Mitochondrial DNA haplogroups and mutations in children with acquired central demyelination
S Venkateswaran1, K Zheng, M Sacchetti
1Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Insights
Mitochondrial DNA variants are linked to pediatric acquired demyelinating syndromes (PD-ADS) and an increased risk of developing multiple sclerosis (MS) in children. Further research is needed to confirm these findings.
Area of Science:
- Genetics
- Neurology
- Immunology
Background:
- Pediatric acquired demyelinating syndromes (PD-ADS) are CNS disorders with varied outcomes, including progression to multiple sclerosis (MS).
- Mitochondrial DNA (mtDNA) variants have been implicated in various autoimmune and neurological conditions, including MS in adults.
Purpose of the Study:
- To investigate the association between specific mitochondrial DNA (mtDNA) variants and the risk of PD-ADS in children.
- To explore the relationship between these mtDNA variants and the subsequent diagnosis of multiple sclerosis (MS) in pediatric patients.
Main Methods:
- An exploratory analysis was conducted on 213 children with PD-ADS and 166 healthy sibling controls.
- Genotyping of 31 single nucleotide polymorphisms (SNPs) was performed, focusing on haplogroup-defining SNPs and those previously linked to MS.
Main Results:
- No primary Leber hereditary optic neuropathy (LHON) or other known pathogenic mtDNA mutations were found.
- The haplogroup J-associated variant (13708A) was more frequent in PD-ADS patients (13.0%) versus controls (6.2%), with an odds ratio (OR) of 2.27.
- Haplogroup M was associated with an earlier age of PD-ADS onset. Haplogroup H was linked to an increased risk of MS diagnosis (OR 2.60).
Conclusions:
- Mitochondrial DNA variants show a potential association with the risk of developing PD-ADS and progressing to MS in children.
- Replication of these findings in an independent cohort of pediatric patients is essential to validate the observed associations.
Objective:
We investigated mitochondrial DNA (mtDNA) variants in children with a first episode of acquired demyelinating syndromes (PD-ADS) of the CNS and their relationship to disease phenotype, including subsequent diagnosis of multiple sclerosis (MS).
Methods:
This exploratory analysis included the initial 213 children with PD-ADS in the prospective Canadian Pediatric Demyelinating Study and 166 matched healthy sibling controls from the Canadian Autism Genome Project. A total of 31 single nucleotide polymorphisms (SNPs) were analyzed, including haplogroup-defining SNPs and mtDNA variants previously reported to be associated with MS.
Results:
Primary Leber hereditary optic neuropathy (LHON) mutations and other known pathogenic mtDNA mutations were absent in both patients with pediatric acquired demyelinating syndromes and controls. The 13708A haplogroup J-associated variant, previously linked to adult MS, was more frequent among subjects with PD-ADS (13.0%) compared to controls (6.2%; odds ratio [OR] 2.27; 95% confidence interval [CI] 1.06 to 4.83) and haplogroup M was associated with an earlier age at onset of PD-ADS (-1.74 years; 95% CI -3.33 to -0.07). In contrast, the haplogroup cluster UKJT, as well as 3 other SNPs, were each associated with a lower risk of PD-ADS. A total of 33 subjects with PD-ADS were diagnosed with MS during a mean follow-up period of 3.11 ± 1.14 (SD) years. No single SNP was associated with the risk of subsequent diagnosis of MS. However, haplogroup H was associated with an increased risk of MS (OR 2.60; 95% CI 1.21 to 5.55).
Conclusion:
These data suggest an association between mtDNA variants and the risk of PD-ADS and of a subsequent MS diagnosis. Replication of these findings in an independent population of subjects with PD-ADS is required.
Related Concept Videos
02:59Animal Mitochondrial Genetics
01:39Mutations