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1.
Nat Commun ; 10(1): 2966, 2019 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-31273213

RESUMO

Mutations in genes encoding components of BAF (BRG1/BRM-associated factor) chromatin remodeling complexes cause neurodevelopmental disorders and tumors. The mechanisms leading to the development of these two disease entities alone or in combination remain unclear. We generated mice with a heterozygous nervous system-specific partial loss-of-function mutation in a BAF core component gene, Smarcb1. These Smarcb1 mutant mice show various brain midline abnormalities that are also found in individuals with Coffin-Siris syndrome (CSS) caused by SMARCB1, SMARCE1, and ARID1B mutations and in SMARCB1-related intellectual disability (ID) with choroid plexus hyperplasia (CPH). Analyses of the Smarcb1 mutant animals indicate that one prominent midline abnormality, corpus callosum agenesis, is due to midline glia aberrations. Our results establish a novel role of Smarcb1 in the development of the brain midline and have important clinical implications for BAF complex-related ID/neurodevelopmental disorders.


Assuntos
Anormalidades Múltiplas/genética , Agenesia do Corpo Caloso/genética , Corpo Caloso/crescimento & desenvolvimento , Face/anormalidades , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Micrognatismo/genética , Pescoço/anormalidades , Proteína SMARCB1/genética , Anormalidades Múltiplas/diagnóstico por imagem , Agenesia do Corpo Caloso/diagnóstico por imagem , Agenesia do Corpo Caloso/patologia , Alelos , Animais , Criança , Pré-Escolar , Corpo Caloso/citologia , Corpo Caloso/diagnóstico por imagem , Modelos Animais de Doenças , Embrião de Mamíferos , Face/diagnóstico por imagem , Feminino , Deformidades Congênitas da Mão/diagnóstico por imagem , Humanos , Lactente , Deficiência Intelectual/diagnóstico por imagem , Mutação com Perda de Função , Imagem por Ressonância Magnética , Masculino , Camundongos , Camundongos Transgênicos , Micrognatismo/diagnóstico por imagem , Pescoço/diagnóstico por imagem , Neuroglia/patologia , Cultura Primária de Células
2.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(6): 541-546, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31208506

RESUMO

OBJECTIVE: To study the value of fast spin-echo diffusion weighted imaging (TSE-DWI) apparent diffusion coefficient (ADC) in children aged 2-12 years with intellectual disability (ID)/global developmental delay (GDD) who have normal conventional brain MRI findings. METHODS: A total of 578 children with normal conventional brain MRI findings who met the diagnostic criteria for ID/GDD and 375 normal children were enrolled. Their imaging and clinical data were collected. All children underwent scanning with brain TSE-DWI sequence and routine sequence. ADC values of each brain region were compared between normal children with different ages, as well as between children with different degrees of ID/GDD in each age group. The influence of Adaptive Behavior Assessment System-II (ABAS-II) score on ADC values of each brain region was analyzed. RESULTS: For the normal children, the ADC values of the frontal and temporal white matter, the corpus callosum, the inner capsule, the centrum semiovale, the cerebellar dentate nucleus, the optic radiation, the thalamus, the lenticular nucleus, and the caudate nucleus gradually decreased with age (P<0.05). ADC values of the deep white matter, the shallow white matter, the deep gray matter nuclei, and the shallow gray matter increased with the increase in the degree of ID/GDD in the ID/GDD children aged 4-6 years (P<0.05). In the children with ID/GDD, the ADC values of the deep white matter, the shallow white matter, and the deep gray matter nuclei decreased with age (P<0.05). The ADC values of the children with ID/GDD decreased with the increase in ABAS-II score (P<0.05). CONCLUSIONS: ADC can reflect the subtle structural changes of brain regions in children with ID/GDD who have normal conventional brain MRI findings. It may be associated with social adaptation. It can provide an objective basis for the quantitative diagnosis of ID/GDD in children.


Assuntos
Deficiência Intelectual , Substância Branca , Encéfalo , Criança , Pré-Escolar , Imagem de Difusão por Ressonância Magnética , Humanos , Deficiência Intelectual/diagnóstico por imagem , Imagem por Ressonância Magnética
3.
Seizure ; 66: 81-85, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30818181

RESUMO

PURPOSE: Mutations in SZT2 have been previously reported in several cases of early onset epilepsy and intellectual disability. In this study we investigate potential causal mutations in two male siblings affected by early onset epilepsy, intellectual disability and macrocephaly. METHODS: We use family-based whole-exome sequencing to identify candidate variants. RESULTS: We report the identification of two potential causal SZT2 mutations in compound heterozygous state. We observe considerable differences in the clinical phenotype severity of the two affected individuals. The cerebral MRI revealed no abnormalities in the older affected brother, while in the youngest one it revealed a right frontal polymicrogiria. Moreover, while good seizure control was achieved in the older affected individual the younger brother is affected by pharmacoresistant epilepsy, progressive spastic paraplegia, cortical myoclonus and a more severe intellectual disability. We also analyzed the relative location of the reported pathogenic mutations in the SZT2 protein. CONCLUSION: Variable phenotypic expressivity is observed for this condition, while the location and type of mutations in SZT2 also has a potential impact on epilepsy severity. These findings extend our knowledge of epileptogenic conditions related to SZT2 and mTOR signaling.


Assuntos
Epilepsia/genética , Saúde da Família , Deficiência Intelectual/genética , Megalencefalia/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Adulto , Análise Mutacional de DNA , Epilepsia/complicações , Epilepsia/diagnóstico por imagem , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/diagnóstico por imagem , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Megalencefalia/complicações , Megalencefalia/diagnóstico por imagem , Sequenciamento Completo do Exoma , Adulto Jovem
4.
BMC Med Genet ; 20(1): 16, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30642272

RESUMO

BACKGROUND: KBG syndrome is a very rare autosomal dominant disorder, characterized by macrodontia, distinctive craniofacial findings, skeletal findings, post-natal short stature, and developmental delays, sometimes associated with seizures and EEG abnormalities. So far, there have been over 100 cases of KBG syndrome reported. CASE PRESENTATION: Here, we describe two sisters of a non-consanguineous family, both presenting generalized epilepsy with febrile seizures (GEFS+), and one with a more complex phenotype associated with mild intellectual disability, skeletal and dental anomalies. Whole exome sequencing (WES) analysis in all the family members revealed a heterozygous SCN9A mutation, p.(Lys655Arg), shared among the father and the two probands, and a novel de novo loss of function mutation in the ANKRD11 gene, p.(Tyr1715*), in the proband with the more complex phenotype. The reassessment of the phenotypic features confirmed that the patient fulfilled the proposed diagnostic criteria for KBG syndrome, although complicated by early-onset isolated febrile seizures. EEG abnormalities with or without seizures have been reported previously in some KBG cases. The shared variant, occurring in SCN9A, has been previously found in several individuals with GEFS+ and Dravet syndrome. CONCLUSIONS: This report describe a novel de novo variant in ANKRD11 causing a mild phenotype of KGB syndrome and further supports the association of monogenic pattern of SCN9A mutations with GEFS+. Our data expand the allelic spectrum of ANKRD11 mutations, providing the first Brazilian case of KBG syndrome. Furthermore, this study offers an example of how WES has been instrumental allowing us to better dissect the clinical phenotype under study, which is a multilocus variation aggregating in one proband, rather than a phenotypic expansion associated with a single genomic locus, underscoring the role of multiple rare variants at different loci in the etiology of clinical phenotypes making problematic the diagnostic path. The successful identification of the causal variant in a gene may not be sufficient, making it necessary to identify other variants that fully explain the clinical picture. The prevalence of blended phenotypes from multiple monogenic disorders is currently unknown and will require a systematic re-analysis of large WES datasets for proper diagnosis in daily practice.


Assuntos
Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Epilepsia Generalizada/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Deficiência Intelectual/genética , Mutação , Fenótipo , Proteínas Repressoras/genética , Convulsões Febris/genética , Anormalidades Dentárias/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/etiologia , Anormalidades Múltiplas/fisiopatologia , Adolescente , Alelos , Doenças do Desenvolvimento Ósseo/diagnóstico por imagem , Doenças do Desenvolvimento Ósseo/etiologia , Doenças do Desenvolvimento Ósseo/fisiopatologia , Brasil , Eletroencefalografia , Epilepsia Generalizada/fisiopatologia , Facies , Feminino , Loci Gênicos , Heterozigoto , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/etiologia , Deficiência Intelectual/fisiopatologia , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Linhagem , Convulsões Febris/fisiopatologia , Anormalidades Dentárias/diagnóstico por imagem , Anormalidades Dentárias/etiologia , Anormalidades Dentárias/fisiopatologia , Sequenciamento Completo do Exoma
5.
J Hum Genet ; 64(4): 341-346, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30692597

RESUMO

The genetic causes of combined pituitary hormone deficiency remain elusive in most patients. Recently, incompletely penetrant heterozygous mutations in ROBO1 have been described in patients with pituitary stalk interruption syndrome. Herein, we identified a novel homozygous slice site mutation in ROBO1 (c.1342+1G>A) using a trio whole-exome sequencing strategy in a 5-year-old Japanese boy who had combined pituitary hormone deficiency, psychomotor developmental delay, severe intellectual disability, sensorineural hearing loss, strabismus, and characteristic facial features, including a broad forehead, micrognathia, and arched eyebrows. Magnetic resonance imaging delineated anterior pituitary hypoplasia, ectopic posterior pituitary, invisible pituitary stalk, thinning of the corpus callosum, and hypoplasia of the pons and midbrain. The phenotypically normal parents (first cousins) were heterozygous for the mutation. The results provide further evidence of ROBO1 being involved in the development of the pituitary gland. A recessive mutation of ROBO1 is a potential novel cause of a syndromic disorder associated with combined pituitary hormone deficiency.


Assuntos
Perda Auditiva Neurossensorial/genética , Hipopituitarismo/genética , Deficiência Intelectual/genética , Proteínas do Tecido Nervoso/genética , Receptores Imunológicos/genética , Pré-Escolar , Corpo Caloso/diagnóstico por imagem , Corpo Caloso/fisiopatologia , Perda Auditiva Neurossensorial/complicações , Perda Auditiva Neurossensorial/diagnóstico por imagem , Perda Auditiva Neurossensorial/fisiopatologia , Humanos , Hipopituitarismo/complicações , Hipopituitarismo/diagnóstico por imagem , Hipopituitarismo/fisiopatologia , Deficiência Intelectual/complicações , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Mutação , Sítios de Splice de RNA/genética , Sequenciamento Completo do Exoma
6.
J Hum Genet ; 64(4): 291-296, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30692598

RESUMO

A rare form of osteogenesis imperfecta (OI) caused by Wingless-type MMTV integration site family 1 (WNT1) mutations combines central nervous system (CNS) anomalies with the characteristic increased susceptibility to fractures. We report an additional case where arachnoid cysts extend the phenotype, and that also confirms the association of intellectual disabilities with asymmetric cerebellar hypoplasia here. Interestingly, if the cerebellum is normal in this disorder, intelligence is as well, analogous to an association with similar delays in a subset of patients with sporadic unilateral cerebellar hypoplasia. Those cases typically appear to represent vascular disruptions, and we suggest that most brain anomalies in WNT1-associated OI have vascular origins related to a role for WNT1 in CNS angiogenesis. This unusual combination of benign cerebellar findings with effects on higher functions in these two situations raises the possibility that WNT1 is involved in the pathogenesis of the associated sporadic cases as well. Finally, our patient reacted poorly to pamidronate, which appears ineffective with this form of OI, so that a lack of improvement is an indication for molecular testing that includes WNT1.


Assuntos
Sistema Nervoso Central/fisiopatologia , Deficiência Intelectual/genética , Osteogênese Imperfeita/genética , Proteína Wnt1/genética , Cistos Aracnóideos/diagnóstico por imagem , Cistos Aracnóideos/fisiopatologia , Sistema Nervoso Central/anormalidades , Sistema Nervoso Central/diagnóstico por imagem , Cerebelo/anormalidades , Cerebelo/diagnóstico por imagem , Cerebelo/fisiopatologia , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/fisiopatologia , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/fisiopatologia , Mutação , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/fisiopatologia , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/fisiopatologia , Pamidronato/administração & dosagem , Pamidronato/efeitos adversos
7.
Medicine (Baltimore) ; 97(38): e12437, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30235725

RESUMO

Fetal adducted thumbs have been described in association with hydrocephalus and other abnormalities, but in cases without other structural malformations the determination of prognosis and recurrence risk is challenging. The aim of our study is to analyze the characteristics, natural history, and postnatal outcome of such cases.A retrospective study was conducted over a period of 4 years in a tertiary referral center. All fetuses diagnosed as adducted thumbs without other structural malformations comprised the study group. Prenatal sonographic features and neonatal outcome are documented.There were 4 cases of fetal adducted thumbs diagnosed during the study period. No cases demonstrated other structural malformations throughout the gestation. A smaller head was noted in 2 cases during the follow-up, and all cases presented with polyhydramnios on the first or ensuing scans. Three cases died after birth due to swallowing or breathing difficulty, and the surviving 1 showed convulsion and mental retardation.Fetal adducted thumb might be an early and specific sonographic marker of impaired neurodevelopment. Close follow-up and genetic investigation should be performed in these cases. Ultrasound examination plays an important role in the prenatal diagnosis and counseling of cases without detailed prenatal genetic analysis.


Assuntos
Feto/diagnóstico por imagem , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico por imagem , Deformidades da Mão/diagnóstico por imagem , Deficiência Intelectual/diagnóstico por imagem , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Diagnóstico Pré-Natal/instrumentação , Paraplegia Espástica Hereditária/diagnóstico por imagem , Polegar/anormalidades , Polegar/diagnóstico por imagem , Ultrassonografia Pré-Natal/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Variações do Número de Cópias de DNA/genética , Feminino , Feto/anormalidades , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/mortalidade , Idade Gestacional , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/mortalidade , Imagem por Ressonância Magnética/métodos , Masculino , Poli-Hidrâmnios/diagnóstico por imagem , Gravidez , Estudos Retrospectivos , Paraplegia Espástica Hereditária/genética , Paraplegia Espástica Hereditária/mortalidade , Polegar/patologia
8.
Handb Clin Neurol ; 155: 191-203, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29891058

RESUMO

The presence of spasticity and pyramidal features is a hallmark of some of hereditary ataxias, such as autosomal-recessive spastic ataxia of Charlevoix-Saguenay, other primary spastic ataxias, Friedreich ataxia, or ataxia with isolated vitamin E deficiency. Certain spastic paraplegias, such as spastic paraplegia 7, may present as an ataxic phenotype and often share common pathophysiologic pathways with cerebellar ataxias. Because of the rarity and genetic heterogeneity of these conditions, their molecular diagnosis remains challenging and time consuming. Herein we review the clinical, epidemiologic, and genetic features of the best-defined spastic ataxias with a focus on autosomal-recessive spastic ataxia of Charlevoix-Saguenay, one of the most frequent ataxias worldwide, which presents with a unique early-onset spastic ataxia phenotype. We briefly discuss other genetic and metabolic multisystem disorders where spastic ataxia is a secondary feature. Emphasis is placed on their typical age of onset and key clinical and imaging features that enable discrimination between these complex diseases.


Assuntos
Deficiência Intelectual , Doenças Metabólicas/complicações , Espasticidade Muscular , Atrofia Óptica , Ataxias Espinocerebelares , Feminino , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/genética , Imagem por Ressonância Magnética , Masculino , Doenças Metabólicas/diagnóstico por imagem , Doenças Metabólicas/genética , Espasticidade Muscular/complicações , Espasticidade Muscular/diagnóstico por imagem , Espasticidade Muscular/epidemiologia , Espasticidade Muscular/genética , Atrofia Óptica/complicações , Atrofia Óptica/diagnóstico por imagem , Atrofia Óptica/epidemiologia , Atrofia Óptica/genética , Ataxias Espinocerebelares/complicações , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/epidemiologia , Ataxias Espinocerebelares/genética , Deficiência de Vitamina E/complicações
9.
J Genet ; 97(1): 35-46, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29666323

RESUMO

Schinzel-Giedion syndrome (SGS) is a rare autosomal dominant inheritance disorder. Heterozygous de novo mutations in the SETBP1 gene have been identified as the genetic cause of SGS. Here, we report a novel case with the syndrome with a novel insertion mutation in SETBP1. We also present a review of SGS cases, and first revise diagnostic criteria of SGS based on clinicalfindings and/or SETBP1 mutation worldwide. A revised diagnostic criteria and typing of SGS can be determined. Type I (complex and classic type) SGS patients present a development delay and typical facial features (prominent forehead, midface retraction, and short and upturned nose) associated with hydronephrosis or two of the characteristic skeletal anomalies (a sclerotic skull base, wideoccipital synchondrosis, increased cortical density or thickness, and broad ribs). Type II (middle type) patients show development delay and the distinctive facial phenotype (midface retraction, short and upturned nose), lacking both hydronephrosis and typical skeletal abnormalities, with existence of SETBP1mutation. Type III (simple type) patients with SETBP1 alteration show their major symptom is development delay, in which expressive language delay is the most striking feature. Central nervous system involvement with development delay in which expressive language delay is much more obviously affected is the most prominent feature of SGS. There is another indication that severity of phenotype of SGS may be inversely correlated with degree of SETBP1 alteration, besides gain-of-function or dominant-negative effects in SETBP1 alteration causing SGS.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Craniofaciais/diagnóstico , Deformidades Congênitas da Mão/diagnóstico , Deficiência Intelectual/diagnóstico , Unhas Malformadas/diagnóstico , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/genética , Sequência de Bases , Proteínas de Transporte/genética , Criança , Anormalidades Craniofaciais/diagnóstico por imagem , Anormalidades Craniofaciais/genética , Análise Mutacional de DNA , Eletroencefalografia , Feminino , Deformidades Congênitas da Mão/diagnóstico por imagem , Deformidades Congênitas da Mão/genética , Heterozigoto , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/genética , Unhas Malformadas/diagnóstico por imagem , Unhas Malformadas/genética , Proteínas Nucleares/genética , Mutação Puntual/genética
10.
J Genet ; 97(1): 205-211, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29666339

RESUMO

Emanuel syndrome is caused due to an additional derivative chromosome 22 and is characterized by severe intellectual disability, microcephaly, failure to thrive, preauricular tags or pits, ear anomalies, cleft or high-arched palate, micrognathia, kidney abnormalities, congenital heart defects and genital abnormalities in males. In 99% of the cases, one of the parents is a carrier of balanced translocation between chromosomes 11 and 22. It occurs due to malsegregation of the gametes with 3:1 segregation. In this case series, we describe four patients with diverse manifestations of this condition. The craniosynostosis observed in one case is a novel finding which has never been reported previously. This study aims to widen the phenotypic spectrum of Emanuel syndrome and provide cytogenetic microarray based breakpoints in two of the cases, thus supporting close clustering of the breakpoints of this common recurrent chromosomal rearrangement.


Assuntos
Transtornos Cromossômicos/genética , Transtornos Cromossômicos/patologia , Cromossomos Humanos Par 22/genética , Fissura Palatina/genética , Fissura Palatina/patologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Hipotonia Muscular/genética , Hipotonia Muscular/patologia , Criança , Transtornos Cromossômicos/diagnóstico por imagem , Fissura Palatina/diagnóstico por imagem , Feminino , Cardiopatias Congênitas/diagnóstico por imagem , Humanos , Lactente , Deficiência Intelectual/diagnóstico por imagem , Cariotipagem , Masculino , Hipotonia Muscular/diagnóstico por imagem , Fenótipo
11.
J Neurol ; 265(6): 1419-1425, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29666984

RESUMO

BACKGROUND: Epilepsy, ataxia, sensorineural deafness, and tubulopathy (EAST syndrome) is a rare channelopathy due to KCNJ10 mutations. So far, only mild cerebellar hypoplasia and/or dentate nuclei abnormalities have been reported as major neuroimaging findings in these patients. METHODS: We analyzed the clinical and brain MRI features of two unrelated patients (aged 27 and 23 years) with EAST syndrome carrying novel homozygous frameshift mutations (p.Asn232Glnfs*14and p.Gly275Valfs*7) in KCNJ10, detected by whole exome sequencing. RESULTS: Brain MRI examinations at 8 years in Patient 1 and at 13 years in Patient 2 revealed a peculiar brain and spinal cord involvement characterized by restricted diffusion of globi pallidi, thalami, brainstem, dentate nuclei, and cervical spinal cord in keeping with intramyelinic edema. The follow-up studies, performed, respectively, after 19 and 10 years, showed mild cerebellar atrophy and slight progression of the brain and spinal cord T2 signal abnormalities with increase of the restricted diffusion in the affected regions. CONCLUSION: The present cases harboring novel homozygous frameshift mutations in KCNJ10 expand the spectrum of brain abnormalities in EAST syndrome, including mild cerebellar atrophy and intramyelinic edema, resulting from abnormal function of the Kir4.1 inwardly rectifying potassium channel at the astrocyte endfeet, with disruption of water-ion homeostasis.


Assuntos
Mutação da Fase de Leitura , Perda Auditiva Neurossensorial/diagnóstico por imagem , Perda Auditiva Neurossensorial/genética , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/genética , Canais de Potássio Corretores do Fluxo de Internalização/genética , Convulsões/diagnóstico por imagem , Convulsões/genética , Substância Branca/diagnóstico por imagem , Adulto , Atrofia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Progressão da Doença , Humanos , Masculino , Medula Espinal/diagnóstico por imagem , Medula Espinal/patologia , Substância Branca/patologia , Adulto Jovem
12.
Dev Med Child Neurol ; 60(7): 687-694, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29667705

RESUMO

AIM: A population-based observational study design was used to describe the epidemiology of intellectual disability in cerebral palsy (CP) in terms of clinical and neuroimaging associations, and to report the impact of intellectual disability on utilization of health services and length of survival. METHOD: Population CP registry data were used to retrospectively assess the frequency of intellectual disability and strength of associations between intellectual disability and mobility, epilepsy, vision, hearing, communication, and neuroimaging patterns (n=1141). Data linkage was undertaken to assess usage of hospital inpatient and emergency department services. Survival analysis was performed in a 30-year birth cohort (n=3248). RESULTS: Intellectual disability, present in 45% of the cohort, was associated with non-ambulation (47% vs 8%), later walking (mean 2y 7mo vs 1y 9mo), hypotonic (8% vs 1%) or dyskinetic (9% vs 5%) CP, a quadriplegic pattern of motor impairment (42% vs 5%), epilepsy (52% vs 12%), more emergency and multi-day hospital admissions, and reduced 35-year survival (96% vs 71%). Grey matter injuries (13% vs 6%), malformations (18% vs 6%), and miscellaneous neuroimaging patterns (12% vs 4%) were more common in people with intellectual disability. INTERPRETATION: Intellectual disability adds substantially to the overall medical complexity in CP and may increase health and mortality disparities. WHAT THIS STUDY ADDS: Cerebral maldevelopments and grey matter injuries are associated with higher intellectual disability rates. Health care is more 'crisis-driven' and 'reactive' in children with co-occurring intellectual disability. Length of survival is reduced in individuals with CP and co-occurring intellectual disability.


Assuntos
Paralisia Cerebral/complicações , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/etiologia , Paralisia Cerebral/diagnóstico por imagem , Paralisia Cerebral/epidemiologia , Paralisia Cerebral/mortalidade , Pré-Escolar , Estudos de Coortes , Planejamento em Saúde Comunitária , Feminino , Idade Gestacional , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/mortalidade , Modelos Logísticos , Imagem por Ressonância Magnética , Masculino , Análise de Sobrevida
13.
Int J Dev Neurosci ; 67: 51-54, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29604340

RESUMO

Pitt-Hopkins syndrome (PTHS), belonging to the group of 18q-syndromes, is a rare genetic disorder caused by mutations in TCF4. PTHS is characterized by distinctive facial appearance, intermittent hyperventilation, intellectual disability and developmental delay. Although patients with PTHS generally have various systemic symptoms, most of them with a TCF4 mutation manifest the central nervous system (CNS) disorders. We described the first Chinese case with Pitt-Hopkins syndrome based on clinical presentations and genetic findings. In addition to the typical features of PTHS, the girl also had paroxysms of tachypnea followed by cyanosis and recurrent seizures. Comprehensive medical examinations were performed including metabolic screening, hepatic and renal function evaluation, abdominal and cardiac ultrasounds. The presence of epileptic discharges in electroencephalography and abnormal brain magnetic resonance imaging were found. High-throughput sequencing was used to detect genetic mutations associated with CNS disorders. Sanger sequencing was used to confirm the mutations in the patient. The c.2182C>T (p.Arg728Ter) mutation was a de novo nonsense mutation at exon 18 in the TCF4 gene of the patient. In conclusion, we have identified a de novo nonsense mutation of TCF4 carried by a Chinese girl with PTHS. The patient underwent anti-epileptic therapy (sodium valproate, levetiracetam, clonazepam), resulting in a reduction of the seizures.


Assuntos
Hiperventilação/complicações , Hiperventilação/genética , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Mutação/genética , Fator de Transcrição 4/genética , Anticonvulsivantes/uso terapêutico , Pré-Escolar , Epilepsia/tratamento farmacológico , Epilepsia/etiologia , Facies , Saúde da Família , Feminino , Humanos , Hiperventilação/diagnóstico por imagem , Deficiência Intelectual/diagnóstico por imagem , Imagem por Ressonância Magnética
14.
J Hum Genet ; 63(6): 749-753, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29556033

RESUMO

Here we report a Japanese patient with new compound heterozygous truncating variants in the PCDH12 gene. As compared to the previously reported families who had congenital microcephaly, intrauterine growth retardation, intracranial calcification, and neonatal seizure associated with dysplasia of the midbrain-hypothalamus-optic tract, the present patient showed no midbrain-hypothalamus dysplasia or congenital/postnatal microcephaly, but dyskinetic cerebral palsy and severe intellectual disability as well as multifocal epilepsy. To understand phenotypic spectrum associated with PCDH12 variants, more reports are needed.


Assuntos
Caderinas/genética , Paralisia Cerebral/genética , Discinesias/genética , Epilepsia/genética , Adolescente , Anticonvulsivantes/uso terapêutico , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Paralisia Cerebral/diagnóstico por imagem , Discinesias/diagnóstico por imagem , Eletroencefalografia , Epilepsia/diagnóstico por imagem , Epilepsia/tratamento farmacológico , Heterozigoto , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/genética , Imagem por Ressonância Magnética , Masculino , Fenótipo
15.
Brain Dev ; 40(4): 334-338, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29254829

RESUMO

Arthrogryposis multiplex congenita (AMC) is characterized by heterogeneous multiple congenital contractures appearing at birth. Mutations in X-linked zinc-finger gene ZC4H2 were recently identified in some families and individuals with variable forms of AMC associated with dysmorphic signs, intellectual disability and spastic paresis. We present a non-consanguineous Japanese female presenting AMC with severe intellectual disability and spastic quadriplegia who also had progressive brain atrophy. Microarray-based comparative genomic hybridization identified 395 kb microdeletions at Xq11.2 which only included ZC4H2 gene. Previous reports showed that affected females have lesser symptoms and slight abnormality on brain MRI compared to male due to X-inactivation. Our case, however, showed severe manifestation than as ever reported as well as progressive diffuse brain atrophy, which implicated contribution of other genetic or environmental factors or extremely skewed X inactivation.


Assuntos
Artrogripose/genética , Encefalopatias/genética , Proteínas de Transporte/genética , Deficiência Intelectual/genética , Artrogripose/diagnóstico por imagem , Artrogripose/patologia , Atrofia/diagnóstico por imagem , Atrofia/genética , Atrofia/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encefalopatias/diagnóstico por imagem , Encefalopatias/patologia , Pré-Escolar , Feminino , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/patologia
16.
Prenat Diagn ; 38(2): 117-122, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29240237

RESUMO

OBJECTIVE: Congenital diaphragmatic hernia (CDH) is associated with Simpson-Golabi-Behmel syndrome (SGBS), but few cases diagnosed prenatally have been reported. The aim of this series is to highlight the association of nonisolated CDH with SGBS type I on prenatal ultrasound and emphasize the importance of genetic testing, fetal autopsy, and family history in confirming this diagnosis. METHOD: Retrospective review of 3 cases of SGBS type I in a single tertiary care centre. Family history, fetal ultrasound, autopsy findings, and genetic testing for GPC3 was performed for each case. RESULTS: Fetal ultrasound findings in the second trimester were CDH, omphalocele, increased nuchal fold, renal anomaly, and cleft lip and palate. Fetal autopsy confirmed the prenatal ultrasound findings and also showed dysmorphic facial features and premalignant lesions on renal and gonadal histology. Microarray and DNA analysis of the GPC3 gene confirmed the diagnosis of SGBS type I in each case. CONCLUSION: Nonisolated CDH in a male fetus suggests a diagnosis of SGBS type I. Fetal autopsy, pedigree analysis, and genetic testing for GPC3 are all essential to confirming the diagnosis. The histological findings of ovotestes and nephroblastomatosis indicate that cancer predisposition is established early in fetal life.


Assuntos
Arritmias Cardíacas/diagnóstico por imagem , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico por imagem , Gigantismo/diagnóstico por imagem , Glipicanas/genética , Cardiopatias Congênitas/diagnóstico por imagem , Hérnias Diafragmáticas Congênitas/diagnóstico por imagem , Deficiência Intelectual/diagnóstico por imagem , Ultrassonografia Pré-Natal , Anormalidades Múltiplas/genética , Arritmias Cardíacas/embriologia , Arritmias Cardíacas/genética , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/embriologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Gigantismo/embriologia , Gigantismo/genética , Cardiopatias Congênitas/embriologia , Cardiopatias Congênitas/genética , Hérnias Diafragmáticas Congênitas/embriologia , Hérnias Diafragmáticas Congênitas/genética , Humanos , Deficiência Intelectual/embriologia , Deficiência Intelectual/genética , Masculino , Gravidez , Estudos Retrospectivos
17.
Brain Dev ; 40(2): 126-129, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28823645

RESUMO

BACKGROUND: Epilepsy with myoclonic absences (EMAs) is a rare epileptic disorder characterized by a predominant type of seizures, myoclonic absences (MAs). The pathophysiology of MAs in patients with EMAs remains unknown. Here, we report the first characterization of the ictal phase of MAs by single photon emission computed tomography (SPECT). METHODS: We evaluated 1 male (Patient 1) and 1 female (Patient 2) patient with EMAs, aged 8 and 4years at first SPECT investigation, respectively. We performed ictal and interictal 99 mTc-ethyl cysteinate dimer (ECD) SPECT. We then generated images of subtraction ictal SPECT co-registered to MRI (SISCOM) from the interictal and ictal data to evaluate topographic changes in cerebral blood flow (CBF) during MAs as compared to the interictal state. RESULTS: In Patient 1, the CBF increased in the perirolandic areas, thalamus, caudate nucleus, and precuneus, and decreased in the middle frontal gyrus and bilateral orbitofrontal regions. In Patient 2, CBF increased in the thalamus, putamen, and globus pallidus. In contrast to the CBF in Patient 1, CBF was decreased in the precuneus. CONCLUSIONS: Using SPECT, we showed that, in addition to the thalamus and basal ganglia, the perirolandic cortical motor area is involved in MAs. We hypothesize that in MAs the blood perfusion in the perirolandic cortical motor area might have changed under the influence of the cortico-thalamic network oscillation features. The CBF properties observed by means of our SPECT procedure may represent key features of the pathophysiological mechanisms underlying MAs.


Assuntos
Encéfalo/diagnóstico por imagem , Epilepsias Mioclônicas/diagnóstico por imagem , Epilepsia Tipo Ausência/diagnóstico por imagem , Tomografia Computadorizada de Emissão de Fóton Único , Encéfalo/fisiopatologia , Mapeamento Encefálico , Circulação Cerebrovascular , Criança , Pré-Escolar , Epilepsias Mioclônicas/fisiopatologia , Epilepsia Tipo Ausência/fisiopatologia , Feminino , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/fisiopatologia , Masculino , Fluxo Sanguíneo Regional
18.
Radiology ; 286(1): 217-226, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28786752

RESUMO

Purpose To identify developmental neuroradiologic findings in a large cohort of carriers who have deletion and duplication at 16p11.2 (one of the most common genetic causes of autism spectrum disorder [ASD]) and assess how these features are associated with behavioral and cognitive outcomes. Materials and Methods Seventy-nine carriers of a deletion at 16p11.2 (referred to as deletion carriers; age range, 1-48 years; mean age, 12.3 years; 42 male patients), 79 carriers of a duplication at 16p11.2 (referred to as duplication carriers; age range, 1-63 years; mean age, 24.8 years; 43 male patients), 64 unaffected family members (referred to as familial noncarriers; age range, 1-46 years; mean age, 11.7 years; 31 male participants), and 109 population control participants (age range, 6-64 years; mean age, 25.5 years; 64 male participants) were enrolled in this cross-sectional study. Participants underwent structural magnetic resonance (MR) imaging and completed cognitive and behavioral tests. MR images were reviewed for development-related abnormalities by neuroradiologists. Differences in frequency were assessed with a Fisher exact test corrected for multiple comparisons. Unsupervised machine learning was used to cluster radiologic features and an association between clusters and cognitive and behavioral scores from IQ testing, and parental measures of development were tested by using analysis of covariance. Volumetric analysis with automated segmentation was used to confirm radiologic interpretation. Results For deletion carriers, the most prominent features were dysmorphic and thicker corpora callosa compared with familial noncarriers and population control participants (16%; P < .001 and P < .001, respectively) and a greater likelihood of cerebellar tonsillar ectopia (30.7%; P < .002 and P < .001, respectively) and Chiari I malformations (9.3%; P < .299 and P < .002, respectively). For duplication carriers, the most salient findings compared with familial noncarriers and population control participants were reciprocally thinner corpora callosa (18.6%; P < .003 and P < .001, respectively), decreased white matter volume (22.9%; P < .001, and P < .001, respectively), and increased ventricular volume (24.3%; P < .001 and P < .001, respectively). By comparing cognitive assessments to imaging findings, the presence of any imaging feature associated with deletion carriers indicated worse daily living, communication, and social skills compared with deletion carriers without any radiologic abnormalities (P < .005, P < .002, and P < .004, respectively). For the duplication carriers, presence of decreased white matter, callosal volume, and/or increased ventricle size was associated with decreased full-scale and verbal IQ scores compared with duplication carriers without these findings (P < .007 and P < .004, respectively). Conclusion In two genetically related cohorts at high risk for ASD, reciprocal neuroanatomic abnormalities were found and determined to be associated with cognitive and behavioral impairments. © RSNA, 2017 Online supplemental material is available for this article.


Assuntos
Transtorno Autístico , Encéfalo/diagnóstico por imagem , Deleção Cromossômica , Transtornos Cromossômicos , Variações do Número de Cópias de DNA/genética , Deficiência Intelectual , Imagem por Ressonância Magnética/métodos , Adolescente , Adulto , Transtorno Autístico/diagnóstico por imagem , Transtorno Autístico/epidemiologia , Transtorno Autístico/genética , Encéfalo/patologia , Criança , Pré-Escolar , Transtornos Cromossômicos/diagnóstico por imagem , Transtornos Cromossômicos/epidemiologia , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 16/genética , Análise por Conglomerados , Estudos Transversais , Feminino , Deleção de Genes , Duplicação Gênica/genética , Humanos , Lactente , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/genética , Masculino , Pessoa de Meia-Idade , Adulto Jovem
19.
Congenit Anom (Kyoto) ; 58(3): 105-107, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-28787104

RESUMO

Coffin-Siris syndrome (CSS) is characterized by growth deficiency, intellectual disability, microcephaly, dysmorphic features, and hypoplastic nails of the fifth fingers and/or toes. Variants in the genes encoding subunits of the BAF complex as well as in SOX11 encoding the transcriptional factor under the control of BAF complex are associated with CSS. We report a new patient with a novel SOX11 mutation. He showed the CSS phenotype and coarctation of the aorta. Sox11 is known to be associated with cardiac outflow development in mouse studies. Therefore, cardiac anomalies might be an important complication in patients with SOX11 mutations.


Assuntos
Anormalidades Múltiplas/genética , Coartação Aórtica/genética , Face/anormalidades , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Micrognatismo/genética , Mutação , Pescoço/anormalidades , Fatores de Transcrição SOXC/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/patologia , Coartação Aórtica/diagnóstico por imagem , Coartação Aórtica/patologia , Pré-Escolar , Angiografia por Tomografia Computadorizada , Ecocardiografia , Face/diagnóstico por imagem , Face/patologia , Expressão Gênica , Deformidades Congênitas da Mão/diagnóstico por imagem , Deformidades Congênitas da Mão/patologia , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/patologia , Masculino , Micrognatismo/diagnóstico por imagem , Micrognatismo/patologia , Pescoço/diagnóstico por imagem , Pescoço/patologia , Fenótipo
20.
J Child Neurol ; 33(1): 106-113, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29246092

RESUMO

PAK3-related intellectual disability is caused by mutations in the gene encoding the p21-activated kinase (PAK) protein. It is characterized by mild to moderate cognitive impairment, micro/normocephaly, and a neurobehavioral phenotype characterized by short attention span, anxiety, restlessness, aggression, and self-abusive behaviors. The authors report a patient with a novel PAK3 mutation, who presented with intellectual disability, severe automutilation, and epilepsy. His magnetic resonance imaging changes were most likely secondary to lacerations from parenchymal contusions. His behavior was difficult to manage with behavior interventions or multiple medications. After finding low levels of dopamine and borderline low serotonin metabolites in the spinal fluid, treatment with low dose L-dopa/carbidopa and 5-hydroxytryptophan significantly improved his self-injurious behavior. This is the first case of PAK3-related intellectual disability presenting with severe self-injury with improvement following treatment. The patient's response to neurotransmitter replacement therapy raises the question if this treatment intervention might help other individuals suffering genetic syndromes and self-injurious behaviors.


Assuntos
5-Hidroxitriptofano/uso terapêutico , Carbidopa/uso terapêutico , Deficiência Intelectual/fisiopatologia , Levodopa/uso terapêutico , Psicotrópicos/uso terapêutico , Comportamento Autodestrutivo/tratamento farmacológico , Comportamento Autodestrutivo/fisiopatologia , Adolescente , Encéfalo/diagnóstico por imagem , Dopamina/metabolismo , Combinação de Medicamentos , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/genética , Masculino , Mutação , Comportamento Autodestrutivo/diagnóstico por imagem , Comportamento Autodestrutivo/genética , Serotonina/metabolismo , Síndrome , Quinases Ativadas por p21/genética
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