Phenotypic features and therapeutic approach in ARS2 deficiencies

Abstract

Background: Aminoacyl-transfer RNA (tRNA) synthetases (ARSs) are crucial for protein translation. ARSs are divided into two groups: ARS1, functioning in the cytosol, and ARS2, in the mitochondria. Recessive genetic variants in these genes lead to impaired enzymatic function, causing severe disorders. Advances in genome sequencing have led to an increasing number of ARS2 deficiency diagnoses, but treatments for ARS deficiencies are currently limited to supportive. Recently, based on positive results of amino acid supplementation in ARS1 deficiencies, amino acid treatment has been tried in ARS2 deficiencies with some success. However, it is difficult to discern treatment effects from the natural history due to the broad phenotypic spectrum, the multitude of genetic variants and the progressive nature of the disease. To evaluate treatment effects, a clear understanding of the natural history of ARS2 deficiencies is necessary. This review aims to summarize the clinical symptoms, outcomes and treatments of all patients with recessive ARS2 deficiencies described in the literature.

Methods: A review of all published clinical symptoms and treatment effects of patients with ARS2 deficiencies onto July 2024 was performed. Clinical symptoms were categorized using Human Phenotype Ontology terms. Only disease-modifying treatments were included.

Results: A total of 774 patients across 19 ARS2 deficiencies were identified. 49% were female. The median age of symptom onset was 1 year (range: 0-63 years) and overall mortality was 22%, varying between 0% and 50% depending on the specific ARS2 deficiency. The median age of death was 1 year (range: 0-57 years). Neurological symptoms were most prevalent, with 68% of all patients showing magnetic resonance imaging abnormalities and 65% experiencing neurodevelopmental abnormality. Muscle tone abnormalities were common, with hypertonia observed in 38% and hypotonia in 30% of patients. While many symptoms were widespread across ARS2 deficient patients, certain subtypes exhibited specific symptoms. For example, hearing impairment was present in all HARS2 deficient patients, and almost all MARS2 deficient patients had ataxia. Several subtypes showed progressive neurodegeneration and motor function decline. Amino acid supplementation was administered to seven patients: one FARS2 deficient patient and six RARS2 deficient patients showed potential benefits, though seizures persisted in four patients. Other treatments included a KARS deficient patient who showed improvements in seizure control following a ketogenic diet and multivitamin supplementation, as well as two DARS2 deficient patients who experienced improvements in central motor function after treatment with succinic acid derivatives. However, due to the limited number of cases, the overall effectiveness of these treatments remains unclear.

Discussion and conclusion: ARS2 deficiencies present a broad clinical spectrum, with overlapping symptoms such as neurodevelopmental abnormalities and subtype-specific manifestations like hearing impairment. The mechanisms behind these variations are not fully understood. Treatment has been described in ten patients, with mostly (but not always) positive observed effects. The findings of this review can serve as a reference for improving diagnosis, therapeutic care and trial readiness for patients with ARS2 deficiencies.