Smith-Magenis Syndrome Research Articles

Dietary regimens modify early onset of obesity in mice haploinsufficient for Rai1.

Smith-Magenis syndrome is a complex genomic disorder in which a majority of individuals are obese by adolescence. While an interstitial deletion of chromosome 17p11.2 is the leading cause, mutation or deletion of the RAI1 gene alone results in most features of the disorder. Previous studies have shown that heterozygous knockout of Rai1 results in an obese phenotype in mice and that Smith-Magenis syndrome mouse models have a significantly reduced fecundity and an altered transmission pattern of the mutant Rai1 allele, complicating large, extended studies in these models. In this study, we show that breeding C57Bl/6J Rai1+/− mice with FVB/NJ to create F1 Rai1+/− offspring in a mixed genetic background ameliorates both fecundity and Rai1 allele transmission phenotypes. These findings suggest that the mixed background provides a more robust platform for breeding and larger phenotypic studies. We also characterized the effect of dietary intake on Rai1+/− mouse growth during adolescent and early adulthood developmental stages. Animals fed a high carbohydrate or a high fat diet gained weight at a significantly faster rate than their wild type littermates. Both high fat and high carbohydrate fed Rai1+/− mice also had an increase in body fat and altered fat distribution patterns. Interestingly, Rai1+/− mice fed different diets did not display altered fasting blood glucose levels. These results suggest that dietary regimens are extremely important for individuals with Smith- Magenis syndrome and that food high in fat and carbohydrates may exacerbate obesity outcomes.

Retinoic acid induced-1 (Rai1) regulates craniofacial and brain development in Xenopus

Retinoic acid induced-1 (RAI1) is an important yet understudied histone code reader that when mutated in humans results in Smith–Magenis syndrome (SMS), a neurobehavioral disorder accompanied by signature craniofacial abnormalities. Despite previous studies in mouse and human cell models, very little is known about the function of RAI1 during embryonic development. In the present study, we have turned to the model vertebrates Xenopus laevis and Xenopus tropicalis to better understand the developmental roles of Rai1. First we demonstrate that the Rai1 protein sequence is conserved in frogs, especially in known functional domains. By in situ hybridization we revealed expression of rai1 in the developing craniofacial tissues and the nervous system. Knockdown of Rai1 using antisense morpholinos resulted in defects in the developing brain and face. In particular, Rai1 morphants display midface hypoplasia and malformed mouth shape analogous to defects in humans with SMS. These craniofacial defects were accompanied with aberrant neural crest migration and reduction in the size of facial cartilage elements. Rai1 morphants also had defects in axon patterns and decreased forebrain ventricle size. Such brain defects correlated with a decrease in the neurotrophic factor, bdnf, and increased forebrain apoptosis. Our results emphasize a critical role of Rai1 for normal neural and craniofacial development, and further the current understanding of potential mechanisms that cause SMS.

Three rare diseases in one Sib pair: RAI1, PCK1, GRIN2B mutations associated with Smith–Magenis Syndrome, cytosolic PEPCK deficiency and NMDA receptor glutamate insensitivity

The National Institutes of Health Undiagnosed Diseases Program evaluates patients for whom no diagnosis has been discovered despite a comprehensive diagnostic workup. Failure to diagnose a condition may arise from the mutation of genes previously unassociated with disease. However, we hypothesized that this could also co-occur with multiple genetic disorders. Demonstrating a complex syndrome caused by multiple disorders, we report two siblings manifesting both similar and disparate signs and symptoms. They shared a history of episodes of hypoglycemia and lactic acidosis, but had differing exam findings and developmental courses. Clinical acumen and exome sequencing combined with biochemical and functional studies identified three genetic conditions. One sibling had Smith–Magenis Syndrome and a nonsense mutation in the RAI1 gene. The second sibling had a de novo mutation in GRIN2B, which resulted in markedly reduced glutamate potency of the encoded receptor. Both siblings had a protein-destabilizing homozygous mutation in PCK1, which encodes the cytosolic isoform of phosphoenolpyruvate carboxykinase (PEPCK-C). In summary, we present the first clinically-characterized mutation of PCK1 and demonstrate that complex medical disorders can represent the co-occurrence of multiple diseases.

The use of fluorescence in situhybridization techniques in the detection of microdeletion syndromes

Background Microdeletion syndromes are a heterogenous group of disorder caused by the deletion of specific regions of chromosomal DNA causing haplo insufficiencies for important genes [1]. These deletions are difficult to visualize using standard cytogenetic techniques. Fluorescence in situ hybridization (FISH) can resolve these submicroscopic deletions to a lower limit of approximately 3MB and has therefore become the method of choice for the diagnosis of these disorders. Deoxyribonucleic acid (DNA) FISH probes can be used in metaphase and interphase cells to detect these specific regions of deletion probes [2]. The region deleted is known as typically deleted region (TDR) or critical region. There are different microdeletion syndromes such as Prader-Willi/Angelman syndrome, William’s, DiGeorge, SmithMagenis and Miller-Dieker syndromes. Of these, FISH probes for Prader-Willi/Angelman, William’s and DiGeorge syndromes are currently available in our laboratory. This study aimed to compare between cultured and uncultured peripheral blood using Fluorescence in situ hybridization technique for the detection of microdeletion syndromes and to study the concordance rate between the two methods.

Autism spectrum symptoms in Smith–Magenis syndrome and Williams syndrome: comparisons and contrasts

Objectives: Genetic syndromes with distinctive cognitive and behavioural phenotypes — such as Smith–Magenis syndrome (SMS) and Williams syndrome (WS) — offer unique opportunities to explore the links between specific genes and neurodevelopmental disorders. While some studies have reported the occurrence of autistic symptoms in SMS, evidence for such symptomatology in WS is scarcer. This study is the first to compare and contrast levels of autistic symptoms in SMS and WS.Methods: Parents/caregivers of 11 individuals with SMS and 14 individuals with WS completed the Social Communication Questionnaire.Results: Results indicate that both syndromes present, albeit in distinct degrees, behavioural signs of the autistic spectrum. The SMS group scored significantly higher on both current and lifetime symptoms. The mean lifetime form score of the SMS group (particularly males) was consonant with the presence of an autism spectrum disorder. Regarding the WS group, even though the mean score was below the clinical threshold, it was still above what has been reported in typically developing samples.Conclusion: Our study contributes to a better definition of the neurobehavioural profiles of SMS and WS, as it offers comparisons and contrasts that may, in turn, prove beneficial for early diagnosis and intervention.

Effects of Behavior Problems, Family Functioning, and Family Coping on Parent Stress in Families with a Child with Smith-Magenis Syndrome

Smith Magenis Syndrome (SMS) is a rare genetic syndrome most commonly caused by a microdeletion on chromosome 17 p11.2. It is associated with a pattern of physical, developmental, and behavioral characteristics including intellectual disability, sleep disturbance, and a variety of behavior problems. The purpose was to examine the relationship between maladaptive behaviors in children with SMS and parent stress, and to determine whether family functioning and effective parent coping strategies may alleviate the impact of child maladaptive behaviors on parent stress. Data were collected on 25 individuals with SMS ages 1.4 to 19.4 years old. Parents were interviewed using the Vineland Adaptive Behavior Scale (VABS; Sparrow et al. 1984), the Achenbach Child Behavior Checklist (CBCL; Achenbach 1991), the Family Assessment Device-General Functioning Scale (Epstein et al. 1983), the Family Crisis Oriented Personal Evaluation Scales (McCubin et al. 1991), the Parental Stress Index-3rd edition (Abidin 1995), and the Stress Index for Parents of Adolescents (Abidin 1995). Using multiple hierarchical regression analyses we found that maladaptive behaviors (CBCL internalizing and externalizing behaviors) affected parent stress; however, we also saw that parent stress was alleviated in well-functioning families. Maladaptive behaviors did not have a significant negative impact on life stress.

Expression in the human brain of retinoic acid induced 1, a protein associated with neurobehavioural disorders

Retinoic acid induced 1 (RAI1) is a protein of uncertain mechanism of action which nevertheless has been the focus of attention because it is a major contributing factor in several human developmental disorders including Smith–Magenis and Potocki–Lupski syndromes. Further, RAI1 may be linked to adult neural disorders with developmental origins such as schizophrenia and autism. The protein has been extensively examined in the rodent but very little is known about its distribution in the human central nervous system. This study demonstrated the presence of RAI1 transcript in multiple regions of the human brain. The cellular expression of RAI1 protein in the human brain was found to be similar to that described in the mouse, with high levels in neurons, but not glia, of the dentate gyrus and cornus ammonis of the hippocampus. In the cerebellum, a second region of high expression, RAI1 was present in Purkinje cells, but not granule cells. RAI1 was also found in neurons of the occipital cortex. The expression of this retinoic acid-induced protein matched well in the hippocampus with expression of the retinoic acid receptors. The subcellular distribution of human neuronal RAI1 indicated its presence in both cytoplasm and nucleus. Overall, human RAI1 protein was found to be a highly expressed neuronal protein whose distribution matches well with its role in cognitive and motor skills.

The analysis of genetic aberrations in children with inherited neurometabolic and neurodevelopmental disorders.

Inherited encephalopathies include a broad spectrum of heterogeneous disorders. To provide a correct diagnosis, an integrated approach including genetic testing is warranted. We report seven patients with difficult to diagnose inborn paediatric encephalopathies. The diagnosis could not be attained only by means of clinical and laboratory investigations and MRI. Additional genetic testing was required. Cytogenetics, PCR based tests, and array-based comparative genome hybridization were performed. In 4 patients with impaired language abilities we found the presence of microduplication in the region 16q23.1 affecting two dose-sensitive genes: WWOX (OMIM 605131) and MAF (OMIM 177075) (1 case), an interstitial deletion of the 17p11.2 region (2 patients further diagnosed as Smith-Magenis syndrome), and deletion encompassing first three exons of Myocyte Enhancer Factor gene 2MEF2C (1 case). The two other cases represented progressing dystonia. Characteristic GAG deletion in DYT1 consistently with the diagnosis of torsion dystonia was confirmed in 1 case. Last enrolled patient presented with clinical picture consistent with Krabbe disease confirmed by finding of two pathogenic variants of GALC gene and the absence of mutations in PSAP. The integrated diagnostic approach including genetic testing in selected examples of complicated hereditary diseases of the brain is largely discussed in this paper.

Mosaic microdeletion of 17p11.2–p12 and duplication of 17q22–q24 in a girl with Smith–Magenis phenotype and peripheral neuropathy

We report on a girl with a de novo mosaic derivative chromosome 17 involving a 7.4 Mb deletion of chromosome region 17p11.2 to 17p12 and a duplication of a 12.35 Mb region at 17q22 to 17q24. She was ascertained because of developmental delay, peripheral neuropathy, brachydactyly and minor anomalies. The derivative chromosome was present in approximately 12% of lymphocytes based on FISH studies, and was detected by array comparative genomic hybridization. To our knowledge, this is the third case of mosaicism involving deletion of the 17p11.2 region and the lowest level of mosaicism reported in a patient with Smith-Magenis syndrome (SMS).

Inherited dup(17)(p11.2p11.2): Expanding the phenotype of the Potocki–Lupski syndrome

Potocki-Lupski syndrome (PTLS, OMIM: 610883) is a microduplication syndrome characterized by infantile hypotonia, failure to thrive, cardiovascular malformations, developmental delay, intellectual disability, and behavior abnormalities, the latter of which can include autism spectrum disorder. The majority of individuals with PTLS harbor a de novo microduplication of chromosome 17p11.2 reciprocal to the common recurrent 3.6 Mb microdeletion in the Smith-Magenis syndrome critical region. Here, we report on the transmission of the PTLS duplication across two generations in two separate families. Individuals in these families presented initially with developmental delay, behavior problems, and intellectual disability. We provide a detailed review of the clinical and developmental phenotype of inherited PTLS in both families. This represents the second report (second and third families) of PTLS in a parent-child pair and exemplifies the under-diagnosis of this and likely other genetic conditions in adults with intellectual disability and/or psychiatric disorders.

Diet-Induced Over-Expression of Flightless-I Protein and Its Relation to Flightlessness in Mediterranean Fruit Fly, Ceratitis capitata

The Mediterranean fruit fly (medfly), Ceratitis capitata is among the most economically important pests worldwide. Understanding nutritional requirement helps rearing healthy medfly for biocontrol of its population in fields. Flight ability is a high priority criterion. Two groups of medfly larvae were reared with two identical component diets except one with fatty acids (diet A) and another without it (diet B). Adults from larvae reared on diet B demonstrated 20±8% of normal flight ability, whereas those from larvae reared on diet A displayed full flight ability of 97±1%. Proteomes were profiled to compare two groups of medfly pupae using shotgun proteomics to study dietary effects on flight ability. When proteins detected in pupae A were compared with those in pupae B, 233 and 239 proteins were, respectively, under- and over-expressed in pupae B, while 167 proteins were overlapped in both pupae A and B. Differential protein profiles indicate that nutritional deficiency induced over-expression of flightless-I protein (fli-I) in medfly. All proteins were subjected to Ingenuity Pathway Analysis (IPA) to create 13 biological networks and 17 pathways of interacting protein clusters in human ortholog. Fli-I, leucine-rich repeat (LRR)-containing G protein-coupled receptor 2, LRR protein soc-2 and protein wings apart-like were over-expressed in pupae B. Inositol-1,4,5-trisphosphate receptor, protocadherin-like wing polarity protein stan and several Wnt pathway proteins were under-expressed in pupae B. These results suggest down-regulation of the Wnt/wingless signaling pathway, which consequently may result in flightlessness in pupae B. The fli-I gene is known to be located within the Smith-Magenis syndrome (SMS) region on chromosome 17, and thus, we speculate that nutritional deficiency might induce over-expression of fli-I (or fli-I gene) and be associated with human SMS. However, more evidence would be needed to confirm our speculation.

Neurodevelopmental features of Smith–Magenis syndrome: strengths and weaknesses

Objectives: This study examined data on multidimensional functioning in a group of individuals with Smith–Magenis syndrome (SMS).Methods: Parents of 19 children, adolescents, and young adults with SMS were interviewed on developmental, physical, medical, behavioral, and social-communicative aspects.Results: The data presented here provided relevant neurodevelopmental information, and focused not only on problems and deficits, but also on areas of relative strength, particularly social.Discussion: Our study contributed to further the understanding on the prevalence of a broad set of characteristics in a sample of individuals with SMS from a wide age range.

The nature of social preference and interactions in Smith–Magenis syndrome

This natural observation study was designed to evaluate hypothesized elevated 'attention-seeking' and preference for adult attention in Smith-Magenis syndrome. Ten children with Smith-Magenis syndrome were observed across one school day, together with an age matched sample of 10 children with Down syndrome. Levels of attention given to, and vigilance for, adults and peers were recorded and compared. Sequences of behaviour were analyzed to evaluate the temporal relationships between giving and receiving attention during adult-child interactions. Compared to children with Down syndrome, children with Smith-Magenis syndrome gave preferential attention to adults and looked towards adults significantly more than they looked towards peers. Sequential analyses revealed that while children with Smith-Magenis syndrome did not initiate interactions with adults more than children with Down syndrome did, reciprocity between child and adult social behaviours in Smith-Magenis syndrome within interactions was compromised. This less synchronous sequence of child and adult interactions in Smith-Magenis syndrome may be the result of children with Smith-Magenis syndrome attempting to initiate interaction at times when it is unavailable. The marked preference for interacting with adults over peers in Smith-Magenis syndrome indicates atypicality of social interaction in this syndrome.

Copy Number Variation: What Is It and What Has It Told Us About Child Psychiatric Disorders?

Copy number variation is now recognized as an important class of risk factor for several child psychiatric disorders. In this article, we first explain what copy number variants (CNVs) are. We then consider key findings and what these have told us about the etiology of these conditions. Finally, we discuss whether these findings can yet translate into clinical practice.

Evolution and diversity of copy number variation in the great ape lineage

Copy number variation (CNV) contributes to disease and has restructured the genomes of great apes. The diversity and rate of this process, however, have not been extensively explored among great ape lineages. We analyzed 97 deeply sequenced great ape and human genomes and estimate 16% (469 Mb) of the hominid genome has been affected by recent CNV. We identify a comprehensive set of fixed gene deletions (n = 340) and duplications (n = 405) as well as >13.5 Mb of sequence that has been specifically lost on the human lineage. We compared the diversity and rates of copy number and single nucleotide variation across the hominid phylogeny. We find that CNV diversity partially correlates with single nucleotide diversity (r2 = 0.5) and recapitulates the phylogeny of apes with few exceptions. Duplications significantly outpace deletions (2.8-fold). The load of segregating duplications remains significantly higher in bonobos, Western chimpanzees, and Sumatran orangutans—populations that have experienced recent genetic bottlenecks (P = 0.0014, 0.02, and 0.0088, respectively). The rate of fixed deletion has been more clocklike with the exception of the chimpanzee lineage, where we observe a twofold increase in the chimpanzee–bonobo ancestor (P = 4.79 × 10−9) and increased deletion load among Western chimpanzees (P = 0.002). The latter includes the first genomic disorder in a chimpanzee with features resembling Smith-Magenis syndrome mediated by a chimpanzee-specific increase in segmental duplication complexity. We hypothesize that demographic effects, such as bottlenecks, have contributed to larger and more gene-rich segments being deleted in the chimpanzee lineage and that this effect, more generally, may account for episodic bursts in CNV during hominid evolution.

Circadian abnormalities in mouse models of smith–magenis syndrome: Evidence for involvement of RAI1

Smith-Magenis syndrome (SMS; OMIM 182290) is a genomic disorder characterized by multiple congenital anomalies, intellectual disability, behavioral abnormalities, and disordered sleep resulting from an ~3.7 Mb deletion copy number variant (CNV) on chromosome 17p11.2 or from point mutations in the gene RAI1. The reciprocal duplication of this region results in another genomic disorder, Potocki-Lupski syndrome (PTLS; OMIM 610883), characterized by autism, intellectual disability, and congenital anomalies. We previously used chromosome-engineering and gene targeting to generate mouse models for PTLS (Dp(11)17/+), and SMS due to either deletion CNV or gene knock-out (Df(11)17-2/+ and Rai1(+/-) , respectively) and we observed phenotypes in these mouse models consistent with their associated human syndromes. To investigate the contribution of individual genes to the circadian phenotypes observed in SMS, we now report the analysis of free-running period lengths in Rai1(+/-) and Df(11)17-2/+ mice, as well as in mice deficient for another known circadian gene mapping within the commonly deleted/duplicated region, Dexras1, and we compare these results to those previously observed in Dp(11)17/+ mice. Reduced free-running period lengths were seen in Df(11)17-2/+, Rai1(+/-) , and Dexras1(-/-) , but not Dexras1(+/-) mice, suggesting that Rai1 may be the primary gene underlying the circadian defects in SMS. However, we cannot rule out the possibility that cis effects between multiple haploinsufficient genes in the SMS critical interval (e.g., RAI1 and DEXRAS1) either exacerbate the circadian phenotypes observed in SMS patients with deletions or increase their penetrance in certain environments. This study also confirms a previous report of abnormal circadian function in Dexras1(-/-) mice.

Daytime somnolence in an adult with smith–magenis syndrome

Daytime somnolence in an adult with smith–magenis syndrome

Response to Benn

Response to Benn

English

Introduction Many neurodevelopmental disorders with intellectual disability and autism spectrum disorder syndromes have overlapping genetic and molecular connections. Effective treatments for such genetic neurodevelopmental disorders have not been established yet. Possible reasons include the lack of suitable disease models of human neurons and a limited understanding of the etiological and neurobiological mechanisms of the brain. The reprogramming technology of somatic cells allows the generation of induced pluripotent stem cells from the patients’ fibroblasts that subsequently differentiate into neuronal cells carrying the genetic variations that cause the specific disorders. Investigation into monogenic neurodevelopmental disorders has proved advantageous in their analysis, and there are a number of successful reports that have been published. This approach has a promising potential, but some technical caveats need to be addressed like the variability observed between cell lines that emerge after reprogramming. Another challenge involves differentiating the reprogrammed cells into cell types that are implicated in the disease phenotypes, with minimum heterogeneity and variability. Modelling monogenic neurological disorders with genetic mutations has been successful and is considered as a basic tool for establishing functional human neurons to reveal disease specific phenotypes. This critical review discusses the use of cellular reprogramming to study intellectual disability and neurodevelopmental disorders. Conclusion Methodology and analysis need to be improved to detect important differences between controls and patients’ cell lines. Technology has been improving over the last few years. Studies with improved induced pluripotent stem cell technologies in diseases that show highly penetrant and early onset syndromes, such as Smith-Magenis syndrome, PotockiLupski syndrome, Pitt-Hopkins syndrome and mental retardation type 1, will not only improve the understanding of these respective syndromes but also provide useful insights into the complex nature of brain disorders, including autism spectrum disorders.

Fisioterapia en el síndrome de Smith-Magenis: a propósito de un caso

The Smith-Magenis syndrome is a genetic psychomotor development disorder included in the group of rare diseases. In the clinical case presented, we performed an initial assessment of coordination, gait and balance using four different tests. These were psychomotor development test (TEPSI scale), Purdue pegboard, time up and go test, and a circuit designed specifically for this clinical case. At the end of the 3 months of treatment, and based on recreational type activities, a final assessment was made with the same tests. Significant objectives differences in the results as well as subjective improvement reported by the patient's parents were found. Although there is little evidence on physiotherapy treatment for this syndrome, in accordance with the results found, we believe that this treatment is totally justified in the comprehensive approach to patients suffering this disorder.