Abstract
Leukodystrophies (LDs) are a heterogeneous group of progressive neurological disorders and characterized by primary involvement of white matter of the central nervous system (CNS). This is the first report of the Iranian LD Registry database to describe the clinical, radiological, and genomic data of Persian patients with leukodystrophies. From 2016 to 2019, patients suspicious of LDs were examined followed by a brain magnetic resonance imaging (MRI). A single gene testing or whole-exome sequencing (WES) was used depending on the neuroradiologic phenotypes. In a few cases, the diagnosis was made by metabolic studies. Based on the MRI pattern, diagnosed patients were divided into cohorts A (hypomyelinating LDs) versus cohort B (Other LDs). The most recent LD classification was utilized for classification of diagnosed patients. For novel variants, in silico analyses were performed to verify their pathogenicity. Out of 680 registered patients, 342 completed the diagnostic evaluations. In total, 245 patients met a diagnosis which in turn 24.5% were categorized in cohort A and the remaining in cohort B. Genetic tests revealed causal variants in 228 patients consisting of 213 variants in 110 genes with 78 novel variants. WES and single gene testing identified a causal variant in 65.5% and 34.5% cases, respectively. The total diagnostic rate of WES was 60.7%. Lysosomal disorders (27.3%; GM2-gangliosidosis-9.8%, MLD-6.1%, KD-4.5%), amino and organic acid disorders (17.15%; Canavan disease-4.5%, L-2-HGA-3.6%), mitochondrial leukodystrophies (12.6%), ion and water homeostasis disorders (7.3%; MLC-4.5%), peroxisomal disorders (6.5%; X-ALD-3.6%), and myelin protein disorders (3.6%; PMLD-3.6%) were the most commonly diagnosed disorders. Thirty-seven percent of cases had a pathogenic variant in nine genes (ARSA, HEXA, ASPA, MLC1, GALC, GJC2, ABCD1, L2HGDH, GCDH). This study highlights the most common types as well as the genetic heterogeneity of LDs in Iranian children.
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Data availability
The variants identified in the current study have been deposited in the ClinVAR (persistent link: https://www.ncbi.nlm.nih.gov/clinvar/submitters/506651/).
Change history
05 September 2023
A Correction to this paper has been published: https://doi.org/10.1007/s10048-023-00733-9
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Acknowledgements
We appreciate the patients and their families for their willingness to participate in this research. We also express our gratitude to Drs. Marjo van der Knaap, pediatric neurologist and leukodystrophy specialist at the Emma Children’s Hospital, University Medical Center in Amsterdam, the Netherlands, and Ali Fatemi, Pediatric Neurologist and leukodystrophy expert at the Moser Center for Leukodystrophies, Kennedy Krieger Institute, and Department of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, USA, for their continued support and encouragement.
Funding
Research reported in this publication was supported and funded by the Tehran University of Medical Sciences (grant no.: 96–02-30–35551) and by the National Institute for Medical Research Development (electronic application no.: 983886).
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Conceptualization: Ali Reza Tavasoli and Mahmoudreza Ashrafi. Data curation: Ali Reza Tavasoli, Reyhaneh kameli, Sareh Hosseinpour, Ehsan Razmara, Zahra Rezaei, Raziyeh Mashayekhi, Mohammad Barzegar, Reza Azizimalamiri, Morteza Rezvani Kashani, Nahideh Khosroshahi, Maryam Rasulinezhad, Morteza Heidari, Man Amanat, Alireza Abdi, Bahram Mohammadi, Mahmoud Mohammadi, Gholam Reza Zamani, Reza Shervin Badv, Abdolmajid Omrani, Sedigheh Nikbakht, Ali Hosseini Bereshneh, Mojtaba Movahedinia, Hossein Farshad Moghadam, Hossein Shojaaldini Ardakani, Masood Ghahvechi Akbari, Mehran Beiraghi Tousi, Mohammad Vafaee Shahi, Firouzeh Hosseini, Masoud Hassanvand Amouzadeh, Seyed Ahmad Hosseini, Ali Nikkhah, Ali Khajeh, Bahram Yarali, Mohammad Rohani, Parviz Karimi, Hadi Montazer Lotf Elahi, Seyyed Mohamad Mahdi Hosseiny, Masoumeh Sadat Sadeghzadeh, Hossein Mohebbi, Maryam Hosseini Moghadam, Mahdieh Soveizi, Bahareh Rabbani, and Ali Rabbani. Formal analysis: Zahra Zamani, Nejat Mahdieh, and Hajar Aryan. Investigation: Neda Pak, Hooman Alizadeh, Nejat Mahdieh, Masoud Garshasbi, and Hassan Vahidnezhad. Methodology: Zahra Zamani and Ali Reza Tavasoli. Project administration: Ali Reza Tavasoli. Resources: Reyhaneh Kameli, Sareh Hosseinpour, Ehsan Razmara, and Ali Reza Tavasoli. Supervision: Mahmoudreza Ashrafi, Ali Reza Tavasoli, and Masoud Garshasbi. Software: Ehsan Razmara. Visualization: Reyhaneh Kameli, Sareh Hosseinpour. Writing—original draft: Reyhaneh kameli, Ali Hosseini Bereshneh, Ehsan Razmara, and Sareh Hosseinpour. Writing—review and editing: Ali Reza Tavasoli and Masoud Garshasbi.
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The study protocol was approved by the ethical committee of Children’s Medical Center, Tehran, Iran (IR.TUMS.MEDICINE.REC.1396.3082) and the National Institute for Medical Research Development (IR.NIMAD.REC.1399.066). According to local national ethical requirements and in line with the Declaration of Helsinki, each patient or their legal guardians signed informed consent at the participating centers. Sampling was only done if the consent did not exclude data sharing.
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Ashrafi, M., Kameli, R., Hosseinpour, S. et al. High genetic heterogeneity of leukodystrophies in Iranian children: the first report of Iranian Leukodystrophy Registry. Neurogenetics 24, 279–289 (2023). https://doi.org/10.1007/s10048-023-00730-y
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DOI: https://doi.org/10.1007/s10048-023-00730-y