Behavior patterns in Duchenne muscular dystrophy: Report on the Parent Project Muscular Dystrophy behavior workshop 8–9 of December 2006, Philadelphia, USA

Abstract

Eighteen participants representing clinicians, scientists, parents, industry, and public health agencies involved in the assessment and treatment of children with Duchenne muscular dystrophy (DMD) from Australia, Canada, the Netherlands, the UK and the USA met in Philadelphia on December 8–9, 2006 to attend a workshop addressing behavioral issues among children and young adults with DMD. The workshop, sponsored by Parent Project Muscular Dystrophy (PPMD–USA), was organized in response to parent and clinician concerns regarding behavior associated with DMD, and its subsequent impact on patient and family quality of life. For the purposes of clarification, in this report the term “behavior” is defined as readily observable external actions and responses, as well as internal affective/emotional states. The aims of the workshop were to (1) evaluate current findings and determine whether characteristic behaviors occur among boys and young men with DMD, (2) examine etiological factors contributing to behavior patterns in DMD, and (3) develop recommendations for research and intervention strategies. DMD is a genetic disorder occurring in approximately one in 3300 live male births. Mutations in the dystrophin gene result in an absence of dystrophin or a non-functional dystrophin protein. The different types and locations of the mutation are highly variable across individuals, and it is unclear to what extent this has an impact on the phenotype. However, in all cases progressive muscle degeneration ensues, with morbidity typically occurring in the second or third decade of life. Muscle degeneration has understandably been the primary focus of research and treatment, and much less emphasis has been placed on behavioral functioning. There is, however, emerging evidence of central nervous system (CNS) involvement resulting in cognitive and neurobehavioral disorders. In addition, because of the debilitating and fatal nature of the disorder, significant psychosocial factors must also be considered. Behavioral functioning has a significant impact on quality of life and can also directly affect medical care, in particular as it is related to things like treatment adherence and behavioral response to medication. Research to date is limited, and studies have typically focused on one component of physiological, cognitive, or emotional functioning in DMD. The complex interactions between these various factors have not been clearly defined. As such, greater understanding of these interactions is necessary for appropriate patient care and treatment planning. John Morley (Australia) began the workshop by reviewing the role of dystrophin in the brain. In the non-DMD CNS, clusters of dystrophin are most abundant on the soma and proximal dendrites of pyramidal cells in the cerebral cortex and hippocampus, and of Purkinje cells in the cerebellum. In particular, dystrophin is localized at postsynaptic densities of GABAergic inhibitory synapses, and is also colocalized with dystrobrevins in Purkinje cells of the cerebellum [1Knuesel I. Mastrocola M. Zuellig R.A. Bornhauser B. Schaub M.C. Fritschy J.M. Altered synaptic clustering of GABAA receptors in mice lacking dystrophin (mdx mice).Eur J Neurosci. 1999; 11: 4457-4462Crossref PubMed Scopus (180) Google Scholar, 2Grady R.M. Wozniak D.F. Ohlemiller K.K. Sanes J.R. Cerebellar synaptic defects and abnormal motor behaviour in mice lacking α- and β-dystrobrevin.J Neurosci. 2006; 26: 2841-2851Crossref PubMed Scopus (69) Google Scholar]. The mdx mouse, which lacks the full-length (427 kDa) dystrophin, is a widely used animal model of DMD. In cerebellar Purkinje cells of the mdx mouse there is a marked decrease in the number of GABAA receptor clusters immunoreactive for α1 and α2 subunits at the postsynaptic density [[1]Knuesel I. Mastrocola M. Zuellig R.A. Bornhauser B. Schaub M.C. Fritschy J.M. Altered synaptic clustering of GABAA receptors in mice lacking dystrophin (mdx mice).Eur J Neurosci. 1999; 11: 4457-4462Crossref PubMed Scopus (180) Google Scholar]. Wallis and colleagues [[3]Wallis T. Bubb W.A. McQuillan J.A. Balcar V.J. Rae C. For want of a nail. Ramifications of a single gene deletion, dystrophin, in the brain of the mouse.Front Biosci. 2004; 9: 74-84Crossref PubMed Scopus (12) Google Scholar] reported no difference in expression of the gene for GABAA receptor α1 subunit in the cerebellum of young (3–4 months old) mdx mice compared to wild-type controls. Dr. Morley’s lab measured the expression of the GABAA receptor α1 subunit in mdx and littermate control cerebellum using Western blot analysis and found no significant difference in the overall expression of GABAA receptor α1 subunit in the membrane fraction preparation (unpublished observations). These findings support the suggestion that the absence of full-length dystrophin leads to a disruption in the targeting or stabilization of the receptors at the postsynaptic membrane, resulting in a reduced number of GABAA receptor clusters. Although this may have broad implications, the reduction in GABAA receptor clusters at inhibitory synapses has been specifically shown to have a functional impact in two regions of the CNS. In the cerebellum, the amplitude and frequency of spontaneous miniature inhibitory postsynaptic currents (mIPSCs) in Purkinje cells of the mdx mouse are significantly lower than in littermate controls, with the reduction being more marked for large compared to small amplitude mIPSCs, which is consistent with a reduction in the number of postsynaptic GABAA receptor clusters. Interestingly, those channels located appropriately at the postsynaptic sites appear to function normally [[4]Anderson J.L. Head S.I. Morley J.W. Altered inhibitory input to Purkinje cells of dystrophin-deficient mice.Brain Res. 2003; 982: 280-283Crossref PubMed Scopus (34) Google Scholar]. Synaptic plasticity is also disrupted in cerebellar Purkinje cells of the mdx mouse, as demonstrated by a substantial reduction in long-term depression (LTD). The blunting of LTD occurred in the presence of pharmacological blockers of GABA, indicating that the consequences of an absence of dystrophin are not restricted to GABAergic-related functions [[5]Anderson J.L. Head S.I. Morley J.W. Long term depression is reduced in cerebellar Purkinje cells of dystrophin-deficient mdx mice.Brain Res. 2004; 1019: 289-292Crossref PubMed Scopus (39) Google Scholar]. An impairment of calcium homeostasis is a compelling candidate underlying the disruption in cerebellar long-term plasticity in mdx mice, and could be due to a direct impact of the dystrophin-deficiency on membrane transport of calcium, or possibly by disrupting the phosphorylation of calcium by enzymes normally localized at the postsynaptic density. In contrast, there is a marked enhancement of both short-term and long-term synaptic plasticity and of neuronal excitability in the hippocampus of the mdx mouse compared to littermate controls, possibly resulting from the reduced number of GABA receptor clusters lowering the threshold for NMDA receptor activation [[6]Vaillend C. Billard J.M. Laroche S. Impaired long-term spatial and recognition memory and enhanced CA1 hippocampal LTP in the dystrophin-deficient DMDmdx mouse.Neurobiol Dis. 2004; 17: 10-20Crossref PubMed Scopus (118) Google Scholar]. Although the specific role of dystrophin in the CNS remains unclear at this time, current hypotheses speculate that an absence of dystrophin alters neuronal function by disrupting ion channel localization, which in turn disrupts the electrophysiology of neurons with downstream consequences for calcium homeostasis and synaptic plasticity. This disruption of neuronal function may lead to potential changes in cognition, behavioral functioning, sleep patterns, and response to medication. While research has focused predominantly on the impact of deficient dystrophin in the cerebellum and hippocampus, it is important to remember that dystrophin is also distributed throughout other cortical and subcortical regions. Dr. Morley also pointed out that some boys with DMD are not only lacking the full-length dystrophin protein, but also one or more of the five smaller dystrophin isoforms that are localized in the CNS to a greater or lesser extent. Study of the genotype–phenotype relationship in boys with DMD, especially in regard to behavior and cognition, coupled with investigation using appropriate animal models is essential if we are to understand the role of dystrophin in the CNS. It has long been known that cognitive difficulties are associated with DMD, and the workshop reviewed how cognition might impact behavior. Sue Cotton (Australia) described her meta-analysis of 32 studies examining age, IQ, and disease severity among 1224 individuals with DMD [7Cotton S. Voudouris N. Greenwood K.M. Intelligence and Duchenne muscular dystrophy: full-scale, verbal, and performance intelligence quotients.Dev Med Child Neurol. 2001; 43: 497-501Crossref PubMed Google Scholar, 8Cotton S. Voudouris N. Greenwood K.M. Association between intellectual functioning and age in children with Duchenne muscular dystrophy: further results from a meta-analysis.Dev Med Child Neurol. 2005; 73: 257-265Crossref Scopus (77) Google Scholar]. Her results showed that full-scale IQ scores were shifted down about one standard deviation from the normative population. The mean full-scale IQ value was 80.2 with a standard deviation of 19.3. Thirty-five percent of the children in the DMD sample had IQ scores in the mental retardation range (scores ⩽ 70), which is greater than in the general population (approximately 2%). However, it is notable that there is a continuum of intellectual ability in DMD, with scores ranging from impaired (⩽70) to very superior (scores ⩾ 130), and that the majority of children perform within normal limits. Comparison of verbal and performance IQ scores did not fully support the commonly held belief that verbal scores are always depressed when compared to performance (nonverbal) scores among children with DMD. The group mean for performance IQ (PIQ) was about five points higher than for verbal IQ (VIQ), but examination of individual VIQ–PIQ discrepancy scores showed a wide and variable range of presentations, with some children clearly excelling on the verbal tests in comparison to nonverbal. Thus, although on average children with DMD show relative verbal weakness, this may have limited clinical significance for individual children. Dr. Cotton emphasized the need for more specific profile analyses and noted that children who took the Wechsler intelligence tests were particularly susceptible to doing poorly on the Vocabulary, Arithmetic and Digit Span subtests. Dr. Cotton also compared children with DMD of different ages in a cross-sectional analysis, which suggested that full-scale and performance IQ scores generally remained constant across the age groups, but that verbal IQ may increase with age. Her data showed that children 11 years and below had poorer logical verbal abstract reasoning, language development, mathematical/computational ability, general knowledge, and appreciation of social norms and practices when compared to older children. Longitudinal studies measuring intellectual functioning are needed to show whether verbal skills of children with DMD improve over time. Based on her results, Dr. Cotton concluded that the classification of an individual child with DMD as either mentally retarded or not is of limited value when considering his daily behavior and function. The variability in IQ subtest scores observed in group studies of DMD indicates that more comprehensive neuropsychological assessments are necessary to gain insight into the cognitive factors contributing to behavioral functioning in individual patients. The general trend toward improvement in VIQ scores with age has interesting implications for behavior, as issues may evolve over time; younger children may manifest more difficulties with neurodevelopmental issues such as language comprehension and expression, while older children may struggle more with problems arising from their progressive physical abilities and medical complications. Veronica J. Hinton (USA) discussed studies of more specific neuropsychological skills among children with DMD and how they may be related to relevant behavioral concerns. She reviewed her work showing that among 81 children with DMD whose IQ was above 70, performance on particular tests (including Digit Span and Story Recall), was selectively weak regardless of general intellectual level [[9]Hinton V.J. Nereo N.E. DeVivo D.C. Goldstein E. Stern Y. Poor verbal working memory across intellectual level in boys with Duchenne dystrophy.Neurology. 2000; 54: 2127-2132Crossref PubMed Scopus (119) Google Scholar]. Moreover, when children with DMD were compared to their unaffected siblings of comparable age and receptive vocabulary level, selective deficits were found on the same tests, as well as on other measures that required the children to listen to verbal information [[10]Hinton V.J. Nereo N.E. DeVivo D.C. Goldstein E. Stern Y. Selective deficits in verbal working memory associated with a known genetic etiology: the neuropsychological profile of Duchenne muscular dystrophy.J Int Neuropsychol Soc. 2001; 7: 45-54Crossref PubMed Scopus (84) Google Scholar]. They did not significantly differ on tests of visual-spatial skills, rote memory, or abstract reasoning. Further data from a follow-up study comparing children with DMD to their unaffected siblings on a range of verbal and memory tasks demonstrated the children with DMD were weaker on tasks of sentence recall or following verbal directions, yet their other language and verbal rote memory skills were not significantly different from their siblings [[11]Hinton V.J. Fee R. Goldstein E. De Vivo D.C. Verbal and memory skills in Duchenne muscular dystrophy.Dev Med Child Neurol. 2007; 49: 123-128Crossref PubMed Scopus (51) Google Scholar]. This pattern of poorer immediate verbal memory span has generally been consistent across research studies examining this skill in DMD, although there are varying interpretations as to what such a deficit might reflect – including language, attention and/or memory deficits. Dr. Hinton proposed that children with DMD have a core deficit of limited verbal span, such that their ability to listen to and process verbal information lags behind their peers. She discussed a number of theoretical constructs that might form the basis of this deficit including limited storage space in the hypothetical phonological loop, compromised cortico-cerebellar circuitry, and/or imperfect ability to “chunk” information. Although the basis is unknown, the idea is operationalized by simple tasks requiring processing of increasing amounts of verbal information. To this end, Dr. Hinton presented cross-sectional data of 112 children ages 5–12 with DMD and compared them to sibling controls and normative data on different levels of the Token Test for Children. The boys with DMD accurately completed tasks involving short verbal instructions, yet lagged behind their peers about two years on tasks involving longer verbal instructions (unpublished observations). Dr. Hinton hypothesized that such a developmental lag might be particularly problematic among younger children, where the effects may be more generalized and may present as early language delays. Among school age children the effects might not be readily obvious, yet could have broad impact on daily life and behavior. Children with a weakness in immediate verbal memory span may be described as non-compliant, inattentive or forgetful. Deficits in this area may indirectly affect behavior and emotional adjustment, in that behavioral problems that start upon entry into formal schooling may be the result of the child’s difficulty understanding and encoding novel academic information and teacher expectations [[12]Hinton V.J. Nereo N.E. DeVivo D.C. Goldstein E. Stern Y. Investigation of poor achievement in children with Duchenne muscular dystrophy.Learn Disabil Res Pract. 2004; 19: 146-154Crossref PubMed Google Scholar]. Jos Hendriksen (Netherlands) concluded session one by providing an overview of academic strengths and weaknesses in DMD. Dr. Hendriksen proposed that children with DMD have particular difficulty with automatization, placing them at increased risk for developing a specific learning disability. Substantial research has confirmed this, finding that boys with DMD are at a higher risk of developing reading problems [13Billard C. Gillet P. Barthez M. Hommet C. Bertrand P. Reading ability and processing in Duchenne muscular dystrophy and spinal muscular atrophy.Dev Med Child Neurol. 1998; 40: 12-20Crossref PubMed Scopus (89) Google Scholar, 14Hendriksen J.G.M. Vles J.S.H. Are boys with Duchenne at risk for reading disabilities?.Pediatr Neurol. 2006; 34: 296-300Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar], with 20% of them having serious reading problems and another 20% having moderate reading problems. Although fewer studies have been published on other academic skills, there is also evidence that shows that children with DMD have poor math and writing skills and that their performance in these academic areas is as compromised as their performance on reading tests [12Hinton V.J. Nereo N.E. DeVivo D.C. Goldstein E. Stern Y. Investigation of poor achievement in children with Duchenne muscular dystrophy.Learn Disabil Res Pract. 2004; 19: 146-154Crossref PubMed Google Scholar, 15Worden D.K. Vignos P.J. Intellectual function in childhood progressive muscular dystrophy.Pediatrics. 1962; 29: 968-977PubMed Google Scholar]. Thus, children with DMD are at increased risk for the three types of specific learning disabilities: dyslexia (reading disorder), dyscalculia (mathematics disorder), and dysgraphia (disorder of written communication). It is generally agreed upon that automatization of skills is one of the core deficits in these learning difficulties: automatization of phonemes (sound-symbol relationships) and words in dyslexia, automatization of numbers and procedures in dyscalculia, and automatization of sizes and shapes in dysgraphia. Failure in the process of automatization leads to inaccurate, inefficient, and dysfluent academic skills. The cerebellum has been theorized to play an important role in this process. Moreover, the cerebellum has been hypothesized to be involved in dyslexia [[16]Nicolson R.I. Fawcett A.J. Do cerebellar deficits underlie phonological deficits in dyslexia?.Dev Sci. 2006; 9: 259-262Crossref PubMed Scopus (26) Google Scholar] and its involvement in DMD might explain the higher incidence of reading problems in DMD. Dr. Hendriksen emphasized that for all children language arts (reading and writing) become increasingly important methods of obtaining new academic material and demonstrating competence as they matriculate, and weaknesses can be cumulative over time. Dr. Hendriksen also discussed how behavior problems frequently occur conjointly with specific learning disabilities and that struggling to learn will impact on any child’s quality of life and emotional adjustment. Early detection of and interventions for learning disabilities are therefore important and all boys with DMD should receive screening at a young age. He showed how early intervention strategies in his clinic, aimed at training and improving phonological skills, helped boys with DMD develop more adequate reading skills and self esteem (unpublished observations). The goal of the second session was to review what is currently known about specific patterns of behavior among boys with DMD. This includes behaviors that are a response to disease-associated variables (e.g., stressors, medical interventions), as well as behaviors that might be considered neurodevelopmental in nature. Jos Hendriksen (Netherlands) began this session by discussing psychosocial adjustment. Psychosocial adjustment is a general term referring to emotional, behavioral, and social functioning, and is believed to be a central aspect of quality of life. Although psychosocial adjustment can be sensitive to stressors that are not disease specific, it provides a good estimate of how a child is coping with DMD. Dr. Hendriksen noted that the psychosocial adjustment of boys with DMD occurs within the context of normative development as well as declines in physical functioning. Therefore, their behavior should be assessed from a developmental perspective, in which there are normal stressors (e.g., first bad grade at school) and illness related stressors (e.g., falling down and becoming wheelchair dependent). Studies examining psychosocial, behavioral, and emotional functioning in boys with DMD have been relatively sparse. Results have been equivocal, but there is evidence that some boys with DMD are at increased risk for experiencing depression [[17]Fitzpatrick C. Barry C. Garvey C. Psychiatric disorder among boys with Duchenne muscular dystrophy.Dev Med Child Neurol. 1986; 28: 589-595Crossref PubMed Scopus (49) Google Scholar]. Dr. Hendriksen reported the results of the largest study to date on psychosocial adjustment in boys with DMD [[18]Hendriksen JGM, Poysky J, Schrans DGM, Vles JSH. Psychosocial adjustment in males with Duchenne muscular dystrophy. Submitted for publication.Google Scholar]. The psychosocial adjustment of 351 boys with DMD was assessed by a parent-completed rating scale, the Psychosocial Adjustment and Role Skills Scale (PARS-III) [[19]Stein R.E.K. Jessup D.J. Manual for Personal Adjustment and Role Skills Scale III (PARS-III). Albert Einstein College of Medicine, New York1990Google Scholar]. This scale proved to be reliable and valid for the DMD population. Results indicated that most boys with DMD cope relatively well with the disorder, but a minority (approximately 17%) are at increased risk for psychosocial problems. Further analysis indicated that boys with DMD ages 8–10 years of age have significantly poorer total adjustment scores when compared to other boys with DMD. Dr. Hendriksen speculated that this may be a response to stressors associated with decreases in physical functioning leading up to the loss of ambulation (which typically occurs around this age). In general, total adjustment scores improved with age, suggesting that the boys grow into better adjustment. There was one exception, however; peer relations were negatively correlated with age – suggesting that peer relations become more problematic as the boys grow older. It was hypothesized that decreases in physical functioning and health may result in reduced access to social and recreational opportunities. Dr. Hendriksen reported that, in light of the higher risk for maladjustment in this population, parents may need practical recommendations for building self esteem and teaching their children with DMD how to deal with stressful and emotional issues. He recommended using a strategy known as “Emotion Coaching” [[20]Gottman J. Declaire J. Raising an emotionally intelligent child: the heart of parenting. Simon and Schuster, New York1997Google Scholar] that involves: (1) being aware of the child’s emotions (2) recognizing emotions as an opportunity for intimacy and teaching (3) listening empathically and validating the child’s emotions, (4) helping the child to verbally label emotions, (5) setting limits while helping the child to solve the problem. Dr. Hendriksen also referred to recent research showing that parents of DMD boys are at an increased risk for depression and stress [21Abi Daoud M.S. Dooley J.M. Gordon K.E. Depression in parents of children with Duchenne muscular dystrophy.Ped Neurol. 2004; 31: 16-19Abstract Full Text Full Text PDF Scopus (57) Google Scholar, 22Nereo N.E. Fee R.J. Hinton V.J. Parental stress in mothers of boys with Duchenne muscular dystrophy.J Pediatr Psychol. 2003; 28: 473-484Crossref PubMed Scopus (77) Google Scholar]. Although the exact implications have not been documented in this population, it is likely that this can have an impact on the parent-child relationship, resulting in an indirect effect on the child’s psychosocial adjustment. Kate Bushby (UK) presented data from a study of 82 children with neuromuscular disease [[23]Darke J. Bushby K. Le Couteur A. McConachie H. Survey of behavior problems in children with neuromuscular diseases.Eur J Pediatr Neurol. 2006; 10: 129-134Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar]. Among the responders, parents of 37 boys with DMD and 8 boys with Becker muscular dystrophy (BMD) answered questions about their child’s behavior, communication and social skills. The results indicated that DMD/BMD boys had unexpectedly high levels of social and communication difficulties, both when compared to the general population and to children with other neuromuscular disorders. In this sample, 18% of boys with DMD and 50% of boys with BMD were identified by their parents as having poor social interactions, while 30% with DMD and 43% with BMD were identified as having problems with communication. Of note is that 5% of DMD and 37% of BMD cases reported having a preexisting diagnosis of an autism spectrum disorder. These findings suggest that social interactions and communication are areas of weakness for boys with DMD/BMD, even if they do not have autism. Further, the children who were identified as having significant behavioral concerns were all more likely to be identified as having learning disabilities. The possibility of the behaviors being reactive responses to the challenges children may face in their school was discussed, along with the possibility that these behaviors are part of the phenotypic presentation of the disorders. Veronica J. Hinton (USA) reported that the above findings were similar to those from a study of parent ratings of behavior in a sample of 181 boys with DMD [[24]Hinton V.J. Nereo N.E. Fee R.J. Cyrulnik S. Social behavior problems in Duchenne muscular dystrophy.J Dev Behav Pediatr. 2006; 27: 470-476Crossref PubMed Scopus (69) Google Scholar]. Her group found that about a third of the boys were reported to have significant social problems (e.g., being immature, having poor peer relationships) and these rates were significantly higher than the normative sample, unaffected sibling controls and a comparison group of children with cerebral palsy. Notably, the younger children with DMD were more likely than the older children to have increased social problems. Further, within the DMD group, approximately a quarter of the sample had significant problems with being withdrawn and having poor attention. Veronica J. Hinton (USA) then reviewed the literature examining autism spectrum disorders in DMD. The term “autism spectrum disorders” collectively refers to a group of diagnoses that have similar behavioral presentations including Autistic Disorder, Asperger’s Disorder, and Pervasive Developmental Disorder – Not Otherwise Specified. Case studies describing children with DMD and autism have been published [25Komoto J. Usui S. Otsuki S. Terao A. Infantile autism and Duchenne muscular dystrophy.J Autism Dev Disord. 1984; 14: 191-195Crossref PubMed Scopus (51) Google Scholar, 26Wu J.Y. Kuban K.C. Allred E. Shapiro F. Darras B.T. Association of Duchenne muscular dystrophy with autism spectrum disorder.J Child Neurol. 2005; 20: 790-795Crossref PubMed Scopus (95) Google Scholar], and there is emerging evidence that the prevalence of autism spectrum disorders among boys with DMD is higher than expected in the general population. Dr. Hinton presented data showing that boys with DMD tend to have greater difficulty identifying facial affect compared to controls [[27]Hinton V.J. Fee R.J. DeVivo D.C. Goldstein E. Poor facial affect recognition among boys with Duchenne muscular dystrophy.J Autism Dev Disord. 2006; ([Epub ahead of print])PubMed Google Scholar], a characteristic often associated with autism spectrum disorders. She then discussed an ongoing study of 65 children with DMD or BMD, in which 26% of the children with DMD (but none of the control children) scored above the cut-off on a screening measure of autistic behaviors [[28]Hinton V.J. Batchelder A. Cyrulnik S. Fee R.J. Kiefel J. Autism and Duchenne muscular dystrophy.J Int Neuropsychol Soc. 2006; 12: 72PubMed Google Scholar]. For those who scored above the cut-off, Dr. Hinton administered a comprehensive structured interview to each child’s mother and found that up to 16% of the children met criteria for an autism spectrum disorder. These children were all described by their mothers as having significant qualitative abnormalities in reciprocal social interactions and communication, along with restricted or repetitive behaviors, all presenting before the age of 3 years. Thus, this study also indicated that DMD is associated with higher than expected rates of autistic disorder. The possibility of sample bias inflating the rates was discussed, as was the fact that most children with DMD are not autistic. During discussion, participants reported concern that boys with DMD may demonstrate problems with “theory of mind”. This term, which has been theorized to be one of the core deficits in autism, refers to the ability to take another’s perspective, understand the connection between external factors and emotional state, and apply this knowledge to social problem solving. Dr. Hinton suggested that language difficulties, the tendency of being withdrawn, avoiding eye contact, having difficulty reading facial affect, and problems with theory of mind are a constellation of behaviors that may fall on a continuum in DMD. The number of children on the extreme end of this continuum results in an increase in the prevalence of autism spectrum disorders observed in DMD. There may also be a number of DMD boys on the milder end of the