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Autism spectrum conditons in myotonic dystrophy type 1 A study on 57 individuals with congenital and childhood forms.

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American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 147B:918 –926 (2008)
Autism Spectrum Conditons in Myotonic Dystrophy
Type 1: A Study on 57 Individuals With Congenital
and Childhood Forms
Anne-Berit Ekström,1,2* Louise Hakenäs-Plate,3 Lena Samuelsson,4 Már Tulinius,2 and Elisabet Wentz5,6
Department of Pediatrics, Northern Älvsborg County Hospital, Trollhättan, Sweden
Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, Göteborg University, Sweden
Child Neuropsychiatry Clinic, Sahlgrenska University Hospital, Göteborg, Sweden
Department of Clinical Genetics, Sahlgrenska Academy, Göteborg University, Sweden
Child and Adolescent Psychiatry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Göteborg University, Sweden
The Vårdal Institute, The Swedish Institute for Health Sciences, Sweden
Myotonic dystrophy type 1 (DM1) is an autosomal
dominant disorder, caused by an expansion of a
CTG triplet repeat in the DMPK gene. The aims of
the present study were to classify a cohort of
children with DM1, to describe their neuropsychiatric problems and cognitive level, to estimate
the size of the CTG expansion, and to correlate
the molecular findings with the neuropsychiatric
problems. Fifty-seven children and adolescents
(26 females; 31 males) with DM1 (CTG repeats
> 40) were included in the study. The following
instruments were used: Autism Diagnostic
Interview-Revised (ADI-R), 5–15, Griffiths
Mental Development Scales, and the Wechsler
Scales. Based on age at onset and presenting
symptoms, the children were divided into four
DM1 groups; severe congenital (n ¼ 19), mild congenital (n ¼ 18), childhood (n ¼ 18), and classical
DM1 (n ¼ 2). Forty-nine percent had an autism
spectrum disorder (ASD) and autistic disorder
was the most common diagnosis present in 35% of
the subjects. Eighty-six percent of the individuals with DM1 had mental retardation (MR),
most of them moderate or severe MR. ASD was
significantly correlated with the DM1 form; the
more severe the form of DM1, the higher the
frequency of ASD. The frequency of ASD increased with increasing CTG repeat expansions.
ASD and/or other neuropsychiatric disorders
such as attention deficit hyperactivity disorder,
and Tourette’s disorder were found in 54% of the
total DM1 group. In conclusion, awareness of
ASD comorbidity in DM1 is essential. Further
studies are warranted to elucidate the molecular
Abbreviation used: ASC, autism spectrum conditions; ‘‘ADHD’’,
attention deficit hyperactivity disorder; TD, Tourette’s disorder.
Grant sponsor: The Health and Medical Care Executive Board
of the Västra Götaland Region; Grant sponsor: The Research and
Development Department of the Northern Älvsborg/Bohus
County Council; Grant sponsor: The Linnéa and Josef Carlsson
Foundation; Grant sponsor: The Häggquist Family Foundation;
Grant sponsor: The Western Sweden Muscle Foundation.
*Correspondence to: Anne-Berit Ekström, Department of
Pediatrics, Northern Älvsborg County Hospital, S-461 85 Trollhättan, Sweden. E-mail:
Received 6 July 2007; Accepted 14 November 2007
DOI 10.1002/ajmg.b.30698
ß 2008 Wiley-Liss, Inc.
etiology causing neurodevelopmental symptoms
such as ASD and MR in DM1.
ß 2008 Wiley-Liss, Inc.
neuropsychiatry; mental retardation; ADI-R; genetics; adolescence
Please cite this article as follows: Ekström A-B,
Hakenäs-Plate L, Samuelsson L, Tulinius M, Wentz
E. 2008. Autism Spectrum Conditons in Myotonic
Dystrophy Type 1: A Study on 57 Individuals With
Congenital and Childhood Forms. Am J Med Genet
Part B 147B:918–926.
Myotonic dystrophy type 1 (DM1) is an autosomal dominant
multisystemic disorder, caused by an expanded CTG repeat in
the 30 untranslated region of the myotonic dystrophy protein
kinase (DMPK) gene on chromosome 19q13.3. DM1 is characterized by anticipation, that is progressive expansion of the
repeat size occurring on transmission, with earlier onset and
increasing severity of the disease in successive generations
[Höweler et al., 1989; Brook et al., 1991; Harper et al., 1992].
The RNA gain-of function plays a major role in the
pathophysiology of the disease. The mutant expanded gene is
transcribed into RNA CUG expansions that accumulate in
nuclear foci, alter the activity of RNA-binding proteins and
disrupt the splicing of pre-mRNA with abnormal function of
different target genes [Mahadevan et al., 1992; Mankodi et al.,
2000; Kanadia et al., 2003; Ho et al., 2005; Lin et al., 2006]. The
altered alternative splicing of pre-mRNA partly explains the
multisystemic features of DM1, the variation in severity, and
the age at onset [Harley et al., 1992; Harper, 2001; Harper
et al., 2004]. DM1 is divided into four subgroups with specific
clinical features: congenital, childhood, classical and late
onset/asymptomatic [Vanier, 1960; Harper and Dyken, 1972;
Koch et al., 1991; de Die-Smulders, 2000; Harper, 2001].
Childhood onset neuropsychiatric disorders (COND) include
conditions such as autism spectrum conditions (ASC), attention deficit/hyperactivity disorder (ADHD) and Tourette’s
disorder (TD) [APA, 1994]. COND, and especially ASC, have
been described in association with DM1 in sporadic cases in
the literature [Yoshimura et al., 1989; Saccomani et al., 1992;
Blondis et al., 1996; Paul and Allington-Smith, 1997; Steyaert
et al., 1997]. Behavioral abnormalities with social withdrawal
and mental retardation (MR) have also been reported [Roig
et al., 1994; Thompson et al., 1995]. In 2000, Goossens and
co-workers [Goossens et al., 2000] presented 24 children and
adolescents with childhood DM1. Sixty-three percent had a
Autism Spectrum Conditions in DM1
Fig. 1. Recruitment of the study population. Study 1: [Kroksmark et al., 2005], Study 2: Present study. M, male; F, female; y, years.
psychiatric diagnosis with predominantly ADHD (33%) and
anxiety disorders (25%), but mood and adjustment disorders
were also found. Between 1999 and 2001, we performed a study
on 42 children and adolescents under the age of 18 with
confirmed diagnosis of DM1, living in the western and southern health care regions of Sweden [Kroksmark et al., 2005].
Three of the children had previously been given a diagnosis of
either attention deficit hyperactivity disorder (ADHD; n ¼ 2) or
autism (n ¼ 1). However, additional individuals in the study
group exhibited neuropsychiatric symptoms. In the present
study, we have therefore made an in-depth examination of
COND and cognitive functioning in 57 individuals with
different childhood onset forms of DM1, including 41 children
and adolescents from the first study. The aims of the current
study were: (i) to classify a cohort of children with DM1, (ii) to
investigate their neuropsychiatric problems and cognitive
level, (iii) to estimate the size of the CTG expansion, and
(iv) to correlate the molecular findings with the neuropsychiatric symptomatology.
Study Population
In 2003, 41 individuals from the study by Kroksmark et al.
[2005] accepted to participate in a study with in-depth
neurological, neuropsychiatric and neuropsychological examination. In addition, another 16 children and adolescents
accepted to participate (Fig. 1). Thus, a total of 57 individuals
with a confirmed diagnosis of DM1 with CTG repeat expansions greater than 40 were included in the present study;
26 females and 31 males. They were all recruited from
pediatric rehabilitation centers in the western and southern
TABLE I. The Koch Diagnostic Criteria of Childhood DM1
1. Age at onset between 1 and 10 years of age
2. An uneventful pre- and neonatal history
3. Normal development within the first year of life
4. Increasing problems as toddlers, such as
(a) Failure to thrive, accompanied by abdominal symptoms
(b) Variable degree of mental retardation
(c) Variable degree of muscle hypotonia
(d) Clinical myotonia not observed before school age
health care regions of Sweden. According to age at onset and
presenting clinical symptoms, the children were divided into
four subgroups: severe congenital (n ¼ 19); mild congenital
(n ¼ 18); childhood (n ¼ 18) and classical (n ¼ 2). In our
previous study, we divided the congenital DM1 subgroup into
severe and mild congenital type [Kroksmark et al., 2005]. All
children with congenital DM1 had symptoms presenting in
utero, or from birth. The difference between severe and mild
congenital DM1 was that all the children in the former
category had a life-threatening disease at birth, with low
Apgar score, need for resuscitation and/or respiratory assistance. For the definitions of childhood DM1 we used the
diagnostic criteria defined by Koch et al. [1991] (see Table I).
Classical DM1 was defined as symptoms presenting in
adolescence with slowly progressive muscular weakness,
myotonia and/or multiorgan involvement [Harper, 2001].
The present study was performed as a part of a crosssectional, multidisciplinary study of children and adolescents
with DM1 at Göteborg University, Sweden. The characteristics
and prevalence of oral motor dysfunction have been presented
recently [Sjogreen et al., 2007]. Written informed consent was
obtained from each patient or his or her parents. The study was
approved by the Human Ethics Committees at the Medical
Faculties at Göteborg University (western region) and Lund
University (southern region), Sweden.
Neuropsychiatric Evaluation
The first author (ABE), a pediatric neurologist with
several years of experience in neuropsychiatry, interviewed
one or both parents of all 57 individuals thoroughly, regarding
neuropsychiatric problems, such as ASC, ADHD and TD.
The following instruments were used:
Autism Diagnostic Interview-Revised (ADI-R) [Lord et al.,
1994], a standardized, investigator-based semi-structured
caregiver interview, was used to interview the parents, by a
clinical child psychologist (LHP) with ADI-R training and
several years of experience of the instrument. The instrument
has been shown to be valid and reliable in diagnosing ASC and
to discriminate individuals with autism from individuals with
MR when the non-verbal age is above 18 months. According to
ICD-10 and DSM-IV the diagnosis of autistic disorder (AD)
Ekström et al.
requires specific types of abnormalities in three key areas of
functioning: reciprocal social interaction, language and communication, and restricted, repetitive and stereotyped behavior, together with evidence of delayed or deviant development
in at least one of these areas before 36 months of age. The
interview contains 84 questions and provides separate scores
in the distinct areas, as well as early history, with specific
threshold scores; 10 for reciprocal social interaction, 8 for
communication for verbal individuals and 7 for non-verbal, 3
for restricted, repetitive behavior, and 1 for deviation in early
development. The cut-off scores provide an algorithm where
four points indicate deficits in all areas and render a diagnosis
of AD. The cognitive level was taken in account when
evaluating the results on ADI-R. ADI-R was performed for all
57 participants, but as four individuals were at a non-verbal
age, younger than 18 months, results from only 53 individuals
are presented.
The Social Communication Questionnaire (SCQ, previously
known as the Autism Screening Questionnaire) [Berument
et al., 1999], which is a parent questionnaire regarding core
diagnostic features of autism, was also used. The items cover
aspects of behavior identical to those in ADI-R. The checklist
for tics and Tourette’s disorder was used to assign diagnoses of
TD/chronic tic disorder [Leckman et al., 1988] as outlined in
the DSM-IV [APA, 1994].
The Five to Fifteen (FTF) [Kadesjo et al., 2004] is a parent
questionnaire which covers the core symptoms of ADHD and
related neurodevelopmental disorders. The instrument has
only been validated for children with normal intelligence
between 5 and 15 years of age, and not for DM1, and the
instrument was not used in patients of a non-verbal age of
5 years or younger. In most cases, the parents had difficulties
completing the SCQ and FTF on their own. For this reason,
ABE used the questionnaires to interview the parents.
Diagnostic Classification
Medical records were reviewed and a neurological assessment was performed. All children were videotaped during
neurological and motor examinations. The tapes were analyzed retrospectively by ABE, LHP, and a child psychiatrist
(EW). The latter had several years of experience in child
neuropsychiatry, both as a clinician and researcher, and is
working as a senior consultant in a child neuropsychiatric unit
specialized in tertial referrals. Neuropsychiatric diagnoses
were assigned according to the DSM-IV criteria [APA, 1994]
and were made conjointly by ABE, EW and LHP on the basis
of all available information. In addition, specific symptom
checklists were used, on which all participants were scored
with regard to COND (ASC; ADHD and TD) as outlined in
DSM-IV. Regarding other psychiatric disorders, the diagnoses
were assigned according to DSM-IV. Although the two
clinicians (ABE and LHP) had a good training and experience,
we wanted to qualify the diagnostic procedure even more by
making the diagnostic assessment together with the senior
consultant. We were anxious not to overestimate the rate of
ASC were divided into the following subgroups:
AD was diagnosed according to the DSM-IV criteria. At least
6 out of 12 criteria had to be met; at least two from the first
domain, and one from the second and third domain each.
Furthermore, there had to be a delay or abnormal functioning
in at least one of the following areas before the age of 3 years:
social interaction, language as used in social communication
and symbolic or imaginative play.
Autistic-like condition (ALC): if the individual met four or
more, but not the full DSM-IV criteria for AD. The severity of
the autistic symptoms was of the same degree as in AD;
however, the pattern of symptoms was not typical enough to
assign a diagnosis of AD. Neither pervasive developmental
disorder, not otherwise specified (PDD-NOS) or atypical
autism - two concepts widely used in parallel - has any specific
operationalized diagnostic criteria or algorithms in the
DSM-IV. Efforts have been made by researchers to tighten
up the definition, by suggesting specific diagnostic criteria and
an algorithm. With this approach, autistic-like condition is
used when an individual has the same problem with social
interaction as in AD, but does not fulfill all the criteria for AD.
The strict definition of the condition makes it possible to
compare data across research groups.
Asperger syndrome (AS) was diagnosed according to the
criteria outlined by Gillberg and Gillberg [Gillberg and
Gillberg 1989; Leekam et al., 2000]. Motor clumsiness and
limited facial expressions are both symptoms of Asperger
syndrome and DM1; hence, we used the DSM-IV criteria also
for AS.
ADHD was diagnosed as follows: mainly inattentive type,
mainly hyperactive/impulsive type, or combined type according to the DSM-IV criteria in individuals with normal or
borderline IQ. In individuals with clinically significant problems in the area of hyperactivity and/or attention combined
with MR, the diagnosis ‘‘ADHD’’ was made.
Global Cognitive Assessment
Depending on the age of the proband, LHP administered the
Griffiths Mental Developmental Scales, part II Griffiths
[Griffiths, 1970], the Wechsler Primary and Preschool Scale
of Intelligence (WPPSI-R) [Wechsler, 1989], the Wechsler
Intelligence Scale for children (WISC-III) [Wechsler, 1992] or
the Wechsler Adult Intelligence Scale (WAIS-III) [Wechsler,
For the cognitive level, the following definitions were used:
Normal IQ 85, borderline IQ: 70–84, mild MR: 50–69,
moderate MR: 35–49, severe MR: 20–34.
Assessment of Motor Function
Gross motor function was assessed using the Hammersmith
functional motor scale designed by Scott et al. [1982]. The
performance is scored on a three-point scale: 0 (unable),
1 (needs self-reinforcement), and 2 (succeeds). The maximum
score is 40. Children less than 6 years old were excluded, as
performance on this motor assessment test has been shown to
be age-related [Kroksmark et al., 2005].
Genetic Analyses
DNA was extracted from peripheral blood using a Puregene
DNA Isolation Kit (Gentra Systems, Minneapolis, MN) and
digested with restriction endonucleases EcoR1 and Pst1,
respectively. Fragments were separated on a 0.8% agarose
gel and subjected to Southern blot using the probe pM10M-6
[Brook et al., 1992]. Because of deletion/insertion polymorphism, EcoR1 blots show alleles of 9 or 10 kilobases (kb)
in normal individuals, whereas Pst1 blots show fragments
of approximately 1.2 kb. CTG expansions in patients were
estimated relative to a size marker from the Pst1 blots. As most
patients show a smear rather than a distinct band, because of
somatic mosaicism, the approximate midpoint of the smear
was reported.
Statistical Analyses
The SPSS 12.0.1 and SAS 8.2 packages for Windows were
used to analyze data. Due to small samples, non-parametric
tests were used for comparison between groups. The two
individuals with classical DM1 were excluded from the
statistical analyses. For tests between groups, Fisher’s Exact
Autism Spectrum Conditions in DM1
test was used for dichotomous variables, the Mantel–Haenszel
Chi Square test was used for ordered categorical variables
and the Mann–Whitney U-test for continuous variables. For
describing and testing the relationship between two continuous variables, the Spearman correlation coefficient was
calculated. In order to adjust for gender, analyses with van
Elteren’s test or partial Spearman correlation were performed.
All tests were two-tailed and conducted at a 5% significance
Table II presents the baseline characteristics for classification of DM1, the age at assessment, the range of CTG repeat
expansions in the patients as well as in their transmitting
parents, motor function and cognitive level. A male preponderance (15 out of 19 individuals) was found in the severe
congenital group, in contrast to an almost even distribution of
males and females in the other two groups. There were no
significant differences in age across DM1 groups. Five children
were floppy during the neonatal period and had been slow
suckers but did not require nasogastric feeding. These children
were diagnosed as having the childhood instead of the mild
congenital type, as the symptoms were regarded as mild and
their overall development during the first year was normal.
Unilateral subluxation of the hip was found in one patient with
childhood DM1 and one of the girls with classical DM1 was
born with unilateral pes equino varus adductus, but presented
no other characteristics of congenital or childhood DM1.
Inheritance and Molecular Data
The participants represented 47 families. In ten children
from seven families, the disease was paternally transmitted.
Six out of these 10 children represented three sibling pairs with
two siblings in each pair. The disease was maternally inherited
in 45 children from 38 families. In 14 of the children there were
six affected sibling pairs; four siblings in one family, two
siblings in each of the others. Two children were adopted
from other countries and there was no information on their
biological parents. All individuals in the severe congenital
group inherited the disorder from the mother. For paternal
inheritance in the different DM1 types, see Table II. The
approximate CTG repeat expansions in the patients are shown
in Figure 2. Significant differences in repeat size were found
between severe and mild congenital DM1 (P ¼ 0.0011) and
between severe congenital and childhood DM1 (P < 0.0001),
but not between mild congenital and childhood DM1. The CTG
repeat expansions were significantly larger when inherited
maternally (P ¼ 0.0012). Occurrence of both maternal and
paternal inheritance was present only in the mild congenital
and childhood forms of DM1, and the expansion size in the
affected mothers did not differ statistically from the size of
the triplet expansions in the affected fathers. There was a
positive correlation between the CTG repeats in the transmitting parent and the child in both maternal and paternal
inheritance (r ¼ 0.375, P < 0.05 and r ¼ 0.697, P < 0.05).
Neuropsychiatric Disorders
Forty-nine percent (n ¼ 28) of the children and adolescents
with DM1 had ASC. The single most common diagnosis among
the ASC was AD, present in 35% (n ¼ 20) of the study group. In
Table III all ASC diagnoses are presented. The individuals
with ASC had, according to the DSM-IV criteria, mainly
impairment in social interaction and communication and to
lesser degree problems in the area of restricted repetitive and
stereotyped patterns of behavior, interests and activities, but
enough to fulfill the criteria for ASC. One female had AS and
met the criteria for AS both of Gillberg and Gillberg and the
TABLE II. Baseline Characteristics in Individuals With DM 1
Baseline characteristics
Median age at time of investigation (range)
Median no. of CTG repeats (range)
Median no. of CTG repeats in
Affected mothers (range)
Affected fathers (range)
Cognitive level
Median Hammersmith score (range)
Gestational and neonatal period
Preterm delivery (gestational weeks)
Cesarean section/vacuum extraction
Low Apgar scoreb
Median days of assisted respiration (range)
Sucking difficulties/sucking difficulties
requiring nasogastric tube
Neonatal hypotonia
Congenital contract. and skeletal deformities
Severe cong. DM1
(n ¼ 19)
Mild cong. DM1
(n ¼ 18)
Childhood DM1
(n ¼ 18)
Classical DM1
(n ¼ 2)
9.2 (2.5–21.3)
9.1 (2.5–21.3)
14.8 (4.2–15.2)
1,600 (730–2,400)
1,650 (730–2,400)
1,565 (1,365–1,650)
13.2 (3.2–18.7)
10.9 (4.0–14.8)
14.0 (3.2–18.7)
1,000 (130–2,100)
1,015 (530–2,100)
975 (130–1,400)
14.2 (8.1–21.0)
13.2 (8.6–17.3)
14.2 (8.1–21.0)
930 (260–1,300)
940 (400–1,100)
975 (260–1,300)
16.4 (15.5–17.1)
700 (100–1,700)
500 (100–1,250)
625 (65–1,450)
650 (70–1,250)
525 (65–900)
290 (50–525)
22 (2–38)
27 (18–35)
35.5 (27–40)
39 (38–40)
10 (34–37)
17 (1–99)
3 (33–36)
16.4 (15.5–17.2)
550 (475–625)
550 (475–625)
Two children with mild congenital DM1 were adopted, parental transmission unknown.
Low Apgar score was defined as <5 at 5 min of age; cong., congenital; no, number of; NIQ, normal IQ; BIQ, borderline IQ; MMR, mild mental retardation;
ModMR, moderate mental retardation; SMR, severe mental retardation; congenital contract., congenital contractures.
Ekström et al.
Fig. 2.
The size of the CTG repeat expansions in the different DM1 forms.
Twelve individuals met the criteria for AD according to the
ADI-R algorithm. As shown in Table IV, the mean scores of
the different sub-domains of the ADI-R were high in the
whole DM1 group. Regarding the ‘‘repetitive’’ behavioral subdomain, none of the individuals with ASC exhibited selfinjurious behavior.
ASC was significantly correlated with the DM1 subgroup;
the more severe the type of DM1, the higher the frequency of
ASC (P ¼ 0.004). ASC was significantly more common in severe
congenital as opposed to childhood DM1 (P ¼ 0.004) and more
common in mild congenital than in childhood DM1 (P ¼ 0.006).
ASC was overrepresented in severe and mild congenital as
opposed to childhood DM1 (P ¼ 0.001). ASC was not correlated
to the level of MR, gender, inheritance or motor function. The
frequency of ASC increased with increasing CTG repeat
expansions (P ¼ 0.019, rs ¼ 0.32).
Four patients had ADHD symptomatology. One female and
one male; both with childhood form of DM1 and mild MR had
the inattentive type of ‘‘ADHD.’’ Additionally, two males with
moderate MR had a diagnosis of ‘‘ADHD’’ of the combined type,
one with severe congenital and the other with mild congenital
Three males had a tic disorder; two with chronic motor or
vocal tics, childhood DM1 and moderate MR. The third male
had both TD and AD with mild congenital DM1 and moderate
MR. Thirty-one individuals (54%); 18 males and 13 females had
TABLE III. Autism Spectrum Conditions and Mental
Retardation in the Study Population
DM1 form
Severe cong. (M/F)
Mild cong. (M/F)
Childhood (M/F)
Classical (M/F)
Severe MR (M/F)
Moderate MR (M/F)
Mild MR (M/F)
Borderline IQ (M/F)
Normal IQ (M/F)
(n ¼ 20)
(n ¼ 7)
(n ¼ 1)
(n ¼ 29)
AD, autistic disorder; ALC, autistic-like condition; AS, Asperger syndrome;
ASC, autism spectrum conditions; DM1, Myotonic dystrophy type1; cong.,
congenital; M, male; F, female; Intellect., intellectual level; MR, mental
at least one COND, as shown in Figure 3. One female had AD
and selective mutism. Only one individual with ASC had a
history of absence epilepsy. This girl had previously been
treated with valproic acid.
Most of the participants were kind, calm, easily fatigued,
passive and had a low pace. The individuals talked fairly well
even though they were withdrawn. They did not use language
in a socially spontaneous way and they were not good at taking
social initiatives. Some children exhibited social anxiety. The
symptoms of fatigue and excessive day-time sleepiness were
frequently reported by the parents, although we lacked
instruments to quantify the extent of these symptoms.
Level of Intellectual Functioning
The prevalence of MR in the different DM1 forms is
presented in Table III. The more severe the type of DM1, the
more severe the MR (P ¼ 0.0235). Maternal inheritance was
more common in the more severe forms of MR (P < 0.001).
There was a positive correlation between the size of the CTG
repeat expansion and the severity of MR (P < 0.0001, rs ¼ 0.66).
No correlation was found between motor function and MR in
any of the subgroups of DM1.
In the present study, based on a relatively large sample of
children and adolescents with both congenital and childhood
DM1, half the group had ASC, and AD was the single most
common diagnosis among the ASC. The ASC diagnoses were
not just restricted to the individuals with the congenital forms
of DM1, but also occurred in individuals with childhood DM1.
Correlations were observed both between ASC and severity of
DM1, as well as between ASC and CTG expansions; the larger
the expansion the higher the risk of ASC. In contrast, no
correlations were found between ASC and gender, inheritance
or motor function. To our knowledge, this is the first time a
systematic investigation and report of ASC in children and
adolescents with DM1 has been conducted.
In the general population, the reported rate of ASC varies
from 0.5% to 1.1% [Fombonne, 2005; Gillberg et al., 2006;
Petersen et al., 2006]. Tuberous sclerosis, Fragile X, Angelman
and Down syndrome are some examples of genetic syndromes
that have been described in children with ASC [Zafeiriou et al.,
2007]. Rogers et al. [2001] performed a study on predominantly
young boys with Fragile X, which is an another trinucleotide
repeat expansion disorder, where AD was present in 33%.
Clifford et al. [2007] found a high percentage of AD in a study on
Autism Spectrum Conditions in DM1
TABLE IV. Mean ADI-R Scores of the Different Sub-Domains
Social interaction
n cut off 10
n cut off 8
n cut off 7
Repetitive behavior
ncut off 3
Dev. in early development
ncut off 1
Severe cong.DM1 (n ¼ 16)
Mild cong. DM1 (n ¼ 17)
Childhood DM1 (n ¼ 18)
Classical DM1 (n ¼ 2)
6 (38%)
7 (41%)
3 (17%)
8 (50%)
9 (56 %)
16 (100%)
2 (12%)
2 (12%)
6 (35%)
16 (94 %)
3 (17%)
5 (28%)
12 (67%)
The maximum score for Social interaction is 30; Communication: 26; Repetitive behavior: 12; and Deviation in early development: 5.
Dev., Deviation; n cut off: number of individuals with scores exceeding cut off for the specific sub-domain.
both children and adults with fragile X where 18% of the males
and 10% of the females had AD. In DM1, we also found a high
rate of AD, with confirmed diagnoses in 35% of the patients.
The prevalence of ASC in children with MR is reported to be
higher than in the general population; 20.5% of children with
severe MR and 5.3% in mild MR [Nordin and Gillberg, 1996]. In
a review of 32 studies on ASC in 2001, Fombonne [Fombonne,
2003] found that 30% of children with AD were in the normal
intelligence range, 30% had mild to moderate MR and 40% had
severe to profound MR. Eighty-six percent of the patients in
this study with DM1 had MR, in the majority of cases moderate
to severe MR. However, the prevalence of ASC did not correlate
with the degree of MR, although the results show a tendency of
trend towards an effect of IQ.
In the current study, most of the individuals with DM1 and
ASC fit the description of the passive type of ASC delineated by
Wing [1997], with reduced spontaneous social interaction
but passive acceptance of approaches from others. In ASC,
repetitive behavior and stereotypies is common in addition
to self-injurious behavior [Nordin and Gillberg, 1998; Billstedt
et al., 2005]. In our group, however, none of the subjects
exhibited self-destructive behavior. The behavioral phenotype of the individuals in our study population is further
characterized by reduced initiative and low pace, partly due to
both fatigue and excessive day-time sleepiness. Day-time
somnolence has been reported in childhood DM1 [Quera
Salva et al., 2006], but not previously, to our knowledge, in
individuals with congenital DM1. Day-time sleepiness has
been found to correlate with corpus callosum atrophy in
adults with DM1 [Giubilei et al., 1999]. In congenital
DM1, MRI studies have shown corpus callosum hypoplasia
[Hashimoto et al., 1995a,b; Martinello et al., 1999]. Whether or
not this is an additional cause of the excessive day-time
sleepiness in children has not been investigated.
We could not confirm the high rate of ADHD in childhood
DM1 reported by Goossens et al. [2000]. The instrument used
in their study to assess ADHD was the Dutch version of the
Diagnostic Interview for Children and Adolescents (DICA)
Fig. 3. Childhood onset neuropsychiatric disorders among the individuals with DM1.
Ekström et al.
[Welner et al., 1987]. In the present study, we used the FTF to
assign ADHD diagnoses. The FTF covers a broad problem area,
especially pertaining to COND.
One of the limitations of the study is that only twelve out of
20 diagnosed individuals with AD fulfilled the ADI-R logarithm for autism. ADI-R was only one of the instruments used
to collect information on autistic symptoms and does not
include an observation of the child. Our impression was that
the parents had a tendency to recognize and report fewer
symptoms and problems in the interviews and this might have
impacted on our results. Aberrant personality traits and
deficits in emotional recognition are described in adults with
DM1 [Delaporte, 1998; Winblad et al., 2005] and may be a
contributing explanation of the ADI-R results if the interviewed parent also had DM1. For this reason, the diagnosis of
ASC in children and adolescents with DM1 should not merely
be based on the results of the ADI-R. In the present study the
ASC diagnoses were also based on observations by three of the
authors, personal examination (pediatric neurologist and
clinical psychologist) and/or by joint analysis of the videotapes,
although conjoint diagnostic procedure is a potential risk of
bias. Separately diagnostic assignment would have provided
the possibility of analyzing inter-clinician concordance, which
was not the case in our study.
Deficits in using and understanding facial information are
thought to, at least in part, account for the social disability in
children with ASC [Frith, 1989]. In several studies, children
with ASC have been found to have reduced ability to recognize
facial expressions of emotions [Hobson, 1986a,b; Celani
et al., 1999]. It has been argued that autistic symptoms in
DM1 can be caused by difficulties in interpreting facial
expressions secondary to poor non-verbal communication in
parents with DM1. In that case, the dominating autistic
feature in the children with DM1 would be difficulties with
reciprocal communication. However, the results on the ADI-R
did not indicate any problems with respect to reciprocal
communication, specifically. A further argument against
maternally induced autistic features is that the prevalence of
ASC did not differ between individuals with maternally or
paternally inherited DM1. Winblad et al. [2005] described
reduced empathy and cooperativeness in adults with DM1.
Apparently, since one of the diagnostic criteria of AD is
evidence of delayed or deviant development before 36 months
of age, individuals with adult onset of DM1 cannot have AD.
However, children and adults with DM1 have many behavioral
features in common, suggesting that the genetic impact on the
symptoms is not insignificant.
From an ASC etiological point of view, there is great genetic
heterogeneity [Veenstra-Vanderweele et al., 2004; Szatmari
et al., 2007], as well as heterogeneity regarding structural
abnormalities [Brambilla et al., 2003]. However, emerging
evidence has been presented, indicating that ASC is caused by
affected functional brain networks during early development.
This is supported by widespread growth abnormalities
throughout the brain [Muller, 2007]. We have not performed
neuroimaging in our study population, but several studies
present a wide range of different brain abnormalities in
children with congenital DM1, such as ventriculomegaly,
hyperintensity of white matter, mild atrophy of the frontal
cerebral cortex, hypoplasia of the corpus callosum, brainstem
hypoplasia and cerebellar abnormalities [Hashimoto et al.,
1995a,b; Trevisan et al., 1996; Martinello et al., 1999; Kuo
et al., 2005]. Some of the structural brain abnormalities
present in children with DM1 are well in line with those
described in AD, such as agenesis of the corpus callosum
[Chung et al., 2004; Vidal et al., 2006], cerebellar abnormality
[Allen and Courchesne, 2003], brainstem pathology [Rodier,
2002], and contribute to the explanation of the occurrence of
ASC in at least congenital DM1, although neuroimaging
studies in childhood DM1 are lacking. The MRI changes
described in the studies of congenital DM1 have occurred
before or at birth, indicating that the origin of the abnormalities is mainly developmental [Tanabe et al., 1992; Hashimoto
et al., 1995a,b; Di Costanzo et al., 2002].
The length of the pathological CUG mRNA determines
nuclear foci formation with a gain-of mRNA function and
altered cellular function [Davis et al., 1997; Ranum and
Cooper, 2006]. This is one of the molecular explanations of
the observed correlations between the CTG repeat size and
disease severity. In addition, the pathophysiology of congenital
DM1 includes aberrant methylation at the DM1 locus
[Filippova et al., 2001]. In adult onset DM1, the pathological
mRNA transcripts accumulate in nuclear foci in cortical
neurons and sequester regulatory proteins of the muscle-blind
protein (MBLN) family, which indirectly affects the activity of
the CELF protein family (CUG binding protein and ETR3-like
factor). Proteins from the MBNL and CELF families regulate
the alternative splicing of specific pre-mRNAs, resulting in
expression of isoforms of the proteins Tau, N-methylD-aspartate receptor 1 (NMDAR1) and of amyloid precursor
protein (APP) [Jiang et al., 2004; Leroy et al., 2006; Ranum and
Cooper, 2006]. An important question is whether these protein
isoforms have an impact on the developing brain, and in what
way the spliceopathy may affect emerging symptoms of ASC
and MR in children with congenital and childhood DM1. Like
Fragile X syndrome, DM1 might be considered as a network
disorder [Belmonte and Bourgeron, 2006]. In what way the
gain-of function of the RNA transcripts could cause disruption
of regulatory networks, and whether it is reasonable to
interpret the occurrence of ASC as a consequence of accumulation of inappropriate splice products of Tau, NMDAR1, APP
or other still unknown proteins, remains to be determined.
Indisputably, cerebral involvement is a direct consequence of
the genetic disorder [de Leon and Cisneros, 2007; Meola and
Sansone, 2007].
The occurrence of ASC in almost half of the patients in our
sample indicates that ASC is common in children and
adolescents with DM1. Awareness of this comorbidity is crucial
and may help to understand why patients with DM1 may
not function as well as expected in their activities of daily
life. Furthermore, knowledge of ASC is essential in planning
educational support and rehabilitation care for these patients.
In the effort to diagnose ASC in individuals with DM1, several
diagnostic tools should be used; both interviews and observational instruments. We believe that within the group of
patients with unexplained ASC, MR and mild hypotonia,
individuals with DM1, especially with the childhood onset
form, will be discovered. Early identification of ASC is of
great clinical importance in order to instigate ameliorative
multimodal supports and interventions. Our findings of
ASC need to be confirmed by other researchers. It would be
valuable to include the Autism Diagnostic Observation ScaleGeneric (ADOS-G), an instrument based on interaction with
and observation of the index child [Lord et al., 2000], in the
research protocols in future studies investigating the prevalence of ASC in children and adolescents with DM1 as well as
teacher reports to give further insight in to individual
functioning socially in different settings. In addition, future
trials to examine whether the social deficit exhibited by
children with DM1 includes impairment of face recognition
and emotion perception similar to the findings in adults with
DM1 would be of great interest. Finally, further studies
including MRI, PET and SPECT studies from human and
mouse models are warranted to elucidate what molecular
events cause neuronal impairment with symptoms of ASC and
MR in children with congenital and childhood forms of DM1.
Hopefully, further advances in the research concerning DM1 in
children, will shed light on the pathophysiology of ASC.
Autism Spectrum Conditions in DM1
The authors are grateful to all the children, adolescents
and parents for their participation in this study. The study
was supported by grants from the Health and Medical
Care Executive Board of the Region of Västra Götaland,
the Research and Development Department of the Northern
Älvsborg/Bohus County Council, the Linnéa and Josef
Carlsson Foundation, the Häggquist Family Foundation and
the Western Sweden Muscle Foundation. The authors gratefully acknowledge physiotherapist Anna-Karin Kroksmark
for her assessment of motor function, valuable comments
and assistance. Parts of this article were presented at the
6th European Pediatric Neurology Society Congress in
Göteburg, Sweden, September 14–17, 2005.
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