Phenotypic diversity of brain MRI patterns in mitochondrial aminoacyl-tRNA synthetase mutations

Abstract

Background and purpose: Mitochondrial aminoacyl-tRNA synthetases-encoded by ARS2 genes-are evolutionarily conserved enzymes that catalyse the attachment of amino acids to their cognate tRNAs, ensuring the accuracy of the mitochondrial translation process. ARS2 gene mutations are associated with a wide range of clinical presentations affecting the CNS. Methods: Two senior neuroradiologists analysed brain MRI of 25 patients (age range: 3 d-25 yrs.; 11 males; 14 females) with biallelic pathogenic variants of 11 ARS2 genes in a retrospective study conducted between 2002 and 2019.Results: Though several combinations of brain MRI anomalies were highly suggestive of specific aetiologies (DARS2, EARS2, AARS2 and RARS2 mutations), our study detected no MRI pattern common to all patients. Stroke-like lesions were associated with pathogenic SARS2 and FARS2 variants. We also report early onset cerebellar atrophy and calcifications in AARS2 mutations, early white matter involvement in RARS2 mutations, and absent involvement of thalami in EARS2 mutations. Finally, our findings show that normal brain MRI results do not exclude the presence of ARS2 mutations: 5 patients with normal MRI images were carriers of pathogenic IARS2, YARS2, and FARS2 variants.Conclusion: Our study extends the spectrum of brain MRI anomalies associated with pathogenic ARS2 variants and suggests ARS2 mutations are largely underdiagnosed

IARS2-related disease manifesting as sideroblastic anemia and hypoparathyroidism: A case report

“…Our study and three other studies (11,12,13) reported a total of 4 patients with hypoparathyroidism, which enhancing the spectrum of endocrine system clinical manifestations. The most accepted pathophysiological mechanism of hypothalamicpituitary axis dysfunction is associated with endocrine glands' high energy demands; impaired mitochondrial ATP production and/or oxidative stress may greatly reduce the ability to secrete hormone or maintain normal feedback (15).…”

Genotype–phenotype correlation in IARS2‐related diseases: A case report and review of literature

“…Additionally, another nonsense variant in the same case, Trp520*, is a similar truncation event to the frameshift variant Val499Glyfs*14 in present case. 10 Conversely, a Pro67Ser homozygote was also reported with similar neurological manifestations, it should be noted that codon 67 is still proximal to aminoacyl‐tRNA synthetase domain. 9 As it is characterized by the domain functions, mutations in the catalytic aminoacyl‐tRNA synthetase domain likely affect the essential translation fidelity.…”

“… 7 , 8 From 2018 to 2021, eighteen individuals with pathogenic variants in IARS2 gene have been noted with a wide clinical spectrum. 9 , 10 , 11 Among 26 reported patients from nineteen families with differing ethnic backgrounds, 15 patients (58%) have neurologic manifestations, 12 patients (46%) have Leigh disease, 7 , 9 , 10 , 11 , 12 4 patients (15%) have West syndrome, 9 , 11 4 patients (15%) have sideroblastic anemia, 9 3 patients (12%) have cardiomyopathy, 9 , 12 and 3 patients (12%) have isolated cataract. 13 However, approximately 27% of the patients with pathogenic variants in IARS2 have CAGSSS spectrum.…”

Aminoacyl-tRNA synthetases in human health and disease

“…For example, damaging biallelic variants in HARS2 and LARS2 cause Perrault syndrome, an autosomal recessive disorder characterized by sensorineural deafness in both males and females, and ovarian dysgenesis in affected females ( Pierce et al, 2011 ; Pierce et al, 2013 ). While there remains much to learn about these disorders, the fact that biallelic defects in mitochondrial aaRS enzymes do not all lead to identical phenotypes suggests that the underlying disease mechanisms might involve alterations in non-canonical ‘moonlighting’ function rather than solely defects in aminoacylation ( Roux et al, 2021 ).…”