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Proposal of a multimodal management of the behavioral disorders in SMS. Treatment of SMS is complex and includes: geneticists, neuropediatricians/neurologists, somnologists, developmental and behavioral pediatricians, psychiatrists, speech and language therapists, neuropsychologists, psychomotor therapists
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Smith-Magenis syndrome is a complex neurodevelopmental disorder that includes intellectual deficiency, speech delay, behavioral disturbance and typical sleep disorders. Ninety percent of the cases are due to a 17p11.2 deletion encompassing the RAI1 gene; other cases are linked to mutations of the same gene. Behavioral disorders often include outbur...
Contexts in source publication
Context 1
... social integration in SMS adults is driven by intel- lectual deficiency but also by persistent chronic behavioral disturbance. Thus, an appropriate strategy should be started early in childhood and should integrate the diffe- rent behavioral modalities (Fig. ...
Context 2
... far, as for many orphan diseases, no general consen- sus on the treatment of behavioral disorders in SMS has been reached, and there are no recommendations on the prescription of psychotropic drugs [54]. However, an optimal strategy should integrate all the parameters detailed in Fig. ...
Similar publications
Smith–Magenis syndrome (SMS; OMIM #182290) is a complex genetic disorder characterized by distinctive physical features, developmental delay, cognitive impairment, and a typical behavioral phenotype. SMS is caused by interstitial 17p11.2 deletions, encompassing multiple genes and including the retinoic acid-induced 1 gene (RAI1), or by mutations in...
Smith-Magenis syndrome (SMS) is a complex genetic disorder characterized by developmental delay, behavioural problems and circadian rhythm dysregulation. About 90% of SMS cases are due to a 17p11.2 deletion containing retinoic acid induced1 (RAI1) gene, 10% are due to heterozygous mutations affecting RAI1 coding region. Little is known about RAI1 r...
Smith–Magenis syndrome (SMS), a neurodevelopmental disorder characterized by dysmorphic features, intellectual disability (ID), and sleep disturbances, results from a 17p11.2 microdeletion or a mutation in the RAI1 gene. We performed exome sequencing on 6 patients with SMS-like phenotypes but without chromosomal abnormalities or RAI1 variants. We i...
Citations
... In addition, to direct genetic effects, this may have impacted the natural course of and accessibility to services. SMS requires multidisciplinary management, including psycho-education, parental guidance, and specific treatments [25]. If these are not provided, a less favorable course with respect to mental health could be hypothesized. ...
Aim:
Smith-Magenis syndrome (SMS) is a rare genetic neurodevelopmental disorder caused by a 17p11.2 deletion or pathogenic variant in the RAI1 gene. SMS is associated with developmental delay, intellectual disability (ID), and major sleep and behavioral disturbances. To explore how genetic variants may affect intellectual functioning and behavior, we compared intellectual and behavioral phenotypes between individuals with a 17p11.2 deletion and pathogenic RAI1 variant.
Method:
We reviewed available clinical records from individuals (aged 0-45 years) with SMS, ascertained through a Dutch multidisciplinary SMS specialty clinic.
Results:
We included a total of 66 individuals (n = 47, 71.2% with a 17p11.2 deletion and n = 19, 28.8% with a pathogenic RAI1 variant) for whom data were available on intellectual functioning, severity of ID (n = 53), and behavioral problems assessed with the Child Behavior Checklist (CBCL, n = 39). Median full-scale IQ scores were lower (56.0 vs. 73.5, p = 0.001) and the proportion of individuals with more severe ID was higher (p = 0.01) in the 17p11.2 deletion group. Median total CBCL 6-18 scores (73.5 vs. 66.0, p = 0.02) and scores on the sub-scales somatic complaints (68.0 vs. 57.0, p = 0.001), withdrawn/depressed behavior (69.5 vs. 55.0, p = 0.02), and internalizing behavior (66.0 vs. 55.0, p = 0.002) were higher in the RAI1 group.
Conclusion:
The results of this study suggest that 17p11.2 deletions are associated with a lower level of intellectual functioning and less internalizing of problems compared to pathogenic RAI1 variants. The findings of this study may contribute to personalized-management strategies in individuals with SMS.
... These behavioral problems have traditionally been identified in the behavioral profile of individuals with SMS (Udwin et al, 2001;Howlin and Udwin, 2002;Elsea and Williams, 2011;Hildenbrand and Smith., 2012;Osorio et al, 2013;Garayzábal & Lens, 2014;Gnanavel, 2014;Shayota and Elsea, 2019), and they may, in part, be related to neurocognitive impairment, environmental contingencies, change-related anxiety, level of impulsivity, speech delay and the degree of sleep disturbance (Sloneem et al., 2011;Poisson et al., 2015;Shayota and Elsea, 2019). ...
Background
The Smith-Magenis syndrome (SMS) shows a collection of neurodevelopmental problems including mild to moderate intellectual disability, change-related anxiety, impulsivity, speech delay, Attention-Deficit/Hyperactivity Disorder (ADH) and sleep disturbances. Sleep disorders, when present, have been treated in several populations with consecutive improvements in cognitive and behavioral aspects.
Aims
To better understand the existing relationships between sleep disturbances and behavioral problems in SMS syndrome this study describes the sleep and behavior problems in the SMS and explores the possible relation between both.
Methods and procedures
17 individuals with SMS (50% males; 11.2 ± 4.9 years old) and 12 individuals with typical development (50% male; 11.1 ± 4.4 years old) were investigated using the Sleep Disturbance Scale for Children and the Child Behavior Checklist.
Results
A high percentage (60%) of individuals with SMS have an indication of sleep disorders, being the most frequent disorders the sleep-wake transition disorders, and disorders of initiating and maintaining sleep with sleep latency higher than acceptable and total sleep time below acceptable. More than 94% of the SMS group presented clinical or borderline scores on the total behavioral problems scale. The most common behavioral problems were Externalizing Problems, Thought and Attention, ADH and Aggressive problems. There was a positive correlation between disorders of initiating and maintaining sleep, sleep-wake transition disorders, disorders of arousal, disorders of excessive somnolence and behavioral problems.
Conclusions and implications
The worse the sleep disturbances investigated, the more severe the behavioral problems characteristics reinforcing the importance to address the sleep problems in the treatment of SMS individuals.
... The aim of the assessment is to determine if the person with ID is experiencing more inattention, hyperactive, or impulsivity symptoms than is expected for their developmental age, with associated functional impairment [63]. Functional impairment from ADHD in a person with ID can present in different ways, including hyperactivity presenting as challenging behaviour [64] which can impact on their access to activities, use of illicit drugs for self-medication, impulsive aggression, or not achieving their maximum potential. Rating scales for ADHD can supplement clinical findings; however, there are not many validated tools for ADHD in people with ID. ...
Attention deficit hyperactivity disorder (ADHD) is characterised by inattention or hyperactivity/ impulsivity or both. The onset of ADHD is in childhood, but in a proportion of cases some symptoms continue into adulthood. There is a strong association among ADHD, intellectual disability (ID), problem behaviour, and autism spectrum disorder (ASD). The prevalence of ADHD in persons with ID and ASD is significantly higher than the general population, ranging between 10% and 28%. It might be difficult to diagnose ADHD in persons with ID and low-functioning ASD. The stringent use of categorical diagnostic criteria might limit the identification of the disorder since some criteria may not be applicable, particularly for those with more severe cognitive and communication impairments. Observation of a person’s distractibility that is not consistent with their developmental level may help when considering the symptom of inattention in an individual with ID, while hyperactivity and impulsivity are better indicated by fidgeting most of the time, appearing ‘on the go’, and being unable to remain seated for a long time and to wait for one’s turn, which can often lead to verbal or physical aggression, irritability, mood fluctuations, or self-harming behaviour.Although ADHD in the non-ID population is a widely researched area, the lack of high-quality research in ADHD in ID has been a barrier to the advancement of treatment in this patient group, with most studies having named ID as an exclusion criterion. Drug treatment such as psychostimulants like methylphenidate along with psychosocial interventions is effective in a high proportion of cases to improve ADHD symptoms. In people with ID, the overall effect size of psychostimulants is smaller than that reported in the general population, while the adverse effect profile is similar in both populations.KeywordsAttention deficit hyperactivity disorderADHDPsychostimulantsMethylphenidateIntellectual disabilitiesChildrenAdults
... For example, in Prader Willi syndrome, growth hormone therapy has been suggested to help with not only obesity/food seeking, but can also potentially help address cognitive and behavioral issues (Grugni et al. 2016). In Smith-Magenis syndrome, the use of melatonin and betaantagonists can help address some of the sleep and behavioral issues associated with the condition (Poisson et al. 2015). ...
Genetic testing to identify genetic syndromes and copy number variants (CNVs) via whole genome platforms such as chromosome microarray (CMA) or exome sequencing (ES) is routinely performed clinically, and is considered by a variety of organizations and societies to be a “first-tier” test for individuals with developmental delay (DD), intellectual disability (ID), or autism spectrum disorder (ASD). However, in the context of schizophrenia, though CNVs can have a large effect on risk, genetic testing is not typically a part of routine clinical care, and no clinical practice guidelines recommend testing. This raises the question of whether CNV testing should be similarly performed for individuals with schizophrenia. Here we consider this proposition in light of the history of genetic testing for ID/DD and ASD, and through the application of an ethical analysis designed to enable robust, accountable and justifiable decision-making. Using a systematic framework and application of relevant bioethical principles (beneficence, non-maleficence, autonomy, and justice), our examination highlights that while CNV testing for the indication of ID has considerable benefits, there is currently insufficient evidence to suggest that overall, the potential harms are outweighed by the potential benefits of CNV testing for the sole indications of schizophrenia or ASD. However, although the application of CNV tests for children with ASD or schizophrenia without ID/DD is, strictly speaking, off-label use, there may be clinical utility and benefits substantive enough to outweigh the harms. Research is needed to clarify the harms and benefits of testing in pediatric and adult contexts. Given that genetic counseling has demonstrated benefits for schizophrenia, and has the potential to mitigate many of the potential harms from genetic testing, any decisions to implement genetic testing for schizophrenia should involve high-quality evidence-based genetic counseling.
... Certain rare congenital disorders have also been associated with onychotillomania. Smith-Magenis syndrome is a neurodevelopmental disorder characterized by developmental delay, intellectual deficiency, dysmorphic facial features, and behavioral abnormalities, including nail picking, finger and hand biting, head banging, and aggression [45,64]. Onychotillomania can also be seen in patients with Lesch-Nyhan syndrome, an X-linked recessive disorder caused by a deficiency in the HPRT enzyme, which is responsible for purine recycling. ...
Onychophagia (nail biting) and onychotillomania (nail picking) are chronic nail conditions categorized as body-focused repetitive behavior (BFRB) disorders. Due to a limited awareness of their clinical presentations, embarrassment on the part of patients, and/or comorbid psychiatric conditions, these conditions are frequently underrecognized and misdiagnosed. This article reviews the prevalence, etiology, diagnostic criteria, historical and physical exam findings, and treatment options for these conditions. The PubMed/MEDLINE database was searched for relevant articles. Onychophagia and onychotillomania are complex disorders necessitating a detailed patient history and physical examination and a multidisciplinary treatment approach for successful diagnosis and management. Due to the dearth of clinical trials for treatment of nail biting and nail picking, large clinical trials are necessary to establish standardized therapies.
... At school, SMS children demonstrate longterm memory, perceptual skills and closure as points of strength while they have relevant weaknesses in short-term memory, sequential processing, and math skills [19,53,[55][56][57]. Moreover, scholastic performance is often lowered by maladaptive conduct, hyperactivity, and distractibility [19,58]. ...
... Their penetrance and severity are influenced by several determinants, e.g. age, sleep, communicative skills, cognitive level, developmental comorbidities, environmental context, and the underlying genetic defect [8,21,30,51,52,54,58,[63][64][65][66][67][68][69]. When the diagnostic process was less straightforward, many subjects were diagnosed with psychiatric disorders, attention deficit hyperactivity disorder (ADHD), or ASD before the diagnosis of SMS was reached [15,59]. ...
Smith-Magenis syndrome (SMS) is a complex genetic disorder characterized by distinctive physical features, developmental delay, cognitive impairment, and a typical behavioral phenotype. SMS is caused by interstitial 17p11.2 deletions (90%), encompassing multiple genes and including the retinoic acid-induced 1 gene (RAI1), or by pathogenic variants in RAI1 itself (10%). RAI1 is a dosage-sensitive gene expressed in many tissues and acting as transcriptional regulator. The majority of individuals exhibit a mild-to-moderate range of intellectual disability. The behavioral phenotype includes significant sleep disturbance, stereotypes, maladaptive and self-injurious behaviors. In this review, we summarize current clinical knowledge and therapeutic approaches. We further discuss the common biological background shared with other conditions commonly retained in differential diagnosis.
... As SMS patients typically exhibit signs during infancy, increased awareness of SMS would better equip primary care providers to initiate early intervention [13]. Early indicators in SMS, including hypotonia, lethargy, and sleep disturbances, are typically conspicuous to the point that basic clinical awareness would warrant suspicion in providers treating undiagnosed SMS patients [13,14]. In regions that lack access to specialist care, telemedicine may prove to be a feasible consideration as video analysis has demonstrated benefit in other neurodevelopmental disorders [15,16]. ...
Smith-Magenis syndrome (SMS) is a severe neurodevelopmental disorder characterized by intellectual disability, sleep abnormalities, behavioral dyscontrol, and a distinct somatic phenotype. This report describes the case of a 10-year-old female with SMS who presented with aggression, self-injurious behavior, impulsivity, and attention deficits. She had failed trials of several stimulants and clonidine prior to presentation. An evening-dosed, delayed-release/extended-release methylphenidate formulation was added to her regimen, and she demonstrated significant improvement in her presenting symptoms. To our knowledge, this is the first published case of the use of an evening-dosed, delayed-release/extended-release methylphenidate formulation in a patient with SMS. This case highlights the need for further research on the role of these medications in managing behavioral and attentional symptoms associated with SMS.
... Both SMS and PTLS are characterized by developmental delays, language disorders, and intellectual disability. SMS also manifests as self-injurious behavior, irritability, sleep disorders, obesity, behavioral abnormalities, and distinct facial and skeletal deformities (Marta et al., 2012;Poisson A et al., 2015;Gupta et al., 2016;Spruyt et al., 2016). SMS is rarely diagnosed in childhood, and its clinical symptoms become more obvious with age (Lee et al., 2012;Gouard et al., 2020). ...
Smith-Magenis syndrome and Potocki-Lupski syndrome are rare autosomal dominant diseases. Although clinical phenotypes of adults and children have been reported, fetal ultrasonic phenotypes are rarely reported. A retrospective analysis of 6,200 pregnant women who received invasive prenatal diagnosis at Fujian Provincial Maternal and Child Health Hospital between October 2016 and January 2021 was performed. Amniotic fluid or umbilical cord blood was extracted for karyotyping and single nucleotide polymorphism array analysis. Single nucleotide polymorphism array analysis revealed six fetuses with copy number variant changes in the 17p11.2 region. Among them, one had a copy number variant microdeletion in the 17p11.2 region, which was pathogenically analyzed and diagnosed as Smith-Magenis syndrome. Five fetuses had copy number variant microduplications in the 17p11.2 region, which were pathogenically analyzed and diagnosed as Potocki-Lupski syndrome. The prenatal ultrasound phenotypes of the six fetuses were varied. The parents of two fetuses with Potocki-Lupski syndrome refused verification. Smith-Magenis syndrome in one fetus and Potocki-Lupski in another were confirmed as de novo. Potocki-Lupski syndrome in two fetuses was confirmed to be from maternal inheritance. The prenatal ultrasound phenotypes of Smith-Magenis syndrome and Potocki-Lupski syndrome in fetuses vary; single nucleotide polymorphism array analysis is a powerful diagnostic tool for these diseases. The ultrasonic phenotypes of these cases may enrich the clinical database.
... region [2][3][4]. Manifestations are variable and include intellectual disability (ID), severe sleep disturbances and psychiatric comorbidity such as autism spectrum disorders (ASD), attention-deficit-hyperactivity disorder (ADHD) [5][6][7]. Typical behavioural manifestations include problems with emotion dysregulation, self-injurious behaviour and aggressive or stereotypical behaviour, posing a great burden on patients and caregivers [8]. ...
Background
Smith–Magenis syndrome (SMS) is a rare genetic neurodevelopmental disorder characterized by intellectual disability and severe behavioural and sleep disturbances. Often, patients with SMS are diagnosed with attention-deficit/hyperactivity disorder (ADHD). However, the effectiveness of methylphenidate (MPH), the first-line pharmacological treatment for ADHD, in patients with SMS is unclear. Our objective is to examine the effectiveness of MPH for ADHD symptoms in individuals with SMS, proposing an alternative trial design as traditional randomized controlled trials are complex in these rare and heterogeneous patient populations.
Methods and analysis
We will initiate an N-of-1 series of double-blind randomized and placebo-controlled multiple crossover trials in six patients aged ≥ 6 years with a genetically confirmed SMS diagnosis and a multidisciplinary established ADHD diagnosis, according to a power analysis based on a summary measures analysis of the treatment effect. Each N-of-1 trial consists of a baseline period, dose titration phase, three cycles each including randomized intervention, placebo and washout periods, and follow-up. The intervention includes twice daily MPH (doses based on age and body weight). The primary outcome measure will be the subscale hyperactivity/inattention of the Strengths and Difficulties Questionnaire (SDQ), rated daily. Secondary outcome measures are the shortened version of the Emotion Dysregulation Inventory (EDI) reactivity index, Goal Attainment Scaling (GAS), and the personal questionnaire (PQ). Statistical analysis will include a mixed model analysis. All subjects will receive an assessment of their individual treatment effect and data will be aggregated to investigate the effectiveness of MPH for ADHD in SMS at a population level.
Conclusions
This study will provide information on the effectiveness of MPH for ADHD in SMS, incorporating personalized outcome measures. This protocol presents the first properly powered N-of-1 study in a rare genetic neurodevelopmental disorder, providing a much-needed bridge between science and practice to optimize evidence-based and personalized care.
Trial registration
This study is registered in the Netherlands Trial Register (NTR9125).
... Frequently, spoken language production has been reported as a weak language skill regarding comprehension skills (Dykens et al., 1997;Gropman et al., 2006;Garayzábal et al., 2011;Garayzábal, Osório, Lens, & Sampaio, 2014;Howlin & Udwin, 2002;Shayota & Elsea, 2019;Udwin et al., 2001). Discrepancy between comprehension and production probably exacerbates behavioral disorders and seems to be quite typical of the syndrome (Garayzábal et al., 2011;Poisson et al., 2015). ...
... Concerning language, several studies, despite its scarcity, have pointed out difficulties in grammar and their poor vocabulary learning, being comprehension better preserved than production (Dykens et al., 1997;Garayzábal et al., 2011;Gropman et al., 2006;Howlin & Udwin, 2002;Poisson et al., 2015;Udwin et al., 2001). The results obtained through language assessment are in the line of previous studies. ...
... Up to now, early stimulation of neurocognitive functions has not been documented (Poisson et al., 2015). Future research must explore the cognitive and language relation functioning in this neurodevelopmental disorder, looking for early intervention programs. ...
Smith–Magenis syndrome (SMS) is a rare neurodevelopmental disorder with mild-to-moderate intellectual disability. Speech and language impairments have not been well described as part of the SMS phenotype. This study reports the speech and language characteristics presented by a classical SMS case, a 20-year-old woman with positive deletion in the region 17p11.2. The case presented a borderline IQ on verbal and performance Wechsler scales. Language standardized tests (i.e., Peabody, Token test, CEG test and Boehm test) and naturalistic language sample (i.e. conversation and story generation) were used to assess speech and language performance. Speech characteristics included imprecise speech, with a high speech rate, hoarse voice, hypernasality and intelligibility deficits. The performance in all standardized tests was poor. Socio-communicative deficits included repetitive and persistent verbal behavior, difficulties in the use of linguistic strategies to repair communication breakdowns, limited vocabulary production and short overall length utterances with reduced grammatical components. The results contribute to expanding knowledge about the SMS phenotype, also to highlight the need to include speech and language evaluation as part of the clinical assessment of SMS and, at the same time, to draw attention to the need to include early communications skills in language intervention programs.
