Autism spectrum conditons in myotonic dystrophy type 1 A study on 57 individuals with congenital and childhood forms.код для вставкиСкачать
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 1 Department of Pediatrics, Northern Älvsborg County Hospital, Trollhättan, Sweden Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, Göteborg University, Sweden 3 Child Neuropsychiatry Clinic, Sahlgrenska University Hospital, Göteborg, Sweden 4 Department of Clinical Genetics, Sahlgrenska Academy, Göteborg University, Sweden 5 Child and Adolescent Psychiatry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Göteborg University, Sweden 6 The Vårdal Institute, The Swedish Institute for Health Sciences, Sweden 2 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: email@example.com 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. KEY WORDS: 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. INTRODUCTION 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 919 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. MATERIALS AND METHODS Study Population In 2003, 41 individuals from the study by Kroksmark et al.  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.  (see Table I). Classical DM1 was defined as symptoms presenting in adolescence with slowly progressive muscular weakness, myotonia and/or multiorgan involvement [Harper, 2001]. Procedure 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) 920 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 disability. 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, 2002]. 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. . 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 level. RESULTS 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 921 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 DSM-IV. TABLE II. Baseline Characteristics in Individuals With DM 1 Baseline characteristics Male/female Median age at time of investigation (range) Male Female Median no. of CTG repeats (range) Male Female Inheritancea Maternal Paternal Median no. of CTG repeats in Affected mothers (range) Affected fathers (range) Cognitive level NIQ/BIQ/MMR/ModMR/SMR Median Hammersmith score (range) Gestational and neonatal period Polyhydramniosis 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 a Severe cong. DM1 (n ¼ 19) Mild cong. DM1 (n ¼ 18) Childhood DM1 (n ¼ 18) Classical DM1 (n ¼ 2) 15/4 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) 8/10 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) 8/10 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) 0/2 16.4 (15.5–17.1) 19 0 13 3 13 5 0 2 700 (100–1,700) — 500 (100–1,250) 625 (65–1,450) 650 (70–1,250) 525 (65–900) — 290 (50–525) 0/1/2/8/8 22 (2–38) 1/2/3/9/3 27 (18–35) 1/1/7/9/0 35.5 (27–40) 1/1/0/0/0 39 (38–40) 13 10 (34–37) 13/2 9 17 (1–99) 5 3 (33–36) 4/3 0 0 2 0 3/3 0 0 0 0 0/0 0 0 19/19 18 11 13/7 17 12 5/0 5 1 0/0 0 1 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. b 922 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 DM1. 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 Male/female DM1 form Severe cong. (M/F) Mild cong. (M/F) Childhood (M/F) Classical (M/F) Intellect. Severe MR (M/F) Moderate MR (M/F) Mild MR (M/F) Borderline IQ (M/F) Normal IQ (M/F) AD (n ¼ 20) ALC (n ¼ 7) AS (n ¼ 1) No ASC (n ¼ 29) 13/7 3/4 0/1 15/14 6/4 5/2 2/1 — 3/0 0/4 — — — 0/1 — — 6/0 3/3 6/9 0/2 5/3 7/2 0/2 1/0 — — 2/2 1/1 0/1 — — — — 0/1 — 3/0 5/7 6/3 0/2 1/2 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 retardation. 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. DISCUSSION 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.  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.  found a high percentage of AD in a study on Autism Spectrum Conditions in DM1 923 TABLE IV. Mean ADI-R Scores of the Different Sub-Domains Social interaction n cut off 10 Communication Verbal n cut off 8 Non-verbal 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) 9.1 6 (38%) 9.2 7 (41%) 5.3 3 (17%) 1.5 0 7.7 8 (50%) 3.3 0 3.4 9 (56 %) 4.3 16 (100%) 3.6 2 (12%) 8.7 2 (12%) 2.3 6 (35%) 3.1 16 (94 %) 4.1 3 (17%) — 0 1.7 5 (28%) 1.7 12 (67%) 0.5 0 — 0 0.5 0 0 0 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 , 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. . 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. 924 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.  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 ACKNOWLEDGMENTS 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. 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