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Background: Intellectual disability (ID) is often associated with behavioral problems or disorders. Mutations in the GRIN2B gene (MRD6, MIM613970) have been identified as a common cause of ID (prevalence of 0.5 – 1% in individuals with ID) associated with EEG and behavioral problems. Methods: We assessed five GRIN2B mutation carriers aged between 3 and 14 years clinically and via standardized questionnaires to delineate a detailed behavioral phenotype. Parents and teachers rated problem behavior of their affected children by completing the Developmental Behavior Checklist (DBC) and the Conners’ Rating Scales Revised (CRS-R:L). Results: All individuals had mild to severe ID and needed guidance in daily routine. They showed characteristic behavior problems with prominent hyperactivity, impulsivity, distractibility and a short attention span. Stereotypies, sleeping problems and a friendly but boundless social behavior were commonly reported. Conclusion: Our observations provide an initial delineation of the behavioral phenotype of GRIN2B mutation carriers. Keywords: GRIN2B mutations, Behavior problems, Hyperactivity, Stereotypies, Intellectual disability Background risk for various behavioral problems and psychiatric disor- Intellectual disability (ID) is defined as impairment of cog- ders [4-6]. Recently, mutations in the GRIN2A and GRIN2B nitive and adaptive functions and occurs with an incidence genes, which encode for subunits of N-methyl-D-aspartate of about 2% in the general population . It is suspected (NMDA) receptors, have been identified in individuals with that the involvement of many genes will be discovered ID, EEG anomalies/seizures and behavioral anomalies . during the upcoming years via identification of novel mu- NMDA receptors are widely expressed in the central ner- tations with major effect sizes. Several recently published vous system. They form the major molecular determinants papers demonstrate that exome sequencing is a powerful of excitatory synapses , and they are implicated in learn- tool for the identification of the genetic basis of ID [2,3]. ing and memory . One of these papers shows that de novo point mutations The prevalence of GRIN2B mutations in intellectually and small indels account for up to 45-55% of patients with disabled children has been estimated to be 0.5-1% . The severe ID with high locus heterogeneity , so it can be behavioral phenotype has not yet been described in greater assumed that the number of gene mutations involved in detail; investigators have merely pointed out that the re- ID is higher than previously expected. spective children show behavioral anomalies. In 2011, a Early diagnosis of ID leads to improvement of single individual with a GRIN2B mutation was identified psychoeducation, genetic counseling of the families and po- within a group of 20 individuals with autism spectrum dis- tentially of therapy in the affected individuals. This is im- orders . The girl had a full scale IQ of 63, met the cri- portant, because children and youths with ID are at high teria for autistic disorder and showed hyperactivity., Three further de novo mutations in GRIN2B, all predicted to be protein-truncating, were reported very recently in a * Correspondence: Inga.Freunscht@lvr.de 1 dataset of 2,500 individuals (1,703 simplex ASD probands Department of Child and Adolescent Psychiatry, Psychosomatics and and 744 controls), but no detailed clinical data are Psychotherapy, University of Duisburg-Essen, Essen 45147, Germany Full list of author information is available at the end of the article © 2013 Freunscht et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Freunscht et al. Behavioral and Brain Functions 2013, 9:20 Page 2 of 11 http://www.behavioralandbrainfunctions.com/content/9/1/20 available . Genetic variations in NMDA receptors have was performed according to the Declaration of Helsinki been implicated in the genetic susceptibility to neuro- protocols and was approved by the local institutional re- logical, psychiatric and learning disorders, e.g. obsessive- view board (ethical votum 08-3663 for MRNET). All par- compulsive disorder , attention deficit/hyperactivity ents gave written consent to publish the data including the disorder (ADHD) , dyslexia , schizophrenia and bi- photographs (Figure 1). The clinical data are summarized polar disorders , Parkinson disease and Huntington in Table 1. disease . It is still an open debate whether patients with GRIN2B mutations present with an unspecific ID Behavioral assessments phenotype with some anomalies in behavior, or with a very Behavioral problems were measured by ratings of parents specific behavioral phenotype that could lead to the suspi- and teachers for all five mutation carriers. The behavioral cion of a GRIN2B mutation on clinical evidence alone. data presented in the case reports are based on parental re- The latter would facilitate making the diagnosis and im- ports and clinical observation. From February to December prove genetic counseling in the families. 2011, questionnaires were sent to the families and filled Four of the individuals reported here were previously out at home. The teachers were contacted by the parents published by us (subjects 1, 2, 5 and 9 within Endele et al., and concomitantly filled in the questionnaires. The individ- 2010 ) with a focus on the identification of the causative uals’ ages at behavioral assessment ranged from 3 / to genetic defect. At that time, the clinical data published 14 / years. The Developmental Behavior Checklist were limited. All other reports dealing with GRIN2B (DBC) and the Conners’ Rating Scales-Revised (CRS-R) mutations also focused on other aspects [7,10-14,17]. questionnaires, described in detail in the following section, Meanwhile, we have identified an additional, previously were used by parents and teachers to assess the behavioral undescribed female. For the first time, we provide a problems. detailed clinical synopsis of the behavioral phenotype asso- ciated with GRIN2B mutations. Developmental behavior checklist (DBC) We used the German version  of the Developmental Individuals and methods Behavior Checklist (DBC)  to assess behavioral and Affected individuals emotional problems in the five mutation carriers with ID The mean age of the 5 children (2 females, 3 males) at the (designed for children aged 4 to 18). The version for pri- last physical examination was 9 years, ranging from mary caregivers/parents, termed DBC-P, includes 96 items 23 months to 13 years. Individuals were identified within that are rated on a three-point scale ranging from 0 (not the study of Endele et al., 2010 , and through sequencing true) to 1 (sometimes/somewhat true) to 2 (often/very of an additional cohort of 93 individuals with ID collected true). The items allow calculation of Total Problem within the German Mental Retardation Network. Affected Behavior Score and classification into one of five subscales individuals and their parents were assessed within the dif- derived from factor analysis: Disruptive, Self-Absorbed, ferent departments of human genetics, pediatric hospitals Communication Disturbance, Anxiety and Social Relating. or departments of child and adolescent psychiatry. We The version for teachers, DBC-T, contains 94 items with obtained written informed consent from the families of the the same scales. Raw scores of the five subscales and the index patients for participation in this study. The study Total Problem Behavior Score can be transformed into Figure 1 Unremarkable facial phenotypes in individuals with GRIN2B mutations. A. Individual 1 at the age of 5 years. B. Individual 3 at the age of 8 years. C. Individual 5 at the age of 2 years. Freunscht et al. Behavioral and Brain Functions 2013, 9:20 Page 3 of 11 http://www.behavioralandbrainfunctions.com/content/9/1/20 Table 1 Clinical data in individuals with de novo GRIN2B mutations Individual 1 Individual 2 Individual 3 Individual 4 Individual 5 (subject 1, Endele et al., 2010) (subject 2, Endele et al., 2010) (subject 5, Endele et al., 2010) (subject 9, Endele et al., 2010) (this report) Mutation Translocation with breakpoint in Translocation with breakpoint in c.2044C > T (p.R682C) c.803_804delCA (p.T268SfsX15) c.1906G > C (p.A636P) GRIN2B GRIN2B Ethnic origin German German German German German Sex Male Male Male Female Female Gestational weeks at birth 41 38 40 39 40 Birth weight [g(SD)] 3535 (mean) 3390 (mean) 4000 (0.9) 3720 (0.9) 3940 (1.1) Birth length [cm(SD)] 52 (−0.4) 52 (mean) 54 (−0.7) 55 (1.8) 53 (0.6) OFC at birth [cm(SD)] 34 (−1.6) 32.5 (−2.1) 34 (−1.2) 34 (−0.5) not reported 3 11 Age at last physical 5 / 12 13 13 1 / 12 12 examination [years] 8 6 8 10 Age at behavioral 6 / 14 14 / 14 / 3 / 12 12 12 12 assessment Height [cm(SD)] 123 (1.8) 150 (mean) 154 (−0.1) 150 (−1.0) 87 (−0.2) Weight [kg(SD)] 23 (1.8) 36 (−1.5) 53 (0.8) 41 (2.0) 10 (−2.3) OFC [cm(SD)] 50 (−1.0) 50 (−2.4) 54 (−0.9) 54.5 (0.2) 47 (−0.8) Intellectual disability Mild Severe Mild Moderate Mild Walking age [months] 23 36 20 24 25 First words [months] 12 - 18 28 10 Seizures -- - - - EEG Left-sided sharp wave Slow dysrhythmia, occipital Normal Normal Sharp wave complexes complexes abortive sharp waves temporoparietal Cranial MRI Normal Hydrocephalus externus Normal Not performed Normal Behavior: -hyperactivity ++ / + + -short attention span ++ + + + -sleep disturbance ++ / + + -aggressiveness ++ + / - -stereotypies ++ + + - -friendliness ++ + + + Others / Cryptorchidism, choanal atresia,// / inguinal hernia Freunscht et al. Behavioral and Brain Functions 2013, 9:20 Page 4 of 11 http://www.behavioralandbrainfunctions.com/content/9/1/20 standardized percentile ranks based on reference popula- gestational week 41 to healthy and unrelated parents. tions comprised of intellectually disabled children. Scores Family history was uneventful. His birth measurements higher than 84 (> 1 Standard Deviation (SD) from mean) were within the normal range (Table 1). According to are termed as clinically relevant. parental account, he showed normal feeding behavior in The German version of the DBC-P shows satisfying the newborn period, slept a lot and showed reduced psychometric properties in internal consistency, retest body movements. At two months of age, the parents ini- reliability and discriminant validity . Standardization tially observed muscular hypotonia and a delayed motor of the parent’s version was based on 721 German chil- development. Physiotherapy was initiated at the age of dren and adolescents with ID . For the DBC-T, an 6 months. The boy walked without support at 23 months. Australian analysis revealed satisfying psychometric He spoke his first two words with 12 months, but speech properties [19,22]. Because of lack of German norms for development subsequently stagnated; he spoke about the teacher’s version, we used the Australian DBC-T 10 words at the age of 3 years. A developmental test standards. (Münchener Funktionelle Entwicklungsdiagnostik, ) performed at age 58 months revealed an Intelligence Conners’ rating scales-revised (CRS-R) Quotient (IQ) within the range of mild ID. His infection The CRS-R  assesses symptoms of attention deficit/ frequency was normal. hyperactivity disorder (ADHD) and related behavioral Brain MRI at age 17 months was normal. An EEG at the problems in children and adolescents (aged 3 to 17). Long age of 2 years was also normal. At the age of 63 months, and short versions are available for ratings by parents, left-sided sharp wave complexes were detected; however, teachers and for adolescent self-report. We used the long seizures were not observed. He carries an apparently bal- German versions for parents (CPRS-R:L) and teachers anced de novo translocation: 46,XY,t(9;12)(p22;p13.1). The (CTRS-R:L). The CPRS-R:L and CTRS:L contain 80 and 59 breakpoint in 12p13.1 disrupts the GRIN2B gene in exon items, respectively, that are rated on a four-point scale with 4. 0 = not true at all (never, seldom), 1 = just a little true (occa- Our diagnostic evaluation at the age of 5 / years re- sionally), 2 = pretty much true (often, quite a bit) and 3 = vealed normal body measurements (Table 1). He had a high very much true (very often, very frequent). Both versions nasal bridge without any other significant facial anomalies provide the following subscales: Oppositional, Cognitive (Figure 1A). He visited a kindergarten for handicapped chil- Problems/Inattention, Hyperactivity, Anxious-Shy, Perfec- dren and had a delay in fine motor skills and coordination tionism, Social Problems, Conners’ ADHD-Index, Conners’ problems; he stumbled and had an unsteady gait. He was Global Index (Restless-Impulsive, Emotional Lability and able to speak in simple sentences, showed severe delay in Total) and DSM-IV Symptom Subscales (Inattentive, receptive speech, and was unable to react properly to verbal Hyperactive-Impulsive and Total). The Psychosomatic demands. He often repeated or imitated sentences spoken subscale is only present in the CPRS-R:L questionnaire. by others without understanding the content and without a Normalized T-Scores according to the US norms are pro- feeling for the context. He showed primary enuresis diurna vided for each subscale with a score of > 60 (> 1 SD from and nocturna and encopresis; he was able to eat bite-sized mean) indicating a mildly atypical (possible significant) food with a spoon; for hygiene and dressing he totally relied problem and scores of > 65 indicating a significant problem on his parents. He was treated with dipiperone (60 mg in (markedly atypical) . We used the CRS-R for behavioral the evening) because of pronounced hyperactivity, in- assessment of our patients, even though there are no spe- creased aggression and major difficulties falling and staying cific norms for children with intellectual disabilities, be- asleep.Hewokeupevery 1–2 hours during the night prior cause no ADHD screening instrument for children with ID to initiation of the neuroleptic treatment. His attention is available. The CRS-R reveals adequate psychometric span did not exceed 10 minutes. He showed temper tan- properties with good internal reliability coefficients, high trums, mostly experienced as unpredictable. Aggressive be- test-retest reliability, and effective discriminatory power havior was seen against other children as well as against [24,25]. The US factor structure was replicated for the adults in terms of pinching, biting and hair pulling in a German version, as the path relations in the German and seemingly uncontrolled and undirected manner. Hand flap- US models are 87% identical. Both models show limitations ping and squeaking sounds occurred when he was thrilled. in predictive power . He showed stereotypic and self-injurious behavior such as jumping, shaking or hitting his head and pulling his hair. Results He preferred strong sensory stimulation like being held Case reports tight, pounding and the aforementioned self-injurious be- Individual 1 havior. Behavioral problems increased in new or unknown This individual (ES06E1083, subject 1 in Endele et al., situations that deviated from his daily routine. His under- 2010 ) was born after an uneventful pregnancy at standing of logical associations and consequences was not Freunscht et al. Behavioral and Brain Functions 2013, 9:20 Page 5 of 11 http://www.behavioralandbrainfunctions.com/content/9/1/20 age-appropriate. He was friendly, sociable and liked to take strangers, he behaved in a trusting manner. Because of his care of a more severely handicapped child in his school. severe ID, he needed intense care and guidance in his Social interaction was not impaired. He approached daily routine. He was restrained during the night to pre- strangers with a trusting and boundless attitude. He acted vent himfromgetting up;ifleftunrestrainedhewould careless and impulsive in traffic, so that intensive guidance move around the house and stay awake for prolonged was necessary to avoid accidents. periods of time. The behavioral assessment by parents and teachers Questionnaires were filled out by the parents at age 14. (DBT, CRS-R:L) was performed at age 6 / Individual 3 Individual 2 The boy (ER14077, subject 5 in Endele et al., 2010 ) was The pregnancy of Individual 2 (ES10E0186, subject 2 in the first of three children born to healthy non- Endele et al., 2010 ) was complicated by bleedings. An consanguineous parents. Family history is otherwise unre- ultrasound examination revealed a microcephaly at ges- markable. Paternal and maternal ages at birth were 29 and tational week 32. The boy was born at gestational week 25 years, respectively. Pregnancy and delivery were un- 38 to healthy and unrelated parents. Family history was complicated. Newborn body measurements were in the uneventful. Birth measurements were normal except for normal range (Table 1). While no significant abnormalities microcephaly (Table 1). Shortly after birth, a right-sided were noted during the first months of life, delayed inguinal hernia, bilateral cryptorchidism and a choanal achievement of developmental milestones became obvious atresia were surgically corrected. At the age of six during the second half of the first year. The boy walked months, a bilateral optic atrophy was diagnosed. In his without support at the age of 20 months. According to his newborn period, he showed normal feeding behavior, parents, first words were spoken around the age of but excessive crying during the night. Later in child- 18 months, but speech remained restricted to single words hood, he was unable to sleep through the night. At age until the age of 3. The boy has no congenital anomalies, three months, the parents observed that their son did no other physical disorders and no history of seizures not smile and did not establish eye contact. He walked (Figure 1B). At age 6 / , a clinical workup was performed without support at the age of 3 years. to identify the cause of his developmental delay. It in- Brain MRI at the age of 9 months showed hydroceph- cluded a metabolic screening, EEG and cranial MRI, which alus externus with asymmetry of ventricles, potentially all revealed normal findings. Assessment of cognitive abil- due to a prenatal subependymal bleeding. An EEG at the ities using the Kaufman Assessment Battery for Children age of 13 months showed irregular slow dysrhythmia and  at that age showed a homogeneous profile of impair- occipital abortive sharp waves, but seizures were not ob- ment in all categories with standard values ranging be- served. He carries a de novo translocation: 46,XY,t(10;12) tween 54 and 60 (mild ID). He was referred to a genetic (q11.23;p13.1), which was assumed to be balanced by con- workup at the age of 8 / years and revisited at the age of ventional karyotyping analysis. However, cloning of the 13 years. At age 8 / , routine genetic testing was nega- breakpoints revealed that GRIN2B is disrupted within tive, including conventional karyotyping, subtelomeric exon 2 in 12p13.1; at the breakpoint in 10q21.1 there is an screening by FISH and FMR1 CGG repeat analysis. additional de novo deletion of 1.1 Mb containing PRKG1 Physical examination at age 13 revealed no somatic abnor- and MBL2. malities. Body measurements were in the normal range Upon our diagnostic evaluation at age 12, normal body (Table 1). The boy carries a missense mutation in the measurements for height and weight were observed GRIN2B gene (c.2044C > T; p.R682C). He showed some (Table 1), but the microcephaly had persisted. His facial impairment in fine motor coordination, but no focal gestalt resembles that of other family members, and no neurologic deficits. He was friendly and cooperative. His dysmorphic facial features were observed. He visited a language skills were simple for his age, but he could talk school for visually impaired children. He was not able to in sentences and understand everyday speech. speak a single word at the age of 12 years, but able to At the age of 13 years, the boy was attending a special understand simple commands. He was not toilet-trained. school for intellectually disabled children. He knew almost He was severely cognitively impaired, friendly but erratic, all letters of the alphabet, was able to read a few words easily distracted and hyperactive with a short attention and write his name. He could arrange the numbers from 1 span. He preferred strong sensory stimulation, like rocking to 20. Teachers described him as friendly with other chil- and loud sounds, and sometimes he hit his head against dren. He preferred playing with younger children and the ground. His pain perception was reduced. He showed liked to play with an elastic strap in his hands. Objects stereotypic behavior like pounding, repetitive movements had to stay at their fixed places, he could not handle varia- of his hands and switching the lights on and off. With tions. He was boundless and had close physical contact Freunscht et al. Behavioral and Brain Functions 2013, 9:20 Page 6 of 11 http://www.behavioralandbrainfunctions.com/content/9/1/20 with others, but also frequent mood swings with episodes examination at the age of 13 years, she was friendly but of retreat and poor aggression control. boundless, exhibited excessive talking, but avoided both Standardized assessment of behavior with the DBC eye and physical contact. Her body measurements were and the CRS-R:L (filled out by parents and teachers) normal for age (Table 1). She had normal proportions and took place at the age of 14 / did not show focal neurological signs. Her appearance re- sembled that of her mother. Dysmorphic features were ab- sent. Apart from mildly limited extension of the elbows, Individual 4 she did not show further anomalies. She developed behav- This girl (HDMR179, subject 9 in Endele et al., 2010 ) ioral problems at an early age, showing hyperactivity, rest- was born following an uneventful pregnancy at 39 weeks lessness, distractibility, echolalia and a very demanding of gestation as the second child of non-consanguineous behavior. She liked to switch the lights on and off in a parents. The family history was unremarkable except for stereotypic manner, and she liked music and loud sounds. Morbus Bechterew in the girl’s mother, the maternal She had problems falling asleep and woke up several times grandfather and a maternal uncle. At the age of 8 months, a night. She suffered from constipation, but was somatic- the girl showed hypotonia and motor delay. She was able ally healthy otherwise. to sit at 16 months, walk unsupported at 24 months and Questionnaires were filled out by parents and teacher at climb up stairs at 29 months of age. Her speech develop- age 14 / . ment was severely delayed. She spoke her first words at the age of 28 months and the first two-word sentences two months later. At that age, global developmental delay Individual 5 was diagnosed and both speech and motor development The girl (ES10E0097) was the first child born to healthy corresponded to an age of 13–15 months. Psychological non-consanguineous parents. Family history was unremark- testing with a non-verbal test (Snijders Oomen Non- able. Paternal and maternal ages at birth were 37 and verbal Intelligence Test Revised, SON-R 2 ½ -7)  at the 28 years, respectively. Pregnancy was complicated by bleed- age of 12 years revealed that she had moderate ID and her ings, but delivery was uncomplicated. The girl had normal development corresponded to 3–4 years of age. She was birth measurements (Table 1). During the first days of life, not toilet-trained. EEG was normal. Fragile X syndrome she presented with myoclonies when falling asleep, but was excluded by molecular analysis of the FMR1 gene. EEG was normal. She had feeding difficulties and cried a Chromosome analysis showed a normal 46,XX karyotype lot. She spoke her first words at the age of 10 months and at a banding level of 550 bands. FISH analysis did not walked without support at the age of 25 months. At the last show a deletion of 17p11.2 (Smith-Magenis syndrome), physical examination, the girl was 23 months old. Her body and subtelomeric imbalances were excluded by MLPA. measurements were normal except for low weight (Table 1). Molecular karyotyping by Affymetrix 6.0 SNP array did She had no facial dysmorphism or other somatic anomalies not show copy number variants responsible for her ID (Figure 1C). and behavioral problems. The girl carries a heterozygous After identification of the missense mutation within deletion of a dinucleotide in exon 3 of the GRIN2B gene the GRIN2B gene (c.1906G > C; p.A636P), an EEG was (mutation c.803_804delCA, p.T268SfsX15). On diagnostic performed again. She presented with sharp wave DBC Subscales Patient 1 (parents) Patient 2 (parents) Patient 3 (parents) Patient 4 (parents) Patient 5 (parents) Figure 2 Parents’ ratings - Developmental Behavior Checklist (DBC). Above-average scores >84. Scores (percentiles), above-average scores >84 Freunscht et al. Behavioral and Brain Functions 2013, 9:20 Page 7 of 11 http://www.behavioralandbrainfunctions.com/content/9/1/20 DBC Subscales Patient 1 (teacher) Patient 3 (teacher) Patient 4 (teacher) Patient 5 (teacher) Figure 3 Teachers’ ratings - Developmental Behavior Checklist (DBC). Above-average scores >84. complexes in the temporoparietal region. Generalization Results of behavioral assessment to both hemispheres was visible. She had no seizures. The results of parents’ and teachers’ ratings by DBC and At age 3 / years, she showed mild ID. She was able to CRS-R:L for all five individuals are illustrated in Figures 2, speak 30–50 single words. She had difficulties falling asleep 3, 4, 5, and Tables 2 and 3 show additional data. Teacher’s and awoke once or twice a night. Sometimes she would stay ratings were not available for Individual 2. Missing data oc- awake for the rest of the night upon awakening. She had a curred when items of a subscale were not answered. short attention span, was unsettled and needed to move In summary, all individuals showed considerable behav- around. She was unable to stay at the table for a whole meal. ioral problems. Despite a somewhat inconsistent pattern Behavioral assessment was conducted at the age of with respect to the total and subscale scores, it should be 3 / years. noticed that the Conners’ ADHD Index, the Conners’ T Scores, above-average scores >60 Oppositional Cognitive Problems/Inattention Hyperactivity Anxious-Shy Perfectionism Patient 1 (parents) Social Problems Patient 2 (parents) Patient 3 (parents) Psychosomatic Patient 4 (parents) Conners' ADHD Index Patient 5 (parents) Conners' Global Index (Restless- Impulsive) Conners' Global Index (Emotional Lability) Conners' Global Index (Total) DSM-IV Symptom Subscales (Inattentive) DSM-IV Symptom Subscales (Hyperactive- Impulsive) DSM-IV Symptom Subscales (Total) Figure 4 Parents’ ratings - Conners’ Rating Scales-Revised (CPRS-R:L). Above-average scores >60. CRS-R:L Subscales Scores (percentiles), above-average scores >84 Freunscht et al. Behavioral and Brain Functions 2013, 9:20 Page 8 of 11 http://www.behavioralandbrainfunctions.com/content/9/1/20 T Scores, above -average scores >60 Oppositional Cognitive Problems/Inattention Hyperactivity Anxious-Shy Perfectionism Patient 1 (teacher) Social Problems Patient 3 (teacher) Patient 4 (teacher) Conners' ADHD Index Patient 5 (teacher) Conners' Global Index (Restless -Impulsive) Conners' Global Index (Emotional Lability) Conners' Global Index (Total) DSM-IV Symptom Subscales (Inattentive) DSM-IV Symptom Subscales (Hyperactive - Impulsive) DSM-IV Symptom Subscales (Total) Figure 5 Teachers’ ratings - Conners’ Rating Scales-Revised (CTRS-R:L). Above-average scores >60. Global Index (Restless-Impulsive) and the DSM-IV Symp- of Individual 1. Communication Disturbance and Anxiety tom Subscale (Inattentive) were rated as mildly or mark- were noticed by the teacher of Individual 4, and Social edly atypical for all individuals by parents and teacher, Relating was mentioned by the parents of Individual 3 indicating a possible significant problem. The Hyperactivity alone. The Total Problem Behavior Score revealed marked subscale and the DSM-IV Symptom Subscale (Hyper- results for Individual 1 (parents’ judgment), Individual 4 active-Impulsive) showed above-average scores for all indi- (teacher) and Individual 5 (parents). viduals except Individual 3. The Conners’ Global Index Overall, the CRS-R:L revealed higher scores than the (Total) and the DSM-IV Symptom Subscale (Total) were DBC. Teachers’ ratings were less often above average rated as average only by the teacher of Individual 3. Cogni- than parents’ ratings. This effect was more obvious for tive Problems/ Inattention were judged as above the nor- the DBC than for the CRS-R:L. mal range in all four children with available data. The Psychosomatic subscale was never rated above average, Discussion and Emotional Lability occurred solely in Individual 1. To the best of our knowledge, the present psychological Results of the DBC were less consistent than those of the examination of five individuals is the first such study in car- CRS-R:L. Self-absorbed behavior was rated as above- riers with mutations in the GRIN2B gene. The results are average by the parents of Individuals 1, 2 and 5. Disruptive relevant in describing this new behavioral phenotype. Four behavior was only rated as clinically relevant by the parents of five IndividualswerereportedpreviouslybyEndeleetal. Table 2 Developmental Behavior Checklist (DBC) results (percentiles) for all individuals, rated by parents and teachers Individual 1 Individual 1 Individual 2 Individual 3 Individual 3 Individual 4 Individual 4 Individual 5 Individual 5 (parents) (teacher) (parents) (parents) (teacher) (parents) (teacher) (parents) (teacher) Disruptive 92* 60 60 52 76 56 82 78 68 Self-absorbed 90* 82 94* 32 58 68 80 90* 74 Communication 74 46 58 74 32 66 90* 28 68 disturbance Anxiety 18 66 32 58 34 70 98* 70 34 Social relating 22 20 80 94* 48 52 48 52 20 Total problem 94* 70 82 66 66 70 90* 86* 64 Behavior sore *: above-average scores (>1SD). CRS-R:L Subscales Freunscht et al. Behavioral and Brain Functions 2013, 9:20 Page 9 of 11 http://www.behavioralandbrainfunctions.com/content/9/1/20 (2010) . “Behavioral anomalies” were noted in these indi- Hyperactivity (4/5), restless-impulsive behavior (5/5), in- viduals, but not further described in detail. The objective attention (4/4), oppositional behavior (3/4), and social prob- of our investigation was to provide a detailed description of lems (3/4) stand out as the main behavioral phenotype the behavioral phenotype associated with GRIN2B muta- (Table 1). Individuals 1, 2, 4 and 5 have severe sleeping tions by using clinical assessment as well as standardized problems. Stereotypic behaviors with preference for strong questionnaires. stimulation (such as pounding, rocking and loud sounds) Our five individuals, 2 females and 3 males, aged 3 to and occasional self-injury are frequent. In social interaction, 14 years, share some distinctive features: they all show all individuals appear as friendly and sociable, and face delay in motor and speech development with ID, pri- others in a boundless and trusting manner. Avoidance of mary enuresis diurna and nocturna, and encopresis. eye contact was described at an early age for Individual 2 They all need intense care. Measurements of IQ in our and during the current examination of Individual 4, but no individuals with GRIN2B mutation range from mild to further autism-related impairments in interaction and com- severe ID. Individuals 1, 3 and 5 are mildly impaired, In- munication were observed. dividual 4 shows a moderate ID and Individual 2 is se- O’Roak et al.  identified a paternally inherited dis- verely retarded, possibly due to an additional de novo ruptive GRIN2B mutation in an individual with evidence deletion of 1.1 Mb in 10q21.2 containing the PRKG1 of early-onset autism spectrum disorder, possible regres- and MBL2 genes. sion and co-morbidity for mild ID. She had an overall IQ Table 3 Conners’ rating scales-revised (CRS-R:L) results (T Scores) for all individuals, rated by parents and teachers Individual 1 Individual 1 Individual 2 Individual 3 Individual 3 Individual 4 Individual 4 Individual 5 Individual 5 (parents) (teacher) (parents) (parents) (teacher) (parents) (teacher) (parents) (teacher) Oppositional 69* x x 56 66* 76* 78* 55 60 Cognitive x x x 63* 68* 67* 74* 87* x problems/ Inattention Hyperactivity 81* 61* 90* 54 57 90* 77* 83* 87* Anxious-shy 43 64* 51 61* 55 90* 70* 42 49 Perfectionism 52 50 65* 60 46 71* 68* 50 44 Social problems x 53 x 90* 56 70* 88* 65* 88* Psychosomatic 43 50 50 59 55 Conners’ 71* 63* 75* 64* 68* 73* 82* 83* 89* ADHD index Conners’ 77* 66* 77* 61* 67* 90* 83* 77* 88* global index (Restless- impulsive) Conners’ 70* 77* 55 49 51 54 51 49 45 global index (Emotional lability) Conners’ 77* 72* 72* 58 62* 82* 73* 68* 82* global index (Total) DSM-IV symptom 71* x x 61* 62* 80* 70* 72* 86* subscales (Inattentive) DSM-IV symptom 76* 61* x 54 57 84* 76* 79* 88* subscales (Hyperactive- impulsive) DSM-IV symptom 75* x x 59 61* 87* 75* 78* 90* Subscales (Total) *: above-average scores (>1SD); x: missing data. Freunscht et al. Behavioral and Brain Functions 2013, 9:20 Page 10 of 11 http://www.behavioralandbrainfunctions.com/content/9/1/20 of 63, met the criteria for autism and she was described as clinical phenotype. One of them (Individual 2) addition- hyperactive. This case further confirms our finding that ally has a de novo deletion of 1.1 Mb within 10q21, which hyperactivity is a major problem in individuals with a might explain the severe ID, additional clinical findings GRIN2B mutation. In a very recently published paper, the and the progressive microcephaly found exclusively in this same group reported on de novo GRIN2B mutations in individual. However, below-average head circumferences four out of 2446 probands with autism spectrum disorder, were observed in four of the five individuals, whereas Indi- leading to the assumption that GRIN2B belongs to the re- vidual 4 had a circumference of +0.2 SD. Individuals 3 and currently mutated genes in ASD/ID phenotypes . No 5 carry missense GRIN2B mutations and have a milder detailed clinical phenotype besides autism was docu- phenotype than the other three individuals. Sharp waves mented in these probands. without clinically apparent seizures were diagnosed in in- The use of standardized questionnaires further contrib- dividuals 1, 2 and 5, suggesting that this and potentially uted to the characterization of the phenotype. Results show other EEG abnormalities might occur prominently in mu- marked behavioral problems in all five individuals, also em- tation carriers. MRI was performed in four individuals phasizing hyperactivity and inattention as a clinical hall- with normal findings in three of them. The evaluation of mark. Self-absorbed behavior is described in three of five further individuals will help to decide whether these ob- individuals. The somewhat inconsistent pattern of problem servations are coincidental and to what extent genotype- behavior mightpartlybedue to theindividuals’ different phenotype correlations exist. ages at diagnostic evaluation (3, 6, and 14 years). Further behavioral assessments in future will clarify if the pheno- Conclusion type with hyperactivity and inattention might become more In conclusion, although specific facial dysmorphism and in- prominent with higher ages. Regarding missing data, no ternal malformations are usually absent in individuals with systematic pattern could be observed. We used the DBC GRIN2B mutations, there does seem to be a characteristic for evaluation of Individual 5 (age 3 / )despite theques- behavioral phenotype consisting of ID, hyperactivity, impul- tionnaire’s age range from 4 to 18 years, because no assess- sivity and distractibility. Stereotypic and stimulatory behav- ment instrument for behavioral problems in younger ior, sleeping problems and a friendly but boundless social children with ID is available. In Individuals 1 and 4, the be- behavior also appear to be associated features. EEG anomal- havioral problems had already led to pharmacological treat- ies are also helpful to define the phenotype of mutation car- ment, so results of the questionnaires might underestimate riers. Long-term follow-ups are required to determine deviant behavior. Furthermore, unequal judgments of par- whether the phenotype becomes more prominent with ents and teachers need to be considered, as they observe higher ages. the individuals in different contexts. Several studies report low correlations between ratings of parents and teachers Abbreviations [30-32]. Variations between different informants argue for ADHD: Attention deficit/hyperactivity disorder; ASD: Autism spectrum disorder; multiaxial assessment of behavior. BMBF: German federal ministry of education and research; CRS-R:L: Conners’ rating scales revised, long version; CPRS-R:L: Conners’ rating scales revised, long The DBC showed less deviant scores than the CRS-R:L. version for parents; CTRS-R:L: Conners’ rating scales revised, long version for A possible explanation is the use of different reference teachers; DBC: Developmental behavior checklist; DBC-P: Developmental populations: Standardization of the DBC is based on chil- behavior checklist version for parents; DBC-T: Developmental behavior checklist version for teachers; EEG: Electroencephalography; ID: Intellectual disability; dren and adolescents with ID, thus accounting for findings IQ: Intelligence quotient; MRD6: Mental retardation, autosomal dominant 6; that children with ID are at an increased risk of developing MRI: Magnetic resonance imaging; MRNET: German mental retardation network; behavioral/emotional disorders [4-6]. Norms of the CRS-R: NGFN: National genome research network; NMDA: N-methyl-D-aspartate; SD: Standard deviation. L are derived from a population of children without ID. Therefore, above-average scores in this questionnaire Competing interests might be more readily met and provide more false positives The authors declare that they have no competing interests. in our five individuals. Nevertheless, we decided to use the Authors’ contributions CRS-R:L due to the absence of a specific ADHD screening IF carried out the psychological evaluation and drafted the manuscript. BP and instrument for children with ID. The DBC does not pro- SE carried out the molecular genetic studies. RB, UM, HP, E-CP, JR, BZ, MZ, DW vide a subscale score for inattention or hyperactivity. So, if investigated the patients and analyzed the clinical data. AR, JH, DW conceived of the study, participated in its design and coordination and helped to draft the DBC results are considered exclusively, behavior problems manuscript. All authors read and approved the final manuscript. might be underestimated. The comparatively high scores in the CRS-R:L indicate that ADHD symptoms are prom- Acknowledgements inent in GRIN2B mutation carriers. We are grateful to the families for their participation in the study. The Institutes for Human Genetics Essen, Erlangen and Heidelberg, Germany, Two of the individuals presented here (Individuals 1 are members of the ‘German Mental Retardation Network’ (MRNET), which and 2) have a translocation disrupting the GRIN2B gene. is funded by the German Federal Ministry of Education and Research These two individuals present with the most severe (BMBF) as a part of the National Genome Research Network (NGFN) Freunscht et al. 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