Hypomyelinating Leukodystrophy with Spinal Cord Involvement Caused by a Novel Variant in RARS: Report of Two Unrelated Patients

Rezaei, Zahra; Hosseinpour, Sareh; Ashrafi, Mahmoud Reza; Mahdieh, Nejat; Alizadeh, Hussain; Mohammadpour, Masoud; Khosroshahi, Nahideh; Amanat, Man; Tavasoli, Ali Reza

doi:10.1055/s-0039-1679911

Cited by 10 publications

(9 citation statements)

References 13 publications

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“…The mild symptoms of patients carrying homozygous c.[5A>G]; [5A>G] indicate that the decrease in the long-form hArgRS-D2G accounts for its pathogenicity, but induces a less severe phenotype possibly due to its intact catalytic activity, MSC incorporation and protein stability. However, the long-form hArgRS is indispensable for protein biosynthesis as revealed by the severe phenotypes of patients carrying the start codon AUG1 mutation either in homozygous form or complex heterozygous form with a functionnull allele (Mendes et al, 2020;Rezaei et al, 2019) , while a low level of the long-form hArgRS-D2G alleviates the symptom, as observed in a patient carrying c.[5A>G]; [96_97del], p.[D2G]; [C32Wfs*39] complex heterozygous mutation (Mendes et al, 2020;Wolf et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…The PMLD-associated mutations of RARS1 were first separately identified by whole exome sequencing (WES) or WES with a filter for HLD1 genes, either with or without clinical research (Nafisinia et al, 2017;Rezaei et al, 2019;Wolf et al, 2014). These mutations induce singlesite substitutions, deletions, mRNA splicing errors or loss of the long-form hArgRS.…”

Section: Recurrent Pathogenic Mutations Of Rars1 Cause Mutations In the Ntd And/or Add2 Domain Of Hargrsmentioning

confidence: 99%

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Distinct pathogenic mechanisms of various RARS1 mutations in Pelizaeus-Merzbacher-like disease

Eriani

Wang

et al. 2021

Sci. China Life Sci.

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Mutations of the genes encoding aminoacyl-tRNA synthetases are highly associated with various central nervous system disorders. Recurrent mutations, including c.[5A>G], p.[D2G]; c.[1367C>T], p.[S456L]; c.[1535G>A], p.[R512Q] and c.[1846_1847del], p.[Y616Lfs*6] of RARS1 gene, which encodes two forms of human cytoplasmic arginyl-tRNA synthetase (hArgRS), are linked to Pelizaeus-Merzbacher-like disease (PMLD) with unclear pathogenesis. Among these mutations, c.[5A>G] is the most extensively reported mutation, leading to a p.[D2G] mutation in the N-terminal extension of the long-form hArgRS. Here, we showed the detrimental effects of R512Q substitution and DC mutations on the structure and function of hArgRS, while the most frequent mutation c.[5A>G], p.[D2G] acted in a different manner without impairing hArgRS activity. The nucleotide substitution c.[5A>G] reduced translation of hArgRS mRNA, and an upstream open reading frame contributed to the suppressed translation of the downstream main ORF. Taken together, our results elucidated distinct pathogenic mechanisms of various RARS1 mutations in PMLD.

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Section: Discussionmentioning

confidence: 99%

Section: Recurrent Pathogenic Mutations Of Rars1 Cause Mutations In the Ntd And/or Add2 Domain Of Hargrsmentioning

confidence: 99%

Distinct pathogenic mechanisms of various RARS1 mutations in Pelizaeus-Merzbacher-like disease

Eriani

Wang

et al. 2021

Sci. China Life Sci.

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“…Intellectual disability (ID) or developmental delay (DD) was identified in the vast majority of these patients while nystagmus, epilepsy, and microcephaly were also common. [7][8][9][10][11][12] Since studies have shown that a broad spectrum of clinical symptoms are linked with RARS1 variants, this study aimed to further investigate the relationships between genotype and/or phenotype in patients with HLD-9. Also, we reviewed the literature and present two examples of patients with HLD9 who had biallelic RARS1 mutations.…”

Section: Introductionmentioning

confidence: 99%

“…More than 20 patients with RARS1 ‐related HLD (known as HLD‐9 in OMIM, MIM#616140) have been reported. Intellectual disability (ID) or developmental delay (DD) was identified in the vast majority of these patients while nystagmus, epilepsy, and microcephaly were also common 7–12 …”

Section: Introductionmentioning

confidence: 99%

RARS1‐related developmental and epileptic encephalopathy

Wan

et al. 2023

Epilepsia Open

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ObjectiveBiallelic variants of RARS1, a gene that encodes the cytoplasmic tRNA synthetase for arginine (ArgRS), are associated with central nervous system (CNS) manifestations, such as hypomyelinating leukodystrophy‐9 and developmental and epileptic encephalopathy (DEE). This study aimed to better understand the RARS1 biallelic mutations and the associated phenotypes, particularly in patients with DEE.MethodsWe identified two patients with RARS1 biallelic mutations and functionally validated these mutations in vitro. Furthermore, we performed a review of the literature.ResultsTwo patients with hypomyelinating leukodystrophy were found to have RARS1 biallelic variants (Patient 1: c.1535G>A (p.Arg512Gln) and c.1382G>A (p.Arg461His); Patient 2: homozygous variants c.5A>T (p.Asp2Val)). Patient 2 had a severe clinical manifestation of DEE. A review of the literature identified 27 patients from five studies. Among the 29 patients, intellectual disability, developmental delay, and hypomyelination were the common symptoms, while 13 of them exhibited DEE and malformations of cortical development. Of the 25 variants identified, c.5A>G (p.Asp2Gly) was identified in 10 patients. ArgRS protein expression and stability were substantially reduced in the two newly identified patients.SignificancePatients with RARS1 biallelic mutations frequently exhibit DEE, a severe phenotype, along with hypomyelinating leukodystrophy. Besides its effects on the white matter, this mutation also influences cortical development. Moreover, the variants c.5A>T (p.Asp2Val), c.1382G>A (p.Arg461His), and c.1535G>A (p.Arg512Gln) are pathogenic and affect the expression of ArgRS by reducing the protein stability.

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“…[ 1 9 ] Deaf people have more severe dental and oral problems compared to healthy individuals. [ 10 ] It is recommended to initiate oral health promotion programs for the deaf to improve their access to dental services. [ 11 ]…”

Section: Introductionmentioning

confidence: 99%

The need for a Smart Phone Application to Facilitate Communication Between Deaf-Mute and Hearing-Impaired Patients and Dentists

Alkadhi

Abdulrahman

Alhawas

et al. 2021

Journal of Family Medicine and Primary Care

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Objective: This study aims to determine the difficulty of communication between deaf-mute and hearing-impaired individuals, and their dentists and the need for an application to facilitate communication. Materials and methods: This is a cross-sectional study. A self-reported questionnaire was distributed among individuals with hearing disability. We measured demographic data, deaf-mute and hearing-impaired patients experience at the dental office, their interest and ability to use modern means of communication, and their willingness to use smartphones, tablets or computers to communicate with their dentists. Fisher's Exact test was used to determine association between different variables with cut-off point ( P < 0.05). Results: 58.5% of individuals with deafness or hearing impairment have visited dental offices. 51% of individuals reported they could not understand their dentists during visits. 45.3% stated that their complaints were understood. 30.2% of the information given by dentists were clear to them and only 24.5% of individuals were given all necessary information. 73.58% of all individuals are willing to use mobile applications to facilitate communication if recommended by their dentists. Conclusions: Many individuals with hearing disability are facing difficulties in communication in the dental office. The majority of them are willing to use a mobile application to help them communicate better with their dentists.

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Hypomyelinating Leukodystrophy with Spinal Cord Involvement Caused by a Novel Variant in RARS: Report of Two Unrelated Patients

Cited by 10 publications

References 13 publications

Distinct pathogenic mechanisms of various RARS1 mutations in Pelizaeus-Merzbacher-like disease

Distinct pathogenic mechanisms of various RARS1 mutations in Pelizaeus-Merzbacher-like disease

RARS1‐related developmental and epileptic encephalopathy

The need for a Smart Phone Application to Facilitate Communication Between Deaf-Mute and Hearing-Impaired Patients and Dentists

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