PMID- 37682448
OWN - NLM
STAT- MEDLINE
DCOM- 20231216
LR  - 20231216
IS  - 1559-1174 (Electronic)
IS  - 1535-1084 (Linking)
VI  - 25
IP  - 4
DP  - 2023 Dec
TI  - Identification of a Novel ARSA Gene Mutation Through High-Throughput Molecular 
      Diagnosis Method in Two Girls with Late Infantile Metachromatic Leukodystrophy.
PG  - 563-572
LID - 10.1007/s12017-023-08757-y [doi]
AB  - 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.
CI  - (c) 2023. The Author(s), under exclusive licence to Springer Science+Business 
      Media, LLC, part of Springer Nature.
FAU - Yari, Abolfazl
AU  - Yari A
AD  - Cellular and Molecular Research Center, Birjand University of Medical Sciences, 
      Birjand, Iran.
FAU - Vafaeie, Farzane
AU  - Vafaeie F
AD  - Cellular and Molecular Research Center, Birjand University of Medical Sciences, 
      Birjand, Iran.
FAU - Karam, Zahra Miri
AU  - Karam ZM
AD  - Physiology Research Center, Institute of Neuropharmacology, Kerman University of 
      Medical Sciences, Kerman, Iran.
AD  - Department of Medical Genetics, Afzalipour Faculty of Medicine, Kerman University 
      of Medical Sciences, Kerman, Iran.
FAU - Hosseini, Mahya
AU  - Hosseini M
AD  - Department of Pediatric, Faculty of Medicine, Birjand University of Medical 
      Sciences, Ghaffari Blvd., Birjand, Iran. mahyahosseini@bums.ac.ir.
FAU - Hashemzade, Hassan
AU  - Hashemzade H
AD  - Department of Pharmaceutics and Pharmaceutical Nanotechnology, School of 
      Pharmacy, Birjand University of Medical Sciences, Birjand, Iran.
FAU - Rahimi, Maryam Sadat
AU  - Rahimi MS
AD  - Cardiovascular Disease Research Center, Razi Hospital, Birjand University of 
      Medical Sciences, Birjand, Iran.
FAU - Ehsanbakhsh, Alireza
AU  - Ehsanbakhsh A
AD  - Department of Radiology, Faculty of Medicine, Birjand University of Medical 
      Sciences, Birjand, Iran.
FAU - Miri-Moghaddam, Ebrahim
AU  - Miri-Moghaddam E
AD  - Department of Molecular Medicine, Cardiovascular Disease Research Center, Faculty 
      of Medicine, Razi Hospital, Birjand University of Medical Sciences, Ghaffari 
      Blvd., Birjand, Iran. miri4@bums.ac.ir.
LA  - eng
GR  - 6317/Birjand University of Medical Sciences/
PT  - Case Reports
PT  - Journal Article
DEP - 20230908
PL  - United States
TA  - Neuromolecular Med
JT  - Neuromolecular medicine
JID - 101135365
RN  - EC 3.1.6.8 (Cerebroside-Sulfatase)
SB  - IM
MH  - Humans
MH  - Female
MH  - Child, Preschool
MH  - *Leukodystrophy, Metachromatic/diagnosis/genetics/pathology
MH  - Cerebroside-Sulfatase/genetics/chemistry/metabolism
MH  - Iran
MH  - Mutation
MH  - Seizures
OTO - NOTNLM
OT  - ARSA
OT  - Aryl sulfatase A
OT  - MLD
OT  - Metachromatic leukodystrophy
OT  - Novel mutation
OT  - Whole exome sequencing
EDAT- 2023/09/08 12:43
MHDA- 2023/12/17 09:45
CRDT- 2023/09/08 11:13
PHST- 2023/07/12 00:00 [received]
PHST- 2023/08/25 00:00 [accepted]
PHST- 2023/12/17 09:45 [medline]
PHST- 2023/09/08 12:43 [pubmed]
PHST- 2023/09/08 11:13 [entrez]
AID - 10.1007/s12017-023-08757-y [pii]
AID - 10.1007/s12017-023-08757-y [doi]
PST - ppublish
SO  - Neuromolecular Med. 2023 Dec;25(4):563-572. doi: 10.1007/s12017-023-08757-y. Epub 
      2023 Sep 8.