Clinical, radiological, and genomic characteristics of mitochondrial leukodystrophies in Iran

Backgrounds: Mitochondrial disorders are a group of genetic disorders with diverse clinicalmanifestations which arise mainly due to impairments of the mitochondrial respiratory chain.This study has been conducted due to the relative lack of sufficient cohort reports on acombination of clinical, genomic, and imaging data of childhood mitochondrialleukodystrophies.Materials and Methods: A total number of ۳۰۱ patients with a definite diagnosis ofleukodystrophy or genetic leukoencephalopathy were enrolled in Myelin Disorders ClinicRegistry (MDCR) system in the time period between ۲۰۱۶ and ۲۰۲۰. All relevant clinicalinformation, neuroimaging, genomic data and their clinical follow-up notes were recorded. Brainimaging and molecular studies were performed; in ۳۹ out of ۳۰۱ cases (۱۲.۹%) a diagnosis ofmitochondrial leukoencephalopathy was approved as the most common type of leukodystrophyor genetic leukoencephalopathy. WES was performed on ۳۶ patients (۹۲.۳۰%), while the singlegenemethod (i.e., Sanger sequencing) was performed on ۳ patients (۷.۷%).Results: All ۳۹ patients were homozygous for the causative variant/mutation. In total, ۳۴patients were diagnosed with previously reported mutations, while novel variants were detectedin ۵ cases. Herein, we also showed that the most common mutations were those that theiraffected genes were involved in the Complex I subunits (n = ۱۴; ۳۵.۸%). Defects in Complex IV(e.g., SURF۱ and APOPT۱) and energy production were placed as the second and third groupsaffecting ۲۳% and ۱۲.۸% of patients, respectively. For novel variants, in silico pathogenicityscores and conservational analysis was performed.Conclusion: In three-dimensional structural models, we showed that the substitutions maychange the protein stability or function. Conservational analysis showed that each novel variantchanges the highly conserved region in putative genes. However, to arrive at a conclusiveconclusion, doing functional analysis is suggested using animal models.

Keywords:

Mitochondrial disorders , leukodystrophies , mutation