Multi‐disciplinary clinical study of Smith‐Magenis syndrome (deletion 17p11.2)

Greenberg, Frank; Lewis, Richard A.; Potocki, Lorraine; Glaze, Daniel G.; Parke, Julie T.; Killian, James M.; Murphy, Mary; Williamson, Daniel; Brown, Frank; Dutton, R.W.; McCluggage, Charles W.; Friedman, Ellen M.; Sulek, Marcelle; Lupski, James R.

doi:10.1002/(sici)1096-8628(19960329)62:3<247::aid-ajmg9>3.3.co;2-9

Cited by 54 publications

(120 citation statements)

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“…30 The disorders in this study, del 2q23.1, SMS and FXS, all clearly share common sleep phenotypes, such as difficulty falling asleep, shorter sleep duration, or night-waking episodes. 31,32 Although RAI1 and FMR1 have been shown to regulate or affect expression of circadian rhythm genes, 23,28 published sleep data suggest that SMS has a more severe sleep phenotype than FXS. 32,33 In addition, from this study, SMS may have more similar sleep phenotype to del 2q23.1 than FXS because of the more frequent concerns for daytime sleepiness and napping.…”

Section: Discussionmentioning

confidence: 99%

MBD5 haploinsufficiency is associated with sleep disturbance and disrupts circadian pathways common to Smith–Magenis and fragile X syndromes

et al. 2014

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Individuals with autism spectrum disorders (ASD) who have an identifiable single-gene neurodevelopmental disorder (NDD), such as fragile X syndrome (FXS, FMR1), Smith-Magenis syndrome (SMS, RAI1), or 2q23.1 deletion syndrome (del 2q23.1, MBD5) share phenotypic features, including a high prevalence of sleep disturbance. We describe the circadian deficits in del 2q23.1 through caregiver surveys in which we identify several frequent sleep anomalies, including night/early awakenings, coughing/ snoring loudly, and difficulty falling asleep. We couple these findings with studies on the molecular analysis of the circadian deficits associated with haploinsufficiency of MBD5 in which circadian gene mRNA levels of NR1D2, PER1, PER2, and PER3 were altered in del 2q23.1 lymphoblastoid cell lines (LCLs), signifying that haploinsufficiency of MBD5 can result in dysregulation of circadian rhythm gene expression. These findings were further supported by expression microarrays of MBD5 siRNA knockdown cells that showed significantly altered expression of additional circadian rhythm signaling pathway genes. Based on the common sleep phenotypes observed in del 2q23.1, SMS, and FXS patients, we explored the possibility that MBD5, RAI1, and FMR1 function in overlapping circadian rhythm pathways. Bioinformatic analysis identified conserved putative E boxes in MBD5 and RAI1, and expression levels of NR1D2 and CRY2 were significantly reduced in patient LCLs. Circadian and mTOR signaling pathways, both associated with sleep disturbance, were altered in both MBD5 and RAI1 knockdown microarray data, overlapping with findings associated with FMR1. These data support phenotypic and molecular overlaps across these syndromes that may be exploited to provide therapeutic intervention for multiple disorders. Significant sleep problems are highly prevalent in individuals with ASD. 2 Parents of children with ASD report 50-80% prevalence of sleep problems compared with a 9-50% prevalence rate reported by parents of age-matched typically developing children. 2 Common sleep etiological factors that are present in children with ASD are rapid eye movement sleep abnormalities, dysregulation of melatonin synthesis, difficulty in settling to sleep, night waking, irregular sleep patterns, short-duration sleep, and daytime sleepiness. 2,3 Persistent sleep problems are thought to adversely affect cognitive, physical, and social function, learning, mood, and behavior in these individuals and, in addition, cause significant stress for families and caretakers. 3 Better understanding of the sleep difficulties experienced by children with ASD may reduce the adverse effects and decrease family stress, possibly with targeted therapies.

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Section: Discussionmentioning

confidence: 99%

MBD5 haploinsufficiency is associated with sleep disturbance and disrupts circadian pathways common to Smith–Magenis and fragile X syndromes

et al. 2014

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“…Abnormal curvature of the spine and scoliosis are present in 50%-75% of individuals with SMS (Greenberg et al 1996).…”

Section: Data Accessmentioning

confidence: 99%

“…>75% of SMS patients exhibit otolaryngologic abnormalities including a hoarse, deep voice (Greenberg et al 1996). 50%-75% exhibit tracheobronchial problems and velopharyngeal insufficiency.…”

Section: Data Accessmentioning

confidence: 99%

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

et al. 2013

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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 (r 2 = 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 3 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.

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“…show clinical signs of nerve damage in the extremities, including muscle weakness, walking difficulties, decreased deep tendon reflexes, and decreased sensitivity to temperature and pain 7) . In addition, developmental and behavioral concerns may be present such as, hyperactivity, impulsiveness, restlessness, distractibility, temper outbursts, and difficulty with sleep as well as progressive hearing loss 8,13) .…”

Section: Approximately Three Quarters Of the Individuals With The Smsmentioning

confidence: 99%

Two cases of Smith-Magenis syndrome

et al. 2009

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=Ab s t r a c t = SmithMagenis syndrome (SMS) is a rare disorder with multiple congenital anomalies caused by a heterozygous interstitial deletion involving chromosome 17p11.2, where the retinoic acid-induced 1 (RAI1) gene is located, or by a mutation of RAI1. Approximately 90% of the patients with SMS have a detectable 17p11.2 microdeletion on fluorescence in-situ hybridization (FISH). SMS is characterized by mental retardation, distinctive behavioral features, craniofacial and skeletal anomalies, speech and developmental delay, and sleep disturbances. Although there are some intervention strategies that help individuals with SMS, there are no reported specific interventions for improving the outcome in children with SMS. Here, we report two cases of SmithMagenis syndrome. ( Ca s eRe p o r t Ca s e1A 9-year-old girl with mental retardation presented to our hospital. The patient was born at 38 weeks gestation; the birth weight was 2,600 g. Development delay was diagnosed by 11 months of age; she could not sit, had a flat, broad nasal bridge, slanting palpebral fissures, protruding forehead, opened mouth, and slanted hands on physical examination.The laboratory findings including the CBC, electrolytes, biochemistry, and thyroid function tests were normal. The patient was reported to have a normal conventional karyotype. The brain MRI showed no specific findings except for a mild ventriculomegaly, and the EEG was normal. At four years of age, the receptive language was at the 24 month level and the expressive language was at the 25 month level.With time the features of the SMS became more apparent.The patient had severe mental retardation, distinctive behavioral features, craniofacial and skeletal anomalies (including brachydactyly), speech and developmental delay, and sleep disturbance (Fig. 1A-1D). On the second cytogenetic study, an interstitial deletion of 17p11.2 was detected by conventional banding and deletion of the FL1 gene was confirmed by FISH using the Cytocell SMS probe (Fig 2A, 2B).

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Multi‐disciplinary clinical study of Smith‐Magenis syndrome (deletion 17p11.2)

Cited by 54 publications

References 0 publications

MBD5 haploinsufficiency is associated with sleep disturbance and disrupts circadian pathways common to Smith–Magenis and fragile X syndromes

MBD5 haploinsufficiency is associated with sleep disturbance and disrupts circadian pathways common to Smith–Magenis and fragile X syndromes

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

Two cases of Smith-Magenis syndrome

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