Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 45
Filtrar
Filtros adicionais











País/Região como assunto
Intervalo de ano
1.
Eur J Hum Genet ; 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488893

RESUMO

NAME OF THE DISEASE (SYNONYMS): Stromme syndrome.Jejunal atresia with microcephaly and ocular anomalies.Apple peel syndrome with microcephaly and ocular anomalies.Ciliopathy phenotype.Primary microcephaly and intellectual disability. OMIM# of the disease 243605. Name of the analysed genes or DNA/chromosome segments CENPF. OMIM# of the gene(s) 600236.Review of the analytical and clinical validity as well as of the clinical utility of DNA-based testing for mutations in CENPF genes in diagnostic, prenatal settings, and for risk assessment in relatives.

3.
Thyroid ; 28(11): 1406-1415, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30296914

RESUMO

BACKGROUND: Thyroid hormones (TH) are essential for brain development and function. The TH transporters monocarboxylate transporter 8 (MCT8) and organic anion transporter1 C1 (OATP1C1) facilitate the transport of TH across the blood-brain barrier and into glia and neuronal cells in the brain. Loss of MCT8 function causes Allan-Herndon-Dudley syndrome (AHDS, OMIM 300523) characterized by severe intellectual and motor disability due to cerebral hypothyroidism. Here, the first patient with loss of OATP1C1 function is described. The patient is a 15.5-year-old girl with normal development in the first year of life, who gradually developed dementia with spasticity and intolerance to cold. Brain imaging demonstrated gray and white matter degeneration and severe glucose hypometabolism. METHODS: Exome sequencing of the patient and parents was performed to identify the disease-causing mutation, and the effect of the mutation was studied through a panel of in vitro experiments, including thyroxine uptake studies, immunoblotting, and immunocytochemistry. Furthermore, the clinical effects of treatment with the triiodothyronine analogue triiodothyroacetic acid (Triac) are described. RESULTS: Exome sequencing identified a homozygous missense mutation in OATP1C1, changing the highly conserved aspartic acid 252 to asparagine (D252N). In vitro, the mutated OATP1C1 displays impaired plasma membrane localization and decreased cellular thyroxine uptake. After treatment with Triac, the clinical condition improved in several domains. CONCLUSIONS: This is the first report of human OATP1C1 deficiency compatible with brain-specific hypothyroidism and neurodegeneration.

4.
Nat Genet ; 50(3): 344-348, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29483653

RESUMO

Transforming growth factor (TGF)-ß1 (encoded by TGFB1) is the prototypic member of the TGF-ß family of 33 proteins that orchestrate embryogenesis, development and tissue homeostasis1,2. Following its discovery 3 , enormous interest and numerous controversies have emerged about the role of TGF-ß in coordinating the balance of pro- and anti-oncogenic properties4,5, pro- and anti-inflammatory effects 6 , or pro- and anti-fibrinogenic characteristics 7 . Here we describe three individuals from two pedigrees with biallelic loss-of-function mutations in the TGFB1 gene who presented with severe infantile inflammatory bowel disease (IBD) and central nervous system (CNS) disease associated with epilepsy, brain atrophy and posterior leukoencephalopathy. The proteins encoded by the mutated TGFB1 alleles were characterized by impaired secretion, function or stability of the TGF-ß1-LAP complex, which is suggestive of perturbed bioavailability of TGF-ß1. Our study shows that TGF-ß1 has a critical and nonredundant role in the development and homeostasis of intestinal immunity and the CNS in humans.

6.
Am J Hum Genet ; 100(6): 907-925, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28575647

RESUMO

Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators.


Assuntos
Cromatina/metabolismo , Haploinsuficiência/genética , Deficiência Intelectual/genética , Transcrição Genética , Fator de Transcrição YY1/genética , Acetilação , Adolescente , Sequência de Bases , Pré-Escolar , Imunoprecipitação da Cromatina , Estudos de Coortes , Elementos Facilitadores Genéticos/genética , Feminino , Ontologia Genética , Haplótipos/genética , Hemizigoto , Histonas/metabolismo , Humanos , Linfócitos/metabolismo , Masculino , Metilação , Modelos Moleculares , Mutação de Sentido Incorreto/genética , Ligação Proteica/genética , Domínios Proteicos , Fator de Transcrição YY1/química
7.
J Med Genet ; 54(7): 460-470, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28377535

RESUMO

BACKGROUND: We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of GRIN2B encephalopathy and explored potential prospects of personalised medicine. METHODS: Data of 48 individuals with de novo GRIN2B variants were collected from several diagnostic and research cohorts, as well as from 43 patients from the literature. Functional consequences and response to memantine treatment were investigated in vitro and eventually translated into patient care. RESULTS: Overall, de novo variants in 86 patients were classified as pathogenic/likely pathogenic. Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy. Six patients presented with a consistent malformation of cortical development (MCD) intermediate between tubulinopathies and polymicrogyria. Missense variants cluster in transmembrane segments and ligand-binding sites. Functional consequences of variants were diverse, revealing various potential gain-of-function and loss-of-function mechanisms and a retained sensitivity to the use-dependent blocker memantine. However, an objectifiable beneficial treatment response in the respective patients still remains to be demonstrated. CONCLUSIONS: In addition to previously known features of intellectual disability, epilepsy and autism, we found evidence that GRIN2B encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD revealing novel phenotypic consequences of channelopathies.


Assuntos
Encefalopatias/genética , Mutação/genética , Receptores de N-Metil-D-Aspartato/genética , Encefalopatias/tratamento farmacológico , Heterozigoto , Humanos , Imagem por Ressonância Magnética , Memantina/uso terapêutico , Terapia de Alvo Molecular , Neuroimagem , Fenótipo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo
8.
Genes (Basel) ; 7(12)2016 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-27916860

RESUMO

Biallelic PIGT variants were previously reported in seven patients from three families with Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3 (MCAHS3), characterized by epileptic encephalopathy, hypotonia, global developmental delay/intellectual disability, cerebral and cerebellar atrophy, craniofacial dysmorphisms, and skeletal, ophthalmological, cardiac, and genitourinary abnormalities. We report a novel homozygous PIGT missense variant c.1079G>T (p.Gly360Val) in two brothers with several of the typical features of MCAHS3, but in addition, pyramidal tract neurological signs. Notably, they are the first patients with MCAHS3 without skeletal, cardiac, or genitourinary anomalies. PIGT encodes a crucial subunit of the glycosylphosphatidylinositol (GPI) transamidase complex, which catalyzes the attachment of proteins to GPI-anchors, attaching the proteins to the cell membrane. In vitro studies in cells from the two brothers showed reduced levels of GPI-anchors and GPI-anchored proteins on the cell surface, supporting the pathogenicity of the novel PIGT variant.

9.
Neuromuscul Disord ; 26(9): 570-5, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27450922

RESUMO

Biallelic mutations in IGHMBP2 cause spinal muscular atrophy with respiratory distress type 1 (SMARD1) or Charcot-Marie-Tooth type 2S (CMT2S). We report three families variably affected by IGHMBP2 mutations. Patient 1, an 8-year-old boy with two homozygous variants: c.2T>C and c.861C>G, was wheelchair bound due to sensorimotor axonal neuropathy and chronic respiratory failure. Patient 2 and his younger sister, Patient 3, had compound heterozygous variants: c.983_987delAAGAA and c.1478C>T. However, clinical phenotypes differed markedly as the elder with sensorimotor axonal neuropathy had still unaffected respiratory function at 4.5 years, whereas the younger presented as infantile spinal muscular atrophy and died from relentless respiratory failure at 11 months. Patient 4, a 6-year-old girl homozygous for IGHMBP2 c.449+1G>T documented to result in two aberrant transcripts, was wheelchair dependent due to axonal polyneuropathy. The clinical presentation in Patients 1 and 3 were consistent with SMARD1, whereas Patients 2 and 4 were in agreement with CMT2S.


Assuntos
Proteínas de Ligação a DNA/genética , Mutação , Atrofias Musculares Espinais da Infância/genética , Atrofias Musculares Espinais da Infância/metabolismo , Fatores de Transcrição/genética , Criança , Pré-Escolar , Evolução Fatal , Feminino , Humanos , Lactente , Masculino , Fenótipo , Insuficiência Respiratória/genética , Insuficiência Respiratória/metabolismo , Irmãos
10.
Genes (Basel) ; 7(8)2016 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-27472364

RESUMO

We report on two brothers with visual impairment, and non-syndromic alopecia in the elder proband. The parents were first-degree Pakistani cousins. Whole exome sequencing of the elder brother and parents, followed by Sanger sequencing of all four family members, led to the identification of the variants responsible for the two phenotypes. One variant was a homozygous nonsense variant in the inhibitory subunit of the cone-specific cGMP phosphodiesterase gene, PDE6H:c.35C>G (p.Ser12*). PDE6H is expressed in the cones of the retina, which are involved in perception of color vision. This is the second report of a homozygous PDE6H:c.35C>G variant causing incomplete achromatopsia (OMIM 610024), thus strongly supporting the hypothesis that loss-of-function variants in PDE6H cause this visual deficiency phenotype. The second variant was a homozygous missense substitution in the lysophosphatidic acid receptor 6, LPAR6:c.188A>T (p.Asp63Val). LPAR6 acts as a G-protein-coupled receptor involved in hair growth. Biallelic loss-of-function variants in LPAR6 cause hypotrichosis type 8 (OMIM 278150), with or without woolly hair, a form of non-syndromic alopecia. Biallelic LPAR6:c.188A>T was previously described in five families from Pakistan.

12.
Eur J Med Genet ; 59(6-7): 342-6, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27182039

RESUMO

Mitochondrial DNA depletion syndromes (MTDPS) represent a clinically and genetically heterogeneous group of autosomal recessive disorders, caused by mutations in genes involved in maintenance of mitochondrial DNA (mtDNA). Biallelic mutations in FBXL4 were recently described to cause encephalomyopathic MTDPS13. The syndrome has infantile onset and presents with hypotonia, feeding difficulties, a pattern of mild facial dysmorphisms, global developmental delay and brain atrophy. Laboratory investigations reveal elevated blood lactate levels, unspecific mitochondrial respiratory chain (MRC) enzyme deficiencies and mtDNA depletion. We report a novel missense variant, c.1442T > C (p.Leu481Pro), in FBXL4 (NM_012160.4) in a Norwegian boy with clinical, biochemical and cerebral MRI characteristics consistent with MTDPS13. The FBXL4 c.1442T > C (p.Leu481Pro) variant was not present in public databases, 149 Norwegian controls nor an in-house database containing whole exome sequencing data from 440 individuals, and it was predicted in silico to be deleterious to the protein function. Activities of MRC enzymes were normal in muscle tissue (complexes I-IV) and cultured skin fibroblasts (complexes I-V) from the patient, but mtDNA depletion was confirmed in muscle, thus supporting the predicted pathogenicity of the FBXL4 c.1442T > C (p.Leu481Pro) variant. On clinical indication of mitochondrial encephalomyopathy, sequencing of FBXL4 should be performed, even when the activity levels of the MRC enzymes are normal.


Assuntos
DNA Mitocondrial/genética , Proteínas F-Box/genética , Encefalomiopatias Mitocondriais/genética , Músculo Esquelético/patologia , Ubiquitina-Proteína Ligases/genética , Criança , Exoma/genética , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Masculino , Erros Inatos do Metabolismo/genética , Encefalomiopatias Mitocondriais/epidemiologia , Encefalomiopatias Mitocondriais/patologia , Mutação de Sentido Incorreto , Noruega/epidemiologia
13.
Neurology ; 86(23): 2171-8, 2016 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-27164704

RESUMO

OBJECTIVE: To determine the phenotypic spectrum caused by mutations in GRIN1 encoding the NMDA receptor subunit GluN1 and to investigate their underlying functional pathophysiology. METHODS: We collected molecular and clinical data from several diagnostic and research cohorts. Functional consequences of GRIN1 mutations were investigated in Xenopus laevis oocytes. RESULTS: We identified heterozygous de novo GRIN1 mutations in 14 individuals and reviewed the phenotypes of all 9 previously reported patients. These 23 individuals presented with a distinct phenotype of profound developmental delay, severe intellectual disability with absent speech, muscular hypotonia, hyperkinetic movement disorder, oculogyric crises, cortical blindness, generalized cerebral atrophy, and epilepsy. Mutations cluster within transmembrane segments and result in loss of channel function of varying severity with a dominant-negative effect. In addition, we describe 2 homozygous GRIN1 mutations (1 missense, 1 truncation), each segregating with severe neurodevelopmental phenotypes in consanguineous families. CONCLUSIONS: De novo GRIN1 mutations are associated with severe intellectual disability with cortical visual impairment as well as oculomotor and movement disorders being discriminating phenotypic features. Loss of NMDA receptor function appears to be the underlying disease mechanism. The identification of both heterozygous and homozygous mutations blurs the borders of dominant and recessive inheritance of GRIN1-associated disorders.


Assuntos
Mutação , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Estudos de Coortes , Consanguinidade , Heterozigoto , Homozigoto , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Transtornos dos Movimentos/genética , Transtornos dos Movimentos/metabolismo , Oócitos , Fenótipo , Convulsões/genética , Convulsões/metabolismo , Xenopus laevis
14.
Hum Mutat ; 37(4): 359-63, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26820108

RESUMO

Strømme syndrome was first described by Strømme et al. (1993) in siblings presenting with "apple peel" type intestinal atresia, ocular anomalies and microcephaly. The etiology remains unknown to date. We describe the long-term clinical follow-up data for the original pair of siblings as well as two previously unreported siblings with a severe phenotype overlapping that of the Strømme syndrome including fetal autopsy results. Using family-based whole-exome sequencing, we identified truncating mutations in the centrosome gene CENPF in the two nonconsanguineous Caucasian sibling pairs. Compound heterozygous inheritance was confirmed in both families. Recently, mutations in this gene were shown to cause a fetal lethal phenotype, the phenotype and functional data being compatible with a human ciliopathy [Waters et al., 2015]. We show for the first time that Strømme syndrome is an autosomal-recessive disease caused by mutations in CENPF that can result in a wide phenotypic spectrum.


Assuntos
Proteínas Cromossômicas não Histona/genética , Ciliopatias/diagnóstico , Ciliopatias/genética , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Atresia Intestinal/diagnóstico , Atresia Intestinal/genética , Microcefalia/diagnóstico , Microcefalia/genética , Proteínas dos Microfilamentos/genética , Mutação , Adulto , Análise Mutacional de DNA , Facies , Feminino , Seguimentos , Genes Recessivos , Estudos de Associação Genética , Heterozigoto , Humanos , Masculino , Linhagem , Fenótipo , Irmãos , Adulto Jovem
15.
Hum Mol Genet ; 24(20): 5845-54, 2015 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-26220973

RESUMO

Import of peroxisomal matrix proteins, crucial for peroxisome biogenesis, is mediated by the cytosolic receptors PEX5 and PEX7 that recognize proteins carrying peroxisomal targeting signals 1 or 2 (PTS1 or PTS2), respectively. Mutations in PEX5 or 12 other PEX genes cause peroxisome biogenesis disorders, collectively named the Zellweger spectrum disorders (ZSDs), whereas mutations in PEX7 cause rhizomelic chondrodysplasia punctata type 1 (RCDP1). Three additional RCDP types, RCDP2-3-4, are caused, respectively, by mutations in GNPAT, AGPS and FAR1, encoding enzymes involved in plasmalogen biosynthesis. Here we report a fifth type of RCDP (RCDP5) caused by a novel mutation in PEX5. In four patients with RCDP from two independent families, we identified a homozygous frame shift mutation c.722dupA (p.Val242Glyfs(∗)33) in PEX5 (GenBank: NM_001131023.1). PEX5 encodes two isoforms, PEX5L and PEX5S, and we show that the c.722dupA mutation, located in the PEX5L-specific exon 9, results in loss of PEX5L only. Both PEX5 isoforms recognize PTS1-tagged proteins, but PEX5L is also a co-receptor for PTS2-tagged proteins. Previous patients with PEX5 mutations had ZSD, mainly due to deficient import of PTS1-tagged proteins. Similarly to mutations in PEX7, loss of PEX5L results in deficient import of PTS2-tagged proteins only, thus causing RCDP instead of ZSD. We demonstrate that PEX5L expression restores the import of PTS2-tagged proteins in patient fibroblasts. Due to the biochemical overlap between RCDP1 and RCDP5, sequencing of PEX7 and exon 9 in PEX5 should be performed in patients with a selective defect in the import of PTS2-tagged proteins.


Assuntos
Condrodisplasia Punctata Rizomélica/genética , Mutação da Fase de Leitura , Peroxissomos/metabolismo , Transporte Proteico/genética , Receptores Citoplasmáticos e Nucleares/genética , Adolescente , Adulto , Criança , Condrodisplasia Punctata Rizomélica/metabolismo , Exoma , Feminino , Humanos , Lactente , Masculino , Linhagem , Receptor 1 de Sinal de Orientação para Peroxissomos , Peroxissomos/genética , Isoformas de Proteínas , Receptores Citoplasmáticos e Nucleares/metabolismo , Análise de Sequência de DNA
16.
Elife ; 4: e06602, 2015 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-26026149

RESUMO

Defective primary ciliogenesis or cilium stability forms the basis of human ciliopathies, including Joubert syndrome (JS), with defective cerebellar vermis development. We performed a high-content genome-wide small interfering RNA (siRNA) screen to identify genes regulating ciliogenesis as candidates for JS. We analyzed results with a supervised-learning approach, using SYSCILIA gold standard, Cildb3.0, a centriole siRNA screen and the GTex project, identifying 591 likely candidates. Intersection of this data with whole exome results from 145 individuals with unexplained JS identified six families with predominantly compound heterozygous mutations in KIAA0586. A c.428del base deletion in 0.1% of the general population was found in trans with a second mutation in an additional set of 9 of 163 unexplained JS patients. KIAA0586 is an orthologue of chick Talpid3, required for ciliogenesis and Sonic hedgehog signaling. Our results uncover a relatively high frequency cause for JS and contribute a list of candidates for future gene discoveries in ciliopathies.


Assuntos
Proteínas de Ciclo Celular/genética , Cerebelo/anormalidades , Predisposição Genética para Doença , Proteínas Mutantes/genética , Retina/anormalidades , Anormalidades Múltiplas/genética , Anormalidades do Olho/genética , Frequência do Gene , Testes Genéticos , Estudo de Associação Genômica Ampla , Heterozigoto , Humanos , Doenças Renais Císticas/genética , RNA Interferente Pequeno/genética
17.
Am J Med Genet A ; 167A(3): 657-63, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25691420

RESUMO

A pair of sisters was ascertained for multiple congenital defects, including marked craniofacial dysmorphisms with blepharophimosis, and severe psychomotor delay. Two novel compound heterozygous mutations in UBE3B were identified in both the sisters by exome sequencing. These mutations include c.1A>G, which predicts p.Met1?, and a c.1773delC variant, predicted to cause a frameshift at p.Phe591fs. UBE3B encodes a widely expressed protein ubiquitin ligase E3B, which, when mutated in both alleles, causes Kaufman oculocerebrofacial syndrome. We report on the thorough clinical examination of the patients and review the state of art knowledge of this disorder.


Assuntos
Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Heterozigoto , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Deformidades Congênitas dos Membros/diagnóstico , Deformidades Congênitas dos Membros/genética , Microcefalia/diagnóstico , Microcefalia/genética , Mutação , Fenótipo , Ubiquitina-Proteína Ligases/genética , Pré-Escolar , Hibridização Genômica Comparativa , Análise Mutacional de DNA , Exoma , Facies , Feminino , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Linhagem
18.
Neurology ; 83(21): 1898-905, 2014 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-25339210

RESUMO

OBJECTIVE: To study the clinical and radiologic spectrum and genotype-phenotype correlation of 4H (hypomyelination, hypodontia, hypogonadotropic hypogonadism) leukodystrophy caused by mutations in POLR3A or POLR3B. METHODS: We performed a multinational cross-sectional observational study of the clinical, radiologic, and molecular characteristics of 105 mutation-proven cases. RESULTS: The majority of patients presented before 6 years with gross motor delay or regression. Ten percent had an onset beyond 10 years. The disease course was milder in patients with POLR3B than in patients with POLR3A mutations. Other than the typical neurologic, dental, and endocrine features, myopia was seen in almost all and short stature in 50%. Dental and hormonal findings were not invariably present. Mutations in POLR3A and POLR3B were distributed throughout the genes. Except for French Canadian patients, patients from European backgrounds were more likely to have POLR3B mutations than other populations. Most patients carried the common c.1568T>A POLR3B mutation on one allele, homozygosity for which causes a mild phenotype. Systematic MRI review revealed that the combination of hypomyelination with relative T2 hypointensity of the ventrolateral thalamus, optic radiation, globus pallidus, and dentate nucleus, cerebellar atrophy, and thinning of the corpus callosum suggests the diagnosis. CONCLUSIONS: 4H is a well-recognizable clinical entity if all features are present. Mutations in POLR3A are associated with a more severe clinical course. MRI characteristics are helpful in addressing the diagnosis, especially if patients lack the cardinal non-neurologic features.


Assuntos
Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Mutação/genética , RNA Polimerase III/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Masculino , Adulto Jovem
19.
Acta Paediatr ; 103(8): 886-91, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24724871

RESUMO

AIM: To investigate whether intrauterine growth restriction (IUGR), resulting in small for gestational age (SGA) infants, is associated with increased susceptibility to psychiatric problems and academic impairment in late teens. METHODS: A cohort of all 10th-grade students in Oslo, Norway, followed up between 2001 and 2004 (n = 2131), was linked with foetal growth data. IUGR was considered equal to SGA at the lowest 2.5th, 5th, and 10th percentiles and appropriate for gestational age (AGA) as the highest 90th percentile. Mental health was evaluated using the Hopkins Symptoms Check List and the Strength and Difficulties Questionnaire, and academic achievements and ambitions were self-reported by the students. RESULTS: Psychiatric problems were equally prevalent in all groups. However, the SGA girls performed inferiorly compared to their AGA peers in the school subjects English [3.6 vs 3.9 (p = 0.03)], mathematics [4.0 vs 4.3 (p = 0.01)] and social science [4.2 vs 4.4 (p = 0.05)], but not for Norwegian. This association was not observed in boys. There was an association between academic impairment and prematurity, occurring more frequently among immigrants (p < 0.001). CONCLUSION: SGA had a small negative impact on academic achievements in adolescent girls, but not boys. There was no association between SGA and psychiatric problems in either gender.


Assuntos
Comportamento do Adolescente , Retardo do Crescimento Fetal , Transtornos Mentais/epidemiologia , Adolescente , Avaliação Educacional , Feminino , Seguimentos , Humanos , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional , Masculino , Transtornos Mentais/etiologia , Noruega/epidemiologia , Prevalência , Adulto Jovem
20.
Orphanet J Rare Dis ; 8: 3, 2013 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-23294540

RESUMO

BACKGROUND: Nineteen patients with deletions in chromosome 6p22-p24 have been published so far. The syndromic phenotype is varied, and includes intellectual disability, behavioural abnormalities, dysmorphic features and structural organ defects. Heterogeneous deletion breakpoints and sizes (1-17 Mb) and overlapping phenotypes have made the identification of the disease causing genes challenging. We suggest JARID2 and ATXN1, both harbored in 6p22.3, as disease causing genes. METHODS AND RESULTS: We describe five unrelated patients with de novo deletions (0.1-4.8 Mb in size) in chromosome 6p22.3-p24.1 detected by aCGH in a cohort of approximately 3600 patients ascertained for neurodevelopmental disorders. Two patients (Patients 4 and 5) carried non-overlapping deletions that were encompassed by the deletions of the remaining three patients (Patients 1-3), indicating the existence of two distinct dosage sensitive genes responsible for impaired cognitive function in 6p22.3 deletion-patients. The smallest region of overlap (SRO I) in Patients 1-4 (189 kb) included the genes JARID2 and DTNBP1, while SRO II in Patients 1-3 and 5 (116 kb) contained GMPR and ATXN1. Patients with deletion of SRO I manifested variable degrees of cognitive impairment, gait disturbance and distinct, similar facial dysmorphic features (prominent supraorbital ridges, deep set eyes, dark infraorbital circles and midface hypoplasia) that might be ascribed to the haploinsufficiency of JARID2. Patients with deletion of SRO II showed intellectual disability and behavioural abnormalities, likely to be caused by the deletion of ATXN1. Patients 1-3 presented with lower cognitive function than Patients 4 and 5, possibly due to the concomitant haploinsufficiency of both ATXN1 and JARID2. The chromatin modifier genes ATXN1 and JARID2 are likely candidates contributing to the clinical phenotype in 6p22-p24 deletion-patients. Both genes exert their effect on the Notch signalling pathway, which plays an important role in several developmental processes. CONCLUSIONS: Patients carrying JARID2 deletion manifested with cognitive impairment, gait disturbance and a characteristic facial appearance, whereas patients with deletion of ATXN1 seemed to be characterized by intellectual disability and behavioural abnormalities. Due to the characteristic facial appearance, JARID2 haploinsufficiency might represent a clinically recognizable neurodevelopmental syndrome.


Assuntos
Cromossomos Humanos Par 6 , Haploinsuficiência , Histonas/metabolismo , Deficiência Intelectual/genética , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Complexo Repressor Polycomb 2/genética , Adolescente , Ataxina-1 , Ataxinas , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Feminino , Marcha , Humanos , Cariotipagem , Masculino , Reação em Cadeia da Polimerase em Tempo Real , Deleção de Sequência
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA