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Using the Consequences of COVID-19 (COCO) dataset (quota sample of the adult Italian population, surveyed seven times by email), we analysed the trend of trust in political (political parties, parliament and local administrations), super partes (president of the Republic, judiciary and police) and international (the European Union and the United Nations) institutions from June 2019 to October 2022. Three latent growth curve models showed that trust in political institutions increased between June 2019 and April 2020 and subsequently decreased below the pre-pandemic level. Trust in super partes institutions decreased slightly between June 2019 and April 2020, decreased from April 2020 to April 2022 and increased in the subsequent months. Trust in international institutions declined between June 2019 and April 2020 and then returned to pre-pandemic levels. Three piecewise decompositions showed different trends in trust for non-populist voters, populist voters and non-voters. Strengths, weaknesses and possible developments of the study are discussed.
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Confianza , Votación , Adulto , Humanos , PoliciaRESUMEN
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.
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Mosaicismo , Hermanos , Síndrome de Smith-Magenis , Humanos , Masculino , Síndrome de Smith-Magenis/genética , Proteínas de Unión al ADN/genética , Femenino , Discapacidad Intelectual/genética , Niño , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Linaje , Mutación/genética , Preescolar , FenotipoRESUMEN
Imprinting Disorders (ImpDis) are a group of congenital syndromes associated with up to four different types of molecular disturbances affecting the monoallelic and parent-of-origin specific expression of genomically imprinted genes. Though each ImpDis is characterized by aberrations at a distinct genetic site and a specific set of postnatal clinical signs, there is a broad overlap between several of them. In particular, the prenatal features of ImpDis are non-specific. Therefore, the decision on the appropriate molecular testing strategy is difficult. A further molecular characteristic of ImpDis is (epi)genetic mosaicism, which makes prenatal testing for ImpDis challenging. Accordingly, sampling and diagnostic workup has to consider the methodological limitations. Furthermore, the prediction of the clinical outcome of a pregnancy can be difficult. False-negative results can occur, and therefore fetal imaging should be the diagnostic tool on which decisions on the management of the pregnancy should be based. In summary, the decision for molecular prenatal testing for ImpDis should be based on close exchanges between clinicians, geneticists, and the families before the initiation of the test. These discussions should weigh the chances and challenges of the prenatal test, with focus on the need of the family.
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Impresión Genómica , Diagnóstico Prenatal , Embarazo , Femenino , Humanos , Pruebas Genéticas/métodosRESUMEN
The prevalence of Beckwith-Wiedemann spectrum (BWSp) is tenfold increased in children conceived through assisted reproductive techniques (ART). More than 90% of ART-BWSp patients reported so far display imprinting center 2 loss-of-methylations (IC2-LoM), versus 50% of naturally conceived BWSp patients. We describe a cohort of 74 ART-BWSp patients comparing their features with a cohort of naturally conceived BWSp patients, with the ART-BWSp patients previously described in literature, and with the general population of children born from ART. We found that the distribution of UPD(11)pat was not significantly different in ART and naturally conceived patients. We observed 68.9% of IC2-LoM and 16.2% of mosaic UPD(11)pat in our ART cohort, that strongly differ from the figure reported in other cohorts so far. Since UPD(11)pat likely results from post-fertilization recombination events, our findings allows to hypothesize that more complex molecular mechanisms, besides methylation disturbances, may underlie BWSp increased risk in ART pregnancies. Moreover, comparing the clinical features of ART and non-ART BWSp patients, we found that ART-BWSp patients might have a milder phenotype. Finally, our data show a progressive increase in the prevalence of BWSp over time, paralleling that of ART usage in the last decades.
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Síndrome de Beckwith-Wiedemann , Impresión Genómica , Síndrome de Beckwith-Wiedemann/epidemiología , Síndrome de Beckwith-Wiedemann/genética , Metilación de ADN/genética , Femenino , Fertilización , Impresión Genómica/genética , Humanos , Embarazo , Técnicas Reproductivas Asistidas/efectos adversosRESUMEN
Rett syndrome caused by MECP2 variants is characterized by a heterogenous clinical spectrum accounted for in 60% of cases by hot-spot variants. Focusing on the most frequent variants, we generated in vitro iPSC-neurons from the blood of RTT girls with p.Arg133Cys and p.Arg255*, associated to mild and severe phenotype, respectively, and of an RTT male harboring the close to p.Arg255*, p.Gly252Argfs*7 variant. Truncated MeCP2 proteins were revealed by Western blot and immunofluorescence analysis. We compared the mutant versus control neurons at 42 days for morphological parameters and at 120 days for electrophysiology recordings, including girls' isogenic clones. A precocious reduced morphological complexity was evident in neurons with truncating variants, while in p.Arg133Cys neurons any significant differences were observed in comparison with the isogenic wild-type clones. Reduced nuclear size and branch number show up as the most robust biomarkers. Patch clamp recordings on mature neurons allowed the assessment of cell biophysical properties, V-gated currents, and spiking pattern in the mutant and control cells. Immature spiking, altered cell capacitance, and membrane resistance of RTT neurons, were particularly pronounced in the Arg255* and Gly252Argfs*7 mutants. The overall results indicate that the specific markers of in vitro cellular phenotype mirror the clinical severity and may be amenable to drug testing for translational purposes.
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Células Madre Pluripotentes Inducidas , Síndrome de Rett , Masculino , Femenino , Humanos , Síndrome de Rett/genética , Síndrome de Rett/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Neuronas , FenotipoRESUMEN
KBG syndrome (KBGS) is a neurodevelopmental disorder caused by the Ankyrin Repeat Domain 11 (ANKRD11) haploinsufficiency. Here, we report the molecular investigations performed on a cohort of 33 individuals with KBGS clinical suspicion. By using a multi-testing genomic approach, including gene sequencing, Chromosome Microarray Analysis (CMA), and RT-qPCR gene expression assay, we searched for pathogenic alterations in ANKRD11. A molecular diagnosis was obtained in 22 out of 33 patients (67%). ANKRD11 sequencing disclosed pathogenic or likely pathogenic variants in 18 out of 33 patients. CMA identified one full and one terminal ANKRD11 pathogenic deletions, and one partial duplication and one intronic microdeletion, with both possibly being pathogenic. The pathogenic effect was established by RT-qPCR, which confirmed ANKRD11 haploinsufficiency only for the three deletions. Moreover, RT-qPCR applied to six molecularly unsolved KBGS patients identified gene downregulation in a clinically typical patient with previous negative tests, and further molecular investigations revealed a cryptic deletion involving the gene promoter. In conclusion, ANKRD11 pathogenic variants could also involve the regulatory regions of the gene. Moreover, the application of a multi-test approach along with the innovative use of RT-qPCR improved the diagnostic yield in KBGS suspected patients.
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Anomalías Múltiples , Enfermedades del Desarrollo Óseo , Discapacidad Intelectual , Anomalías Dentarias , Anomalías Múltiples/genética , Deleción Cromosómica , Facies , Humanos , Discapacidad Intelectual/genética , Fenotipo , Proteínas Represoras/genética , Anomalías Dentarias/diagnóstico , Anomalías Dentarias/genética , Factores de Transcripción/genéticaRESUMEN
Epidemiological data show that men and women have similar probabilities of contracting COVID-19. However, men with COVID-19 tend to have more severe outcomes than women. We performed two studies to analyze the associations between gender, adherence to traditional masculinity ideology, perceived vulnerability to COVID-19, and the adoption of protective behaviors against COVID-19. In Study 1 (quota sample of the Italian adult population, N = 1,142), we found no differences between men and women in terms of the perceived probability of contracting COVID-19. However, compared to women, men perceived themselves to be less likely to suffer severe consequences if falling ill. In Study 2 (Italian community sample, N = 305), a moderated mediation model showed that adherence to traditional masculinity ideology moderated the association between being man and the perceived severity of the consequences of COVID-19, which, in turn, showed negative associations with three protective behaviors against COVID-19. The article ends with a discussion of the strengths and limitations of this research.
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Rubinstein-Taybi syndrome (RSTS) is a rare neurodevelopmental disorder caused by mutations in CREBBP or EP300 genes encoding CBP/p300 lysine acetyltransferases. We investigated the efficacy of the histone deacetylase inhibitor (HDACi) Trichostatin A (TSA) in ameliorating morphological abnormalities of iPSC-derived young neurons from P149 and P34 CREBBP-mutated patients and hypoexcitability of mature neurons from P149. Neural progenitors from both patients' iPSC lines were cultured one week with TSA 20 nM and, only P149, for 6 weeks with TSA 0.2 nM, in parallel to neural progenitors from controls. Immunofluorescence of MAP2/TUJ1 positive cells using the Skeletonize Image J plugin evidenced that TSA partially rescued reduced nuclear area, and decreased branch length and abnormal end points number of both 45 days patients' neurons, but did not influence the diminished percentage of their neurons with respect to controls. Patch clamp recordings of TSA-treated post-mitotic P149 neurons showed complete/partial rescue of sodium/potassium currents and significant enhancement of neuron excitability compared to untreated replicas. Correction of abnormalities of P149 young neurons was also affected by valproic acid 1 mM for 72 h, with some variation, with respect to TSA, on the morphological parameter. These findings hold promise for development of an epigenetic therapy to attenuate RSTS patients cognitive impairment.
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Inhibidores de Histona Desacetilasas/farmacología , Ácidos Hidroxámicos/farmacología , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Neuronas/efectos de los fármacos , Adolescente , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Células Cultivadas , Niño , Proteína p300 Asociada a E1A/genética , Electroencefalografía , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/fisiología , Imagen por Resonancia Magnética , Masculino , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/genética , Mutación , Neuronas/metabolismo , Neuronas/fisiología , Técnicas de Placa-Clamp , Síndrome de Rubinstein-Taybi/diagnóstico por imagen , Síndrome de Rubinstein-Taybi/genética , Síndrome de Rubinstein-Taybi/fisiopatologíaRESUMEN
Rett syndrome (RTT, MIM * 312750) is an X-linked neurodevelopmental disorder caused by pathogenic variants at the Xq28 region involving the gene methyl-CpG-binding protein 2 (MECP2, MIM * 300005). The spectrum of MECP2-related phenotypes is wide and it ranges from asymptomatic female carriers to severe neonatal-onset encephalopathy in males. Abnormal breathing represents one of the leading features, but today little is known about polysomnographic features in RTT females; no data are available about males. We report the case of a male of Moroccan origins with a MECP2 pathogenic variant and a history of encephalopathy and severe breathing disturbances in the absence of dysmorphic features. For the first time we describe in detail the polysomnographic characteristics of a MECP2-mutated male and we show the relevance of severe central apneas, which may represent a new clinical clue to suggest the diagnosis. Moreover, we want to highlight the importance to maintain a high index of suspicion for MECP2-related disorders in the presence of severe hypotonia, apneic crises, and respiratory insufficiency in males to permit an earlier diagnosis and the consequent definition of recurrence risk of the family and to avoid other useless and invasive exams.
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Hipoventilación/patología , Proteína 2 de Unión a Metil-CpG/genética , Mutación , Fenotipo , Síndromes de la Apnea del Sueño/patología , Humanos , Hipoventilación/complicaciones , Hipoventilación/genética , Recién Nacido , Masculino , Síndromes de la Apnea del Sueño/complicaciones , Síndromes de la Apnea del Sueño/genéticaRESUMEN
Maternal uniparental disomy of chromosome 7 is present in 5-10% of patients with Silver-Russell syndrome (SRS), and duplication of 7p including GRB10 (Growth Factor Receptor-Bound Protein 10), an imprinted gene that affects pre-and postnatal growth retardation, has been associated with the SRS phenotype. Here, we report on a 17 year old girl referred to array-CGH analysis for short stature, psychomotor delay, and relative macrocephaly. Array-CGH analysis showed two copy number variants (CNVs): a ~12.7 Mb gain in 7p13-p11.2, involving GRB10 and an ~9 Mb loss in 7q11.21-q11.23. FISH experiments performed on the proband's mother showed a chromosome 7 pericentric inversion that might have mediated the complex rearrangement harbored by the daughter. Indeed, we found that segmental duplications, of which chromosome 7 is highly enriched, mapped at the breakpoints of both the mother's inversion and the daughter's CNVs. We postulate that pairing of highly homologous sequences might have perturbed the correct meiotic chromosome segregation, leading to unbalanced outcomes and acting as the putative meiotic mechanism that was causative of the proband's rearrangement. Comparison of the girl's phenotype to those of patients with similar CNVs supports the presence of 7p in a locus associated with features of SRS syndrome.
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Inversión Cromosómica/genética , Cromosomas Humanos Par 7/genética , Recombinación Genética/genética , Síndrome de Silver-Russell/genética , Adolescente , Variaciones en el Número de Copia de ADN/genética , Femenino , Proteína Adaptadora GRB10/genética , Humanos , Meiosis/genética , Madres , FenotipoRESUMEN
Pathogenic variation in MAPT, GRN, and C9ORF72 accounts for at most only half of frontotemporal lobar degeneration (FTLD) cases with a family history of neurological disease. This suggests additional variants and genes that remain to be identified as risk factors for FTLD. We conducted a case-control genetic association study comparing pathologically diagnosed FTLD patients (n = 94) to cognitively normal older adults (n = 3541), and found suggestive evidence that gene-wide aggregate rare variant burden in MFSD8 is associated with FTLD risk. Because homozygous mutations in MFSD8 cause neuronal ceroid lipofuscinosis (NCL), similar to homozygous mutations in GRN, we assessed rare variants in MFSD8 for relevance to FTLD through experimental follow-up studies. Using post-mortem tissue from middle frontal gyrus of patients with FTLD and controls, we identified increased MFSD8 protein levels in MFSD8 rare variant carriers relative to non-variant carrier patients with sporadic FTLD and healthy controls. We also observed an increase in lysosomal and autophagy-related proteins in MFSD8 rare variant carrier and sporadic FTLD patients relative to controls. Immunohistochemical analysis revealed that MFSD8 was expressed in neurons and astrocytes across subjects, without clear evidence of abnormal localization in patients. Finally, in vitro studies identified marked disruption of lysosomal function in cells from MFSD8 rare variant carriers, and identified one rare variant that significantly increased the cell surface levels of MFSD8. Considering the growing evidence for altered autophagy in the pathogenesis of neurodegenerative disorders, our findings support a role of NCL genes in FTLD risk and suggest that MFSD8-associated lysosomal dysfunction may contribute to FTLD pathology.
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Demencia Frontotemporal/genética , Demencia Frontotemporal/patología , Degeneración Lobar Frontotemporal/genética , Proteínas de Transporte de Membrana/genética , Anciano , Femenino , Demencia Frontotemporal/metabolismo , Degeneración Lobar Frontotemporal/patología , Estudios de Asociación Genética/métodos , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Lisosomas/metabolismo , Masculino , Persona de Mediana Edad , Mutación/genética , Lipofuscinosis Ceroideas Neuronales/genética , Lipofuscinosis Ceroideas Neuronales/patología , Enfermedad de Pick/genética , Factores de RiesgoRESUMEN
Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS) are two imprinting disorders associated with opposite molecular alterations in the 11p15.5 imprinting centres. Their clinical diagnosis is confirmed by molecular testing in 50-70% of patients. The authors from different reference centres for BWS and SRS have identified single patients with unexpected and even contradictory molecular findings in respect to the clinical diagnosis. These patients clinically do not fit the characteristic phenotypes of SRS or BWS, but illustrate their clinical heterogeneity. Thus, comprehensive molecular testing is essential for accurate diagnosis and appropriate management, to avoid premature clinical diagnosis and anxiety for the families.
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Síndrome de Beckwith-Wiedemann/genética , Síndrome de Silver-Russell/genética , Síndrome de Beckwith-Wiedemann/diagnóstico , Cromosomas Humanos Par 11/genética , Metilación de ADN , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas , Humanos , Fenotipo , Síndrome de Silver-Russell/diagnósticoRESUMEN
BACKGROUND/AIMS: Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth disorder predisposing to tumorigenesis caused by abnormal expression or function of imprinted genes of the chromosome 11p15.5 imprinting gene cluster. This real-time PCR-based assay determines the methylation status of a selected CpG island and has been proposed for use in high-throughput methylation analysis. METHODS: Here, we use quantitative analysis of methylated alleles (QAMA) for the detection of methylation status of the KCNQ10T1 gene, in a region immediately upstream of the transcription initiation site, and the CTCF binding site 6, located approximately 2 kb upstream of the SmaI site currently used for clinical laboratory testing. We assayed a series of controls and patients diagnosed with BWS at two different loci at 11p15.5 to assess the diagnostic yield of QAMA PCR for clinical laboratory testing. RESULTS: These results compare favorably with methylation-specific multiple ligation probe amplification (MS-MLPA) analysis at both differentially methylated region (DMR)1 and DMR2. There are several advantages of the QAMA PCR over MS-MLPA. The QAMA PCR is less labor-intensive and therefore more cost-effective and does not require dedicated analysis software. A second advantage is that the assay is amenable to high-throughput analysis. CONCLUSIONS: The small sample size reflects the rare nature of this epigenetic disorder, and the range of ages was quite wide, as was the degree of disease severity. Therefore, further validation with larger cohorts is warranted.
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Síndrome de Beckwith-Wiedemann/diagnóstico , Síndrome de Beckwith-Wiedemann/genética , Metilación de ADN , Reacción en Cadena de la Polimerasa Multiplex , Reacción en Cadena en Tiempo Real de la Polimerasa , Alelos , Islas de CpG , Sondas de ADN/genética , Humanos , Técnicas de Diagnóstico MolecularRESUMEN
Nephropathic cystinosis is a rare lysosomal storage disorder caused by mutations in CTNS gene leading to Fanconi syndrome. Independent studies reported defective clearance of damaged mitochondria and mitochondrial fragmentation in cystinosis. Proteins involved in the mitochondrial dynamics and the mitochondrial ultrastructure were analyzed in CTNS-/- cells treated with cysteamine, the only drug currently used in the therapy for cystinosis but ineffective to treat Fanconi syndrome. CTNS-/- cells showed an overexpression of parkin associated with deregulation of ubiquitination of mitofusin 2 and fission 1 proteins, an altered proteolytic processing of optic atrophy 1 (OPA1), and a decreased OPA1 oligomerization. According to molecular findings, the analysis of electron microscopy images showed a decrease of mitochondrial cristae number and an increase of cristae lumen and cristae junction width. Cysteamine treatment restored the fission 1 ubiquitination, the mitochondrial size, number and lumen of cristae, but had no effect on cristae junction width, making CTNS-/- tubular cells more susceptible to apoptotic stimuli.
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Sistemas de Transporte de Aminoácidos Neutros/genética , Cisteamina/farmacología , Cistinosis/genética , Mitocondrias/metabolismo , Células Cultivadas , Cistinosis/metabolismo , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , GTP Fosfohidrolasas/metabolismo , Humanos , Túbulos Renales Proximales/citología , Túbulos Renales Proximales/efectos de los fármacos , Túbulos Renales Proximales/metabolismo , Proteínas de la Membrana/metabolismo , Mitocondrias/efectos de los fármacos , Dinámicas Mitocondriales/efectos de los fármacos , Proteínas Mitocondriales/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , UbiquitinaciónRESUMEN
Rett syndrome (RTT) is a neurodevelopmental disorder, affecting 1 in 10,000 girls. Intellectual disability, loss of speech and hand skills with stereotypies, seizures and ataxia are recurrent features. Stringent diagnostic criteria distinguish classical Rett, caused by a MECP2 pathogenic variant in 95% of cases, from atypical girls, 40-73% carrying MECP2 variants, and rarely CDKL5 and FOXG1 alterations. A large fraction of atypical and RTT-like patients remain without genetic cause. Next Generation Sequencing (NGS) targeted to multigene panels/Whole Exome Sequencing (WES) in 137 girls suspected for RTT led to the identification of a de novo variant in STXBP1 gene in four atypical RTT and two RTT-like girls. De novo pathogenic variants-one in GABRB2 and, for first time, one in GABRG2-were disclosed in classic and atypical RTT patients. Interestingly, the GABRG2 variant occurred at low rate percentage in blood and buccal swabs, reinforcing the relevance of mosaicism in neurological disorders. We confirm the role of STXBP1 in atypical RTT/RTT-like patients if early psychomotor delay and epilepsy before 2 years of age are observed, indicating its inclusion in the RTT diagnostic panel. Lastly, we report pathogenic variants in Gamma-aminobutyric acid-A (GABAa) receptors as a cause of atypical/classic RTT phenotype, in accordance with the deregulation of GABAergic pathway observed in MECP2 defective in vitro and in vivo models.
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Discapacidad Intelectual/genética , Proteína 2 de Unión a Metil-CpG/genética , Proteínas Munc18/genética , Síndrome de Rett/genética , Adolescente , Adulto , Niño , Femenino , Factores de Transcripción Forkhead/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Discapacidad Intelectual/fisiopatología , Mutación , Proteínas del Tejido Nervioso/genética , Fenotipo , Proteínas Serina-Treonina Quinasas/genética , Receptores de GABA/genética , Receptores de GABA-A/genética , Síndrome de Rett/fisiopatología , Secuenciación del Exoma , Adulto JovenRESUMEN
Cornelia de Lange syndrome (CdLS) is a genetic condition characterized by intellectual disability, peculiar facial dysmorphisms, multiorgan malformations, and growth problems. Majority cases of CdLS are caused by mutations in genes of Cohesin pathway. Although feeding problems are a well-known feature, no specific data have been published about the use of nutritional devices. We analyzed use, type, time of introduction, and duration of nutritional devices in 73 CdLS patients. In total, 29/73 (40%) used a device; nasogastric tube (NGT) in 28/73 (38%) and percutaneous endoscopic gastrostomy (PEG) in 7/73 (10%). NGT was placed during the first days/weeks of life. 19/28 (68%) maintained it for less than 3 months, 7/28 (25%) for a period between 3 and 12 months, while 2/28 (7%) for more than 1 year. PEG was placed within the first year in 4/7 (57%) and removed in two patients after 4 years These data have been matched with a wide number of genetic and clinical variables. Presence of upper limb malformations is positively correlated with the need of a device. From the opposite side, the use of a device positively correlates with a more severe prognosis as regard growth, intellectual development and disease severity. Our data show that nutritional devices are frequently used by CdLS patients, also if the majority of them (93.1%) succeed with time in achieving a normal oral nutrition. Finally, the need, the type of device used and the duration of NGT or/plus PEG can be considered a further sign of worse prognosis of the disease itself.
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Síndrome de Cornelia de Lange/dietoterapia , Apoyo Nutricional/instrumentación , Apoyo Nutricional/métodos , Niño , Preescolar , Estudios de Cohortes , Hibridación Genómica Comparativa , Síndrome de Cornelia de Lange/diagnóstico , Síndrome de Cornelia de Lange/genética , Femenino , Estudios de Asociación Genética , Marcadores Genéticos , Humanos , Lactante , Italia , Masculino , Fenotipo , Índice de Severidad de la EnfermedadRESUMEN
Angelman syndrome (AS, MIM 105830) is a rare neurodevelopmental disorder affecting 1:10-20,000 children. Patients show moderate to severe intellectual disability, ataxia and absence of speech. Studies on both post-mortem AS human brains and mouse models revealed dysfunctions in the extra synaptic gamma-aminobutyric acid (GABA) receptors implicated in the pathogenesis. Taurine is a free intracellular sulfur-containing amino acid, abundant in brain, considered an inhibiting neurotransmitter with neuroprotective properties. As taurine acts as an agonist of GABA-A receptors, we aimed at investigating whether it might ameliorate AS symptoms. Since mice weaning, we orally administered 1 g/kg/day taurine in water to Ube3a-deficient mice. To test the improvement of motor and cognitive skills, Rotarod, Novel Object Recognition and Open Field tests were assayed at 7, 14, 21 and 30 weeks, while biochemical tests and amino acid dosages were carried out, respectively, by Western-blot and high-performance liquid chromatography (HPLC) on frozen whole brains. Treatment of Ube3am-/p+ mice with taurine significantly improved motor and learning skills and restored the levels of the post-synaptic PSD-95 and pERK1/2-ERK1/2 ratio to wild type values. No side effects of taurine were observed. Our study indicates taurine administration as a potential therapy to ameliorate motor deficits and learning difficulties in AS.
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Síndrome de Angelman/tratamiento farmacológico , Taurina/uso terapéutico , Síndrome de Angelman/metabolismo , Síndrome de Angelman/fisiopatología , Animales , Modelos Animales de Enfermedad , Femenino , Aprendizaje/efectos de los fármacos , Masculino , Ratones , Ácido gamma-Aminobutírico/metabolismoRESUMEN
We designate a novel term "isolated lateralized overgrowth" (ILO) for the findings previously described as "isolated hemihypertrophy" and "isolated hemihyperplasia." ILO is defined as lateralized overgrowth in the absence of a recognized pattern of malformations, dysplasia, or morphologic variants. ILO is likely genetically heterogeneous. Further study is required to determine more of the underlying genetic etiologies and potential associations with currently unrecognized patterns of malformation.
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SMC1A encodes one of the proteins of the cohesin complex. SMC1A variants are known to cause a phenotype resembling Cornelia de Lange syndrome (CdLS). Exome sequencing has allowed recognizing SMC1A variants in individuals with encephalopathy with epilepsy who do not resemble CdLS. We performed an international, interdisciplinary study on 51 individuals with SMC1A variants for physical and behavioral characteristics, and compare results to those in 67 individuals with NIPBL variants. For the Netherlands all known individuals with SMC1A variants were studied, both with and without CdLS phenotype. Individuals with SMC1A variants can resemble CdLS, but manifestations are less marked compared to individuals with NIPBL variants: growth is less disturbed, facial signs are less marked (except for periocular signs and thin upper vermillion), there are no major limb anomalies, and they have a higher level of cognitive and adaptive functioning. Self-injurious behavior is more frequent and more severe in the NIPBL group. In the Dutch group 5 of 13 individuals (all females) had a phenotype that shows a remarkable resemblance to Rett syndrome: epileptic encephalopathy, severe or profound intellectual disability, stereotypic movements, and (in some) regression. Their missense, nonsense, and frameshift mutations are evenly spread over the gene. We conclude that SMC1A variants can result in a phenotype resembling CdLS and a phenotype resembling Rett syndrome. Resemblances between the SMC1A group and the NIPBL group suggest that a disturbed cohesin function contributes to the phenotype, but differences between these groups may also be explained by other underlying mechanisms such as moonlighting of the cohesin genes.