RESUMO
Hyperexcitability of brain circuits is a common feature of autism spectrum disorders (ASDs). Genetic deletion of a chromatin-binding protein, retinoic acid induced 1 (RAI1), causes Smith-Magenis syndrome (SMS). SMS is a syndromic ASD associated with intellectual disability, autistic features, maladaptive behaviors, overt seizures, and abnormal electroencephalogram (EEG) patterns. The molecular and neural mechanisms underlying abnormal brain activity in SMS remain unclear. Here we show that panneural Rai1 deletions in mice result in increased seizure susceptibility and prolonged hippocampal seizure duration in vivo and increased dentate gyrus population spikes ex vivo. Brain-wide mapping of neuronal activity pinpointed selective cell types within the limbic system, including the hippocampal dentate gyrus granule cells (dGCs) that are hyperactivated by chemoconvulsant administration or sensory experience in Rai1-deficient brains. Deletion of Rai1 from glutamatergic neurons, but not from gamma-aminobutyric acidergic (GABAergic) neurons, was responsible for increased seizure susceptibility. Deleting Rai1 from the Emx1Cre-lineage glutamatergic neurons resulted in abnormal dGC properties, including increased excitatory synaptic transmission and increased intrinsic excitability. Our work uncovers the mechanism of neuronal hyperexcitability in SMS by identifying Rai1 as a negative regulator of dGC intrinsic and synaptic excitability.
Assuntos
Síndrome de Smith-Magenis , Camundongos , Animais , Síndrome de Smith-Magenis/genética , Transativadores/genética , Transativadores/metabolismo , Fenótipo , Modelos Animais de Doenças , Cromatina , Hipocampo/metabolismo , Convulsões/genética , TretinoínaRESUMO
Haploinsufficiency in retinoic acid induced 1 (RAI1) causes Smith-Magenis syndrome (SMS), a severe neurodevelopmental disorder characterized by neurocognitive deficits and obesity. Currently, curative treatments for SMS do not exist. Here, we take a recombinant adeno-associated virus (rAAV)-clustered regularly interspaced short palindromic repeats activation (CRISPRa) approach to increase expression of the remaining intact Rai1 allele. Building upon our previous work that found the paraventricular nucleus of hypothalamus plays a central role in SMS pathogenesis, we performed paraventricular nucleus of hypothalamus-specific rAAV-CRISPRa therapy by increasing endogenous Rai1 expression in SMS (Rai1±) mice. We found that rAAV-CRISPRa therapy rescues excessive repetitive behavior, delays the onset of obesity, and partially reduces hyperphagia in SMS mice. Our work provides evidence that rAAV-CRISPRa therapy during early adolescence can boost the expression of healthy Rai1 allele and modify disease progression in a mouse model of Smith-Magenis syndrome.
Assuntos
Síndrome de Smith-Magenis , Camundongos , Animais , Síndrome de Smith-Magenis/genética , Síndrome de Smith-Magenis/terapia , Síndrome de Smith-Magenis/metabolismo , Transativadores/genética , Transativadores/metabolismo , Dependovirus/genética , Dependovirus/metabolismo , Haploinsuficiência , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Obesidade/genéticaRESUMO
The terms developmental epileptic encephalopathy with spike-and-wave activation in sleep (DEE-SWAS) and epileptic encephalopathy with spike-and-wave activation in sleep (EE-SWAS) designate a spectrum of conditions that are typified by different combinations of motor, cognitive, language, and behavioral regression linked to robust spike-and-wave activity during sleep. In this study, we aimed at describing the clinical and molecular findings in "(developmental) epileptic encephalopathy with spike-and-wave activation in sleep" (D)EE-SWAS) patients as well as at contributing to the genetic etiologic spectrum of (D)EE-SWAS. Single nucleotide polymorphism (SNP) array and whole-exome sequencing (WES) techniques were used to determine the underlying genetic etiologies. Of the 24 patients included in the study, 8 (33%) were female and 16 (67%) were male. The median age at onset of the first seizure was 4 years and the median age at diagnosis of (D)EE-SWAS was 5 years. Of the 24 cases included in the study, 13 were compatible with the clinical diagnosis of DEE-SWAS and 11 were compatible with the clinical diagnosis of EE-SWAS. Abnormal perinatal history was present in four cases (17%), and two cases (8%) had a family history of epilepsy. Approximately two-thirds (63%) of all patients had abnormalities detected on brain computerized tomography/magnetic resonance (CT/MR) imaging. After SNP array and WES analysis, the genetic etiology was revealed in 7 out of 24 (29%) cases. Three of the variants detected were novel (SLC12A5, DLG4, SLC9A6). This study revealed for the first time that Smith-Magenis syndrome, SCN8A-related DEE type 13 and SLC12A5 gene variation are involved in the genetic etiology of (D)EE-SWAS. (D)EE-SWAS is a genetically diverse disorder with underlying copy number variations and single-gene abnormalities. In the current investigation, rare novel variations in genes known to be related to (D)EE-SWAS and not previously reported genes to be related to (D)EE-SWAS were discovered, adding to the molecular genetic spectrum. Molecular etiology enables the patient and family to receive thorough and accurate genetic counseling as well as a personalized medicine approach.
Assuntos
Sequenciamento do Exoma , Sono , Humanos , Masculino , Feminino , Criança , Turquia , Pré-Escolar , Sono/genética , Polimorfismo de Nucleotídeo Único , Eletroencefalografia , Espasmos Infantis/genética , Lactente , Estudos de Coortes , Epilepsia/genética , AdolescenteRESUMO
Our study aims to define resting energy expenditure (REE) and describe the main nutritional patterns in a single-center cohort of children with Smith-Magenis syndrome (SMS). REE was calculated using indirect calorimetry. Patients' metabolic status was assessed by comparing measured REE (mREE) with predictive REE (pREE). Patients also underwent multidisciplinary evaluation, anthropometric measurements and an assessment of average energy intake, using a 3-day food diary, which was reviewed by a specialized dietitian. Twenty-four patients (13 M) were included, the median age was 9 years (IC 95%, 6-14 years), 84% had 17p11.2 deletion, and 16% had RAI1 variants. REE was not reduced in SMS pediatric patients, and the mREE did not differ from the pREE. In patients with RAI1 variants (16%, n = 3/24), obesity was more prevalent than those with 17p11.2 deletion (100% vs 38%). Lower proteins intake and higher total energy intake were reported in obese and overweight patients, compared to healthy weight children. No significant difference was found between males and females in energy or macronutrient intake. CONCLUSIONS: In SMS, the onset of obesity is not explained by REE abnormalities, but dietary factors seem to be crucial. Greater concern should be addressed to patients with RAI1 variants. A better understanding of the molecular mechanisms causing obesity in SMS patients could set the basis for possible future targeted therapies. WHAT IS KNOWN: ⢠More than 90% of SMS patients after the age of 10 are overweight or obese. WHAT IS NEW: ⢠Onset of overweight and obesity in SMS pediatric patients is not explained by abnormal resting energy expenditure. ⢠The development of syndrome-specific dietary guidelines for SMS patients should be of utmost relevance and are highly needed.
RESUMO
Smith-Magenis syndrome (SMS) is a neurodevelopmental disorder caused by a 17p11.2 deletion or a pathogenic variant of the RAI1 gene, which lies within the 17p11.2 region. Various psychiatric and neurological disorders have been reported in SMS, with most literature focusing on children and adolescents. To provide an overview of the current knowledge on this topic in adults with SMS, we performed a comprehensive scoping review of the relevant literature. Our findings suggest that many manifestations that are common in childhood persist into adulthood. Neuropsychiatric manifestations in adults with SMS include intellectual disability, autism spectrum- and attention deficit hyperactivity disorder-related features, self-injurious and physical aggressive behaviors, sleep-wake disorders, and seizures. Findings of this review may facilitate optimization of management strategies in adults with SMS, and may guide future studies exploring late-onset psychiatric and neurological comorbidities in SMS.
Assuntos
Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Síndrome de Smith-Magenis , Adulto , Criança , Adolescente , Humanos , Síndrome de Smith-Magenis/genética , Síndrome de Smith-Magenis/patologia , Transativadores , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , AgressãoRESUMO
Loss-of-function CHD2 (chromodomain helicase DNA-binding protein 2) mutations are associated with a spectrum of neurodevelopmental disorders often including early-onset generalized seizures, photosensitivity, and epileptic encephalopathies. Patients show psychomotor delay/intellectual disability (ID), autistic features, and behavior disorders, such as aggression and impulsivity. Most reported cases are sporadic with description of germline mosaicism only in two families. We detect the first case of parental gonosomal CHD2 mosaicism disclosed by two brothers showing mild ID, born to healthy parents. The eldest brother has a history of drug-controlled generalized tonic-clonic seizures and displays sleep disorder and aggressive behavior suggestive of Smith-Magenis syndrome (SMS). Analysis of brothers' DNAs by next-generation sequencing (NGS) custom gene panel for pediatric epilepsy and/or ID disclosed in both the same pathogenic CHD2 variant. Additional NGS experiment on genomic DNA from parents' peripheral blood and from buccal swab raised the suspicion of low-grade gonosomal mosaicism in the unaffected mother subsequently confirmed by digital polymerase chain reaction (dPCR). This report underlines as worthwhile CHD2 screening in individuals presenting ID/developmental delay, with/without epilepsy, and behavior and sleep disorders suggestive of SMS. Detecting a CHD2 variant should prime testing probands' parents by NGS coupled to dPCR on different tissues to exclude/confirm gonosomal mosaicism and define the recurrence risk.
Assuntos
Mosaicismo , Irmãos , Síndrome de Smith-Magenis , Humanos , Masculino , Síndrome de Smith-Magenis/genética , Proteínas de Ligação a DNA/genética , Feminino , Deficiência Intelectual/genética , Criança , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Linhagem , Mutação/genética , Pré-Escolar , FenótipoRESUMO
We report a series of four unrelated adults with Smith-Magenis syndrome (SMS) and concomitant features of Birt-Hogg-Dubé (BHD) syndrome based upon haploinsufficiency for FLCN and characteristic renal cell carcinomas and/or evidence of cutaneous fibrofolliculomas. Three of the cases constitute the first known association of histopathologically verified characteristic BHD-associated renal tumors in adults with SMS; the fourth was identified to have histologically confirmed skin fibrofolliculomas. Molecular analysis documented second-hit FLCN mutations in two of the three cases with confirmed BHD renal pathology. These cases suggest the need to expand management recommendations for SMS to include kidney cancer surveillance starting at 20 years of age, as per the screening recommendations for BHD syndrome.
Assuntos
Síndrome de Birt-Hogg-Dubé , Carcinoma de Células Renais , Neoplasias Renais , Neoplasias Cutâneas , Síndrome de Smith-Magenis , Adulto , Humanos , Síndrome de Birt-Hogg-Dubé/complicações , Síndrome de Birt-Hogg-Dubé/diagnóstico , Síndrome de Birt-Hogg-Dubé/genética , Síndrome de Smith-Magenis/complicações , Detecção Precoce de Câncer , Proteínas Proto-Oncogênicas/genética , Proteínas Supressoras de Tumor/genética , Neoplasias Renais/genética , Carcinoma de Células Renais/genética , Neoplasias Cutâneas/genéticaRESUMO
Smith Magenis syndrome (SMS) is a rare neurobehavioral disorder caused by 17p11.2 microdeletion encompassing Retinoic Acid-Induced 1 (RAI1) gene (90% of cases) or by RAI1 point mutation (10% of cases). The neuropsychological phenotype of individuals with 17p11.2 deletion and in those with RAI1 variants mostly overlaps. However, cardiac defects have been described only in patients with a deletion so far. Here, we present the first case of a patient affected by SMS caused by RAI1 variant in whom a severe congenital pulmonary valve stenosis was diagnosed at birth, requiring trans catheter dilatation in the first month of life. This case expands the phenotypic spectrum associated with RAI1 variants in SMS, describing a previously unreported association with a congenital heart disease.
Assuntos
Cardiopatias Congênitas , Síndrome de Smith-Magenis , Cromossomos Humanos Par 17 , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genética , Humanos , Mutação , Síndrome de Smith-Magenis/diagnóstico , Síndrome de Smith-Magenis/genética , Transativadores/genética , Fatores de Transcrição/genéticaRESUMO
Smith-Magenis syndrome (SMS) is a genetic disorder characterized by multiple congenital anomalies, sleep disturbance, behavioral impairment, and intellectual disability. Its genetic cause has been defined as an alteration in the Retinoic Acid-Induced 1 gene. Cardiac anomalies have been reported since the first description of this condition in patients with 17p11.2 deletion. Variable cardiac defects, including ventricular septal defects, atrial septal defects, tricuspid stenosis, mitral stenosis, tricuspid and mitral regurgitation, aortic stenosis, pulmonary stenosis, mitral valve prolapse, tetralogy of Fallot, and total anomalous pulmonary venous connection, have been anecdotally reported and systematic case series are still lacking. Herein, we define the spectrum of the cardiac phenotype and describe for the first time the cardiac function in a large cohort of pediatric patients with SMS. Revision of the literature and correlations between genotype and cardiac phenotype was performed.
Assuntos
Cardiopatias Congênitas/genética , Coração/fisiopatologia , Deficiência Intelectual/genética , Síndrome de Smith-Magenis/genética , Anormalidades Múltiplas/epidemiologia , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Deleção Cromossômica , Feminino , Genótipo , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/fisiopatologia , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/fisiopatologia , Masculino , Fenótipo , Medicina de Precisão , Síndrome de Smith-Magenis/epidemiologia , Síndrome de Smith-Magenis/fisiopatologia , Adulto JovemRESUMO
Haploinsufficiency of Retinoic Acid Induced 1 (RAI1) causes Smith-Magenis syndrome (SMS), a syndromic autism spectrum disorder associated with craniofacial abnormalities, intellectual disability, and behavioral problems. There is currently no cure for SMS. Here, we generated a genetic mouse model to determine the reversibility of SMS-like neurobehavioral phenotypes in Rai1 heterozygous mice. We show that normalizing the Rai1 level 3-4 wk after birth corrected the expression of genes related to neural developmental pathways and fully reversed a social interaction deficit caused by Rai1 haploinsufficiency. In contrast, Rai1 reactivation 7-8 wk after birth was not beneficial. We also demonstrated that the correct Rai1 dose is required in both excitatory and inhibitory neurons for proper social interactions. Finally, we found that Rai1 heterozygous mice exhibited a reduction of dendritic spines in the medial prefrontal cortex (mPFC) and that optogenetic activation of mPFC neurons in adults improved the social interaction deficit of Rai1 heterozygous mice. Together, these results suggest the existence of a postnatal temporal window during which restoring Rai1 can improve the transcriptional and social behavioral deficits in a mouse model of SMS. It is possible that circuit-level interventions would be beneficial beyond this critical window.
Assuntos
Modelos Animais de Doenças , Haploinsuficiência , Relações Interpessoais , Síndrome de Smith-Magenis/genética , Transtornos do Comportamento Social/prevenção & controle , Transativadores/farmacologia , Adolescente , Animais , Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/patologia , Heterozigoto , Humanos , Masculino , Camundongos , Mutação , Fenótipo , Síndrome de Smith-Magenis/patologia , Transtornos do Comportamento Social/genéticaRESUMO
Smith-Magenis syndrome (SMS) is a genetic syndrome most often caused by a deletion on chromosome 17 or more rarely by a mutation in the retinoic acid-induced 1 gene. The aim of this study was to investigate the Developmental Behavior Checklist (DBC) profile of persons with SMS and the associations between behavioural and emotional problems, age, gender, adaptive behaviour and autism symptomatology. Twenty-eight persons with SMS were represented by their parents in this study. DBC Total scores are reduced with age, but they still show a mean that is clearly above the cut-off of 46. The differences between the age groups <9 years and 9-17 years (p = 0.024) and between the age groups <9 years and >18 years (p = 0.007) are significant. We found a significant decrease in behavioural and emotional problems with age in SMS. We did not find a relationship between adapted behaviour and communication and behavioural and emotional problems.
Assuntos
Deficiência Intelectual , Comportamento Problema , Síndrome de Smith-Magenis , Lista de Checagem , Criança , Humanos , Pais , Síndrome de Smith-Magenis/genéticaRESUMO
AIMS: To assess the effectiveness of iPad use on the attention span of a child with Smith Magenis Syndrome (n = 1), compared to attention span while working on the same tasks manually. METHODS: An AB design with a baseline and an intervention phase was used. Three manual tasks were chosen for the baseline, which matched the participant's intellectual age by the Early Intervention Method: a jigsaw puzzle (six pieces), a shape sorter, and matching pictures. These same tasks were performed on an iPad during the intervention phase. Six baseline and nine intervention phase films were included in the analysis. The 15 films were independently scored twice by two observers: once to observe the types of distractions that occurred (such as standing up from the chair, calling the teacher, or turning around on the chair), and a second time to measure the effective working time. RESULTS: iPad use led to a 45% decrease in the number of total distractions. The effective working time improved by 8% and showed a more consistent range compared to working on tasksbmanually. While task enjoyment was not directly measured, the observers and teachers agreed that working on the iPad appeared to be more enjoyable. CONCLUSIONS: In this single case study the participant showed that in his case iPad use can be effective in decreasing his distractions and therefore can improve his attention span. Enjoyment was higher while working with the iPad than performing tasks manually. This technology could therefore create more learning engagement for the participant, which could positively impact his behavior. Further research into iPad implementation for children with intellectual disabilities, poor fine motor skills, and/or attention deficits is needed.
RESUMO
The experience of having a rare disorder was summarised in a large study as 'falling outside the vast field of knowledge of the professionals'. Parents (31 mothers and 17 fathers) of 32 persons with Smith-Magenis syndrome (SMS) participated in this study. A phenomenological approach was used to analyse the data into topics and themes. Four themes emerged: behavioural challenges displayed, parents' strategies for meeting the challenging behaviours, parents' experiences of their own competence and parents' experiences of professionals' competence and understanding regarding children with SMS and their behaviour challenges. We found that parents of children with SMS experience that they are exposed to severe challenging behaviours from their child. The parents believe that they experience more misunderstandings with professionals and that the challenging behaviours increase because there are some specific characteristics of SMS that professionals are not aware of or do not consider in their support services.
Assuntos
Pais , Comportamento Problema , Síndrome de Smith-Magenis/enfermagem , Apoio Social , Adulto , Criança , Feminino , Humanos , Masculino , Pesquisa Qualitativa , Doenças RarasRESUMO
NCOR1 (nuclear receptor corepressor 1) is a transcriptional coregulatory protein that regulates the balance between histone acetylation and histone deacetylation. NCOR1 is listed as one of the 3,230 dose-sensitive genes which very rarely show truncating mutations in the pediatric population without severe diseases, even in a heterozygous state. In a large cohort study of intellectual disability/autism spectrum disorder, splicing mutations were identified in two individuals, however, the truncating effects of these splicing mutations have not been examined at the transcription level. We describe a 3-year-old girl who had behavior consistent with autism spectrum disorder, a bifid uvula, and early-onset scoliosis. Trio exome analysis showed a de novo heterozygous mutation at the splice donor site in exon 19 of NCOR1, c.2182 + 1G > T (NM_00190440.1). Reverse transcription polymerase chain reaction assay confirmed that the splicing mutation results in skipping of exon 19, a shift in the reading frame and then to nonsense-mediated mRNA decay. This patient represents the first patient who has had unequivocal documentation of haploinsufficient for the NCOR1 gene. Based on our observations, we conclude that NCOR1 is indeed a human disease-causing gene. We further suggest that bifid uvula, a micro form of cleft palate, may well be causally related to de novo NCOR1 haploinsufficiency, in that a previously reported deletion mapping study of atypical Smith-Magenis syndrome patients with large deletions and cleft palate identified that NCOR1, the only loss-of-function-intolerant gene within the region, is located in the smallest region of overlap.
Assuntos
Transtorno do Espectro Autista/genética , Haploinsuficiência/genética , Correpressor 1 de Receptor Nuclear/genética , Organogênese , Palato/anormalidades , Escoliose/genética , Transtorno do Espectro Autista/complicações , Sequência de Bases , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Escoliose/complicações , Escoliose/diagnóstico por imagem , Transcrição GênicaRESUMO
BACKGROUND: The 2013 testing guidelines for determining the human epidermal growth factor receptor 2 (HER2) status include new cutoff points for the HER2/chromosome enumeration probe 17 (CEP17) ratio and the average HER2 copy number per cell, and they recommend using a reflex test with alternative chromosome 17 probes (Ch17Ps) to resolve equivocal HER2 results. This study sought to determine the clinical utility of alternative Ch17Ps in equivocal cases and the effects of equivocal results and/or a change in the HER2 status on patients' outcomes. METHODS: The University of Texas MD Anderson Cancer Center database of HER2 dual-probe fluorescence in situ hybridization results from 2000 to 2010 was searched for cases of invasive breast cancer with HER2/CEP17 ratios < 2 and average HER2 copy numbers < 6 per cell. Cases with HER2 copy numbers of 4 to < 6 (the definition of equivocal HER2 results) were analyzed with alternative Ch17Ps for Smith-Magenis syndrome and retinoic acid receptor α genes. Disease-free survival (DFS) and overall survival (OS) were evaluated with respect to the HER2 copy number with multivariate Cox proportional hazards regression. RESULTS: Among the 3630 patients meeting the inclusion criteria, 137 (4%) had equivocal HER2 results. With alternative Ch17Ps, 35 of 57 equivocal HER2 cases (61%) were upgraded to a positive HER2 status, and 22 cases (39%) remained unchanged. The 5-year DFS and OS adjusted hazard ratios (HRs) for copy numbers of 4 to < 6 versus < 4 were 0.6 (95% confidence interval [CI], 0.3-1.2) and 0.5 (95% CI, 0.2-1.0) with P values of .16 and .66, respectively. In comparison with HER2-negative cases, these CIs indicated that equivocal HER2 results were associated with either a protective effect (HR, < 0.5) or no effect (HR, 1.0). CONCLUSIONS: These findings rule out a significant deleterious effect of equivocal HER2 results. Alternative Ch17Ps may erroneously upgrade the HER2 status; therefore, they cannot be considered reliable in clinical practice. Cancer 2017;123:1115-1123. © 2016 American Cancer Society.
Assuntos
Biomarcadores Tumorais , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Cromossomos Humanos Par 17/genética , Receptor ErbB-2/genética , Neoplasias da Mama/diagnóstico , Estudos de Coortes , Variações do Número de Cópias de DNA , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , PrognósticoRESUMO
Smith-Magenis syndrome (SMS) is a complex genetic disorder caused by interstitial 17p11.2 deletions encompassing multiple genes, including the retinoic acid induced 1 gene-RAI1-or mutations in RAI1 itself. The clinical spectrum includes developmental delay, cognitive impairment, and behavioral abnormalities, with distinctive physical features that become more evident with age. No patients have been reported to have had offspring. We here describe a girl with developmental delay, mainly compromising the speech area, and her mother with mild intellectual disabilities and minor dysmorphic features. Both had sleep disturbance and attention deficit disorder, but no other atypical behaviors have been reported. In both, CGH-array analysis detected a 15q13.3 interstitial duplication, encompassing CHRNA7. However, the same duplication has been observed in several, apparently healthy, maternal relatives. We, thus, performed a whole exome sequencing analysis, which detected a frameshift mutation in RAI1, de novo in the mother, and transmitted to her daughter. No other family members carried this mutation. This is the first report of an SMS patient having offspring. Our experience confirms the importance of searching for alternative causative genetic mechanisms in case of confounding/inconclusive findings such as a CGH-array result of uncertain significance. © 2016 Wiley Periodicals, Inc.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/genética , Mães , Mutação , Núcleo Familiar , Fenótipo , Proteínas Repressoras/genética , Síndrome de Smith-Magenis/diagnóstico , Síndrome de Smith-Magenis/genética , Adulto , Criança , Hibridização Genômica Comparativa , Exoma , Fácies , Feminino , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Linhagem , Reprodutibilidade dos TestesRESUMO
Occurrence of moyamoya syndrome in a patient with Smith-Magenis syndrome (SMS) has previously been reported once in a 10-year-old Asian female. We report a second case of moyamoya in a patient with SMS, in a now 25-year-old Asian female diagnosed with both conditions as a child. In addition to describing her medical and surgical history, we provide a detailed report of her omental transposition, in which the omental circulation was anastomosed to the superior thyroid artery and external jugular vein. To our knowledge, this is the first report of omental transposition for moyamoya in which omental vessels are anastomosed to vessels in the neck, as well as the second report of moyamoya in a patient with SMS.
Assuntos
Doença de Moyamoya/diagnóstico , Doença de Moyamoya/cirurgia , Procedimentos Neurocirúrgicos , Síndrome de Smith-Magenis/genética , Adulto , Povo Asiático , Angiografia Cerebral , Revascularização Cerebral/métodos , Feminino , Artéria Gastroepiploica/cirurgia , Humanos , Deficiência Intelectual , Imageamento por Ressonância Magnética , Doença de Moyamoya/diagnóstico por imagemRESUMO
Mitochondrial morphology is governed by the balance of mitochondrial fusion, mediated by mitofusins and optic atrophy 1 (OPA1), and fission, mediated by dynamin-related protein 1 (Drp1). Disordered mitochondrial dynamics alters metabolism, proliferation, apoptosis and mitophagy, contributing to human diseases, including neurodegenerative syndromes, pulmonary arterial hypertension (PAH), cancer and ischemia/reperfusion injury. Post-translational regulation of Drp1 (by phosphorylation and SUMOylation) is an established means of modulating Drp1 activation and translocation to the outer mitochondrial membrane (OMM). This review focuses on Drp1 adaptor proteins that also regulate fission. The proteins include fission 1 (Fis1), mitochondrial fission factor (Mff) and mitochondrial dynamics proteins of 49 kDa and 51 kDa (MiD49, MiD51). Heterologous MiD overexpression sequesters inactive Drp1 on the OMM, promoting fusion; conversely, increased endogenous MiD creates focused Drp1 multimers that optimize OMM scission. The triggers that activate MiD-bound Drp1 in disease states are unknown; however, MiD51 has a unique capacity for ADP binding at its nucleotidyltransferase domain. Without ADP, MiD51 inhibits Drp1, whereas ADP promotes MiD51-mediated fission, suggesting a link between metabolism and fission. Confusion over whether MiDs mediate fusion (by sequestering inactive Drp1) or fission (by guiding Drp1 assembly) relates to a failure to consider cell types used and to distinguish endogenous compared with heterologous changes in expression. We speculate that endogenous MiDs serve as Drp1-binding partners that are dysregulated in disease states and may be important targets for inhibiting cell proliferation and ischemia/reperfusion injury. Moreover, it appears that the composition of the fission apparatus varies between disease states and amongst individuals. MiDs may be important targets for inhibiting cell proliferation and attenuating ischemia/reperfusion injury.
Assuntos
GTP Fosfo-Hidrolases/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , Dinâmica Mitocondrial , Proteínas Mitocondriais/metabolismo , Fatores de Alongamento de Peptídeos/metabolismo , Animais , Dinaminas , GTP Fosfo-Hidrolases/genética , Humanos , Proteínas Associadas aos Microtúbulos/genética , Mitocôndrias/genética , Doenças Mitocondriais/genética , Proteínas Mitocondriais/genética , Fatores de Alongamento de Peptídeos/genéticaRESUMO
We report a 25-year-old female confirmed to have Smith-Magenis syndrome (SMS) due to a de novo RAI1 variant. Her past history is significant for developmental and intellectual delay, early and escalating maladaptive behaviors, and features consistent with significant sleep disturbance, the etiology of which was not confirmed for over two decades. The diagnosis of SMS was initially suspected in 1998 (at age 12 years), but that was 5 years before the initial report of RAI1 variants as causative of the SMS phenotype; cytogenetic fluorescence in situ hybridization studies failed to confirm an interstitial deletion of 17p11.2. Re-evaluation for suspected SMS was pursued with RAI1 sequencing analysis in response to urgent parental concerns of escalating behaviors and aggression with subsequent incarceration of the subject for assault of a health professional. Genetic analysis revealed a de novo RAI1 (NM_030665.3) nonsense variant, c.5536C>T; p.Q1846X. This case illustrates the importance of confirming the SMS diagnosis, which is associated with cognitive and functional impairment, as well as significant psychiatric co-morbidities and behavioral problems. The diagnosis was particularly relevant to the legal discussion and determination of her competence to stand trial. As other similar cases may exist, this report will help to increase awareness of the possibility of a very late diagnosis of SMS, with the need for re-evaluation of individuals suspected to have SMS who were initially evaluated prior to the identification of the RAI1 gene. © 2016 Wiley Periodicals, Inc.
Assuntos
Códon sem Sentido , Estudos de Associação Genética , Fenótipo , Síndrome de Smith-Magenis/diagnóstico , Síndrome de Smith-Magenis/genética , Fatores de Transcrição/genética , Adulto , Deleção Cromossômica , Cromossomos Humanos Par 17 , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Diagnóstico Tardio , Fácies , Feminino , Humanos , Linhagem , Polimorfismo de Nucleotídeo Único , TransativadoresRESUMO
BACKGROUND: Heterozygous C104R or A181E TNF receptor superfamily member 13b (TNFRSF13B) mutations impair removal of autoreactive B cells, weaken B-cell activation, and convey to patients with common variable immune deficiency (CVID) an increased risk for autoimmunity. How mutant transmembrane activator and CAML interactor (TACI) influences wild-type TACI function is unclear; different models suggest either a dominant negative effect or haploinsufficiency. OBJECTIVE: We investigated potential TACI haploinsufficiency by analyzing patients with antibody-deficient Smith-Magenis syndrome (SMS) who possess only 1 TNFRSF13B allele and antibody-deficient patients carrying one c.204insA TNFRSF13B null mutation. METHODS: We tested the reactivity of antibodies isolated from single B cells from patients with SMS and patients with a c.204insA TNFRSF13B mutation and compared them with counterparts from patients with CVID with heterozygous C104R or A181E TNFRSF13B missense mutations. We also assessed whether loss of a TNFRSF13B allele induced haploinsufficiency in naive and memory B cells and recapitulated abnormal immunologic features typical of patients with CVID with heterozygous TNFRSF13B missense mutations. RESULTS: We found that loss of a TNFRSF13B allele does not affect TACI expression, activation responses, or establishment of central B-cell tolerance in naive B cells. Additionally, patients with SMS and those with a c.204insA TNFRSF13B mutation display normal regulatory T-cell function and peripheral B-cell tolerance. The lack of a TNFRSF13B allele did result in decreased TACI expression on memory B cells, resulting in impaired activation and antibody secretion. CONCLUSION: TNFRSF13B hemizygosity does not recapitulate autoimmune features of CVID-associated C104R and A181E TNFRSF13B mutations, which likely encode dominant negative products, but instead reveals selective TACI haploinsufficiency at later stages of B-cell development.