Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Smith-Magenis syndrome (SMS) is a multiple congenital anomaly/mental retardation syndrome and it is characterized by an interstitial deletion of chromosome 17p11.2. SMS patients have a distinct phenotype which is believed to be caused by haploinsufficiency of one or more genes in the associated deleted region. Five non-deletion patients with classical phenotypic features of SMS have been reported with mutations in the retinoic acid induced 1 (RAI1) gene, located within the SMS critical interval. Happloinsufficiency of the RAI1 gene is likely to be the responsible gene for the majority of the SMS features, but other deleted genes in the SMS region may modify the overall phenotype in the patients with 17p11.2 deletions. SMS is usually diagnosed in the clinical genetic setting by FISH analysis using commercially available probes. We detected a submicroscopic deletion in 17p11.2 using array-CGH with a resolution of approximately 1 Mb in a patient with the SMS phenotype, who was not deleted for the commercially available SMS microdeletion FISH probe. Delineation of the deletion was performed using a 32K tiling BAC-array, containing 32,500 BAC clones. The deletion in this patient was size mapped to 2.7 Mb and covered the RAI1 gene. This case enabled the refinement of the SMS minimum deletion to approximately 650 kb containing eight putative genes and one predicted gene. In addition, it demonstrates the importance to investigate deletion of RAI1 in SMS patients.
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PMID:Detection and delineation of an unusual 17p11.2 deletion by array-CGH and refinement of the Smith-Magenis syndrome minimum deletion to approximately 650 kb. 1617 24

Smith-Magenis syndrome is a multiple congenital anomalies/mental retardation syndrome associated with a heterozygous deletion of chromosome 17p11.2. Seizures have not been formally studied in this population. Our objectives were to estimate the prevalence of seizures and electroencephalographic (EEG) epileptiform abnormalities in patients with Smith-Magenis syndrome with defined chromosomal rearrangements and to describe the spectrum of abnormal EEG patterns. Prolonged video-EEGs were obtained in 60 patients. Eighteen percent of patients reported a seizure history; however, abnormal EEGs were identified in 31 of the 60 subjects and 27 of 31 were epileptiform. Generalized epileptiform patterns were the most common (73%). Most patients with either small or large deletions had an abnormal EEG (83%; 75%) in contrast to those with a common deletion (49%). Our results indicate that epileptiform EEG abnormalities are frequent in patients with Smith-Magenis syndrome. Considering that close to one third of individuals with Smith-Magenis syndrome with epileptiform abnormalities also had a history of clinical seizures, cortical hyperexcitability and epilepsy should be considered an important component of the Smith-Magenis syndrome clinical phenotype.
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PMID:Epilepsy and chromosomal rearrangements in Smith-Magenis Syndrome [del(17)(p11.2p11.2)]. 1656 70

The Smith-Magenis syndrome is a rare, complex multisystemic disorder featuring, mental retardation and multiple congenital anomalies caused by a heterozygous interstitial deletion of chromosome 17p11.2. The phenotype of Smith-Magenis syndrome is characterized by a distinct pattern of features including infantile hypotonia, generalized complacency and lethargy in infancy, minor skeletal (brachycephaly, brachydactyly) and craniofacial features, ocular abnormalities, middle ear and laryngeal abnormalities including hoarse voice, as well as marked early expressive speech and language delays, psychomotor and growth retardation, and a 24-hour sleep disturbance. A striking neurobehavioral pattern of stereotypies, hyperactivity, polyembolokoilamania, onychotillomania, maladaptive and self-injurious and aggressive behavior is observed with increasing age. The diagnosis of Smith-Magenis syndrome is based upon the clinical recognition of a constellation of physical, developmental, and behavioral features in combination with a sleep disorder characterized by inverted circadian rhythm of melatonin secretion. Many of the features of Smith-Magenis syndrome are subtle in infancy and early childhood, and become more recognizable with advancing age. Infants are described as looking "cherubic" with a Down syndrome-like appearance, whereas with age the facial appearance is that of relative prognathism. Early diagnosis requires awareness of the often subtle clinical and neurobehavioral phenotype of the infant period. Speech delay with or without hearing loss is common. Most children are diagnosed in mid-childhood when the features of the disorder are most recognizable and striking. While improvements in cytogenetic analysis help to bring cases to clinical recognition at an earlier age, this review seeks to increase clinical awareness about Smith-Magenis syndrome by presenting the salient features observed at different ages including descriptions of the neurologic and behavioral features. Detailed review of the circadian rhythm disturbance unique to Smith-Magenis syndrome is presented. Suggestions for management of the behavioral and sleep difficulties are discussed in the context of the authors' personal experience in the setting of an ongoing Smith-Magenis syndrome natural history study.
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PMID:Neurologic and developmental features of the Smith-Magenis syndrome (del 17p11.2). 1664 92

The Smith-Magenis syndrome (SMS) is a distinct multiple congenital anomaly caused by an interstitial deletion of the chromosome 17 p11.2. The phenotype includes dysmorphic features, mental retardation, speech delay, signs of peripheral neuropathy, and neurobehavioral problems. Also sensorineural and conduction hearing loss are described. In children with speech delay the physician should consider a genetic or syndromal disease.
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PMID:[Speech impairment and the Smith-Magenis syndrome]. 1676 29

Smith-Magenis syndrome (SMS) is a multiple congenital anomalies and mental retardation syndrome associated with an interstitial deletion of chromosome 17 band p11.2. The incidence of this microdeletion syndrome is estimated to be 1 in 25,000 individuals. Persons with SMS have a distinctive neurobehavioral phenotype that is characterized by aggressive and self-injurious behaviors and significant sleep disturbances. From December 1990 through September 1999, 58 persons with SMS were enrolled in a 5-day multidisciplinary clinical protocol. Developmental assessments consisting of cognitive level and adaptive behavior were completed in 57 persons. Most patients functioned in the mild-to-moderate range of mental retardation. In addition, we report that patients with SMS have low adaptive functioning with relative strengths in socialization and relative weakness in daily living skills. These data were analyzed in light of the molecular extent of the microdeletion within 17p11.2. We found that the level of cognitive and adaptive functioning does depend on deletion size, and that a small percentage of SMS patients have cognitive function in the borderline range.
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PMID:Cognitive and adaptive behavior profiles in Smith-Magenis syndrome. 1677 14

We report on an 8-year-old girl with near-complete trisomy 17p syndrome due to a de novo unbalanced t(14;17)(p11.2;p11.2). She has features consistent with the previously described cases with complete trisomy 17p, including pre- and post-natal growth retardation, motor and mental retardation, skeletal anomalies, clinodactyly of the 5th finger, hypertrichosis, as well as facial characteristics including microcephaly, receding forehead, ptosis, low-set malformed ears, smooth philtrum, high-arched palate, and a short broad neck. Fluorescence in situ hybridization showed that the breakpoints were p11.2 for both chromosome 14 and 17. Microsatellite analysis showed that the duplicated 17p was of paternal origin, and indicated that the breakpoint involving 17p11.2 is most likely located within the approximately 1-Mb segment from the centromere, and not involving the proximal Smith-Magenis syndrome (SMS) low copy repeat. We compare the clinical features of our patient with those previously reported to further delineate the phenotype of complete trisomy 17p syndrome.
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PMID:Complete trisomy 17p syndrome in a girl with der(14)t(14;17)(p11.2;p11.2). 1683 29

Smith-Magenis syndrome (SMS) is a mental retardation syndrome with distinctive behavioral characteristics, dysmorphic features and congenital anomalies ascribed to an interstitial deletion of chromosome 17p11.2. Severe sleep disturbances and maladaptative daytime behavior have been linked to an abnormal circadian secretion pattern of melatonin, with a diurnal instead of nocturnal secretion of this hormone. SMS provides a demonstration of a biological basis for sleep disorder in a genetic disease. Considering that clock genes mediate the generation of the circadian rhythm, haploinsufficiency for a circadian system gene, mapping to chromosome 17p11.2 might cause the inversion of the melatonin circadian rhythm in SMS. The disorder of circadian timing in SMS might also affect the entrainment pathway (retinohypothalamic tract), pacemaker functions (suprachiasmatic nucleus) or synthesis and release of melatonin by the pineal gland. Elucidating pathophysiological mechanisms of behavioral phenotypes in genetic disease can provide an original therapeutic approach in SMS: blockade of endogenous melatonin production during the day combined with exogenous melatonin administration in the evening.
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PMID:Inverted rhythm of melatonin secretion in Smith-Magenis syndrome: from symptoms to treatment. 1689 Apr 50

Smith-Magenis syndrome (SMS) is a multiple congenital anomalies/mental retardation disorder characterized by distinct craniofacial features and neurobehavioral abnormalities usually associated with an interstitial deletion in 17p11.2. Heterozygous point mutations in the retinoic acid induced 1 gene (RAI1) have been reported in nine SMS patients without a deletion detectable by fluorescent in situ hybridization (FISH), implicating RAI1 haploinsufficiency as the cause of the major clinical features in SMS. All of the reported point mutations are unique and de novo. RAI1 contains a polymorphic CAG repeat and encodes a plant homeo domain (PHD) zinc finger-containing transcriptional regulator. We report a novel RAI1 frameshift mutation, c.3103delC, in a non-deletion patient with many SMS features. The deletion of a single cytosine occurs in a heptameric C-tract (CCCCCCC), the longest mononucleotide repeat in the RAI1 coding region. Interestingly, we had previously reported a frameshift mutation, c.3103insC, in the same mononucleotide repeat. Furthermore, all five single base frameshift mutations preferentially occurred in polyC but not polyG tracts. We also investigated the distribution of the polymorphic CAG repeats in both the normal population and the SMS patients as one potential molecular mechanism for variability of clinical expression. In this limited data set, there was no significant association between the length of CAG repeats and the SMS phenotype. However, we identified a 5-year-old girl with an apparent SMS phenotype who was a compound heterozygote for an RAI1 missense mutation inherited from her father and a polyglutamine repeat of 18 copies, representing the largest known CAG repeat in this gene, inherited from her mother.
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PMID:RAI1 point mutations, CAG repeat variation, and SNP analysis in non-deletion Smith-Magenis syndrome. 1704 42

MLPA analysis for a panel of syndromes with mental retardation (MRS-MLPA) was used for investigation of 258 mentally retarded and dysmorphic patients with normal conventional karyotypes (P064 probe set, MRC-Holland, for detection of (micro)deletions associated with 1p36-deletion, Sotos, Williams-Beuren, Prader-Willi, Angelman, Miller-Dieker, Smith-Magenis, and 22q11-deletion syndromes). Patients were initially referred for HR-CGH analysis and MRS-MLPA was performed retrospectively. MRS-MLPA analysis revealed imbalances in 15/258 patients (5.8%). Ten deletions were identified, including deletions of 1p36, 5q35 (Sotos syndrome), 7q11 (Williams-Beuren syndrome), 17p11 (Smith-Magenis syndrome), 15q11 (Angelman syndrome) and 22q11. Duplications were detected in 5q35, 7q11, 17p13, 17p11 and 22q11. We reviewed another 170 patients referred specifically for MRS-MLPA analysis. Eighty of these patients were referred with a clinical suspicion of a specific syndrome, which was confirmed in 17 patients (21.3%). The remaining 90 patients were referred because of mental retardation and dysmorphism but without suspicion of a specific syndrome. Seven imbalances, including four duplications, were detected in these 90 patients (7.8%). Clinical data regarding three patients investigated by MRS-MLPA are presented. The imbalances carried by these patients include a small interstitial 1p36 deletion, a small duplication of 5q35 (encompassing the NSD1 gene, which is deleted/mutated in Sotos syndrome) and a duplication of 7q11 (reciprocal of the Williams-Beuren syndrome deletion), respectively. MRS-MLPA allows testing for a number of micro-deletions/-duplications in a single experiment, thereby filling a gap between array techniques and single locus techniques. MRS-MLPA combined with Subtelomeric MLPA represents an attractive first test in a clinical algorithm for mental retardation.
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PMID:MLPA analysis for a panel of syndromes with mental retardation reveals imbalances in 5.8% of patients with mental retardation and dysmorphic features, including duplications of the Sotos syndrome and Williams-Beuren syndrome regions. 1709 Mar 94

The duplication 17p11.2 syndrome, associated with dup(17)(p11.2p11.2), is a recently recognized syndrome of multiple congenital anomalies and mental retardation and is the first predicted reciprocal microduplication syndrome described--the homologous recombination reciprocal of the Smith-Magenis syndrome (SMS) microdeletion (del(17)(p11.2p11.2)). We previously described seven subjects with dup(17)(p11.2p11.2) and noted their relatively mild phenotype compared with that of individuals with SMS. Here, we molecularly analyzed 28 additional patients, using multiple independent assays, and also report the phenotypic characteristics obtained from extensive multidisciplinary clinical study of a subset of these patients. Whereas the majority of subjects (22 of 35) harbor the homologous recombination reciprocal product of the common SMS microdeletion (~3.7 Mb), 13 subjects (~37%) have nonrecurrent duplications ranging in size from 1.3 to 15.2 Mb. Molecular studies suggest potential mechanistic differences between nonrecurrent duplications and nonrecurrent genomic deletions. Clinical features observed in patients with the common dup(17)(p11.2p11.2) are distinct from those seen with SMS and include infantile hypotonia, failure to thrive, mental retardation, autistic features, sleep apnea, and structural cardiovascular anomalies. We narrow the critical region to a 1.3-Mb genomic interval that contains the dosage-sensitive RAI1 gene. Our results refine the critical region for Potocki-Lupski syndrome, provide information to assist in clinical diagnosis and management, and lend further support for the concept that genomic architecture incites genomic instability.
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PMID:Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical interval that can convey an autism phenotype. 1735 70


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