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1.
BMC Med Genet ; 21(1): 21, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005172

RESUMO

BACKGROUND: More than 95% of individuals with RTT have mutations in methyl-CpG-binding protein 2 (MECP2), whose protein product modulates gene transcription. The disorder is caused by mutations in a single gene and the disease severity in affected individuals can be quite variable. Specific MECP2 mutations may lead phenotypic variability and different degrees of disease severity. It is known that low bone mass is a frequent and early complication of subjects with Rett syndrome. As a consequence of the low bone mass Rett girls are at an increased risk of fragility fractures. This study aimed to investigate if specific MECP2 mutations may affects the degree of involvement of the bone status in Rett subjects. METHODS: In 232 women with Rett syndrome (mean age 13.8 ± 8.3 yrs) we measured bone mineral density at whole body and at femur (BMD-FN and BMD-TH) by using a DXA machine (Hologic QDR 4500). QUS parameters were assessed at phalanxes by Bone Profiler-IGEA (amplitude dependent speed of sound: AD-SoS and bone transmission time: BTT). Moreover, ambulation capacity (independent or assisted), fracture history and presence of scoliosis were assessed. We divided the subjects with the most common point mutations in two group based on genotype-phenotype severity; in particular, there has been consensus in recognising that the mutations R106T, R168X, R255X, R270X are considered more severe. RESULTS: As aspect, BMD-WB, BMD-FN and BMD-TH were lower in subjects with Rett syndrome that present the most severe mutations with respect to subjects with Rett syndrome with less severe mutations, but the difference was statistically significant only for BMD-FN and BMD-TH (p < 0.05). Also both AD-SoS and BTT values were lower in subjects that present the most severe mutations with respect to less severe mutations but the difference was not statistically significant. Moreover, subjects with Rett syndrome with more severe mutations present a higher prevalence of scoliosis (p < 0.05) and of inability to walk (p < 0.05). CONCLUSION: This study confirms that MECP2 mutation type is a strong predictor of disease severity in subjects with Rett syndrome. In particular, the subjects with more severe mutation present a greater deterioration of bone status, and a higher prevalence of scoliosis and inability to walk.


Assuntos
Doenças Ósseas/genética , Proteína 2 de Ligação a Metil-CpG/genética , Osteoporose/genética , Síndrome de Rett/genética , Adolescente , Adulto , Densidade Óssea/genética , Doenças Ósseas/diagnóstico por imagem , Doenças Ósseas/fisiopatologia , Criança , Pré-Escolar , Feminino , Fraturas Ósseas/diagnóstico por imagem , Fraturas Ósseas/genética , Fraturas Ósseas/fisiopatologia , Humanos , Masculino , Mutação , Osteoporose/diagnóstico por imagem , Osteoporose/fisiopatologia , Síndrome de Rett/diagnóstico por imagem , Síndrome de Rett/fisiopatologia , Escoliose/diagnóstico por imagem , Escoliose/genética , Escoliose/fisiopatologia , Índice de Gravidade de Doença , Adulto Jovem
2.
Gene ; 732: 144337, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-31958484

RESUMO

Rett syndrome (RTT) is an X-linked severe neurological disorder. Mutations in Methyl-CpG-Binding Protein2 (MECP2) gene are the main cause of RTT disease. In this study, we report the results of screening the MECP2 gene for mutations in 7 Iranian patients with RTT syndrome. MECP2 sequencing identified two novel mutations in the heterozygous state, a splice mutation, c.354G>T, p.Gly119Gly, resulting in a premature splice-donor site and a 20-bp deletion, c.1167-1186del20 (p.P390Rfs), leading to modifying the c-terminal parts of the protein and it also changes the reading frames of all coding sequence downstream of the mutation. Multiple sequence alignment showed that amino acid changes occurred in the well conserved protein regions across species. Based on the results of this study and literature reviews, about 70% of mutations are found in exon 3 and 4 of the MECP2 gene, and mutations in exon 4 are more common than other exons. Therefore, it is recommended that exon 4 to be a priority for screening the genetic analysis of RTT patients.


Assuntos
Proteína 2 de Ligação a Metil-CpG/genética , Mutação , Síndrome de Rett/genética , Sequência de Aminoácidos , Criança , Éxons , Feminino , Genótipo , Humanos , Irã (Geográfico) , Masculino , Proteína 2 de Ligação a Metil-CpG/química , Fenótipo , Homologia de Sequência de Aminoácidos
3.
Hum Genet ; 139(4): 499-512, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31980904

RESUMO

CHD8, which encodes Chromodomain helicase DNA-binding protein 8, is one of a few well-established Autism Spectrum Disorder (ASD) genes. Over 60 mutations have been reported in subjects with variable phenotypes, but little is known concerning genotype-phenotype correlations. We have identified four novel de novo mutations in Chinese subjects: two nonsense variants (c.3562C>T/p.Arg1188X, c.2065C>A/p.Glu689X), a splice site variant (c.4818-1G>A) and a missense variant (c.3502T>A/p.Tyr1168Asn). Three of these were identified from a 445-member ASD cohort by ASD gene panel sequencing of the 96 subjects who remained negative after molecular testing for copy number variation, Rett syndrome, FragileX and tuberous sclerosis complex (TSC). The fourth (p.Glu689X) was detected separately by diagnostic trio exome sequencing. We used diagnostic instruments and a comprehensive review of phenotypes, including prenatal and postnatal growth parameters, developmental milestones, and dysmorphic features to compare these four subjects. In addition to autism, they also presented with prenatal onset macrocephaly, intellectual disability, overgrowth during puberty, sleep disorder, and dysmorphic features, including broad forehead with prominent supraorbital ridges, flat nasal bridge, telecanthus and large ears. For further comparison, we compiled a comprehensive list of CHD8 variants from the literature and databases, which revealed constitutive and somatic truncating variants in the HELIC (Helicase-C) domain in ASD and in cancer patients, respectively, but not in the general population. Furthermore, HELIC domain mutations were associated with a severe phenotype defined by a greater number of clinical features, lower verbal IQ, and a prominent, consistent pattern of overgrowth as measured by weight, height and head circumference. Overall, this study adds to the ASD-associated loss-of-function mutations in CHD8 and highlights the clinical importance of the HELIC domain of CHD8.


Assuntos
Transtorno do Espectro Autista/genética , Códon sem Sentido , Proteínas de Ligação a DNA/genética , Síndrome do Cromossomo X Frágil/genética , Transtornos do Desenvolvimento da Linguagem/genética , Mutação de Sentido Incorreto , Fenótipo , Síndrome de Rett/genética , Fatores de Transcrição/genética , Esclerose Tuberosa/genética , Transtorno do Espectro Autista/enzimologia , Criança , Feminino , Síndrome do Cromossomo X Frágil/enzimologia , Humanos , Transtornos do Desenvolvimento da Linguagem/enzimologia , Masculino , Domínios Proteicos , Síndrome de Rett/enzimologia , Esclerose Tuberosa/enzimologia
4.
Orv Hetil ; 160(51): 2036-2039, 2019 Dec.
Artigo em Húngaro | MEDLINE | ID: mdl-31838863

RESUMO

Here we report on a severe, neonatal onset epileptic encephalopathy manifested in a currently 2-year-old boy with no family history of neurological disease. Extensive clinical investigations were unable to clarify the etiology of the infant's condition characterized by drug-resistant seizures and markedly delayed developmental skills. As in this class of disorders a genetic cause might be identified, a next-generation sequencing (NGS) epilepsy panel examination consisting of 128 genes was initiated for a correct diagnosis. The genetic analysis identified a previously undescribed hemizygous missense mutation in the MECP2 gene. Similarly to other, X-linked dominant disorders, Rett syndrome was originally hypothesized to be lethal in males. This theory, however, has been revised. The aim of this report is to review the wide spectrum of neurodevelopmental diseases observed in male patients carrying mutations in the MECP2 gene classically associated with Rett syndrome in girls. To the author's knowledge, this is the first report in Hungary to document MECP2 mutation of a male patient diagnosed by molecular genetic testing. Orv Hetil. 2019; 160(51): 2036-2039.


Assuntos
Retardo Mental Ligado ao Cromossomo X/genética , Proteína 2 de Ligação a Metil-CpG/genética , Mutação/genética , Síndrome de Rett/genética , Pré-Escolar , Humanos , Hungria , Masculino , Retardo Mental Ligado ao Cromossomo X/diagnóstico , Retardo Mental Ligado ao Cromossomo X/fisiopatologia , Biologia Molecular , Fenótipo , Síndrome de Rett/fisiopatologia
5.
Int J Mol Sci ; 20(15)2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31387202

RESUMO

Rett syndrome (RTT) is a rare, X-linked neurodevelopmental disorder typically affecting females, resulting in a range of symptoms including autistic features, intellectual impairment, motor deterioration, and autonomic abnormalities. RTT is primarily caused by the genetic mutation of the Mecp2 gene. Initially considered a neuronal disease, recent research shows that glial dysfunction contributes to the RTT disease phenotype. In the following manuscript, we review the evidence regarding glial dysfunction and its effects on disease etiology.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Proteína 2 de Ligação a Metil-CpG/deficiência , Neuroglia/metabolismo , Síndrome de Rett/genética , Síndrome de Rett/metabolismo , Animais , Astrócitos/metabolismo , Metabolismo Energético , Estudos de Associação Genética/métodos , Humanos , Oligodendroglia/metabolismo , Fenótipo , Síndrome de Rett/diagnóstico
6.
Int J Mol Sci ; 20(16)2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31409060

RESUMO

Rett syndrome (RTT) is an early-onset neurodevelopmental disorder that primarily affects females, resulting in severe cognitive and physical disabilities, and is one of the most prevalent causes of intellectual disability in females. More than fifty years after the first publication on Rett syndrome, and almost two decades since the first report linking RTT to the MECP2 gene, the research community's effort is focused on obtaining a better understanding of the genetics and the complex biology of RTT and Rett-like phenotypes without MECP2 mutations. Herein, we review the current molecular genetic studies, which investigate the genetic causes of RTT or Rett-like phenotypes which overlap with other genetic disorders and document the swift evolution of the techniques and methodologies employed. This review also underlines the clinical and genetic heterogeneity of the Rett syndrome spectrum and provides an overview of the RTT-related genes described to date, many of which are involved in epigenetic gene regulation, neurotransmitter action or RNA transcription/translation. Finally, it discusses the importance of including both phenotypic and genetic diagnosis to provide proper genetic counselling from a patient's perspective and the appropriate treatment.


Assuntos
Síndrome de Rett/genética , Animais , Regulação da Expressão Gênica , Heterogeneidade Genética , Humanos , Proteína 2 de Ligação a Metil-CpG/genética , Proteína 2 de Ligação a Metil-CpG/metabolismo , Mutação , Síndrome de Rett/diagnóstico , Síndrome de Rett/metabolismo , Transdução de Sinais
7.
Artigo em Inglês | MEDLINE | ID: mdl-31450876

RESUMO

Rett syndrome (RTT) is a neurodevelopmental disorder with a genetic basis that is associated with the mutation of the X-linked methyl-CpG binding protein 2 (MECP2) gene in approximately 90% of patients. RTT is characterized by a brief period of normal development followed by loss of acquired skills and evolution towards impairment of brain and motor functions and multi-organ dysfunction. Originally, RTT was considered lethal in males as it has an X-linked dominant inheritance. However, although this syndrome has a higher incidence in females, rare cases are also documented in males. Here, we describe the case of an 11-year-old male patient with a microduplication MECP2 Xq28. Our patient is currently living, while his older brother with the same mutation died at the age of 9 years. We showed that the role of MECP2 as an epigenetic modulator and the X-chromosome inactivation pattern can explain the lethal clinical form of the older brother with the same microduplication MECP2 Xq28 presented by our patient who is still alive. Given the limited case history of RTT in males, further studies are needed to better characterize this syndrome in males and consequently improve the currently available therapeutic strategies.


Assuntos
Proteína 2 de Ligação a Metil-CpG/genética , Síndrome de Rett/genética , Inativação do Cromossomo X/genética , Criança , Compensação de Dosagem (Genética) , Humanos , Masculino , Proteína 2 de Ligação a Metil-CpG/fisiologia , Mutação , Avaliação de Resultados da Assistência ao Paciente , Irmãos , Inativação do Cromossomo X/fisiologia
8.
Int J Mol Sci ; 20(17)2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31454984

RESUMO

Individuals with mutations in forkhead box G1 (FOXG1) belong to a distinct clinical entity, termed "FOXG1-related encephalopathy". There are two clinical phenotypes/syndromes identified in FOXG1-related encephalopathy, duplications and deletions/intragenic mutations. In children with deletions or intragenic mutations of FOXG1, the recognized clinical features include microcephaly, developmental delay, severe cognitive disabilities, early-onset dyskinesia and hyperkinetic movements, stereotypies, epilepsy, and cerebral malformation. In contrast, children with duplications of FOXG1 are typically normocephalic and have normal brain magnetic resonance imaging. They also have different clinical characteristics in terms of epilepsy, movement disorders, and neurodevelopment compared with children with deletions or intragenic mutations. FOXG1 is a transcriptional factor. It is expressed mainly in the telencephalon and plays a pleiotropic role in the development of the brain. It is a key player in development and territorial specification of the anterior brain. In addition, it maintains the expansion of the neural proliferating pool, and also regulates the pace of neocortical neuronogenic progression. It also facilitates cortical layer and corpus callosum formation. Furthermore, it promotes dendrite elongation and maintains neural plasticity, including dendritic arborization and spine densities in mature neurons. In this review, we summarize the clinical features, molecular genetics, and possible pathogenesis of FOXG1-related syndrome.


Assuntos
Encefalopatias/diagnóstico , Encefalopatias/genética , Fatores de Transcrição Forkhead/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Proteínas do Tecido Nervoso/genética , Biomarcadores , Duplicação Gênica , Humanos , Mutação , Neuroimagem/métodos , Fenótipo , Síndrome de Rett/diagnóstico , Síndrome de Rett/genética
9.
PLoS One ; 14(7): e0218623, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31291284

RESUMO

Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by mutations in the X-linked gene MECP2 (methyl-CpG-binding protein 2). Minimally invasive and accurate biomarkers of disease progression and treatment response could facilitate screening of therapeutic compounds in animal models, enrollment of better-defined participants into clinical trials, and treatment monitoring. In this study, we used a targeted approach based on analysis of brain-enriched microRNAs (miRNAs) circulating in plasma to identify miRNA biomarkers of RTT using Mecp2-mutant mice as a model system and human plasma samples. An "miRNA pair" approach, i.e. the ratio between two miRNAs, was used for data normalization. Specific miRNA pairs and their combinations (classifiers) analyzed in plasma differentiated wild-type from Mecp2 male and female mice with >90% accuracy. Individual miRNA pairs were more effective in distinguishing male (homozygous) animals than female (heterozygous) animals, suggesting that disease severity correlated with the levels of the miRNA biomarkers. In the human study, 30 RTT patients were compared with age-matched controls. The results of this study showed that miRNA classifiers were able to differentiate RTT patients from controls with 85-100% sensitivity. In addition, a comparison of various age groups demonstrated that the dynamics in levels of miRNAs appear to be associated with disease development (involvement of liver, muscle and lipid metabolism in the pathology). Importantly, certain miRNA biomarker pairs were common to both the animal models and human subjects, indicating the similarity between the underlying pathological processes. The data generated in this feasibility study suggest that circulating miRNAs have the potential to be developed as markers of RTT progression and treatment response. Larger clinical studies are needed to further evaluate the findings presented here.


Assuntos
Encéfalo/metabolismo , MicroRNA Circulante/genética , Síndrome de Rett/diagnóstico , Síndrome de Rett/genética , Animais , Biomarcadores/sangue , Encéfalo/fisiopatologia , MicroRNA Circulante/sangue , Modelos Animais de Doenças , Progressão da Doença , Estudos de Viabilidade , Feminino , Regulação da Expressão Gênica , Heterozigoto , Homozigoto , Humanos , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Fígado/fisiopatologia , Masculino , Camundongos , Camundongos Transgênicos , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Mutação , Síndrome de Rett/sangue , Síndrome de Rett/fisiopatologia , Sensibilidade e Especificidade
10.
Int J Mol Sci ; 20(15)2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31344879

RESUMO

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.


Assuntos
Deficiência Intelectual/genética , Proteína 2 de Ligação a Metil-CpG/genética , Proteínas Munc18/genética , Síndrome de Rett/genética , Adolescente , Adulto , Criança , Feminino , Fatores de Transcrição Forkhead/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Deficiência Intelectual/fisiopatologia , Mutação , Proteínas do Tecido Nervoso/genética , Fenótipo , Proteínas Serina-Treonina Quinases/genética , Receptores de GABA/genética , Receptores de GABA-A/genética , Síndrome de Rett/fisiopatologia , Sequenciamento Completo do Exoma , Adulto Jovem
11.
Biochim Biophys Acta Gene Regul Mech ; 1862(9): 194409, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31356990

RESUMO

MeCP2 is an abundant protein, involved in transcriptional repression by binding to CG and non-CG methylated DNA. However, MeCP2 might also function as a transcription activator as MeCP2 is found bound to sparsely methylated promoters of actively expressed genes. Furthermore, Attachment Region Binding Protein (ARBP), the chicken ortholog of MeCP2, has been reported to bind to Matrix/scaffold attachment regions (MARs/SARs) DNA with an unmethylated 5'-CAC/GTG-3' consensus sequence. In our previous study, although we have systemically measured the binding abilities of MBDs to unmethylated CAC/GTG DNA and the complex structures reveal that the MBD2-MBD (MBD of MBD2) binds to the unmethylated CAC/GTG DNA by recognizing the complementary GTG trinucleotide, how the MeCP2-MBD (MBD of MeCP2) recognizes the unmethylated CAC/GTG DNA, especially the MARs DNA, is still unclear. In this study, we investigated the binding characteristics of MeCP2 in recognizing unmethylated 5'-CAC/GTG-3' motif containing DNA by binding and structural studies. We found that MeCP2-MBD binds to MARs DNA with a comparable binding affinity to mCG DNA, and the MeCP2-CAC/GTG complex structure revealed that MeCP2 residues R111 and R133 form base-specific interactions with the GTG motif. For comparison, we also determined crystal structures of the MeCP2-MBD bound to mCG and mCAC/GTG DNA, respectively. Together, these crystal structures illustrate the adaptability of the MeCP2-MBD toward the GTG motif as well as the mCG DNA, and also provide structural basis of a biological role of MeCP2 as a transcription activator and its disease implications in Rett syndrome.


Assuntos
Metilação de DNA/genética , DNA/química , Proteína 2 de Ligação a Metil-CpG/química , Fatores de Transcrição/química , Animais , Sítios de Ligação , Cristalografia por Raios X , DNA/genética , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica/genética , Ribonucleoproteínas Nucleares Heterogêneas/genética , Humanos , Proteínas de Ligação à Região de Interação com a Matriz/genética , Proteína 2 de Ligação a Metil-CpG/genética , Motivos de Nucleotídeos/genética , Regiões Promotoras Genéticas , Ligação Proteica/genética , Conformação Proteica , Domínios Proteicos/genética , Síndrome de Rett/genética , Fatores de Transcrição/genética
12.
Epileptic Disord ; 21(3): 271-277, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31225800

RESUMO

To further characterise CDKL5-related disorder, previously classified as an early-onset seizure variant of Rett syndrome, which is currently considered a specific and independent early-infantile epileptic encephalopathy. We describe the epileptic phenotype and neurocognitive development in three girls with CDKL5 mutations showing severe neurodevelopmental impairment, with different epileptic phenotypes and severity. The patients differed regarding age at epilepsy onset, seizure frequency, duration of "honeymoon periods", as well as EEG features. The "honeymoon period", defined as a seizure-free period longer than two months, represented, in our case series, a good indicator of the epilepsy outcome, but not of the severity of developmental impairment. However, even during the "honeymoon period", the interictal EEG showed epileptiform abnormalities, slowing, or a disappearance of physiological pattern. The natural history of CDKL5 disorder was compared between the three girls, focusing on the relationship between electroclinical features and neurological development. Our findings suggest that CDKL5 mutations likely play a direct role in psychomotor development, whereas epilepsy is one of the clinical features associated with this complex disorder.


Assuntos
Epilepsia/terapia , Mutação/genética , Proteínas Serina-Treonina Quinases/genética , Espasmos Infantis/genética , Criança , Eletroencefalografia/métodos , Epilepsia/genética , Síndromes Epilépticas/diagnóstico , Síndromes Epilépticas/genética , Síndromes Epilépticas/terapia , Feminino , Humanos , Fenótipo , Síndrome de Rett/genética , Convulsões/genética , Espasmos Infantis/diagnóstico , Espasmos Infantis/terapia
13.
Eur J Paediatr Neurol ; 23(4): 609-620, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31105003

RESUMO

Rett syndrome (RTT) is an early-onset neurodevelopmental disorder that is caused by mutations in the MECP2 gene; however, defects in other genes (CDKL5 and FOXG1) can lead to presentations that resemble classic RTT, although they are not completely identical. Here, we attempted to identify other monogenic disorders that share features of RTT. A total of 437 patients with a clinical diagnosis of RTT-like were studied; in 242 patients, a custom panel with 17 genes related to an RTT-like phenotype was run via a HaloPlex-Target-Enrichment-System. In the remaining 195 patients, a commercial TruSight-One-Sequencing-Panel was analysed. A total of 40 patients with clinical features of RTT had variants which affect gene function in six genes associated with other monogenic disorders. Twelve patients had variants in STXBP1, nine in TCF4, six in SCN2A, five in KCNQ2, four in MEF2C and four in SYNGAP1. Genetic studies using next generation sequencing (NGS) allowed us to study a larger number of genes associated with RTT-like simultaneously, providing a genetic diagnosis for a wider group of patients. These new findings provide the clinician with more information and clues that could help in the prevention of future symptoms or in pharmacologic therapy.


Assuntos
Estudos de Associação Genética , Transtornos do Neurodesenvolvimento/genética , Síndrome de Rett , Adolescente , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Proteína 2 de Ligação a Metil-CpG/genética , Mutação , Fenótipo , Síndrome de Rett/genética , Adulto Jovem
14.
Neurology ; 92(22): e2594-e2603, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31053667

RESUMO

OBJECTIVE: To characterize hand stereotypies (HS) in a large cohort of participants with Rett syndrome (RTT). METHODS: Data from 1,123 girls and women enrolled in the RTT Natural History Study were gathered. Standard tests for continuous and categorical variables were used at baseline. For longitudinal data, we used repeated-measures linear and logistic regression models and nonparametric tests. RESULTS: HS were reported in 922 participants with classic RTT (100%), 73 with atypical severe RTT (97.3%), 74 with atypical mild RTT (96.1%), and 17 females with MECP2 mutations without RTT (34.7%). Individuals with RTT who had classic presentation or severe MECP2 mutations had higher frequency and earlier onset of HS. Heterogeneity of HS types was confirmed, but variety decreased over time. At baseline, almost half of the participants with RTT had hand mouthing, which like clapping/tapping, decreased over time. These 2 HS types were more frequently reported than wringing/washing. Increased HS severity (prevalence and frequency) was associated with worsened measures of hand function. Number and type of HS were not related to hand function. Overall clinical severity was worse with decreased hand function but only weakly related to any HS characteristic. While hand function decreased over time, prevalence and frequency of HS remained relatively unchanged and high. CONCLUSIONS: Nearly all individuals with RTT have severe and multiple types of HS, with mouthing and clapping/tapping decreasing over time. Interaction between HS frequency and hand function is complex. Understanding the natural history of HS in RTT could assist in clinical care and evaluation of new interventions.


Assuntos
Mãos , Síndrome de Rett/epidemiologia , Comportamento Estereotipado , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Progressão da Doença , Feminino , Seguimentos , Mãos/fisiopatologia , Humanos , Lactente , Estudos Longitudinais , Proteína 2 de Ligação a Metil-CpG/genética , Pessoa de Meia-Idade , Movimento , Prevalência , Síndrome de Rett/diagnóstico , Síndrome de Rett/genética , Síndrome de Rett/fisiopatologia , Índice de Gravidade de Doença , Adulto Jovem
15.
Rev Chil Pediatr ; 90(2): 152-156, 2019 Apr.
Artigo em Espanhol | MEDLINE | ID: mdl-31095231

RESUMO

INTRODUCTION: Rett syndrome (RTT) is a progressive neurological disorder characterized by regres sion of psychomotor development in previously healthy girls. Most cases are due to pathogenic va riants in the MECP2 gene which encodes for the methyl CpG-binding protein 2. OBJECTIVE: To des cribe the frequency and type of pathogenic variants in the MECP2 gene in Chilean female patients with clinical diagnosis of RTT. PATIENTS AND METHOD: Chilean women with clinical suspicion of RTT were invited to participate in the study. Clinical data were collected through a questionnaire. MECP2 pathogenic variants were analyzed by Sanger sequencing method and Multiplex Ligation-dependent Probe Amplification (MLPA) was used to detect duplications or deletions. RESULTS: The study in cluded 14 patients with suspected RTT, of which eight (57%) patients had pathogenic variants. The other patients remain without molecular diagnosis. CONCLUSIONS: Pathogenic variants in MECP2 are present in Chilean patients with RTT. It is likely that there are other genes or diagnoses involved in patients without MECP2 findings. As of this study, molecular diagnosis is available in Chile.


Assuntos
Proteína 2 de Ligação a Metil-CpG/genética , Síndrome de Rett/genética , Adolescente , Adulto , Criança , Pré-Escolar , Chile , Feminino , Deleção de Genes , Duplicação Gênica , Marcadores Genéticos , Testes Genéticos/métodos , Humanos , Síndrome de Rett/diagnóstico , Adulto Jovem
16.
Brain Dev ; 41(9): 783-789, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31122804

RESUMO

BACKGROUND: Cyclin-dependent kinase-like 5 (CDKL5), which maps to chromosome Xp22.13 and contains 20 coding exons, has been recognized as the gene responsible for early-onset epileptic encephalopathy (EoEE). A retrospective study is carried out to analyze potential genotypic and phenotypic differences between male and female patients with CDKL5 mutations. MATERIALS AND METHODS: Targeted next-generation DNA sequencing was employed to search for mutations in patients with cryptogenic EE. A total of 44 patients with EoEE/infantile spasms (ISs)/West syndrome were enrolled for pathogenic mutation screening. The clinical phenotypes of patients with CDKL5 mutations were analyzed and compared with those of 166 published cases. RESULTS: One novel and three recurrent mutations were found in four enrolled patients (two boys and two girls). One female patient had partial seizures during the early infantile period and epileptic spasms and tonic seizures several weeks thereafter. The other female patient had IS with hypsarrhythmia. The two male patients had IS without typical hypsarrhythmia and were bedridden. Brain MRIs of the male patients revealed brain atrophy and white matter hyperintensity. The female patients exhibited autistic features with hand stereotypies. CONCLUSION: Our study highlights that both girls and boys with IS harbor CDKL5 mutations. Male children with CDKL5 mutations demonstrate a higher frequency of infantile spasms and brain atrophy, whereas female children often exhibit atypical Rett syndrome with EoEE. In addition, male children have a more severe phenotype than female children.


Assuntos
Mutação , Proteínas Serina-Treonina Quinases/genética , Criança , Epilepsia/diagnóstico por imagem , Epilepsia/genética , Feminino , Estudos de Associação Genética , Humanos , Masculino , Hipotonia Muscular/genética , Fenótipo , Síndrome de Rett/genética , Fatores Sexuais
17.
Ann Clin Transl Neurol ; 6(4): 655-668, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31019990

RESUMO

Objective: FOXG1 syndrome is a rare neurodevelopmental disorder associated with heterozygous FOXG1 variants or chromosomal microaberrations in 14q12. The study aimed at assessing the scope of structural cerebral anomalies revealed by neuroimaging to delineate the genotype and neuroimaging phenotype associations. Methods: We compiled 34 patients with a heterozygous (likely) pathogenic FOXG1 variant. Qualitative assessment of cerebral anomalies was performed by standardized re-analysis of all 34 MRI data sets. Statistical analysis of genetic, clinical and neuroimaging data were performed. We quantified clinical and neuroimaging phenotypes using severity scores. Telencephalic phenotypes of adult Foxg1+/- mice were examined using immunohistological stainings followed by quantitative evaluation of structural anomalies. Results: Characteristic neuroimaging features included corpus callosum anomalies (82%), thickening of the fornix (74%), simplified gyral pattern (56%), enlargement of inner CSF spaces (44%), hypoplasia of basal ganglia (38%), and hypoplasia of frontal lobes (29%). We observed a marked, filiform thinning of the rostrum as recurrent highly typical pattern of corpus callosum anomaly in combination with distinct thickening of the fornix as a characteristic feature. Thickening of the fornices was not reported previously in FOXG1 syndrome. Simplified gyral pattern occurred significantly more frequently in patients with early truncating variants. Higher clinical severity scores were significantly associated with higher neuroimaging severity scores. Modeling of Foxg1 heterozygosity in mouse brain recapitulated the associated abnormal cerebral morphology phenotypes, including the striking enlargement of the fornix. Interpretation: Combination of specific corpus callosum anomalies with simplified gyral pattern and hyperplasia of the fornices is highly characteristic for FOXG1 syndrome.


Assuntos
Encéfalo/anormalidades , Encéfalo/patologia , Fatores de Transcrição Forkhead/genética , Proteínas do Tecido Nervoso/genética , Animais , Transtornos Globais do Desenvolvimento Infantil/genética , Transtornos Globais do Desenvolvimento Infantil/patologia , Feminino , Genótipo , Humanos , Deficiência Intelectual/genética , Camundongos Transgênicos , Microcefalia/genética , Fenótipo , Síndrome de Rett/genética
18.
Brain Behav ; 9(5): e01250, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30929312

RESUMO

INTRODUCTION: Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder that primarily affects girls, with an incidence of 1:10,000-20,000. The diagnosis is based on clinical features: an initial period of apparently normal development (ages 6-12 months) followed by a rapid decline with regression of acquired motor skills, loss of spoken language and purposeful hand use, onset of hand stereotypes, abnormal gait, and growth failure. The course of the disease, in its classical form, is characterized by four stages. Three different atypical variants of the disease have been defined. Epilepsy has been reported in 60%-80% of patients with RTT; it differs among the various phenotypes and genotypes and its severity is an important contributor to the clinical severity of the disease. METHODS: In this manuscript we reviewed literature on RTT, focusing on the different genetic entities, the correlation genotype-phenotype, and the peculiar epileptic phenotype associated to each of them. RESULTS: Mutations in MECP2 gene, located on Xq28, account for 95% of typical RTT cases and 73.2% of atypical RTT. CDKL5 and FOXG1 are other genes identified as causative genes in atypical forms of RTT. In the last few years, a lot of new genes have been identified as causative genes for RTT phenotype. CONCLUSIONS: Recognizing clinical and EEG patterns in different RTT variants may be useful in diagnosis and management of these patients.


Assuntos
Epilepsia/genética , Fatores de Transcrição Forkhead/genética , Proteína 2 de Ligação a Metil-CpG/genética , Proteínas do Tecido Nervoso/genética , Proteínas Serina-Treonina Quinases/genética , Síndrome de Rett , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Mutação , Síndrome de Rett/genética , Síndrome de Rett/fisiopatologia , Índice de Gravidade de Doença
19.
PLoS Genet ; 15(4): e1008043, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30973874

RESUMO

Mounting evidence supports that LINE-1 (L1) retrotransposition can occur postzygotically in healthy and diseased human tissues, contributing to genomic mosaicism in the brain and other somatic tissues of an individual. However, the genomic distribution of somatic human-specific LINE-1 (L1Hs) insertions and their potential impact on carrier cells remain unclear. Here, using a PCR-based targeted bulk sequencing approach, we profiled 9,181 somatic insertions from 20 postmortem tissues from five Rett patients and their matched healthy controls. We identified and validated somatic L1Hs insertions in both cortical neurons and non-brain tissues. In Rett patients, somatic insertions were significantly depleted in exons-mainly contributed by long genes-than healthy controls, implying that cells carrying MECP2 mutations might be defenseless against a second exonic L1Hs insertion. We observed a significant increase of somatic L1Hs insertions in the brain compared with non-brain tissues from the same individual. Compared to germline insertions, somatic insertions were less sense-depleted to transcripts, indicating that they underwent weaker selective pressure on the orientation of insertion. Our observations demonstrate that somatic L1Hs insertions contribute to genomic diversity and MeCP2 dysfunction alters their genomic patterns in Rett patients.


Assuntos
Elementos Nucleotídeos Longos e Dispersos , Síndrome de Rett/genética , Adolescente , Adulto , Sequência de Bases , Encéfalo/metabolismo , Estudos de Casos e Controles , Córtex Cerebral/metabolismo , Feminino , Mutação em Linhagem Germinativa , Humanos , Proteína 2 de Ligação a Metil-CpG/genética , Proteína 2 de Ligação a Metil-CpG/metabolismo , Mosaicismo , Mutação , Neurônios/metabolismo , Síndrome de Rett/metabolismo , Homologia de Sequência do Ácido Nucleico , Distribuição Tecidual , Transcrição Genética , Adulto Jovem
20.
Proc Natl Acad Sci U S A ; 116(14): 7071-7076, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30890637

RESUMO

Parvalbumin-positive (PV+) interneurons play a pivotal role in orchestrating windows of experience-dependent brain plasticity during development. Critical period closure is marked by the condensation of a perineuronal net (PNN) tightly enwrapping subsets of PV+ neurons, both acting as a molecular brake on plasticity and maintaining mature PV+ cell signaling. As much of the molecular organization of PNNs exists at length scales near or below the diffraction limit of light microscopy, we developed a superresolution imaging and analysis platform to visualize the structural organization of PNNs and the synaptic inputs perforating them in primary visual cortex. We identified a structural trajectory of PNN maturation featuring a range of net structures, which was accompanied by an increase in Synaptotagmin-2 (Syt2) signals on PV+ cells suggestive of increased inhibitory input between PV+ neurons. The same structural trajectory was followed by PNNs both during normal development and under conditions of critical period delay by total sensory deprivation or critical period acceleration by deletion of MeCP2, the causative gene for Rett syndrome, despite shifted maturation levels under these perturbations. Notably, superresolution imaging further revealed a decrease in Syt2 signals alongside an increase in vesicular glutamate transporter-2 signals on PV+ cells in MeCP2-deficient animals, suggesting weaker recurrent inhibitory input between PV+ neurons and stronger thalamocortical excitatory inputs onto PV+ cells. These results imply a latent imbalanced circuit signature that might promote cortical silencing in Rett syndrome before the functional regression of vision.


Assuntos
Proteína 2 de Ligação a Metil-CpG/metabolismo , Rede Nervosa/metabolismo , Plasticidade Neuronal , Síndrome de Rett/metabolismo , Sinapses/metabolismo , Sinaptotagmina II/metabolismo , Córtex Visual/metabolismo , Animais , Masculino , Proteína 2 de Ligação a Metil-CpG/genética , Camundongos , Rede Nervosa/diagnóstico por imagem , Síndrome de Rett/diagnóstico por imagem , Síndrome de Rett/genética , Sinapses/genética , Sinaptotagmina II/genética , Córtex Visual/diagnóstico por imagem
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