RESUMO
OBJECTIVE: Epilepsy is highly prevalent among patients with intellectual disability (ID), and seizure control is often difficult. Identification of the underlying etiology in this patient group is important for daily clinical care. We assessed the diagnostic yield of whole exome sequencing (WES). In addition, we evaluated which clinical characteristics influence the likelihood of identifying a genetic cause and we assessed the potential impact of the genetic diagnosis on (antiepileptic) treatment strategy. METHODS: One hundred patients with both unexplained epilepsy and (borderline) ID (intelligence quotient ≤ 85) were included. All patients were evaluated by a clinical geneticist, a (pediatric) neurologist, and/or a specialist ID physician. WES analysis was performed in two steps. In step 1, analysis was restricted to the latest versions of ID and/or epilepsy gene panels. In step 2, exome analysis was extended to all genes (so-called full exome analysis). The results were classified according to the American College of Medical Genetics and Genomics guidelines. RESULTS: In 58 patients, the diagnostic WES analysis reported one or more variant(s). In 25 of the 100 patients, these were classified as (likely) pathogenic, in 24 patients as variants of uncertain significance, and in the remaining patients the variant was most likely not related to the phenotype. In 10 of 25 patients (40%) with a (likely) pathogenic variant, the genetic diagnosis might have an impact on the treatment strategy in the future. SIGNIFICANCE: This study illustrates the clinical diagnostic relevance of WES for patients with both epilepsy and ID. It also demonstrates that implementing WES diagnostics might have impact on the (antiepileptic) treatment strategy in this population. Confirmation of variants of uncertain significance in (candidate) genes may further increase the yield.
Assuntos
Epilepsia/diagnóstico , Epilepsia/genética , Sequenciamento do Exoma/métodos , Exoma/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/etiologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Epilepsia/epidemiologia , Feminino , Testes Genéticos/métodos , Humanos , Deficiência Intelectual/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: De novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia. OBJECTIVES: To delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations. METHODS: Diagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of Drosophila-derived Pur-alpha homologues. Finally, we explored genotype-phenotype correlations by analysis of both recurrent mutations as well as mutation classes. RESULTS: We report mutations in PURA (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes. CONCLUSION: We delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and disease severity.
Assuntos
Proteínas de Ligação a DNA/genética , Face/anormalidades , Deficiência Intelectual/genética , Mutação , Fatores de Transcrição/genética , Proteínas de Ligação a DNA/química , Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Anormalidades do Olho/genética , Feminino , Estudos de Associação Genética , Humanos , Recém-Nascido , Hipotonia Muscular/etiologia , Hipotonia Muscular/genética , Gravidez , Homologia Estrutural de Proteína , Síndrome , Fatores de Transcrição/químicaRESUMO
Intellectual disability (ID) affects approximately 1%-3% of humans with a gender bias toward males. Previous studies have identified mutations in more than 100 genes on the X chromosome in males with ID, but there is less evidence for de novo mutations on the X chromosome causing ID in females. In this study we present 35 unique deleterious de novo mutations in DDX3X identified by whole exome sequencing in 38 females with ID and various other features including hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. Based on our findings, mutations in DDX3X are one of the more common causes of ID, accounting for 1%-3% of unexplained ID in females. Although no de novo DDX3X mutations were identified in males, we present three families with segregating missense mutations in DDX3X, suggestive of an X-linked recessive inheritance pattern. In these families, all males with the DDX3X variant had ID, whereas carrier females were unaffected. To explore the pathogenic mechanisms accounting for the differences in disease transmission and phenotype between affected females and affected males with DDX3X missense variants, we used canonical Wnt defects in zebrafish as a surrogate measure of DDX3X function in vivo. We demonstrate a consistent loss-of-function effect of all tested de novo mutations on the Wnt pathway, and we further show a differential effect by gender. The differential activity possibly reflects a dose-dependent effect of DDX3X expression in the context of functional mosaic females versus one-copy males, which reflects the complex biological nature of DDX3X mutations.
Assuntos
RNA Helicases DEAD-box/genética , Deficiência Intelectual/genética , Mutação de Sentido Incorreto/genética , Fenótipo , Caracteres Sexuais , Via de Sinalização Wnt/genética , Substituição de Aminoácidos/genética , Animais , Sequência de Bases , Embrião não Mamífero/metabolismo , Embrião não Mamífero/patologia , Exoma/genética , Feminino , Dosagem de Genes/genética , Humanos , Deficiência Intelectual/patologia , Masculino , Dados de Sequência Molecular , Análise de Sequência de DNA , Peixe-ZebraRESUMO
Many studies have attempted to establish the genotype-phenotype correlation in Rett syndrome (RTT). Cardiorespiratory measurements provide robust objective data, to correlate with each of the different clinical phenotypes. It has important implications for the management and treatment of this syndrome. The aim of this study was to correlate the genotype with the quantitative cardiorespiratory data obtained by neurophysiological measurement combined with a clinical severity score. This international multicenter study was conducted in four European countries from 1999 to 2012. The study cohort consisted of a group of 132 well-defined RTT females aged between 2 and 43 years with extended clinical, molecular, and neurophysiological assessments. Diagnosis of RTT was based on the consensus criteria for RTT and molecular confirmation. Genotype-phenotype analyses of clinical features and cardiorespiratory data were performed after grouping mutations by the same type and localization or having the same putative biological effect on the MeCP2 protein, and subsequently on eight single recurrent mutations. A less severe phenotype was seen in females with CTS, p.R133C, and p.R294X mutations. Autonomic disturbances were present in all females, and not restricted to nor influenced by one specific group or any single recurrent mutation. The objective information from non-invasive neurophysiological evaluation of the disturbed central autonomic control is of great importance in helping to organize the lifelong care for females with RTT. Further research is needed to provide insights into the pathogenesis of autonomic dysfunction, and to develop evidence-based management in RTT. © 2016 Wiley Periodicals, Inc.
Assuntos
Estudos de Associação Genética , Genótipo , Proteína 2 de Ligação a Metil-CpG/genética , Mutação , Fenótipo , Síndrome de Rett/diagnóstico , Síndrome de Rett/genética , Adolescente , Adulto , Alelos , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Índice de Gravidade de Doença , Adulto JovemRESUMO
The analysis of transcriptomics data is able to give an overview of cellular processes, but requires sophisticated bioinformatics tools and methods to identify the changes. Pathway analysis software, like PathVisio, captures the information about biological pathways from databases and brings this together with the experimental data to enable visualization and understanding of the underlying processes. Rett syndrome is a rare disease, but still one of the most abundant causes of intellectual disability in females. Cause of this neurological disorder is mutation of one single gene, the methyl-CpG-binding protein 2 (MECP2) gene. This gene is responsible for many steps in neuronal development and function. Although the genetic mutation and the clinical phenotype are well described, the molecular pathways linking them are not yet fully elucidated. In this study we demonstrate a workflow for the analysis of transcriptomics data to identify biological pathways and processes which are changed in a Mecp2 (-/y) mouse model.
Assuntos
Perfilação da Expressão Gênica , Síndrome de Rett/diagnóstico , Síndrome de Rett/genética , Animais , Criança , Pré-Escolar , Biologia Computacional , Modelos Animais de Doenças , Feminino , Humanos , Lactente , Recém-Nascido , Proteína 2 de Ligação a Metil-CpG/genética , Camundongos , FenótipoRESUMO
Recently, de novo heterozygous loss-of-function mutations in beta-catenin (CTNNB1) were described for the first time in four individuals with intellectual disability (ID), microcephaly, limited speech and (progressive) spasticity, and functional consequences of CTNNB1 deficiency were characterized in a mouse model. Beta-catenin is a key downstream component of the canonical Wnt signaling pathway. Somatic gain-of-function mutations have already been found in various tumor types, whereas germline loss-of-function mutations in animal models have been shown to influence neuronal development and maturation. We report on 16 additional individuals from 15 families in whom we newly identified de novo loss-of-function CTNNB1 mutations (six nonsense, five frameshift, one missense, two splice mutation, and one whole gene deletion). All patients have ID, motor delay and speech impairment (both mostly severe) and abnormal muscle tone (truncal hypotonia and distal hypertonia/spasticity). The craniofacial phenotype comprised microcephaly (typically -2 to -4 SD) in 12 of 16 and some overlapping facial features in all individuals (broad nasal tip, small alae nasi, long and/or flat philtrum, thin upper lip vermillion). With this detailed phenotypic characterization of 16 additional individuals, we expand and further establish the clinical and mutational spectrum of inactivating CTNNB1 mutations and thereby clinically delineate this new CTNNB1 haploinsufficiency syndrome.
Assuntos
Deficiência Intelectual/genética , Microcefalia/genética , Mutação/genética , beta Catenina/genética , Criança , Pré-Escolar , Feminino , Seguimentos , Haploinsuficiência , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Microcefalia/patologia , Fenótipo , SíndromeRESUMO
Rett syndrome (RTT; OMIM 312750) is an X-linked dominant neurodevelopmental disorder leading to cognitive and motor impairment, epilepsy, and autonomic dysfunction in females. Since the discovery that RTT is caused by mutations in MECP2, large retrospective genotype-phenotype correlation studies have been performed. A number of general genotype-phenotype relationships were confirmed and specific disorder profiles were described. Nevertheless, conflicting results are still under discussion, partly due to the variability in classification of mutations, assessment tools, and structure of the data sets. The aim of this study was to investigate relationships between genotype and specific clinical data collected by the same experienced physician in a well-documented RTT cohort, and evaluate its prognostic value in counseling young parents with a newly diagnosed RTT girl regarding her future outcome. The Maastricht-Leuven Rett Syndrome Database is a register of 137 molecularly confirmed clinical RTT cases, containing both molecular and clinical data on examination and follow up by the same experienced physician. Although the general genotype-phenotype relationships were confirmed, the clinical severity was still found to be very variable. We therefore recommend caution in using genotype-phenotype data in the prognosis of outcome for children in Rett syndrome. Early diagnosis, early intervention, and preventive management are imperative for better outcomes and better quality of daily life for RTT females and their families.
Assuntos
Estudos de Associação Genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Proteína 2 de Ligação a Metil-CpG/genética , Síndrome de Rett/genética , Síndrome de Rett/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Bases de Dados Genéticas , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Genótipo , Humanos , Pessoa de Meia-Idade , Mutação , Fenótipo , Prognóstico , Estrutura Terciária de Proteína/genética , Síndrome de Rett/diagnóstico , Análise de Sequência de DNARESUMO
Kabuki Syndrome (KS) is a rare syndrome characterized by intellectual disability and multiple congenital abnormalities, in particular a distinct dysmorphic facial appearance. KS is caused by mutations in the MLL2 gene, encoding an H3K4 histone methyl transferase which acts as an epigenetic transcriptional activator during growth and development. Direct sequencing of all 54 exons of the MLL2 gene in 45 clinically well-defined KS patients identified 34 (75.6%) different mutations. One mutation has been described previously, all others are novel. Clinically, all KS patients were sporadic, and mutations were de novo for all 27 families for which both parents were available. We detected nonsense (n=11), frameshift (n=17), splice site (n=4) and missense (n=2) mutations, predicting a high frequency of absent or non-functional MLL2 protein. Interestingly, both missense mutations located in the C-terminal conserved functional domains of the protein. Phenotypically our study indicated a statistically significant difference in the presence of a distinct facial appearance (p=0.0143) and growth retardation (p=0.0040) when comparing KS patients with an MLL2 mutation compared to patients without a mutation. Our data double the number of MLL2 mutations in KS reported so far and widen the spectrum of MLL2 mutations and disease mechanisms in KS.
Assuntos
Proteínas de Ligação a DNA/genética , Mutação , Proteínas de Neoplasias/genética , Anormalidades Múltiplas/genética , Face/anormalidades , Feminino , Doenças Hematológicas/genética , Humanos , Masculino , Doenças Vestibulares/genéticaRESUMO
Rett syndrome is a unique disorder of neurodevelopment that is characterized by an evolving behavioral and developmental phenotype, which emerges after an apparently normal early infantile period. It almost exclusively affects females. The face of Rett syndrome is said to resemble that of Angelman syndrome, although there seems little objective support for this impression and it is not a concept with universal support. This observational and anthropometric study was carried out to define the key facial characteristics of females with Rett syndrome and to evaluate whether any changes of significance occur with age. Thirty-seven affected Caucasian females, from 2 to 20 years of age, were evaluated. Thirty-five of them had a documented mutation in MECP2 while the remaining two fulfilled the clinical criteria for Rett syndrome and had been diagnosed by an experienced clinician. Few unusual facial features were noted. Almost all facial measurements were within the normal range although head circumference tended to fall below the normal range with increasing age. The pattern of measurements was constant over time, with the exception of increased facial width in the under 3-year-old girls. The face of Rett syndrome does not demonstrate marked prognathism, wide mouth, spaced teeth or striking microcephaly, all features of Angelman syndrome. Thus, while Rett and Angelman syndromes have similar clinical, neurological, and behavioral phenotypes, they do not appear to share similar facial features.
Assuntos
Fácies , Fenótipo , Síndrome de Rett/diagnóstico , Adolescente , Adulto , Síndrome de Angelman/diagnóstico , Síndrome de Angelman/patologia , Antropometria , Criança , Pré-Escolar , Face/anatomia & histologia , Feminino , Cabeça/anatomia & histologia , Humanos , Proteína 2 de Ligação a Metil-CpG/genética , Mutação/genética , Síndrome de Rett/genética , Síndrome de Rett/patologia , Adulto JovemRESUMO
A partial deletion of chromosome band 2p25.3 (2pter) is a rarely described cytogenetic aberration in patients with intellectual disability (ID). Using microarrays we identified deletions of 2p25.3, sized 0.37-3.13 Mb, in three adult siblings and three unrelated patients. All patients had ID, obesity or overweight and/or a square-shaped stature without overt facial dysmorphic features. Combining our data with phenotypic and genotypic data of three patients from the literature we defined the minimal region of overlap which contained one gene, i.e., MYT1L. MYT1L is highly transcribed in the mouse embryonic brain where its expression is restricted to postmitotic differentiating neurons. In mouse-induced pluripotent stem cell (iPS) models, MYT1L is essential for inducing functional mature neurons. These resemble excitatory cortical neurons of the forebrain, suggesting a role for MYT1L in development of cognitive functions. Furthermore, MYT1L can directly convert human fibroblasts into functional neurons in conjunction with other transcription factors. MYT1L duplication was previously reported in schizophrenia, indicating that the gene is dosage-sensitive and that shared neurodevelopmental pathways may be affected in ID and schizophrenia. Finally, deletion of MYT1, another member of the Myelin Transcription Factor family involved in neurogenesis and highly similar to MYT1L, was recently described in ID as well. The identification of MYT1L as candidate gene for ID justifies further molecular studies aimed at detecting mutations and for mechanistic studies on its role in neuron development and on neuropathogenic effects of haploinsufficiency.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 2/genética , Proteínas de Ligação a DNA/genética , Deficiência Intelectual/genética , Fatores de Transcrição/genética , Cariótipo Anormal , Adolescente , Adulto , Índice de Massa Corporal , Criança , Pré-Escolar , Cromossomos Humanos Par 2/metabolismo , Proteínas de Ligação a DNA/metabolismo , Feminino , Haploinsuficiência , Humanos , Hibridização in Situ Fluorescente , Lactente , Deficiência Intelectual/metabolismo , Masculino , Metáfase , Pessoa de Meia-Idade , Neurogênese , Obesidade/genética , Análise de Sequência com Séries de Oligonucleotídeos , Sobrepeso/genética , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/metabolismoRESUMO
Noonan syndrome (NS) is an autosomal dominant disorder caused by mutations in PTPN11, KRAS, SOS1, and RAF1. We performed SOS1, RAF1, BRAF, MEK1, and MEK2 mutation analysis in a cohort of 102 PTPN11- and KRAS-negative NS patients and found pathogenic SOS1 mutations in 10, RAF1 mutations in 4, and BRAF mutations in 2 patients. Three novel SOS1 mutations were found. One was classified as a rare benign variant and the other remains unclassified. We confirm a high prevalence of pulmonic stenosis and ectodermal abnormalities in SOS1-positive patients. Three patients with SOS1 mutations presented with tumors (embryonal rhabdomyosarcoma, Sertoli cell testis tumor, and granular cell tumors of the skin). One patient with a RAF1 mutation had a lesion suggestive for a giant cell tumor. This is the first report describing different tumor types in NS patients with germ line SOS1 mutations.
Assuntos
Mutação , Neoplasias/genética , Síndrome de Noonan/genética , Proteínas Proto-Oncogênicas c-raf/genética , Proteína SOS1/genética , Adolescente , Substituição de Aminoácidos , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA/métodos , Éxons , Duplicação Gênica , Humanos , Leucócitos/fisiologia , MAP Quinase Quinase 1/genética , MAP Quinase Quinase 2/genética , Neoplasias/epidemiologia , Síndrome de Noonan/complicações , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
OBJECTIVES: Rett syndrome (RTT) is a rare disorder causing severe intellectual and physical disability. The cause is a mutation in the gene coding for the methyl-CpG binding protein 2 (MECP2), a multifunctional regulator protein. Purpose of the study was integration and investigation of multiple gene expression profiles in human cells with impaired MECP2 gene to obtain a robust, data-driven insight in molecular disease mechanisms. METHODS: Information about changed gene expression was extracted from five previously published studies, integrated and the resulting differentially expressed genes were analysed using overrepresentation analysis of biological pathways and gene ontology, and network analysis. RESULTS: We identified a set of genes, which are significantly changed not in all but several transcriptomics datasets and were not mentioned in the context of RTT before. We found that these genes are involved in several processes and molecular pathways known to be affected in RTT. Integrating transcription factors we identified a possible link how MECP2 regulates cytoskeleton organisation via MEF2C and CAPG. CONCLUSIONS: Integrative analysis of omics data and prior knowledge databases is a powerful approach to identify links between mutation and phenotype especially in rare disease research where little data is available.
Assuntos
Síndrome de Rett , Humanos , Proteína 2 de Ligação a Metil-CpG/genética , Mutação , Fenótipo , Síndrome de Rett/genética , TranscriptomaRESUMO
In a cohort of 103 females clinically diagnosed with Rett syndrome (RTT), 91 had a detectable MECP2 mutation. Emphasis on details of natural history facilitated grouping of females with the same MECP2 mutation and the development of so-called disorder profiles. Some examples of disorder profiles of different recurrent MECP2 mutations are discussed. RTT females with the frequently recurrent R133C and R306C missense mutations and those with intragenic deletions in the C-terminus of MECP2 deserve more attention in larger studies as their development is different and milder in the long term. RTT females with the T158M missense mutation are often atypical with mainly behavioral characteristics in infancy and childhood but become classic RTT in adolescence after a slower, protracted course.
Assuntos
Proteína 2 de Ligação a Metil-CpG/genética , Mutação de Sentido Incorreto , Síndrome de Rett/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Coleta de Dados , Progressão da Doença , Feminino , Humanos , Pessoa de Meia-Idade , Síndrome de Rett/fisiopatologia , Índice de Gravidade de Doença , Adulto JovemRESUMO
Genotypic and phenotypic data are presented on three adult siblings with mild to moderate mental retardation and mild dysmorphic features. All three siblings showed a chromosome 20 gain at the q-telomere and loss at the p-telomere in routine subtelomeric MLPA screening. Analysis of GTG-banded chromosomes did not detect any abnormalities, but subtelomeric fluorescent in situ hybridization (FISH) confirmed cryptic partial monosomy of chromosome region 20p13 --> 20pter and cryptic partial trisomy of chromosome region 20q13.33 --> 20qter. Furthermore, FISH analysis in the mother showed a cryptic inv(20)(p13q13.33). This explained the cytogenetic mechanism underlying the chromosomal imbalance in the three children, that is, the meiotic formation of a recombinant chromosome 20 due to crossing-over in the inverted segment. All three children thus carried a rec(20)dup(20q)inv(20)(p13q13.33)mat chromosome. SNP array analysis enabled rapid and detailed imbalance sizing and showed a 1.06 Mb loss in 20p13 and a 2.51 Mb gain in 20q13.33, comprising 21 and 78 genes, respectively. The maternal inversion is the largest described thus far for chromosome 20, comprising 94.4% of its length. Such large inversions result in a particularly high risk for live-born unbalanced offspring because the partial monosomy and trisomy segments are small. Moreover, the inversion size is directly related to the percentage of unbalanced gametes due to high crossing-over change within the inverted segment. The fact that all three children carry an identical chromosomal rearrangement has consequences for genetic counseling for carriers of large pericentric inversions, as the recurrence risk is very high.
Assuntos
Deleção Cromossômica , Inversão Cromossômica , Cromossomos Humanos Par 20 , Irmãos , Trissomia , Anormalidades Múltiplas/genética , Adulto , Quebra Cromossômica , Inversão Cromossômica/genética , Mapeamento Cromossômico/métodos , Feminino , Humanos , Padrões de Herança/genética , Masculino , Análise em Microsséries/métodos , Mães , Técnicas de Amplificação de Ácido Nucleico , Polimorfismo de Nucleotídeo Único , Trissomia/diagnóstico , Trissomia/genética , Adulto JovemRESUMO
BACKGROUND: Rett syndrome (RTT) is a neurological disorder characterized by a broad spectrum of symptoms. Communication is a major area of difficulty. Use of eye tracking technology offers a potentially effective method of communication when underpinned by intact oculomotor function. In this study, oculomotor function was assessed using electronystagmography (ENG). However, challenges were encountered when examining individuals with RTT. PURPOSE: To improve oculomotor examination in individuals with RTT by evaluating the challenges encountered during ENG examination. MATERIAL AND METHODS: Oculomotor function was examined in 17 girls and young women with RTT and 16 typically developing (TD) individuals using ENG. Observational analysis of both performance and results indicated that challenges in examination were mainly related to quality of attention and quality of signals. Subsequently these outcome values were explored quantitatively according to percentage looking time for attention and drift for signal quality. RESULTS: A significantly reduced level of attention and suboptimal electrode signals were evident in the RTT group when compared with the TD group for all tests except torsion swing. CONCLUSION: The challenges in testing confirm that regular oculomotor examination should be adjusted to meet the needs of individuals with RTT. It is hypothesized that the RTT group's higher quality of attention on the torsion swing can be explained by the more forceful vestibular rather than visual-ocular stimulus operating in this test. Suggested adaptations include reducing the number of electrodes, changing the picture stimuli and bringing them closer, performing observational assessments rather than ENG, and using virtual reality goggles.
Assuntos
Atenção , Eletronistagmografia/métodos , Movimentos Oculares/fisiologia , Síndrome de Rett/fisiopatologia , Adulto , Feminino , HumanosRESUMO
Determining pathogenicity of genomic variation identified by next-generation sequencing techniques can be supported by recurrent disruptive variants in the same gene in phenotypically similar individuals. However, interpretation of novel variants in a specific gene in individuals with mild-moderate intellectual disability (ID) without recognizable syndromic features can be challenging and reverse phenotyping is often required. We describe 24 individuals with a de novo disease-causing variant in, or partial deletion of, the F-box only protein 11 gene (FBXO11, also known as VIT1 and PRMT9). FBXO11 is part of the SCF (SKP1-cullin-F-box) complex, a multi-protein E3 ubiquitin-ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. Twenty-two variants were identified by next-generation sequencing, comprising 2 in-frame deletions, 11 missense variants, 1 canonical splice site variant, and 8 nonsense or frameshift variants leading to a truncated protein or degraded transcript. The remaining two variants were identified by array-comparative genomic hybridization and consisted of a partial deletion of FBXO11. All individuals had borderline to severe ID and behavioral problems (autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety, aggression) were observed in most of them. The most relevant common facial features included a thin upper lip and a broad prominent space between the paramedian peaks of the upper lip. Other features were hypotonia and hyperlaxity of the joints. We show that de novo variants in FBXO11 cause a syndromic form of ID. The current series show the power of reverse phenotyping in the interpretation of novel genetic variances in individuals who initially did not appear to have a clear recognizable phenotype.
Assuntos
Anormalidades Múltiplas/genética , Comportamento , Proteínas F-Box/genética , Variação Genética , Deficiência Intelectual/genética , Proteína-Arginina N-Metiltransferases/genética , Deleção de Genes , Humanos , SíndromeRESUMO
The aging process of people with intellectual disabilities has been a topic of interest in recent years. Good knowledge of the specific healthcare problems in adults with intellectual disabilities and anticipating on these problems are important issues in providing support and healthcare for these persons. Nevertheless little is known about the aging process of people with specific syndromes, like Rett syndrome. In association with the Dutch Rett syndrome parent association, 70 postal questionnaires were sent to the contact persons of the females aged at least 16 years with a clinical diagnosis of Rett syndrome. The questionnaire consisted of general questions, questions about living conditions, skills, physical and psychiatric morbidity. The response rate was 76% (n = 53). In general adults with Rett syndrome seemed to be reasonably healthy, whereas neurological, respiratory and behavioral morbidity appeared to be of great influence. High care dependency was confirmed. In contrast with underweight, overweight showed to be an under-ascertained feature. The general disorder profile was confirmed, considering the increase with age regarding kyphosis and the better communication and autonomic dysfunction in the oldest age group compared to the younger age groups. Features of autonomic dysfunction deserve more medical attention, especially the interrelation between quality of sleep, respiration and behavior in Rett syndrome. Longitudinal studies including genotype-phenotype analyses are needed for insight in individual changes in support needs and health.
Assuntos
Envelhecimento , Nível de Saúde , Síndrome de Rett/fisiopatologia , Inquéritos e Questionários , Adolescente , Adulto , Análise de Variância , Índice de Massa Corporal , Distribuição de Qui-Quadrado , Feminino , Genótipo , Humanos , Cifose/epidemiologia , Cifose/genética , Cifose/fisiopatologia , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Comunicação não Verbal , Sobrepeso/epidemiologia , Sobrepeso/genética , Sobrepeso/fisiopatologia , Síndrome de Rett/epidemiologia , Síndrome de Rett/genéticaRESUMO
BACKGROUND: Individuals with Rett syndrome (RTT) are notoriously reliant on the use of eye gaze as a primary means of communication. Underlying an ability to communicate successfully via eye gaze is a complex matrix of requirements, with an intact oculomotor system being just one element. To date, the underlying neural and motor pathways associated with eye gaze are relatively under-researched in RTT. PURPOSE: This study was undertaken to plug this gap in knowledge and to further the understanding of RTT in one specific area of development and function, namely oculomotor function. MATERIAL AND METHODS: The eye movements of 18 girls and young women with RTT were assessed by electronystagmography (ENG). This tested their horizontal saccadic and smooth pursuit eye movements as well as optokinetic nystagmus and vestibulo-ocular reflex. Their results were compared with normative data collected from 16 typically developing children and teenagers. RESULTS: Overall, the individuals with RTT demonstrated a range of eye movements on a par with their typically developing peers. However, there were a number of difficulties in executing the ENG testing with the RTT cohort which made quantitative analysis tricky, such as reduced motivation and attention to test materials and low-quality electrode signals. CONCLUSIONS: This study suggests that individuals with RTT have an intact oculomotor system. However, modifications should be made to the ENG assessment procedure to combat problems in testing and add strength to the results. Further investigation into these testing difficulties is warranted in order to inform such modifications.
Assuntos
Nistagmo Patológico/etiologia , Síndrome de Rett/complicações , Adolescente , Adulto , Criança , Pré-Escolar , Eletronistagmografia , Movimentos Oculares/fisiologia , Feminino , Humanos , Unidades de Terapia Intensiva , Nistagmo Patológico/diagnóstico , Adulto JovemRESUMO
This study aimed to determine whether there is a relationship between abnormal foot position and standing and walking ability in individuals with Rett syndrome (RTT), a rare neurological condition primarily affecting females, often accompanied by impaired gross motor function and musculoskeletal deformities. Through means of an online survey, physiotherapists were asked to share information about their work and experience with individuals with RTT. They were asked about their clients' scores on the Rett Syndrome Gross Motor Scale and measures of their foot deformity, passive range of motion of dorsiflexion of the foot, use of supportive footwear, pressure load on the foot, and symmetry in weight bearing. 45 physiotherapists gave answers relating to 67 individuals with RTT who ranged in age from 2 to over 50 years. Almost 80% had an abnormal foot position which required support of special shoes or orthoses. Approximately 55% experienced abnormal pressure load on the foot and 65% demonstrated asymmetrical weight-bearing; 22% could sit independently and 17% were able to stand and walk independently. Of all the variables investigated, only abnormal distribution of pressure on the foot and asymmetry in weight bearing through the legs were found to be (negatively) correlated with standing and walking ability. Physiotherapists can use this information to give advice on othopedic support for the feet of individuals with RTT.
RESUMO
Rett syndrome is a neurodevelopmental disorder that occurs almost exclusively in females. It is characterized by a progressive loss of intellectual functioning and motor skills, and the development of stereotypic hand movements, that occur after a period of normal development. Event-related potentials were recorded to a passive auditory- and visual oddball task in 17 females with Rett syndrome aged between 2 and 60 years, and age-matched controls. Overall the participants with Rett syndrome had longer ERP latencies and smaller ERP amplitudes than the Control group suggesting slowed information processing and reduced brain activation. The Rett groups also failed to show typical developmental changes in event-related brain activity and revealed a marked decline in ERP task modulation with increasing age.