Abstract
Metachromatic leukodystrophy (MLD) is a rare leukoencephalopathy caused by pathogenic mutations in the ARSA gene. It manifests as severe motor symptoms, mental problems, and sometimes, seizures. We aimed to investigate the phenotypic manifestations and genetic causes of MLD in an Iranian family. We present the case of a 3-year-old girl who presented with hypotonia, muscular atrophy, and seizures. Neurological and neuromuscular examinations were performed to evaluate clinical characteristics. Whole exome sequencing (WES) was used to detect disease-causing variants. In silico analysis was performed to predict the pathogenicity of this variant. GROMACS software was utilized for molecular dynamic simulation (MDS). Neurological studies revealed marked slowing of motor conduction velocities and an increased motor unit action potential duration. Brain MRI scan revealed white matter abnormalities. By applying WES, we identified a novel homozygous missense variant (NM_000487.6, c.938G > C, p.R313P) in ARSA. Direct sequencing identified this homozygous variant in her asymptomatic younger sister, whereas both parents carried a heterozygous variant. This mutation has not been reported in genetic databases or in literature. In silico analysis predicted that any variation in this DNA position would cause disease, as it is highly conserved. The c.938G > C variant was classified as a pathogenic variant according to ACMG/AMP guidelines. MDS analysis indicated that c.938G > C had a significant impact on both the structure and stabilization of ARSA, ultimately resulting in impaired protein function. The identification of this variant expands the spectrum of ARSA gene mutations associated with MLD and highlights the importance of genetic testing for the diagnosis of MLD.
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The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available because of privacy or ethical restrictions.
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Acknowledgements
Our sincere gratitude goes to the patient's family for their valuable participation and consent to publish data in this study.
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This research was supported by a grant from Birjand University of Medical Sciences (Grant Number: 6317).
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AY and ZMK were involved in genetic analysis, in silico analysis, molecular dicking, figure preparation, review of the literature and manuscript writing. FV was involved in data collection, molecular docking, molecular dynamic modeling, and manuscript writing. HH was involved in molecular dynamic modeling. MH and MSR were involved in sample preparation, genetic counseling, neurological evaluation, and physical examination. AE was involved in preparation of MRI images. EM-M was involved in study design and review of the final draft. All authors have seen and agreed with the contents of the manuscript.
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Yari, A., Vafaeie, F., Karam, Z.M. et al. Identification of a Novel ARSA Gene Mutation Through High-Throughput Molecular Diagnosis Method in Two Girls with Late Infantile Metachromatic Leukodystrophy. Neuromol Med 25, 563–572 (2023). https://doi.org/10.1007/s12017-023-08757-y
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DOI: https://doi.org/10.1007/s12017-023-08757-y