RESUMO
Cornelia de Lange syndrome (CdLS) is an archetypical genetic syndrome that is characterized by intellectual disability, well-defined facial features, upper limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in any one of seven genes, all of which have a structural or regulatory function in the cohesin complex. Although recent advances in next-generation sequencing have improved molecular diagnostics, marked heterogeneity exists in clinical and molecular diagnostic approaches and care practices worldwide. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria, both for classic CdLS and non-classic CdLS phenotypes, molecular investigations, long-term management and care planning.
Assuntos
Síndrome de Cornélia de Lange , Sequenciamento de Nucleotídeos em Larga Escala , Mutação , Consenso , Síndrome de Cornélia de Lange/diagnóstico , Síndrome de Cornélia de Lange/genética , Síndrome de Cornélia de Lange/fisiopatologia , Síndrome de Cornélia de Lange/terapia , Estudos de Associação Genética , HumanosRESUMO
Autophagy is a catabolic process responsible for the removal of waste and damaged cellular components by lysosomal degradation. It plays a key role in fundamental cell processes, including ER stress mitigation, control of cell metabolism, and cell differentiation and proliferation, all of which are essential for cartilage cell (chondrocyte) development and survival, and for the formation of cartilage. Correspondingly, autophagy dysregulation has been implicated in several skeletal disorders such as osteoarthritis and osteoporosis. To test the requirement for autophagy during skeletal development in zebrafish, we generated an atg13 CRISPR knockout zebrafish line. This line showed a complete loss of atg13 expression, and restricted autophagic activity in vivo. In the absence of autophagy, chondrocyte maturation was accelerated, with chondrocytes exhibiting signs of premature hypertrophy. Focussing on the jaw element, autophagy disruption affected joint articulation causing restricted mouth opening. This gross behavioural phenotype corresponded with a failure to thrive, and death in homozygote atg13 nulls within 17 days. Taken together, our results are consistent with autophagy contributing to the timely regulation of chondrocyte maturation and for extracellular matrix formation.
Assuntos
Proteínas Relacionadas à Autofagia/metabolismo , Condrócitos/citologia , Condrogênese , Articulações/embriologia , Peixe-Zebra/embriologia , Animais , Autofagia , Diferenciação CelularRESUMO
BACKGROUND: Research on women with the fragile-X premutation (FX-p) has been underrepresented within the field of behavioural phenotypes. AIMS: To understand whether the FX-p confers risk for autistic traits, depression and anxiety, independent of maternal status. METHOD: In study 1, mothers of children with fragile-X syndrome (M-FXp; n = 51, mean age 43 years (s.d. = 5.80)) were compared with mothers of autistic children (M-ASD; n = 59, mean age 42 (s.d. = 5.80)), mothers of children with Smith-Magenis syndrome (M-SMS; n = 27, mean age 39 (s.d. = 7.20)) and mothers of typically developing children (M-TD; n = 44, mean age 40 (s.d. = 4.90)). In study 2, the M-FXp group were compared with non-mothers with the FX-p (NM-FXp; n = 17, mean age 32 (s.d. = 9.20)), typically developed non-mothers (NM-TD; n = 28, mean age 31 (s.d. = 6.80)) and the M-TD group. All participants completed an online survey, including measures of IQ, autistic traits, anxiety, depression and positive affect. RESULTS: In study 1: the M-FXp group reported more autistic traits than the M-TD group (P < 0.05, η2 = 0.046). Anxiety and parental stress were elevated in the M-FXp, M-SMS and M-ASD groups relative to the M-TD group (all P ≤ 0.003, η2 = 0.079-0.322). In study 2: a main effect of premutation status indicated that women with the FX-p report elevated autistic traits and anxiety (P ≤ 0.007, η2 = 0.055-0.060); this did not interact with maternal status. CONCLUSIONS: The findings indicate that women with the FX-p show an increased risk for autistic traits and anxiety. This risk is specific to the presence of the FX-p and is not fully accounted for by maternal status or the stress of caring for children with neurodevelopmental disorders.
Assuntos
Transtorno Autístico , Síndrome do Cromossomo X Frágil , Adulto , Ansiedade/epidemiologia , Ansiedade/genética , Transtornos de Ansiedade/epidemiologia , Transtornos de Ansiedade/genética , Transtorno Autístico/epidemiologia , Transtorno Autístico/genética , Criança , Feminino , Proteína do X Frágil da Deficiência Intelectual , Humanos , Saúde MentalRESUMO
In the last twenty years, research using zebrafish as a model organism has increased immensely. With the many advantages that zebrafish offer such as high fecundity, optical transparency, ex vivo development, and genetic tractability, they are well suited to studying developmental processes and the effect of genetic mutations. More recently, zebrafish models have been used to study autophagy. This important protein degradation pathway is needed for cell and tissue homeostasis in a variety of contexts. Correspondingly, its dysregulation has been implicated in multiple diseases including skeletal disorders. In this review, we explore how zebrafish are being used to study autophagy in the context of skeletal development and disease, and the ways these areas are intersecting to help identify potential therapeutic targets for skeletal disorders.
Assuntos
Autofagia , Modelos Animais de Doenças , Músculo Esquelético/metabolismo , Doenças Musculares/metabolismo , Peixe-Zebra , Animais , Homeostase , Doenças Musculares/patologiaRESUMO
Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder associated with unusual facial features, limb abnormalities, a wide range of health conditions, and intellectual disability. Mutations in five genes that encode (SMC1A, SMC3, RAD21) or regulate (NIPBL, HDAC8) the cohesin complex have been identified in up to 70% of individuals. Genetic cause remains unknown for a proportion of individuals. There is substantial heterogeneity in all aspects of CdLS but very little is known about what predicts phenotypic heterogeneity. In this study, we evaluated genotype-phenotype associations in 34 individuals with CdLS. Participants with NIPBL mutations had significantly lower self help skills and were less likely to have verbal skills relative to those who were negative for the NIPBL mutation. No significant differences were identified between the groups in relation to repetitive behavior, mood, interest and pleasure, challenging behavior, activity, impulsivity, and characteristics of autism spectrum disorder whilst controlling differences in self help skills. Significant correlations indicating lower mood, interest and pleasure, and increased insistence on sameness with older age were identified for those who were NIPBL mutation positive. The findings suggest similarities in the behavioral phenotype between those with and without the NIPBL mutation once differences in self help skills are controlled for. However, there may be subtle differences in the developmental trajectory of these behaviors according to genetic mutation status in CdLS.
Assuntos
Transtorno do Espectro Autista/genética , Síndrome de Cornélia de Lange/genética , Estudos de Associação Genética , Proteínas/genética , Transtorno do Espectro Autista/fisiopatologia , Proteínas de Ciclo Celular , Síndrome de Cornélia de Lange/fisiopatologia , Exoma/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Mutação , FenótipoRESUMO
Little is known about the way in which the characteristics of autism spectrum disorder (ASD) develop and manifest across the age span in individuals with genetic syndromes. In this study we present findings from a two and a half year follow-up of the characteristics associated with ASD in three syndromes: Cornelia de Lange (CdLS), Fragile X (FXS), and Cri du Chat (CdCS). Parents and carers of 251 individuals (CdLS=67, CdCS=42, and FXS=142) completed the Social Communication Questionnaire (SCQ) at Time 1 (T1) and again two and a half years later (T2). The FXS and CdLS groups were more likely to meet the cut-offs for both autism and ASD and show greater severity of ASD related behaviors, at both T1 and T2, compared to the CdCS group. Older individuals (>15yrs) with CdLS were more likely to meet the cut off for ASD than younger individuals (≤15 yrs) with the syndrome and more likely to show greater severity of social impairments. In FXS repetitive behaviors were found to become less prominent with age and in CdCS social impairments were reported to be more severe with age. There were no significant changes between T1 and T2 in the severity of ASD characteristics in the CdCS and CdLS groups. The FXS group showed significantly fewer repetitive behaviors and less severe impairments in social interaction over this time frame. The findings suggest that while there may be similarities in overall severity and presentation of ASD characteristics in CdLS and FXS, these characteristics have divergent patterns of development within these groups.
Assuntos
Envelhecimento/psicologia , Transtorno do Espectro Autista/fisiopatologia , Síndrome de Cri-du-Chat/fisiopatologia , Síndrome de Cornélia de Lange/fisiopatologia , Síndrome do Cromossomo X Frágil/fisiopatologia , Adolescente , Adulto , Fatores Etários , Transtorno do Espectro Autista/psicologia , Criança , Comunicação , Síndrome de Cri-du-Chat/psicologia , Síndrome de Cornélia de Lange/psicologia , Feminino , Seguimentos , Síndrome do Cromossomo X Frágil/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e QuestionáriosRESUMO
In this study we describe the levels of clinically significant behavior in participants with Sotos syndrome relative to three matched contrast groups in which the behavioral phenotype is well documented (Autism Spectrum Disorder, ASD; Prader-Willi, and Down syndromes). Parents and carers of 38 individuals with Sotos syndrome (mean age = 17.3; SD = 9.36), completed questionnaires regarding self-injury, aggression, repetitive behavior, autism spectrum phenomenology, overactivity, impulsivity and mood, interest and pleasure. Individuals with Sotos syndrome showed an increased risk of self-injurious behavior, physical aggression, and destruction of property relative to the Down syndrome group but not a greater risk of stereotyped behavior. Impulsivity and levels of activity were also significantly higher relative to those with Down syndrome and comparable to those with ASD. A large proportion of participants met the cut off score for ASD (70.3%) and Autism (32.4%) on the Social Communication Questionnaire. Social impairments were particularly prominent with repetitive behavior and communication impairments less characteristic of the syndrome. Interestingly, preference for routine and repetitive language were heightened in individuals with Sotos syndrome and the repetitive behavior profile was strikingly similar to that observed in individuals with Prader-Willi syndrome. These findings build upon previous research and provide further evidence of the behavioral phenotype associated with Sotos syndrome.
Assuntos
Comportamento Problema , Síndrome de Sotos/psicologia , Adolescente , Agressão , Transtorno do Espectro Autista/psicologia , Transtornos da Comunicação , Síndrome de Down/psicologia , Feminino , Humanos , Comportamento Impulsivo , Masculino , Síndrome de Prader-Willi/psicologia , Síndrome de Sotos/etiologia , Comportamento Estereotipado , Inquéritos e Questionários , Adulto JovemRESUMO
A small number of recent papers have described individuals with intellectual disabilities and microdeletions in chromosome band 19p13.2. However, little is known about the behavioral characteristics of individuals with microdeletions in this area. The current study examines behavioral characteristics of a series of 10 participants ranging in age from 2 to 20 years with 19p13.2 microdeletions. Parents/caregivers completed a series of established behavioral measures which have aided the elucidation of the behavioral phenotypes of a number of genetic neurodevelopmental syndromes. All but the youngest two participants (aged 2 and 3 years) were verbal, ambulant, and classified as "partly able" or "able" with regard to self-help skills. Six of eight participants for whom a screening measure for autism spectrum disorders (ASD) could be deployed met criteria for an ASD. Six of the 10 participants had displayed self-injurious behavior in the month prior to assessment, eight had displayed destruction/disruption of property, and eight had shown physically aggressive behaviors. Repetitive behaviors were prevalent in the sample (with all participants displaying at least one repetitive behavior to a clinically relevant level), as were problems with sleep. Low mood was not prevalent in this group, and nor were overactivity or impulsivity. Full determination of a behavioral phenotype for this group would require a larger sample size, distinguishing between genetic subtypes. However, the current data suggest that ASD characteristics, repetitive, and challenging behaviors (such as aggression and self-injury) might be associated with 19p13.2 microdeletions, providing a basis for future investigation.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 19 , Fenótipo , Adolescente , Agressão/psicologia , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/fisiopatologia , Transtorno do Espectro Autista/psicologia , Criança , Pré-Escolar , Feminino , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Deficiência Intelectual/psicologia , Masculino , Comportamento Autodestrutivo/genética , Comportamento Autodestrutivo/fisiopatologia , Comportamento Autodestrutivo/psicologia , Transtornos do Sono-Vigília/genética , Transtornos do Sono-Vigília/fisiopatologia , Transtornos do Sono-Vigília/psicologia , Adulto JovemRESUMO
Food-related behavior problems are well documented in Prader-Willi syndrome (PWS), with impaired satiety, preoccupation with food and negative food-related behaviors (such as taking and storing food) frequently reported as part of the behavioral phenotype of older children and adults. Food-related behavior problems in other genetic neurodevelopmental syndromes remain less well studied, including those seen in Angelman Syndrome (AS), the 'sister imprinted disorder' of PWS. Food-related behavior problems were assessed in 152 participants each with one of five genetic neurodevelopmental syndromes PWS, AS, 1p36 deletion, Cornelia de Lange, and fragile X. Predictably, levels of food-related behavior problems reported in participants with PWS significantly exceeded those of at least one other groups in most areas (impaired satiety; preoccupation with food; taking and storing food; composite negative behavior). However, in some areas people with AS were reported to display food-related problems at least as severe as those with PWS, with the AS group reported to display significantly more food-related behavior problems than at least one comparison group on measures of taking and storing food, composite negative behaviors, impaired satiety and preoccupation with food. Over 50% of participants in the AS group scored above the median point of the distribution of PWS scores on a measure of taking and storing food. These findings indicate further investigation of eating problems in AS are warranted and have implications for current theoretical interpretations of the behavioral differences between AS and PWS.
Assuntos
Síndrome de Angelman/diagnóstico , Síndrome de Angelman/genética , Síndrome de Prader-Willi/diagnóstico , Síndrome de Prader-Willi/genética , Adolescente , Criança , Pré-Escolar , Deleção Cromossômica , Transtornos Cromossômicos , Cromossomos Humanos Par 1 , Síndrome de Cornélia de Lange , Diagnóstico Diferencial , Feminino , Síndrome do Cromossomo X Frágil , Humanos , Masculino , Fenótipo , Inquéritos e QuestionáriosRESUMO
Purpose of Review: Elevated prevalence of autism characteristics is reported in genetic syndromes associated with intellectual disability. This review summarises recent evidence on the behavioural heterogeneity of autism in the following syndromes: Fragile X, Cornelia de Lange, Williams, Prader-Willi, Angelman, Down, Smith-Magenis, and tuberous sclerosis complex. Key considerations for assessment and support are discussed. Recent Findings: The profile and developmental trajectory of autism-related behaviour in these syndromes indicate some degree of syndrome specificity which may interact with broader behavioural phenotypes (e.g. hypersociability), intellectual disability, and mental health (e.g. anxiety). Genetic subtype and co-occurring epilepsy within syndromes contribute to increased significance of autism characteristics. Autism-related strengths and challenges are likely to be overlooked or misunderstood using existing screening/diagnostic tools and criteria, which lack sensitivity and specificity within these populations. Summary: Autism characteristics are highly heterogeneous across genetic syndromes and often distinguishable from non-syndromic autism. Autism diagnostic assessment practices in this population should be tailored to specific syndromes. Service provisions must begin to prioritise needs-led support.
RESUMO
BACKGROUND: Phenotypic studies have identified distinct patterns of autistic characteristics in genetic syndromes associated with intellectual disability (ID), leading to diagnostic uncertainty and compromised access to autism-related support. Previous research has tended to include small samples and diverse measures, which limits the generalisability of findings. In this study, we generated detailed profiles of autistic characteristics in a large sample of > 1500 individuals with rare genetic syndromes. METHODS: Profiles of autistic characteristics based on the Social Communication Questionnaire (SCQ) scores were generated for thirteen genetic syndrome groups (Angelman n = 154, Cri du Chat n = 75, Cornelia de Lange n = 199, fragile X n = 297, Prader-Willi n = 278, Lowe n = 89, Smith-Magenis n = 54, Down n = 135, Sotos n = 40, Rubinstein-Taybi n = 102, 1p36 deletion n = 41, tuberous sclerosis complex n = 83 and Phelan-McDermid n = 35 syndromes). It was hypothesised that each syndrome group would evidence a degree of specificity in autistic characteristics. To test this hypothesis, a classification algorithm via support vector machine (SVM) learning was applied to scores from over 1500 individuals diagnosed with one of the thirteen genetic syndromes and autistic individuals who did not have a known genetic syndrome (ASD; n = 254). Self-help skills were included as an additional predictor. RESULTS: Genetic syndromes were associated with different but overlapping autism-related profiles, indicated by the substantial accuracy of the entire, multiclass SVM model (55% correctly classified individuals). Syndrome groups such as Angelman, fragile X, Prader-Willi, Rubinstein-Taybi and Cornelia de Lange showed greater phenotypic specificity than groups such as Cri du Chat, Lowe, Smith-Magenis, tuberous sclerosis complex, Sotos and Phelan-McDermid. The inclusion of the ASD reference group and self-help skills did not change the model accuracy. LIMITATIONS: The key limitations of our study include a cross-sectional design, reliance on a screening tool which focuses primarily on social communication skills and imbalanced sample size across syndrome groups. CONCLUSIONS: These findings replicate and extend previous work, demonstrating syndrome-specific profiles of autistic characteristics in people with genetic syndromes compared to autistic individuals without a genetic syndrome. This work calls for greater precision of assessment of autistic characteristics in individuals with genetic syndromes associated with ID.
Assuntos
Transtorno Autístico , Deficiência Intelectual , Esclerose Tuberosa , Humanos , Transtorno Autístico/diagnóstico , Transtorno Autístico/genética , Esclerose Tuberosa/diagnóstico , Esclerose Tuberosa/genética , Estudos Transversais , Deficiência Intelectual/genética , SíndromeRESUMO
The LIM homeodomain transcription factors LMX1A and LMX1B are essential mediators of midbrain dopaminergic neuronal (mDAN) differentiation and survival. Here we show that LMX1A and LMX1B are autophagy transcription factors that provide cellular stress protection. Their suppression dampens the autophagy response, lowers mitochondrial respiration, and elevates mitochondrial ROS, and their inducible overexpression protects against rotenone toxicity in human iPSC-derived mDANs in vitro. Significantly, we show that LMX1A and LMX1B stability is in part regulated by autophagy, and that these transcription factors bind to multiple ATG8 proteins. Binding is dependent on subcellular localization and nutrient status, with LMX1B interacting with LC3B in the nucleus under basal conditions and associating with both cytosolic and nuclear LC3B during nutrient starvation. Crucially, ATG8 binding stimulates LMX1B-mediated transcription for efficient autophagy and cell stress protection, thereby establishing a novel LMX1B-autophagy regulatory axis that contributes to mDAN maintenance and survival in the adult brain.
Assuntos
Família da Proteína 8 Relacionada à Autofagia , Proteínas com Homeodomínio LIM , Mesencéfalo , Neurônios , Fatores de Transcrição , Humanos , Autofagia , Encéfalo/citologia , Encéfalo/metabolismo , Proteínas com Homeodomínio LIM/genética , Proteínas com Homeodomínio LIM/metabolismo , Mesencéfalo/metabolismo , Fatores de Transcrição/metabolismo , Família da Proteína 8 Relacionada à Autofagia/genética , Neurônios/citologiaRESUMO
BACKGROUND: Anxiety symptomatology is common in individuals with intellectual disability (ID). Symptomatology includes both traditional Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) anxiety disorders and autism spectrum disorder (ASD)-related anxiety traits. Some genetic disorders such as Cornelia de Lange (CdLS) and fragile X syndromes (FXS) are at very high risk of anxiety and afford the opportunity to examine prevalence, profiles and associated person characteristics. However, prevalence and associated characteristics of anxiety in these high-risk groups remain poorly described and understood. The aim of the current study was to examine the prevalence and profile of DSM-5 and ASD-related anxiety symptomatology in individuals with CdLS and FXS and associated behavioural and cognitive characteristics. METHODS: Questionnaires and interviews assessing DSM-5 and ASD-related anxiety were conducted with caregivers of individuals with CdLS (n = 49) and FXS (n = 36). RESULTS: DSM-5 anxiety symptomatology was present in both groups with high co-morbidity across anxiety diagnoses. ASD-related anxiety was also prevalent with specific difficulties related to intolerance of uncertainty identified in both groups. Symptomatology was persistent over the lifespan for both groups. Anxiety type was partially associated with repetitive behaviour but not measures of overall ASD phenomenology in CdLS. CONCLUSIONS: DSM-5 and ASD-related anxiety are common in these high-risk syndromes associated with ID. Prospective syndrome specific presentations and associations, which may implicate specific underlying mechanisms, are discussed. Clinicians should be aware of the risk and difficulties involved in assessment of anxiety in individuals with ID, including atypical types, to ensure these individuals do not "miss" diagnoses and support in general clinical practice.
Assuntos
Transtorno do Espectro Autista , Síndrome de Cornélia de Lange , Síndrome do Cromossomo X Frágil , Deficiência Intelectual , Ansiedade/complicações , Ansiedade/epidemiologia , Transtornos de Ansiedade/complicações , Transtornos de Ansiedade/diagnóstico , Transtornos de Ansiedade/epidemiologia , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/psicologia , Síndrome de Cornélia de Lange/complicações , Síndrome do Cromossomo X Frágil/complicações , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/epidemiologia , Estudos ProspectivosRESUMO
BACKGROUND: SATB2-associated syndrome (SAS) is a multisystem neurodevelopmental disorder characterised by intellectual disability, speech delay, and craniofacial anomalies. Although the clinical presentation of SAS is well-delineated, behaviours associated with SAS are less well-defined. Given the varied social profile reported in SAS of a 'jovial' predisposition and autistic behaviours, there may be phenotypic overlap with both Angelman syndrome (AS) and non-syndromal autism. This study aimed to describe behaviours in SAS in relation to chronological age and level of ability and contrast aspects of the behavioural phenotype with AS and non-syndromal autism. METHODS: Informant report questionnaire measures of behaviour, emotion, and autism characteristics were completed for 81 individuals with SAS (aged 1-36 years; 43 male). Within-group associations were analysed, and categorical data were compared between pre-school (1-5 years), school-age (6-15 years), and adolescent and adult SAS sub-groups (16 years and over). Cross-syndrome subscale and item-level analyses were conducted for 63 individuals with SAS (aged 1-27 years; 31 male), who were matched according to age and level of ability to 63 individuals with AS (aged 2-25 years; 32 male) and 63 individuals with non-syndromal autism (aged 3-26 years; 53 male). RESULTS: In SAS, higher rates of overactivity were moderately associated with lower self-help ability, and higher general anxiety scores were reported for males compared with females. Cross-syndrome subscale analyses uncovered several significant differences (p < .01), with comparatively low rates of stereotyped behaviour, overactivity, insistence on sameness and positive affect, and comparatively greater interest and pleasure and compulsive behaviour in individuals with SAS. Item-level analyses revealed a distinct profile of repetitive and autistic behaviours. LIMITATIONS: Developmental analysis was based on a cross-sectional rather than a longitudinal research design, the contribution of pain and sleep to behaviour was not explored, and molecular genetic testing to determine genotype-phenotype behavioural relationships was not possible. CONCLUSIONS: This study highlights the importance of behavioural comparisons to well-delineated groups and the utility of fine-grained item-level analyses to elucidate aspects of behaviour that might be syndrome related or shared across neurodevelopmental disorders. Future research is needed to further describe the distinctive repetitive and autistic behavioural phenotype in SAS.
Assuntos
Anormalidades Múltiplas , Anormalidades Craniofaciais , Deficiência Intelectual , Proteínas de Ligação à Região de Interação com a Matriz , Adolescente , Adulto , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Deficiência Intelectual/complicações , Deficiência Intelectual/psicologia , Masculino , Proteínas de Ligação à Região de Interação com a Matriz/genética , Fenótipo , Fatores de Transcrição/genética , Adulto JovemRESUMO
The experiences of mothers of adult offspring with Angelman, Cornelia de Lange, or Cri du Chat syndrome have not been previously explored in research. The current study focuses on experiences with social and medical services and the impact the rareness of an adult offspring's syndrome has on the experiences of mothers. Eight mothers of adults with Angelman, Cornelia de Lange, or Cri du Chat syndrome were interviewed. Thematic Content Analysis was used to interpret the interviews. Four themes emerged from the analysis: (i) The rarity of their offspring's syndrome, (ii) Uneven medical and social care service provision, (iii) The inertia of social care services, and (iv) Mothers as advocates. Mothers felt that the rareness of their offspring's syndrome did not affect experiences with social care services, but did affect access to medical services and some aspects of day-to-day living. Accessing appropriate social care services was reported to be a lengthy and complex process. These data may help inform care service providers about how best to support adults with rare genetic syndromes and their families.
Assuntos
Deficiência Intelectual/genética , Mães/psicologia , Doenças Raras/genética , Apoio Social , Feminino , HumanosRESUMO
PURPOSE OF REVIEW: While previous reviews have extended descriptions of the behavioural phenotype of Cornelia de Lange syndrome (CdLS) significantly, potential changes with age across the lifespan have been neglected. Age-related difference in the behavioural phenotype constitutes preliminary evidence of change with age. Documenting and understanding the developmental trajectories of behaviours is informative as it enables identification of risk periods for behavioural challenges and compromised mental health. RECENT FINDINGS: Recent cross sectional, longitudinal and mixed design studies report differing presentations of the behavioural phenotype across the lifespan. Of particular interest are autistic characteristics and behaviours consistent with compromised mental health, particularly anxiety and negative affect, which are reported to be more common and severe in older individuals. Preliminary evidence for identified causal pathways with consideration of biological, cognitive and environmental factors are discussed. SUMMARY: Older individuals with CdLS appear to be at greater risk of poorer psychological wellbeing than younger peers with significant implications for risk informed preventive and early interventions. Further work is required to document the behavioural phenotype across the lifespan with consideration of multiple factors that may influence the trajectory and extent of negative outcomes.
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Síndrome de Cornélia de Lange/psicologia , Longevidade , Ansiedade/complicações , Transtorno Autístico/complicações , Estudos Transversais , Síndrome de Cornélia de Lange/complicações , Síndrome de Cornélia de Lange/terapia , Humanos , FenótipoRESUMO
Unique socio-behavioural phenotypes are reported for individuals with different neurodevelopmental disorders. Here, the effects of adult familiarity and nature of interaction on social anxiety and social motivation were investigated in individuals with fragile X (FXS; n = 20), Cornelia de Lange (CdLS; n = 20) and Rubinstein-Taybi (RTS; n = 20) syndromes, compared to individuals with Down syndrome (DS; n = 20). The Social Anxiety and Motivation Rating Scale was employed whilst participants completed four social tasks, each administered separately by a familiar adult, and also by an unfamiliar adult. Compared to participants with DS, those with FXS and RTS exhibited high levels of social anxiety but similar levels of social motivation. Participants with CdLS showed heightened social anxiety and reduced social motivation only during interactions with an unfamiliar adult when active participation was voluntary.
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Síndrome de Cornélia de Lange/psicologia , Síndrome de Down/psicologia , Síndrome do Cromossomo X Frágil/psicologia , Motivação , Fobia Social , Síndrome de Rubinstein-Taybi/psicologia , Comportamento Social , Adulto , Feminino , Humanos , Masculino , Adulto JovemRESUMO
Age-related behavioural change in Cornelia de Lange syndrome is poorly understood. We report a 7 year follow-up study of adaptive behaviour, autism spectrum disorder symptomatology, language skills and behavioural characteristics in 30 individuals with Cornelia de Lange syndrome, compared with 18 individuals with Cri du Chat syndrome. The proportion of individuals with Cornelia de Lange syndrome meeting criteria for autism spectrum disorder on the Autism Diagnostic Observation Schedule increased, although patterns of change were complex. For both syndrome groups, absolute levels of adaptive ability were stable and receptive language improved, suggesting that changes over time do not result from an overall decline in ability. Reliable change index scores indicate heterogeneity within both groups in the occurrence of improvement or decline.
Assuntos
Transtorno do Espectro Autista/diagnóstico , Síndrome de Cri-du-Chat/diagnóstico , Síndrome de Cornélia de Lange/diagnóstico , Adaptação Psicológica , Adulto , Síndrome de Cornélia de Lange/epidemiologia , Feminino , Seguimentos , Humanos , MasculinoRESUMO
Protein kinase B/AKT is a highly connected protein involved in a range of signaling pathways. Although it is known to regulate several proteins in the apoptotic pathway, its system-level effects remain poorly understood. We investigated the dynamic interactions between AKT and key apoptotic proteins and constructed a deterministic ordinary differential equation protein interaction model of extrinsic apoptosis. Incorporating AKT and its indirect inhibitor, phosphatase and tensin homolog (PTEN), this was used to generate predictions of system dynamics. Using eigen analysis, we identified AKT and cytochrome c as the protein species most sensitive to perturbations. Cell death assays in Type II HCT116 colorectal carcinoma cells revealed a tendency toward Type I cell death behavior in the XIAP-/- background, with cells displaying accelerated TRAIL-induced apoptosis. Finally, AKT inhibition experiments implicated AKT and not PTEN in influencing apoptotic proteins during early phases of TRAIL-induced apoptosis.