Mitochondrial DNA haplogroups and mutations in children with acquired central demyelination
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Abstract
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.
Footnotes
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Study funding: Funding provided as part of the Canadian Pediatric Demyelinating Disease Network Grant from the Multiple Sclerosis Society of Canada Scientific Research Foundation to A.B.-O., B.B., D.L.A., and A.D.S., with a subcontract to D.K.S. D.K.S. is also supported by a grant (R01NS058988) from the National Institutes of Neurological Disorders and Stroke.
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Editorial, page 768
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See page 781
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Supplemental data at www.neurology.org
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- ADEM
- acute disseminated encephalomyelitis
- ADS
- acquired demyelinating syndrome
- CI
- confidence interval
- LHON
- Leber hereditary optic neuropathy
- MS
- multiple sclerosis
- mtDNA
- mitochondrial DNA
- OR
- odds ratio
- PD-ADS
- first episode of acquired demyelinating syndrome
- SNP
- single nucleotide polymorphism
- Received May 4, 2010.
- Accepted September 13, 2010.
- Copyright © 2011 by AAN Enterprises, Inc.
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