNA-ala for the translation of mitochondrial proteins. AARS2 mutation carriers developed ALSP with an average age of onset around 29 years of age (range 15-44 years) (Lynch et al, 2016(Lynch et al, , 2017(Lynch et al, , 2019Taglia et al, 2018;Wang et al, 2018;Axelsen et al, 2021). It is intriguing why these two seemingly unrelated genes, CSF1R and AARS2, give rise to the same leukodystrophy.…”