J Autism Dev Disord (2013) 43:24842490
DOI 10.1007/s10803-013-1796-9
BRIEF REPORT
Brief Report: Regression Timing and Associated Features
in MECP2 Duplication Syndrome
S. U. Peters R. J. Hundley A. K. Wilson
C. M. B. Carvalho J. R. Lupski M. B. Ramocki
Published online: 2 March 2013
Springer Science+Business Media New York 2013
Abstract The aim of this study was to determine the
frequency, timing, and associated features of develop-
mental regression in MECP2 duplication syndrome. We
also examined whether duplication size was associated
with regression. Comprehensive psychological evaluations
were used to assess 17 boys with MECP2 duplication
syndrome. Information about regression was gathered via
parent report. Eight of 17 boys exhibited regression in
language skills, while seven of 17 exhibited regression in
other skill areas. Regression in other skill areas coin-
cided with seizure onset and with a prior autism diagnosis
in six of seven participants. Regression was not associated
with duplication size. Questions remain as to why some
boys regress, and future work is necessary to understand
the underlying mechanism(s) that causes regression.
Keywords Regression
MECP2
Seizures
S. U. Peters
R. J. Hundley
Departments of Pediatrics and Psychiatry, Vanderbilt University,
Nashville, TN, USA
S. U. Peters (&)
R. J. Hundley
A. K. Wilson
Vanderbilt Kennedy Center for Research on Human
Development, PMB 74; 230 Appleton Place, Nashville,
TN 37203-5721, USA
e-mail: sarika.u.peters@vanderbilt.edu
C. M. B. Carvalho
J. R. Lupski
Department of Molecular and Human Genetics,
Baylor College of Medicine, Houston, TX, USA
M. B. Ramocki
Department of Pediatrics, Section of Pediatric Neurology and
Developmental Neuroscience, Baylor College of Medicine,
Houston, TX, USA
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Introduction
Mutations in the methyl CpG-binding protein 2 gene
(MECP2) were first identified as a primary cause of Rett
syndrome (RTT) in females (Amir 1999). The more
recently described MECP2 duplication syndrome is the
most common subtelomeric duplication identified in a
clinical population surveyed by high resolution human
genome analyses using array Comparative Genomic
Hybridization (aCGH). This duplication syndrome pri-
marily affects males, and is an X-linked genomic disorder
(Lupski 2009) characterized by infantile hypotonia, absent
to limited speech, severe intellectual disability, progressive
neurological difficulties (including spasticity and seizures),
recurrent respiratory infections, and gastrointestinal diffi-
culties (Friez et al. 2006; Ramocki et al. 2009; Van Esch
2012). Phenotypic features are due to a MECP2 gene
dosage effect as further evidenced by a more severe phe-
notype conveyed by triplication of this locus (Carvalho
et al. 2011). Features of autism spectrum disorder (ASD),
including repetitive behaviors, sensory processing diffi-
culties, and difficulties with social affect are present in a
large proportion of affected individuals (Peters et al. 2013;
Ramocki et al. 2009). Females are less often affected, and
the spectrum of phenotypes ranges from mild to the same
severity as affected boys depending on the underlying
genetic factors (Bijlsma et al. 2012; Grasshoff et al. 2011).
Developmental regression, inclusive of a partial or com-
plete loss of acquired highest spoken language skills
(including babbling), and a loss of motor skills are major
diagnostic criteria for classic Rett Syndrome (RTT) (Neul
et al. 2010). Because RTT is rarely diagnosed prior to the
regression phase, studies of regression are based primarily
on retrospective parental report (Neul et al. 2010). The
phenomenon of regression is less clear within MECP2
J Autism Dev Disord (2013) 43:24842490
duplication syndrome. Prior studies based on retrospective
parental report reveal that regression can occur within
MECP2 duplication syndrome (del Gaudio et al. 2006;
Ramocki et al. 2009), but the frequency, timing, and
associated features of regression have not been formally
characterized.
Regression is typically defined as a partial or complete
loss of skills related to language, socialization, self-help
skills, and/or motor skills. In ASD and RTT, the loss of
skills occurs at an early age (usually between 15 and
30 months), and may or may not be associated with seizure
onset or medical illness (Barger et al. 2012; Neul et al.
2010; Ozonoff et al. 2008). In some situations, a child may
exhibit developmental delays prior to a loss of skills (early
onset pattern), or no delays may be apparent before the loss
(Ozonoff et al. 2008). A recent study based on video
analysis found that approximately 38.5 % of children with
ASD exhibited a regressive course (Ozonoff et al. 2011). In
ASD, studies suggest that regression occurs within the
context of intact motor abilities and even advanced motor
milestones, suggesting a different pattern and course from
that which occurs in RTT and MECP2 duplication syn-
drome (Bernabei et al. 2007; Jones and Campbell 2010). In
MECP2 duplication syndrome, all boys have early onset
developmental delays and there are some reports of sei-
zures and associated regression, occurring at varying ages
(i.e. late childhood to early adolescence) and with varying
percentages (Vignoli et al. 2012). A prior study of MECP2
duplication syndrome revealed that 3 out of 9 boys
exhibited regression/loss of skills at the time of evaluation
(Ramocki et al. 2009). In one of these cases, the onset of
regression occurred at a younger age (36 months). In the
two other cases, however, a loss of skills occurred during
late childhood and coincided with the onset of seizures.
It is unclear whether regression is a core phenotypic
feature of MECP2 duplication syndrome that occurs sec-
ondary to overexpression of MECP2 directly and with
variable phenotypic expression, or whether regression only
occurs in a small proportion of individuals due to factors
indirectly related to MECP2 overexpression. We have not
been able to reliably predict when or in which children
regression will occur, and it is unknown as to whether
duplication size predicts regression. A better understanding
of regression in this patient population is essential in order
to facilitate prognosis and to help families and physicians
make the best long-term treatment plans and choices for
affected individuals. It is also important to inform future
preclinical and clinical therapeutic trials. In this study, we
examined a larger cohort of 17 boys with MECP2 dupli-
cation syndrome. Our goal was to determine the average
age of regression, the skills that were lost (language, social,
self-help, or motor skills), whether regression coincides
with seizures and/or medical illness, whether losses are
2485
gradual or sudden, and whether a prior diagnosis of ASD
predicts a later decline in skills. We also examined whether
or not duplication size corresponded to a loss of skills.
Methods
Participants
The participants (n = 17) were all male and ranged
between the ages of 310 years. Females were not included
given that their phenotype is more variable (Grasshoff et al.
2011). All participants with a confirmed genetic diagnosis
were offered enrollment and were ascertained as part of
their attendance at the first ever worldwide conference on
MECP2 duplication syndrome. All were additionally
evaluated by a pediatric clinical neurologist (M.B.R.) prior
to study enrollment. This study was approved by the
Institutional Review Boards at Vanderbilt University and
Baylor College of Medicine, and all families gave
informed consent to participate.
Genetic Testing
All participants had an established clinical diagnosis. To
independently confirm the diagnosis and to determine the
size, genomic extent and gene content for each rearrange-
ment, we designed a tiling-path oligonucleotide microarray
spanning 4.6 MB across the MECP2 region on Xq28.
The custom 4 9 44 k Agilent Technologies (Santa Clara,
CA, USA) microarray was designed using the Agilent
e-array website (http://earray.chem.agilent.com/earray/).
We selected 22,000 probes covering Chromosome X:
150,000,000154,600,000 (NCBI build 36), including the
MECP2 gene, which represents an average distribution of 1
probe per 250 bp. Probe labeling and hybridization were
performed as previously described (Carvalho et al. 2011).
To estimate duplication size, we calculated the distance
between breakpoints/coordinates (i.e. where probe signals
traversed from no gain to gain, signaling increased dosage
of the genomic interval complementary to the interrogating
oligonucleotide probe).
Instruments
To assess regression, we utilized the Autism Diagnostic
InterviewRevised (ADI-R) questions regarding regres-
sion. A portion of the ADI-R contains questions about early
milestones, symptom onset, and regression. Since the ADI-
R questions regarding language-regression require the
minimum use of at least five different words (other than
mama and dada) on a daily basis for at least 3 months, a
research-based regression interview was designed as an
123
2486
extension of the ADI-R to capture sub-threshold losses of
skills as separated into language (e.g. loss of cooing, bab-
bling, vocal imitation, use of 3 or more words, communi-
cative intent), and non-language skills (hand use, motor
skills, self-help skills, social interest, and curiosity) (Luy-
ster et al. 2005; Parr et al. 2011). This interview utilizes the
same coding and similar questions to the ADI-R, and is
being utilized as part of the (ASD) Simons Simplex Col-
lection (SSC). Information regarding the age of the loss,
duration of the loss, as well as any association with phys-
ical illness is captured. There are also questions regarding
any recovery of skills after the loss (or whether the skills
loss persists).
Participants also received a comprehensive develop-
mental evaluation. The Vineland Adaptive Behavior
ScalesSecond Edition (VABS-II) was completed as a
semi-structured interview with parents to assess overall
adaptive behavior. Visual reception/nonverbal cognitive
abilities and fine motor skills (nonverbal cognitive abili-
ties), gross motor skills, and expressive/receptive language
abilities were assessed using the Bayley Scales of Infant
and Toddler Development-Third Edition (BSID-III). This
instrument was selected given the developmental level of
our participants. For our participants who were mobile
(n = 9), we also completed the Autism Diagnostic
Observation Schedule, Module 1 to assess Social Affect
(inclusive of communication and reciprocal social inter-
action) and Restricted/Repetitive behaviours related to
ASD. Our assessments were based on the recently revised
ADOS algorithms (Gotham et al. 2007) which include the
domains of Social Affect and Restricted-Repetitive
Behaviors. All participants (regardless of their chronolog-
ical age) received Module 1, which is appropriate for
individuals who are nonverbal. In order to assess skills
such as joint attention, it is important that the participant
have some mobility. Even in cases where we could not
perform the ADOS due to loss of mobility (n = 8), we
conducted detailed interviews (i.e. the ADI-R, clinical
interview) to determine whether or not there was a prior
diagnosis of ASD. We detail the results for part of our
sample (n = 9) on these measures elsewhere (Peters et al.
2013).
Statistical Analysis
For the purposes of all analyses, language regression was
analyzed separately from regression in other skill areas. We
utilized descriptive statistics to examine the average age
(mean, median) and age range of language and non-lan-
guage regression. Because of the small sample size, non-
parametric statistics (MannWhitney U test) were used to
compare any differences between regressors versus non-
regressors for chronological age. To check whether an
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J Autism Dev Disord (2013) 43:24842490
autism diagnosis was related to regression status (language
and non-language), we used contingency analysis. To
determine the relationship between duplication size and
regression (separated into language vs. non-language), we
used bivariate correlations.
Results
Table 1 lists the number of boys who exhibited language
regression versus no language regression, and then
regression in other skill areas versus no loss in other
skill areas. Six boys exhibited losses in both language and
non-language areas. Two boys exhibited language losses
alone (without any losses to date in other skill areas). One
boy exhibited losses in other skill areas, but his parents
noted that he never attained enough language (e.g. even
cooing or babbling skills) to exhibit a loss in any language
skills. Six of eight boys who exhibited a language regres-
sion had a prior ASD diagnosis, but five of nine boys
without language regression also had a prior ASD diag-
nosis and hence there was no significant association
(Contingency Coefficient = .20; p = .40). Six of seven
boys with regression in other skill areas had a prior ASD
diagnosis, while five of ten without regression in other skill
areas had a prior ASD diagnosis (Contingency Coeffi-
cient = .34; p = .12). There are no significant differences
in chronological age between language regressors and non-
regressors (p = .37), or between boys who exhibit regres-
sion in other skills versus no regression in other skills
(p = .23).
Table 2 characterizes the skills that were lost amongst
the boys who did exhibit regression. For language skills, it
was most common for boys to exhibit losses in lower level
skills such as babbling, cooing, and the meaning/intent of
communication. Two of the eight boys with language
regression alone (without losses in motor skills) were able,
with intensive therapy, to recover language skills at the
level that they functioned at prior to the loss. The most
common losses in other skill areas included loss of
motor skills (related to posture, gait, and coordination),
curiosity, and hand use. One boy with a regression in
other skill areas re-learned to walk (but he still
Table 1 Language regression, regression in other skills, and prior
autism diagnosis
Number (n) Prior autism diagnosis
No Language regression 9 5/9
Language regression 8 6/8
No regression in other skills 10 5/10
Regression in other skills 7 6/7
J Autism Dev Disord (2013) 43:24842490
maintained a loss of language skills), but all others had not
recovered skills that they lost.
Table 3 shows the average age of skills loss, the age
range of regression onset, and whether or not losses were
associated with seizures. In the majority of cases (6/7),
regression in other skill areas was associated with sei-
zure onset. In five of these six cases, the participants had
been given a formal diagnosis of intractable epilepsy by
a pediatric neurologist (based on EEG findings and clinical
evaluation). In the sixth case, the parent described several
staring spells, although a formal diagnosis of epilepsy
has not been given. Confirmed seizure onset in our patients
ranged between 36 and 84 months of age; all but one had a
seizure onset of age 5 (60 months) and later. In five of six
cases, the age of onset for language regression coincided
with the age of onset for regression in other skill areas. In
one case, the age of language regression occurred at
24 months, but he did not begin to lose motor skills until
84 months of age, which coincided with the onset of
intractable seizures (absence, myoclonic, and atonic sei-
zures). Not surprisingly, boys who exhibited regression in
other skill areas (n = 7) were significantly lower func-
tioning on all of our developmental parameters
(p range = .003.023) as compared to boys who had not
regressed (See Table 4). This was primarily attributable to
a loss of mobility (i.e. walking) and hand use, which hin-
dered their ability to interact with manipulatives. Most of
these participants previously had some level of language
use (at least babbling vowel-consonant sounds), were able
to walk, engage in functional play, and had developed
some self-help skills (e.g. feeding themselves) prior to
regression and the onset of intractable epilepsy.
The results of genetic analyses reveal that all subjects
duplicate the MECP2 gene; three boys (BAB 2769,
BAB3255, BAB3259) have partial genomic triplications.
Duplications (and partial triplications) ranged in size
between .31 and 4.7 MB (See Fig. 1). There was no
relationship between duplication size and language
regression (p = .26) or between duplication size and
regression in other skill areas (p = .41). We also did
not find any significant relationships between duplication
size and refractory epilepsy, and one participant with
refractory epilepsy and significant regression actually had
the smallest duplication size of all of our participants
(BAB2625).
Table 2 Number of participants showing a loss of skills by domain
Cooing Babbling Vocal Use of 3 or Communicative
imitation more words intent
5/8 7/8 4/8 2/8 6/8
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Discussion
In this study, we examined in greater detail regression
timing and related features in MECP2 duplication syn-
drome. We found that 9 of 17 boys exhibited a loss of
language and/or motor skills, with six boys exhibiting a
loss across both areas. The majority of boys who lost
language skills lost subthreshold skills such as cooing and
babbling. It is notable that on the original ADI-R, most of
our participants would not have met the threshold criteria
for a loss of language skills (i.e. use of at least five different
words other than mama or dada for a period of at least
3 months). This extension of the ADI-R may therefore
have some utility in capturing subthreshold losses in lower
functioning populations (Parr et al. 2011; Richler et al.
2006). When examining the timing and course of regres-
sion in MECP2 duplication syndrome, it appears that in
comparison to ASD and to RTT, the onset of skills loss is
later. In addition, the regression in MECP2 duplication
syndrome may be distinct from that which occurs within
ASD. When within the context of refractory epilepsy in
particular, the losses of skills in our participants are dra-
matic (e.g. loss of mobility, head control, self-help skills,
and/or language, and hand use), and, in some cases, with
little recovery of functioning. The size of the duplications
in our subset of participants with refractory epilepsy was
quite variable and in fact, our participant with the smallest
duplication size exhibited a significant regression within
the context of early onset seizures at 36 months. More
broadly, our results demonstrate that loss of skills in
MECP2 duplication syndrome is not related to duplication
size/gene content. It is unclear whether regression associ-
ated with MECP2 duplication syndrome therefore repre-
sents: (1) consequences of an epileptic encephalopathy
(interestingly 3/5 of the boys with intractable epilepsy were
clinically diagnosed with Lennox-Gastaut syndrome), (2)
whether regression phenotypes and epilepsy simply repre-
sent common downstream effects of MeCP2 overproduc-
tion on neurons or neural networks in associated brain
regions, (3) whether a secondary cause such as genetic
background or CNS infection and/or CNS inflammation
contributes to both regression and epilepsy, or (4) whether
the clinical outcome represents a complex combination of
these possibilities. The timing of seizure onset and corre-
lation with behavioral phenotypes has not been studied in
Hand Motor skills (posture, Self-help Social Curiosity
use gait, coordination) skills engagement
4/7 7/7 4/7 3/7 5/7
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Table 3 Average age of regression

Average age of loss (mean, SD) Range of ages for losses (months) Loss associated with seizures

Language regression 39.12 months; 13.58 months 2460 4/8

Regression in other skills 54.57 months; 20.82 months 3084 6/7

Table 4 Comparison of developmental scores between regression and non-regression groups

Cognitive skills Receptive language Expressive language Fine motor Gross motor

Regression (n = 7) 8.00 4.50 7.00 10.00 11.00

Non-regression (n = 10) 15.00 10.00 10.00 15.00 18.00
Data are depicted in age equivalents (months) and are shown as the Median for each group
GABRA3

SLC6A8
ABCD1
L1CAM

MECP2
IRAK1

G6PD
FLNA

F8
Cen Tel

153.0
149.0

151.0

154.0
152.0

Fig. 1 Genomic region harboring duplications in our cohort of 17 Genomic coordinates are given relative to NCBI Build 36 for the X
patients analyzed by oligonucleotide array CGH. Solid red bars chromosome. *Duplication is larger than the resolution of our custom
represent duplications and blue bars represent triplicated regions. aCGH ([4.7 MB) (Color figure online)

mouse models, but may offer further clues as to etiology/
mechanisms and treatment.
While over 50 % of our sample exhibited a loss of skills
at some point during development (for a period of at least
6 months), it is notable that two boys with language
regression alone were able to recover functioning with the
assistance of intensive speech/language therapy. Further
studies will be required in order to examine whether the
majority of boys with MECP2 duplication syndrome will/
will not recover any function post-regression. At a
minimum, our results suggest the need for year-round
therapeutic services, constant repetition of skills and con-
cepts, and within the context of regression, retraining of
lost skills. In cases where there has been loss of hand-use
and mobility, there may be utility in using alternative
methods of communication, such as eye-gaze technology
as is being utilized in RTT (Djukic et al. 2012). In com-
parison to previous studies (Ramocki et al. 2009), our
results reflect a higher percentage of boys with MECP2
duplication syndrome exhibiting a loss of skills. This may

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still reflect an underestimate of true level of regression
since our sample only included boys between the ages of
310. More specifically, future studies should include older
individuals as there are reports of refractory epilepsy,
neurological declines, and sudden death in boys who are in
later adolescence-early adulthood (Van Esch 2012).
Regardless of age, given our findings and those of another
recent study (Vignoli et al. 2012), we do suggest that if a
patient without epilepsy presents with regression, then a
careful history to assess for subtle seizures and an EEG
study is indicated.
A limitation of our study is that we relied on parental
reports of regression as opposed to retrospective or even
prospective video studies. As has been demonstrated in
studies of individuals with ASD, there may be some benefit
to using video studies, since retrospective parent reports do
not always correspond to what is noted on video analysis
(particularly as related to social communication skills)
(Ozonoff et al. 2011). More specifically, this study of ASD
participants demonstrated that less than half of the partic-
ipants whose home videos displayed clear evidence of a
decline in social-communication were reported to have had
a regression by parents. Similarly, less than half of the
participants were reported by their parents as having early
onset delays in spite of clear evidence of social commu-
nication delays from video analysis. As applied to MECP2
duplication syndrome, future studies should incorporate
retrospective video analysis in cases where a genetic
diagnosis occurs after a regression. In cases where genetic
diagnosis occurs prior to any loss of skills, we propose
longitudinal, prospective developmental assessments that
incorporate objective video analysis across settings (clinic
and home) to document the earliest detection of skill loss
and timing and may offer further clues for intervention and
treatment.
A recent study demonstrated that duplication of the
MECP2 gene causes immune dysfunction due in part to the
suppression of IFN-c production from T helper cells in
both mice and humans (Yang et al. 2012). Although not
examined within this study, future studies should examine
whether insidious infection or neuro-inflammation con-
tribute to regression and epilepsy in affected patients. The
seizures in the subset of boys reported here are excep-
tionally refractory to medical treatment, and in fact 2/5
boys have also failed the ketogenic diet, and 2/5 have failed
vagus nerve stimulation. These data suggest that the
mechanism of epileptogenesis in this syndrome may be
distinct from the pathways currently targeted by available
epilepsy medications; and the question remains whether or
not excellent seizure control would prevent or reverse
regression in affected patients. Furthermore, if underlying
infection or inflammation has a role, then could targeted
treatment potentially prevent epilepsy, regression, and
2489
perhaps partially improve other neurological phenotypes
and overall quality of life? Further studies in mouse models
and in human patients are needed to dissect the underlying
pathogenesis of disease in affected patients and to develop
treatments that decrease both morbidity and mortality.
Therapeutics that specifically decrease gene expression or
levels of the MeCP2 protein should theoretically improve
or potentially reverse some clinical phenotypes.
Acknowledgments Funding for this project has been provided by a
Vanderbilt Kennedy Center Hobbs Discovery Grant (to SUP), by
5P30HD015052-30 (to Elisabeth Dykens PI), and by NINDS grant
5K08NS062711 (to M.B.R.). We also wish to thank the individuals
and families who so graciously participated in this study as part of the
first conference on MECP2 duplication syndrome.
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