Mitochondrial DNA haplogroups and
mutations in children with acquired
S. Venkateswaran, MD
K. Zheng, MD
D. Gagne, MSc
D.L. Arnold, MD
A.D. Sadovnick, PhD
S.W. Scherer, PhD
B. Banwell, MD
A. Bar-Or, MD
D.K. Simon, MD, PhD
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 pheno-
type, including subsequent diagnosis of multiple sclerosis (MS).
Methods: This exploratory analysis included the initial 213 children with PD-ADS in the prospec-
tive 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 as-
sociated with MS.
Results: Primary Leber hereditary optic neuropathy (LHON) mutations and other known patho-
genic mtDNA mutations were absent in both patients with pediatric acquired demyelinating syn-
dromes 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. Neurology®2011;76:774–780
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.
Approximately 3%–5% of patients with multiple sclerosis (MS) experience initial MS symp-
toms as children.1At the time of the first episode of an acquired demyelinating syndrome
(ADS) of the CNS in the pediatric population, referred to as PD-ADS, it is difficult to predict
which patients eventually will be diagnosed with MS. This emphasizes the need for biomarkers
predictive of MS outcome.
A role for mitochondrial dysfunction and oxidative stress in MS pathogenesis has been
suggested.2Mitochondrial complex I and complex III activity is reduced in the motor cortex of
patients with secondary progressive MS compared to controls, and oxidative DNA damage is
e-Pub ahead of print on February 2, 2011, at www.neurology.org.
From Neuroimmunology (S.V., D.G., A.B.-O.), Brain Imaging Centre (D.L.A.), and Experimental Therapeutics Program (A.B.-O.), Montreal
Neurological Institute, McGill University, Montreal, Canada; Children’s Hospital of Eastern Ontario (S.V.), Ottawa, Canada; Beth Israel Deaconess
Medical Center and Harvard Medical School (K.Z., M.S., D.K.S.), Boston, MA; University of British Columbia (A.D.S.), Vancouver; and The
Hospital for Sick Children (S.W.S., B.B.), University of Toronto, Toronto, Canada.
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.
Disclosure: Author disclosures are provided at the end of the article.
See page 781
Address correspondence and
reprint requests to Dr. D.K.
Simon, Beth Israel Deaconess
Medical Center and Harvard
Medical School, 330 Brookline
Avenue, Room CLS-638,
Boston, MA 02215
Copyright © 2011 by AAN Enterprises, Inc.
increased in MS plaques compared to normal-
appearing white matter.3Mitochondrial hap-
logroup J has been associated with the
presentation of optic neuritis4and haplo-
group J or K with heterogeneous phenotypes.5
The association of the K haplogroup with
adult MS risk has recently been replicated.6
Other mtDNA variants, such as 13966G or
14798C, have been published in rare case re-
ports of patients with MS.7A restriction en-
donuclease splice variant in the 15927/15928
region of the mitochondrial tRNA (thr) gene
was reportedly more frequent in patients with
MS with severe optic neuropathy compared to
controls, although the specific mutation respon-
sible for this association was not identified.8
An increased frequency of MS also has been
reported in pedigrees of patients with Leber he-
reditary optic neuropathy (LHON),9which is
caused by mutations in mtDNA, and optic
nerve involvement is common in both condi-
tions. Primary LHON mutations (3460A,
11778A, 14484C10) have been identified in rare
subjects with MS-like illnesses, an observation
not reproduced in all studies.11Among patients
with MS presenting with severe optic neuropa-
thy, very rarely primary and combinations of
secondary LHON mutations have been repor-
ted.12Conversely, case reports exist of white
mutations.13,14To date, primary or secondary
LHON mutations have not been found in chil-
dren with MS,15,16or children with MS and se-
vere optic neuropathy.17
These data, although mixed, raise the possi-
bility of a role for mtDNA mutations in MS.
However, a comprehensive analysis of mtDNA
mutations and haplogroups in PD-ADS has not
been carried out. An association of mtDNA ge-
netic variants with PD-ADS or MS would sug-
gest a role for mitochondrial dysfunction in the
a consequence of the disease process. Here,
we analyzed mtDNA variants in a well-
characterized prospective cohort of children
followed from onset of an initial demyeli-
METHODS Subjects. DNA samples were analyzed from the
first 213 Canadian children enrolled from onset of an initial
demyelinating event between September 2004 and October
2008. All participants were less than 16 years of age (with the
exception of one subject presenting at age 16.8 years), and have
been followed prospectively as part of the multicenter 8-year
Canadian Pediatric Demyelinating Disease study.
ADS is defined as neurologic dysfunction lasting at least 24
hours presenting as optic neuritis, transverse myelitis, acute
disseminated encephalomyelitis (ADEM), monofocal-other
(monofocal deficits localized to brain regions extrinsic to the
optic nerve or spinal cord), or multifocal CNS demyelination.18
All children were examined quarterly in year 1 and annually
thereafter, as well as at time of any new neurologic event.
The diagnosis of MS was conferred if clinical features and
examination confirmed a second demyelinating attack, separated
30 days or more from the onset of the first attack and involving
new areas of the nervous system.18MRI evidence of clinically
silent lesions was not used for the diagnosis of MS in this study,
and the diagnosis of MS was determined as of the data closure
date of November 2009.
Extensive laboratory investigations were performed in all
participants to exclude other diagnoses, as previously described.19
One patient (who died of an illness clinically characterized as
ADEM) was subsequently excluded based on autopsy studies
showing mitochondrial Leigh syndrome. None of the children
included in this study met the criteria for recurrent ADEM, mul-
tiphasic ADEM, or neuromyelitis optica.
Race for the patient and for both biological parents was di-
vided into 4 categories: white, black, Asian, and mixed. Ancestry
was divided into European, Asian, Caribbean, South/Central
American, Middle Eastern, African, Aboriginal, and mixed. The
patients with PD-ADS were ethnically diverse, representative of
the general pediatric population in Canada, with 62% of the
children of maternal and paternal European descent.
DNA samples from 166 age-, sex-, and ethnicity-matched
controls were obtained from the healthy sibling cohort of the
Canadian Autism Genome Project.20The mean age ? SD of
subjects with PD-ADS at study entry was 10.2 ? 4.3 years
(range 0.6–16.8 years). The mean age ? SD for controls
(10.77 ? 5.0 years) was not significantly different from that of
the subjects with PD-ADS. Controls ranged in age more broadly
from 1 to 27, with all but 19 being age 16 or less. These 19
subjects above the age of 16 were included to optimize matching
by race and ancestry.
Standard protocol approvals, registrations, and patient
consents. This study was approved by the individual institu-
tions comprising the Canadian Pediatric Demyelinating Disease
Network and the Canadian Autism Genome Project. Written
informed consent was obtained from all patients or their parents
or legal guardians.
Selection of mtDNA variants. A total of 31 mtDNA vari-
ants or mutations were analyzed, including 11 variants selected
to define the most common haplogroups21(table 1). mtDNA
mutations previously implicated (but not confirmed) in MS also
were analyzed (4298A,2213966G,2314798C,2315927A,24and
15928A24). The 3 most common primary LHON mutations—
3460A, 11778A, and 14484C—as well as secondary LHON
mtDNA variants—3394C, 4216C, 4917G, and 13708A—and
one variant with an uncertain association with LHON
(15257A)10were also analyzed, as were mutations associated with
LHON plus dystonia: 14459A25and 14596A.26We additionally
screened for the most common mtDNA mutations associated
with mitochondrial encephalopathy with ragged red fibers
(8344G), mitochondrial encephalomyopathy, lactic acidosis,
Neurology 76 March 1, 2011
and stroke-like episodes (3243G), neuropathy, ataxia, and
retinitis pigmentosa (8993G),27and the 4336C28and 5460A29
variants variably reported in association with neurodegenera-
tive disease. The 10398G variant was included both for hap-
logroup analyses and due to variable reports of an association
with a lower risk of PD,30,31and an earlier age at onset in
spinocerebellar ataxia type 2.32
Genotyping methods. Genotyping was performed using Se-
quenom matrix-assisted laser desorption ionization– time of
flight mass spectrometry through the Harvard Partners Center
for Genetics and Genomics High Throughput Genotyping Fa-
cility (Boston, MA). A subset of samples was also analyzed by
restriction endonuclease assay or direct sequencing; in each case
this confirmed the validity of the Sequenom results. For each
sample that tested positive for the 15927A mutation, the muta-
tion was confirmed by restriction endonuclease analysis as previ-
ously described.30Because this restriction endonuclease analysis
does not distinguish between the 15927A and 15928A variants,
presence of the 15927A variant also was confirmed in each case
by direct sequencing. The restriction endonuclease analysis indi-
cated heteroplasmy in each case (a mix of wild-type and mutant
mtDNA). TA cloning of the DNA (Invitrogen TOPO TA clon-
ing kit) of a subset of these cases, followed by selection of at least
20 clones for PCR amplification and repeat restriction endonu-
clease analysis for the 15927A mutation, revealed some clones
positive and others negative for the mutation, confirming the
Haplogroup analysis. Haplogroups were defined based on
previously grouped mitochondrial SNPs in European popula-
tions21(see table 1).
Data collection. Clinical information from individual centers
Toronto, Canada. Laboratory samples were shipped and stored at
the Montreal Neurological Institute, and DNA samples were geno-
typed through the Harvard Partners Center for Genetics and
Genomics High Throughput Genotyping Facility (Boston, MA).
Statistical analyses. Unpaired Student t test (2-tailed) was
performed for comparisons of ages at onset. Fisher exact test
(2-tailed) was used for comparisons of mutation or haplogroup
frequencies and for comparisons of the frequency of dichoto-
mous clinical features. As an exploratory study, we did not apply
a correction factor for multiple comparisons, warranting future
confirmatory studies. Subjects with insufficient SNPs to deter-
mine a genotype were classified as “missing data”; those with
SNPs that did not fit into a prespecified haplogroup were catego-
rized as “unknown.”
RESULTS Demographics and clinical information.
At time of analysis, 213 children with confirmed
PD-ADS were followed for a mean of 3.11 ? 1.14
(SD) years (range 0.76–5.80 years) from presenta-
tion. Demographic and clinical data are presented in
table 2. To date, 33 of the 213 children (15.5%)
have been diagnosed with MS (mean interval be-
tween initial and second demyelinating events of
0.82 ? 0.65 years; table e-1 on the Neurology®Web
site at www.neurology.org). This is consistent with
published data indicating a relatively short mean in-
terval of less than 1 year between a first and second
demyelinating event in children.33The mean age at
onset of PD-ADS was older for subjects with PD-
ADS subsequently diagnosed with MS (13.09 ?
2.93 years) compared to those not diagnosed with
MS during the follow-up period (9.71 ? 4.38 years;
p ? 0.001). Twelve of the 213 children had a mater-
nal family history of MS and only one of these chil-
dren has a confirmed MS diagnosis thus far. There
was no maternal family history of known mitochon-
drial disease for any of the 213 children.
LHON mutations. None of the 213 ADS cases or 166
controls had a primary LHON mutation (11778A,
14484C, 3460A). The frequency of the 13708A vari-
ant, a SNP associated with the J haplogroup and con-
sidered to be a “secondary” LHON mutation due to
its apparent influence on the penetrance of a primary
Table 2Clinical neurologic presentation of 213 children with PD-ADS
Monophasic ADS at
(n ? 180), n (%)
MS (n ? 33),
OR (95% CI);
p value (2-tailed
Fisher exact test)
53 (29.4)8 (24.4)0.7 (0.3 to 1.8); 0.7
47 (26.1) 1 (3.1) 0.09 (0.02 to 0.53); 0.002c
42 (23.3) 4 (12.1) 0.45 (0.16 to 1.31); 0.17
Multifocal ON and TMe
7 (3.9) 2 (6.1) 1.6 (0.36 to 7.15); 0.63
19 (10.6)9 (27.3)3.2 (1.3 to 7.8); 0.02
7 (3.9) 9 (27.3)9.3 (3.3 to 26.4); ?0.001c
Abbreviations: ADEM ? acute disseminated encephalomyelitis; ADS ? acquired demyeli-
nating syndrome; CI ? confidence interval; MS ? multiple sclerosis; ON ? optic neuritis;
OR ? odds ratio; PD-ADS ? first episode of acquired demyelinating syndrome; TM ? trans-
aClinical phenotypes based solely on neurologic examination without consideration of MRI
bPresenting phenotypes were unclassified for 5 subjects with monophasic ADS.
dIncludes patients with ADEM who had concurrent ON or TM.
eNone of these patients were diagnosed with neuromyelitis optica at follow-up.
in the brain extrinsic to the optic nerve or spinal cord; multifocal: other neurologic dysfunc-
tion ? clinical findings attributable to greater than one location in the brain or spinal cord,
other than ADEM; may include ON or TM as part of symptom constellation.
Table 1 Defined haplogroups
Haplogroup Single nucleotide polymorphisms
4216C, 13708A (?14766C)
7028T, 9055G, 10398G, 13708G, 16391G
7028T, 10398A, 13368A
7028T, 10398A, 12308G
4580A, 7028T, 10398A
7028T, 8251A, 10398A
1719A, 7028T, 10398A, 16391A
Neurology 76 March 1, 2011
LHON mutation,34was present in 13% of subjects
with PD-ADS compared to 6.2% of controls (odds
ratio [OR] 2.27; 95% confidence interval [CI] 1.063
to 4.834; p ? 0.04). The frequency of another sec-
ondary LHON mutation, 4917G, was lower in the
subjects with PD-ADS (6.2%) compared to controls
(11.3%) (OR ? 0.45; 95% CI 0.22 to 0.92; p ?
0.03). Neither of these variants was associated with
risk of conversion to MS during the study period. A
single patient with PD-ADS harbored the 15257A
variant; none had the 3394C variant.
15927A and 15928A mtDNA variants. A prior study
found that a restriction endonuclease variant in the
mitochondrial tRNA threonine gene was present at a
higher frequency in patients with MS compared to
controls.24This restriction endonuclease variant
could be caused either by the 15927A variant or by
the 15928A variant. There was a trend toward a
higher frequency of the 15927A variant in PD-ADS
(8/209; 3.8%) compared to controls (2/162; 1.2%)
(p ? 0.09). The mutation was heteroplasmic in each
of these 8 cases, representing a potentially important
observation as heteroplasmy is a common feature of
pathogenic mtDNA mutations. Of the 8 children
with the 15927A mutation, 3 (37.5%) were diag-
nosed with MS during the period of follow-up, com-
pared to 30 out of 180 (16.7%) children diagnosed
with MS who do not have the mutation (p ? 0.10).
Among the 8 children positive for the 15927A
mtDNA mutation, clinical presentations, ethnicities,
and age at onset varied. The mean age at onset of
PD-ADS was 7.9 ? 1.8 years for the 8 cases positive
for the 15927A mutation compared to 10.3 ? 0.3
years among the negative cases (p ? 0.16). The fre-
quency of the 15928A variant was lower in subjects
with PD-ADS (6.6%) compared to controls (13.3%)
(OR 0.47; 95% CI 0.23 to 0.94; p ? 0.034). The
risk of MS was not significantly different among sub-
jects with PD-ADS with this variant compared to
those without this variant. None of the analyses were
significant when combining all subjects with either
the 15927A or the 15928A variants.
Other mtDNA variants and mutations. The haplo-
group T–associated 13368A variant, which was
genotyped for the purpose of haplogroup analyses,
was less frequent among subjects with PD-ADS com-
pared to controls (OR 0.46; 95% CI 0.23 to 0.93;
p ? 0.03). Frequencies of the 4336C, 5460A,
10398G, 13966G, and 14798C variants were not
different between groups, and no single SNP was as-
sociated with an altered risk of being diagnosed with
MS. None of the subjects with PD-ADS or control
subjects harbored the 3243G, 4298A, 8334G,
8993G, 14459A, or 14596A mutations.
Haplogroup analysis. Mitochondrial haplogroups
could be defined unambiguously by the genotyped
SNPs in 90% of patients with ADS and in 93% of
controls (table 3). In the PD-ADS group, haplo-
group H was the most common (40.8%), followed
by M (15%), U (8.5%), T (6.1%), J (5.6%), X
(4.7%), K (3.3%), I (4.2%), W (0.9%), and V
(0.5%). No significant differences were observed for
the frequencies of any individual haplogroup in sub-
jects with PD-ADS compared to controls. However,
the haplogroup cluster UKJT, which has been associ-
ated with a reduced risk of PD,35was present at a
lower frequency in the subjects with PD-ADS
(23.5%) compared to controls (34.3%; OR 0.587;
95% CI 0.37 to 0.92; p ? 0.02). Haplogroup M was
Table 3 Frequencies of haplogroups in PD-ADS and controlsa
(n ? 213), n (%)
(n ? 166), n (%) OR (95% CI); p value
(n ? 137), n (%)
n ? 142), n (%) OR (95% CI); p value
87 (40.8)71 (42.8) 0.9 (0.6 to 1.4); 0.7565 (47.4) 64 (45.1) 1.1 (0.7 to 1.8); 0.7
9 (4.2)2 (1.2) 3.6 (0.87 to 15.0); 0.127 (5.1)2 (1.4)3.8 (0.9 to 16.2); 0.1
12 (5.6) 7 (4.2) 1.4 (0.54 to 3.4); 0.64 11 (8.0)7 (4.9) 1.7 (0.65 to 4.3); 0.34
7 (3.3) 13 (7.8) 0.4 (0.16 to 1.0); 0.065 (3.6)12 (8.5)0.4 (0.15 to 1.15); 0.13
32 (15.0) 14 (8.4) 1.9 (1.0 to 3.7); 0.06 8 (5.8)5 (3.5) 1.7 (0.57 to 5.1); 0.41
13 (6.1) 18 (10.8) 0.53 (0.26 to 1.11); 0.38 (5.8)17 (11.9)0.45 (0.19 to 1.1); 0.09
18 (8.5) 20 (12.0) 0.67 (0.35 to 1.31); 0.312 (8.8) 18 (12.6)0.66 (0.31 to 1.4); 0.34
1 (0.5)4 (2.4) 0.19 (0.03 to 1.3); 0.181 (0.7)3 (2.1)0.34 (0.48 to 2.4); 0.62
2 (0.9) 3 (1.8) 0.52 (0.1 to 2.6); 0.662 (1.5) 3 (2.1) 0.67 (0.14 to 3.5); 1.0
10 (4.7) 2 (1.2) 4.0 (0.98 to 16.6); 0.084 (2.9)2 (1.4) 2.1 (0.44 to 9.98); 0.44
22 (10.3)12 (7.2)1.5 (0.7 to 3.0); 0.37 14 (10.2) 9 (6.3) 1.68 (0.72 to 3.9); 0.28
Abbreviations: CI ? confidence interval; OR ? odds ratio; PD-ADS ? first episode of acquired demyelinating syndrome.
aComparisons of haplogroups between all patients and controls as well as a subgroup comparison of only Caucasian patients with PD-ADS of European
descent with Caucasian controls of European descent did not show significant differences in haplogroup frequencies.
Neurology 76March 1, 2011
present at a higher frequency in subjects with PD-
ADS (15.0%) compared to controls (8.4%; p ?
Among the 87 children with PD-ADS with haplo-
group H, 20 (23%) were diagnosed with MS during
haplogroup children (OR 2.60; 95% CI 1.21 to 5.55;
p ? 0.02). None of the haplogroups (individually or
ciated with a significantly different age at onset of PD-
ADS, with the exception of haplogroup M, which was
associated with an earlier mean age at onset of 8.7 ?
0.75 years, vs 10.43 ? 0.32 years for non-M haplo-
group patients (p ? 0.04).
Subgroup analysis of Caucasian subjects of European
descent. As the majority of our patients and controls
were Caucasian and of European ancestry (both bio-
logical parents), we conducted a subgroup analysis of
this relatively homogenous population. The mean
age of patients was 10.27 ? 4.5 years vs 10 ? 4 years
for controls. Findings were similar to the entire
group comparisons. Haplogroup analysis did not re-
veal any differences in frequencies of haplogroups ex-
cept for the haplogroup T–associated variant
13368A, which was decreased in the PD-ADS group
(6.6%) compared to controls (14.8%) (OR 0.4; 95%
CI 0.18 to 0.9; p ? 0.03). There was a trend for an
increased frequency of 13708A in subjects with PD-
ADS (OR 2.24; 95% CI 0.98 to 5.1; p ? 0.07). The
UKJT cluster frequency was lower in the PD-ADS
group (OR 0.6; 95% CI 0.36 to 0.99; p ? 0.04).
Haplogroup H among this subgroup of Caucasian
subjects with PD-ADS was associated with a trend
toward higher risk for MS (p ? 0.32).
DISCUSSION Our study is unique in the analysis of
mtDNA in an unbiased cohort of prospectively re-
cruited children with PD-ADS, a proportion of
whom are representative of the youngest at-risk pop-
ulation for MS. A potentially important finding is
that mitochondrial haplogroup H subjects with PD-
ADS were significantly more likely to have a subse-
quent diagnosis of MS, compared to children with
PD-ADS with non-H haplogroups. This suggests
that haplogroup H, which represented 41% of all
patients with PD-ADS in this study, confers a higher
risk of an MS diagnosis in these children at risk.
However, as an exploratory study without correction
for multiple comparisons, this finding should not be
considered conclusive until replicated. Haplogroup
M had a borderline association with an increased risk
of PD-ADS and was associated with an earlier age at
onset of ADS, an interesting finding as this haplo-
group is more common in children of non-European
ethnicities, a group generally considered to be at
lower risk for demyelinating events.
While a higher proportion of the patients with
PD-ADS had the mtDNA 15927A tRNA threonine
mutation compared to pediatric healthy controls,
this did not meet statistical significance and thus the
association of this mutation with PD-ADS remains
uncertain. The potential pathogenicity of the
15927A mutation is nonetheless of interest, and sup-
ported by its identification in subjects of several dif-
ferent haplogroups, as well as the presence of
heteroplasmy in all 8 patients. This mutation is quite
rare in adult (predominantly Caucasian) subjects, be-
ing found in none of 213 controls and only 1 of 271
subjects with PD.30Of the 8 children with PD-ADS
with the 15927A mutation, 3 (37.5%) were diag-
nosed with MS during the follow-up period, com-
pared to 15.5% among subjects with PD-ADS
diagnosed with MS who lack this mutation (p ?
0.1). Further studies in a larger population of pa-
tients with PD-ADS are needed to determine
whether or not these trends represent a true influence
of the 15927A variant on the risk of PD-ADS or MS.
None of the PD-ADS cohort harbored primary
LHON mutations. Given the very low frequency
(approximately 0.5%) of primary LHON mutations
in a previously reported adult MS population,9the
current study may have been underpowered to find
rare primary LHON mutations. The 13708A com-
plex I gene variant was present at an increased fre-
quency in our PD-ADS group, similar to a previous
study of adult patients with MS showing a higher
frequency of secondary LHON mutations compared
to their control population.36In the current study,
this variant was not associated with a specific clinical
subtype or severity of ADS presentation, or with a
higher likelihood of a diagnosis of MS.
A limitation of this study is that the age- and
ethnicity-matched Canadian controls who were
available for analysis consisted of healthy siblings of
children with autism spectrum disorder rather than
children without a family history of neurologic disor-
ders. A previous study identified that 7.2% of pa-
tients with autism had mitochondrial respiratory
chain abnormalities (all had severe autism), although
no mtDNA mutations were identified.37Case reports
have described children with clinical features of au-
tism and other neurologic deficits in association with
mtDNA mutations (e.g., G8363A38and A4323G39),
and children with proven mitochondrial electron
chain defects can manifest with autism and neuro-
logic deficits.40However, there are no reports dem-
onstrating mtDNA mutations in healthy family
members of affected children with autism. Still, we
Neurology 76 March 1, 2011
acknowledge that our control population may not be
entirely representative of the general population.
A complex interaction between genes and environ-
ment is thought to underlie the pathobiology of MS,
ADS. Our results do not support the hypothesis of a
major role for primary LHON mutations in children
presenting with ADS, but raise the possibility that spe-
cific mitochondrial variants or haplogroups may influ-
ence the age at onset of PD-ADS and subsequent MS
risk. Further study in larger PD-ADS populations is re-
quired to confirm such observations.
Coinvestigators are listed in alphabetical order by site–investigator: Mark
Awuku, MD (Windsor Regional Hospital, Site Investigator); Louise Rob-
erts, RN (Windsor Regional Hospital, Site Coordinator); J. Burke Baird,
MD (Sudbury Regional Hospital, Site Investigator); Nancy Cacciotti, RN
(Sudbury Regional Hospital, Site Coordinator); Brenda Banwell, MD
(The Hospital for Sick Children, Site Investigator); Melissa McGowan,
MHK, Julia O’Mahony, BSc, Emily Ursell, BSc, Courtney Fairbrother,
BA, Julia Kennedy, MSc, Jennifer Hamilton, Samantha Irwin, MSc, San-
dra Magalhaes, MSc (The Hospital for Sick Children, Site Coordinators);
Virender Bhan, MBBS (Dalhousie University, Site Investigator); Trudy
Campbell, NP, Lucy Sagar, BSc, MEd (Dalhousie University, Site Coor-
dinators); Frances Booth, MD, Namrata Shah, MD, Ruth Ann Marrie,
MD, PhD (Winnipeg Health Sciences Centre, Site Investigators); Joan
Kupchak, RN (Winnipeg Health Sciences Centre, Site Coordinator);
David Buckley, MD (Janeway Children’s Health and Rehabilitation Cen-
tre, Site Investigator); Dianne McGrath, RN, Sharon Penney, RN (Jane-
way Children’s Health and Rehabilitation Centre, Site Coordinators);
Mary Connolly, MD (BC Children’s Hospital, Site Investigator); Shelia
Kent, RN (BC Children’s Hospital, Site Coordinator); Pamela Cooper,
MD (Rouge Valley-Centenary HC, Site Investigator); Loris Aro, RN
(Rouge Valley-Centenary HC, Site Coordinator); Marie-Emmanuelle Di-
lenge, MD (Montreal Children’s Hospital, Site Investigator); Heather
Davies, MSc (Montreal Children’s Hospital, Site Coordinator); Asif
Doja, MD, Daniela Pohl, MD, PhD, Sharon Whiting, MD (Children’s
Hospital of Eastern Ontario, Site Investigators); Chantal Horth, Sheila
Ledoux (Children’s Hospital of Eastern Ontario, Site Coordinators);
Francois Grand’Maison, MD (Ho ˆpital Charles LeMoyne, Site Investiga-
tor); Julie Lafrenie `re, RN, BScN (Ho ˆpital Charles LeMoyne, Site Coordi-
nator); Simon Levin, MD (Children’s Hospital of Western Ontario, Site
Investigator); Mala Ramu, BA (Children’s Hospital of Western Ontario,
Site Coordinator); Anne Lortie, MD (Sainte-Justine Hospital, Site Inves-
tigator); Sophie Morin, RN, Fabiola Breault, RN, Stephanie Pellerin, RN
(Sainte-Justine Hospital, Site Coordinators); E. Athen MacDonald, MD
(Kingston General Hospital, Site Investigator); Vee McBride, RN, BScN
(Kingston General Hospital, Site Coordinator); Jean Mah, MD, MSc
(Alberta Children’s Hospital, Site Investigator); Caitlin Wright, BSc, Na-
tarie Liu, BSc, Catherine Riddell (Alberta Children’s Hospital, Site Coor-
dinators); Brandon Meaney, MD, Dave Callen, PhD, MD (McMaster
Children’s Hospital, Site Investigators); Leah Morgenstern, RN, Laurie
Wyllie, RN, Heather Neuman, RN (McMaster Children’s Hospital, Site
Coordinators); David Meek, MD (Saint John Regional Hospital, Site
Investigator); Alison Crowell, RN, BScN (Saint John Regional Hospital,
Site Coordinator); Noel Lowry, MD (Royal University Hospital, Site In-
vestigator); Doris Newmeyer, RN (Royal University Hospital, Site Coor-
dinator); Guillaume Se ´bire, MD (Universite ´ de Sherbrooke, Site
Investigator); Christian Houde, RN (Universite ´ de Sherbrooke, Site Co-
ordinator); Kati Wambera, MA, MD, Colleen Adams, MD (Victoria
General Hospital, Site Investigators); Laurie Robson, RN (Victoria Gen-
eral Hospital, Site Coordinator); Ellen Wood, MD (IWK Health Centre,
Site Investigator); Elaine Woolridge, RN, Edythe Smith, RN (IWK
Health Centre, Site Coordinators); Jerome Yager, MD (Children’s
Stollery Hospital, Site Investigator); Marjorie Berg, RN, Hope Chick, RN
(Children’s Stollery Hospital, Site Coordinators); Conrad Yim, MD, PhD
(Trillium Health Centre, Site Investigator); Leanne Montgomery, RN
(Trillium Health Centre, Site Coordinator).
The authors thank Julia Kennedy, Sandra Magalhaes, and Katherine San-
som for their assistance.
Dr. Venkateswaran, Dr. Zheng, M. Sacchetti, and D. Gagne report no
disclosures. Dr. Arnold serves on scientific advisory boards for Biogen
Idec, Genentech, Inc., and Teva Pharmaceutical Industries Ltd.; has re-
ceived speaker honoraria from Biogen Idec; holds a patent re: Method of
evaluating the efficacy of drug on brain nerve cells; serves as a consultant
for Biogen Idec, Elan Corporation, GlaxoSmithKline, and Roche; and has
received research support from Biogen Idec and the Canadian Institutes of
Health Research. Dr. Sadovnick has received funding for travel and
speaker honoraria from Bayer Canada, Teva Pharmaceutical Industries
Ltd., EMD Serono, Inc., and Biogen Idec; and has received research sup-
port from the MS Society of Canada Scientific Research Foundation. Dr.
Scherer reports no disclosures. Dr. Banwell serves on a scientific advisory
board for Biogen Idec; serves on the editorial boards of Neurology®and
Multiple Sclerosis; and receives research support from the Multiple Sclero-
sis Society of Canada, the Multiple Sclerosis Scientific Research Founda-
tion, and the Canadian Institutes of Health Research. Dr. Bar-Or serves
on scientific advisory boards for DioGenix, Inc., Ono Pharmaceutical Co.
Ltd., and Roche; serves on the editorial board of Neurology®; has received
speaker honoraria from Biogen Idec, Bayhill Therapeutics, Bayer Schering
Pharma (Berlex), Eli Lilly and Company, Genentech, Inc., GlaxoSmith
Kline, Merck Serono, Novartis, Wyeth, and Teva Pharmaceutical Indus-
tries Ltd.; and receives research support from Biogen Idec, Genentech,
Inc., and Teva Pharmaceutical Industries Ltd. Dr. Simon has served as a
consultant for Gerson Lehrman Group (GLG), UCB, and Link Medicine;
and receives research support from the NIH/NINDS, the Michael J. Fox
Foundation, and the National Parkinson Foundation.
Received May 4, 2010. Accepted in final form September 13, 2010.
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