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A Comprehensive Study of Mutation and Phenotypic Heterogeneity of Childhood Mitochondrial Leukodystrophies Publisher Pubmed



Hosseinpour S1 ; Razmara E2 ; Heidari M3 ; Rezaei Z3 ; Ashrafi MR3 ; Dehnavi AZ3, 4 ; Kameli R5 ; Bereshneh AH6 ; Vahidnezhad H7, 8 ; Azizimalamiri R9 ; Zamani Z10 ; Pak N11 ; Rasulinezhad M3 ; Mohammadi B3 Show All Authors
Authors
  1. Hosseinpour S1
  2. Razmara E2
  3. Heidari M3
  4. Rezaei Z3
  5. Ashrafi MR3
  6. Dehnavi AZ3, 4
  7. Kameli R5
  8. Bereshneh AH6
  9. Vahidnezhad H7, 8
  10. Azizimalamiri R9
  11. Zamani Z10
  12. Pak N11
  13. Rasulinezhad M3
  14. Mohammadi B3
  15. Ghabeli H3
  16. Ghafouri M3
  17. Mohammadi M12
  18. Zamani GR12
  19. Badv RS12
  20. Saket S13
  21. Rabbani B14
  22. Mahdieh N14, 15
  23. Ahani A16
  24. Garshasbi M17
  25. Tavasoli AR3, 18

Source: Brain and Development Published:2024


Abstract

Objective: Mitochondrial leukodystrophies (MLs) are mainly caused by impairments of the mitochondrial respiratory chains. This study reports the mutation and phenotypic spectrum of a cohort of 41 pediatric patients from 39 distinct families with MLs among 320 patients with a molecular diagnosis of leukodystrophies. Methods: This study summarizes the clinical, imaging, and molecular data of these patients for five years. Results: The three most common symptoms were neurologic regression (58.5%), pyramidal signs (58.5%), and extrapyramidal signs (43.9%). Because nuclear DNA mutations are responsible for a high percentage of pediatric MLs, whole exome sequencing was performed on all patients. In total, 39 homozygous variants were detected. Additionally, two previously reported mtDNA variants were identified with different levels of heteroplasmy in two patients. Among 41 mutant alleles, 33 (80.4%) were missense, 4 (9.8%) were frameshift (including 3 deletions and one duplication), and 4 (9.8%) were splicing mutations. Oxidative phosphorylation in 27 cases (65.8%) and mtDNA maintenance pathways in 8 patients (19.5%) were the most commonly affected mitochondrial pathways. In total, 5 novel variants in PDSS1, NDUFB9, FXBL4, SURF1, and NDUSF1 were also detected. In silico analyses showed how each novel variant may contribute to ML pathogenesis. Conclusions: The findings of this study suggest whole-exome sequencing as a strong diagnostic genetic tool to identify the causative variants in pediatric MLs. In comparison between oxidative phosphorylation (OXPHOS) and mtDNA maintenance groups, brain stem and periaqueductal gray matter (PAGM) involvement were more commonly seen in OXPHOS group (P value of 0.002 and 0.009, respectively), and thinning of corpus callosum was observed more frequently in mtDNA maintenance group (P value of 0.042). © 2023 The Japanese Society of Child Neurology
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