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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(7): 686-689, 2019 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-31302911

RESUMO

OBJECTIVE: To explore the pathogenesis of two fetuses from one family affected with Joubert syndrome (JS). METHODS: Whole exome sequencing was employed to screen potential mutations in both fetuses. Suspected mutations were verified by Sanger sequencing. Impact of intronic mutations on DNA transcription was validated by cDNA analysis. RESULTS: Two novel TCTN1 mutations, c.342-8A>G and c.1494+1G>A, were identified in exons 2 and 12, respectively.cDNA analysis confirmed the pathogenic nature of both mutations with interference of normal splicing resulting in production of truncated proteins. CONCLUSION: The genetic etiology of the family affected with JS has been identified.Above findings have enriched the mutation spectrum of TCTN1gene and facilitated understanding of the genotype-phenotype correlation of JS.


Assuntos
Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Anormalidades do Olho/genética , Doenças Renais Císticas/genética , Proteínas de Membrana/genética , Retina/anormalidades , Anormalidades Múltiplas/diagnóstico , Anormalidades do Olho/diagnóstico , Humanos , Doenças Renais Císticas/diagnóstico , Mutação , Linhagem , Sequenciamento Completo do Exoma
2.
BMJ Case Rep ; 12(4)2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015250

RESUMO

Joubert syndrome (JS) and JS-related disorders are a group of developmental delay, multiple congenital anomalies and complex midbrain-hindbrain malformations. A few cases of JS with multiple pituitary hormone deficiency (MPHD) have been reported in literature. Here, we presented an unusual presentation of JS in a newborn with MPHD. This case is intended to draw attention to the rare association of JS and MDPH by increasing the awareness of this syndrome.


Assuntos
Cerebelo/anormalidades , Anormalidades do Olho/complicações , Terapia de Reposição Hormonal/métodos , Doenças Renais Císticas/complicações , Hormônios Hipofisários/deficiência , Retina/anormalidades , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/tratamento farmacológico , Anormalidades Múltiplas/etiologia , Anormalidades Múltiplas/genética , Assistência ao Convalescente , Encéfalo/diagnóstico por imagem , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/etiologia , Deficiências do Desenvolvimento/genética , Diagnóstico Diferencial , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/tratamento farmacológico , Doenças dos Genitais Masculinos/diagnóstico , Doenças dos Genitais Masculinos/etiologia , Humanos , Hipoglicemia/diagnóstico , Hipoglicemia/etiologia , Recém-Nascido , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/tratamento farmacológico , Imagem por Ressonância Magnética , Masculino , Pênis/anormalidades , Hormônios Hipofisários/metabolismo , Esteroides/administração & dosagem , Esteroides/uso terapêutico , Resultado do Tratamento
3.
Orphanet J Rare Dis ; 14(1): 61, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30819232

RESUMO

BACKGROUND: Warts Hypogammaglobulinemia Immunodeficiency Myelokathexis (WHIM) syndrome is a primary immunodeficiency characterized by recurrent bacterial infections, severe chronic neutropenia, with lymphopenia, monocytopenia and myelokathexis which is caused by heterozygous gain of functions mutations of the CXC chemokine receptor 4 (CXCR4). WHIM patients display an increased incidence of non-hematopoietic conditions, such as congenital heart disease suggesting that abnormal CXCR4 may put these patients at increased risk of congenital anomalies. Studies conducted on CXCR4 and SDF-1-deficient mice have demonstrated the role of CXCR4 signaling in neuronal cell migration and brain development. In particular, CXCR4 conditional knockout mice display abnormal cerebellar morphology and poor coordination and balance on motor testing. RESULTS: In order to evaluate a possible neurological involvement in WHIM syndrome subjects, we performed neurological examination, including International Cooperative Ataxia Rating Scale, cognitive and psychopathological assessment and brain Magnetic Resonance Imaging (MRI) in 6 WHIM patients (age range 8-51 years) with typical gain of functions mutations of CXCR4 (R334X or G336X). In three cases (P3, P5, P6) neurological evaluation revealed fine and global motor coordination disorders, balance disturbances, mild limb ataxia and excessive talkativeness. Brain MRI showed an abnormal orientation of the cerebellar folia involving bilaterally the gracilis and biventer lobules together with the tonsils in four subjects (P3, P4, P5, P6). The neuropsychiatric evaluation showed increased risk of internalizing and/or externalizing problems in four patients (P2, P3, P4, P6). CONCLUSIONS: Taken together, these observations suggest CXCR4 gain of function mutations can be associated with cerebellar malformation, mild neuromotor and psychopathological dysfunction in WHIM patients.


Assuntos
Cerebelo/anormalidades , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/diagnóstico por imagem , Imagem por Ressonância Magnética , Transtornos Mentais/etiologia , Malformações do Sistema Nervoso/etiologia , Verrugas/complicações , Verrugas/diagnóstico por imagem , Adolescente , Adulto , Cerebelo/diagnóstico por imagem , Criança , Feminino , Mutação com Ganho de Função , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/patologia , Pessoa de Meia-Idade , Receptores CXCR4/genética , Verrugas/genética , Verrugas/patologia , Adulto Jovem
4.
Dev Biol ; 448(1): 36-47, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30695685

RESUMO

Joubert syndrome (JBTS) is a predominantly autosomal recessive neurodevelopmental disorder that presents with characteristic malformations of the cerebellar vermis, superior cerebellar peduncles and midbrain in humans. Accompanying these malformations are a heterogeneous set of clinical symptoms, which frequently include deficits in motor and muscle function, such as hypotonia (low muscle tone) and ataxia (clumsiness). These symptoms are attributed to improper development of the hindbrain, but no direct evidence has been reported linking these in JBTS. Here, we describe muscle developmental defects in a mouse with a targeted deletion of the Abelson helper integration site 1 gene, Ahi1, one of the genes known to cause JBTS in humans. While FVB/NJ Ahi1-/- mice display no gross malformations of the cerebellum, deficits are observed in several measures of motor function, strength, and body development. Specifically, Ahi1-/- mice show delayed physical development, delays in surface reflex righting as neonates, and reductions in grip strength and spontaneous locomotor activity as adults. Additionally, Ahi1-/- mice showed evidence of muscle-specific contributions to this phenotype, such as reductions in 1) myoblast differentiation potential in vitro, 2) muscle desmin expression, and 3) overall muscle mass, myonuclear domain, and muscle fiber cross-sectional area. Together, these data suggest that loss of Ahi1 may cause abnormalities in the differentiation of myoblasts to mature muscle cells. Moreover, Ahi1 loss impacts muscle development directly, outside of any indirect impact of cerebellar malformations, revealing a novel myogenic cause for hypotonia in JBTS.


Assuntos
Anormalidades Múltiplas/embriologia , Diferenciação Celular , Cerebelo/anormalidades , Anormalidades do Olho/embriologia , Doenças Renais Císticas/embriologia , Desenvolvimento Muscular , Transtornos do Neurodesenvolvimento/metabolismo , Proteínas Proto-Oncogênicas/deficiência , Retina/anormalidades , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Animais , Cerebelo/embriologia , Cerebelo/patologia , Desmina/genética , Desmina/metabolismo , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Locomoção/genética , Camundongos , Camundongos Knockout , Força Muscular/genética , Mioblastos/metabolismo , Mioblastos/patologia , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Proteínas Proto-Oncogênicas/metabolismo , Reflexo de Endireitamento/genética , Retina/embriologia , Retina/patologia
5.
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
6.
Neurosci Lett ; 688: 14-25, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29802918

RESUMO

Structural birth defects of the cerebellum, or cerebellar malformations, in humans, have long been recognized. However, until recently there has been little progress in elucidating their developmental pathogenesis. Innovations in brain imaging and human genetic technologies over the last 2 decades have led to better classifications of these disorders and identification of several causative genes. In contrast, cerebellar malformations in model organisms, particularly mice, have been the focus of intense study for more than 70 years. As a result, many of the molecular, genetic and cellular programs that drive formation of the cerebellum have been delineated in mice. In this review, we overview the basic epochs and key molecular regulators of the developmental programs that build the structure of the mouse cerebellum. This mouse-centric approach has been a useful to interpret the developmental pathogenesis of human cerebellar malformations. However, it is becoming apparent that we actually know very little regarding the specifics of human cerebellar development beyond what is inferred from mice. A better understanding of human cerebellar development will not only facilitate improved diagnosis of human cerebellar malformations, but also lead to the development of treatment paradigms for these important neurodevelopmental disorders.


Assuntos
Doenças Cerebelares/patologia , Cerebelo/anormalidades , Cerebelo/crescimento & desenvolvimento , Animais , Humanos , Neurogênese/genética , Neurogênese/fisiologia
8.
Handb Clin Neurol ; 155: 117-127, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29891054

RESUMO

The nervous system is vulnerable to intrinsic and extrinsic metabolic perturbations. In particular, the cerebellum, with its large Purkinje cells and its high density of neurons and glial cells, has high metabolic demand and is highly vulnerable to metabolic derangements. As a result, many disorders of intermediary metabolism will preferentially and sometimes selectively target the cerebellum. However, many of these disorders present in a multisystem fashion with ataxia being a part of the neurologic symptom complex. The presentation of these disorders depends on the time of onset and type of metabolic derangement. Early infantile or intrauterine-onset diseases will present in a young child typically with global hypotonia and both nystagmus and ataxia become more apparent later in life, while later-onset diseases usually present primarily with ataxia. It is important to note that the majority of these disorders are progressive if they are untreated. This chapter provides a review of acquired and genetic metabolic disorders that target the cerebellum, and discusses their diagnostic evaluation and therapy.


Assuntos
Ataxia/complicações , Cerebelo/anormalidades , Cerebelo/patologia , Doenças Metabólicas/complicações , Ataxia/diagnóstico por imagem , Ataxia/patologia , Ataxia/terapia , Cerebelo/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Doenças Metabólicas/diagnóstico por imagem , Doenças Metabólicas/genética , Doenças Metabólicas/terapia
9.
Handb Clin Neurol ; 155: 175-189, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29891057

RESUMO

X-linked cerebellar ataxias (XLCA) are an expanding group of genetically heterogeneous and clinically variable conditions characterized by cerebellar dysgenesis (hypoplasia, atrophy, or dysplasia) caused by gene mutations or genomic imbalances on the X chromosome. The neurologic features of XLCA include hypotonia, developmental delay, intellectual disability, ataxia, and other cerebellar signs. Normal cognitive development has also been reported. Cerebellar defects may be isolated or associated with other brain malformations or extraneurologic involvement. More than 20 genes on the X chromosome, mainly encoding for proteins involved in brain development and synaptic function that have been constantly or occasionally associated with a pathologic cerebellar phenotype, and several families with X-linked inheritance have been reported. Given the excess of males with ataxia, this group of conditions is probably underestimated and families of patients with neuroradiologic and clinical evidence of a cerebellar disorder should be counseled for high risk of X-linked inheritance.


Assuntos
Ataxia/genética , Doenças Cerebelares/genética , Cerebelo/anormalidades , Genes Ligados ao Cromossomo X/genética , Ataxia/fisiopatologia , Humanos
10.
Handb Clin Neurol ; 155: 3-23, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29891067

RESUMO

The embryologic development of the cerebellum extends over a long time period, thus making it vulnerable to a broad spectrum of malformations and disruptions. Knowledge of the main steps of fetal posterior fossa development; the normal imaging patterns at different stages of embryogenesis; the large spectrum of cerebellar malformations; and their clinical presentations enables diagnosis and precise counseling of parents. Sonography is the most important imaging method for the screening of cerebellar malformations since it is noninvasive, widely available, and safe for both mother and child. The ultrasonographic approach for the evaluation of the fetal posterior fossa is based on the classic transabdominal visualization of axial planes with addition when indicated of a more comprehensive, multiplanar transvaginal or transfundal approach, including coronal and sagittal imaging planes. Fetal magnetic resonance imaging (MRI) has become an adjunct to prenatal ultrasound since the 1980s. Good-quality images have been obtained thanks to the implementation of fast and ultrafast MRI sequences. Fetal MRI has higher-contrast resolution than prenatal sonography and may contribute to the differentiation of normal from abnormal tissue. Both prenatal neurosonography and fetal MRI enable accurate prenatal diagnosis of most posterior fossa anomalies.


Assuntos
Doenças Cerebelares/complicações , Doenças Fetais/diagnóstico , Imagem por Ressonância Magnética/métodos , Ultrassonografia/métodos , Doenças Cerebelares/diagnóstico por imagem , Cerebelo/anormalidades , Cerebelo/diagnóstico por imagem , Doenças Fetais/diagnóstico por imagem , Feto/diagnóstico por imagem , Humanos , Diagnóstico Pré-Natal
11.
Handb Clin Neurol ; 155: 49-59, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29891076

RESUMO

Although preterm birth is best known to result in adverse neurodevelopmental outcomes through injury of the supratentorial structures, including intraventricular hemorrhage and periventricular leukomalacia, the cerebellum has become increasingly recognized as an important target for injury and adverse motor and cognitive outcomes. Undergoing the most dramatic growth during the preterm period, the cerebellum is vulnerable to large and small hemorrhages, as well as hypoplasia resulting from a number of potentially modifiable risk factors. These factors include contact with intraventricular blood, crossed cerebrocerebellar diaschisis, postnatal glucocorticoid exposure, pain and opioid exposure, nutrition and somatic growth, cardiorespiratory factors, and socioeconomic status. Strategies targeting these factors may result in prevention of the motor and cognitive deficits seen after cerebellar hemorrhage or hypoplasia.


Assuntos
Doenças Cerebelares/complicações , Cerebelo/anormalidades , Transtornos Cognitivos/etiologia , Deficiências do Desenvolvimento/etiologia , Doenças do Prematuro/fisiopatologia , Doenças Cerebelares/diagnóstico por imagem , Cerebelo/diagnóstico por imagem , Hemorragia Cerebral , Deficiências do Desenvolvimento/diagnóstico por imagem , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro
12.
Handb Clin Neurol ; 155: 91-103, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29891079

RESUMO

The terminology of nonprogressive congenital ataxia (NPCA) refers to a clinically and genetically heterogeneous group of disorders characterized by congenital or early-onset ataxia, but no progression or even improvement on follow-up. Ataxia is preceded by muscular hypotonia and delayed motor (and usually language) milestones. We exclude children with prenatal, perinatal, and postnatal acquired diseases, malformations other than cerebellar hypoplasia, and defined syndromic disorders. Patients with NPCA have a high prevalence of cognitive and language impairments, in addition to increased occurrence of seizures, ocular signs (nystagmus, strabismus), behavior changes, and microcephaly. Neuroimaging is variable, ranging from normal cerebellar anatomy to reduced cerebellar volume (hypoplasia in the proper sense), and enlarged interfolial spaces, potentially mimicking atrophy. The latter appearance is often called "hypoplasia" as well, in view of the static clinical course. Some patients had progressive enlargement of cerebellar fissures, but a nonprogressive course. There is no imaging-clinical-genetic correlation. Dominant, recessive, and X-linked inheritance is documented for NPCA. Here, we focus on the still rather short list of dominant and recessive genes associated with NPCA, identified in the last few years. With future advances in genetics, we expect a rapid expansion of knowledge in this field.


Assuntos
Ataxia , Cerebelo/anormalidades , Transtornos Cognitivos/etiologia , Ataxia/diagnóstico por imagem , Ataxia/genética , Ataxia/fisiopatologia , Cerebelo/diagnóstico por imagem , Transtornos Cognitivos/diagnóstico por imagem , Transtornos Cognitivos/genética , Humanos , Neuroimagem
13.
Vet Microbiol ; 220: 107-112, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29885794

RESUMO

Congenital tremor in pigs involves several etiologies, including pestivirus, which may cause neurological injuries in different animal species. To evaluate whether bovine viral diarrhea virus (BVDV), an important pestivirus, is one of the etiological agents of congenital tremor in swine, gilts and the fetuses were challenged at 45 days of gestation with BVDV-2. Four pregnant gilts were inoculated oronasally, four gilts underwent fetal intrauterine inoculation, and two gilts constituted the control group. Antibody titers were determined by virus neutralization (VN), and viral RNA was detected by RT-PCR. Blood samples were collected from all gilts and piglets born to obtain whole blood and serum for analysis. One third of the neonates were euthanized at three days old, and samples of the encephalon, brain stem and spinal cord were collected for anatomopathological evaluation and viral RNA detection. The piglets that remained alive were clinically evaluated every day, and blood sampling was performed regularly for 35 days. The piglets from gilts in both inoculation treatment groups showed no clinical neurological signs and were born with no viral RNA in their blood and organs. Piglets born from oronasally inoculated gilts did not present antibodies against BVDV-2 at birth, although they were acquired by passive maternal transfer. In contrast, intrauterine-inoculated piglets were born with high antibody titers (80 to 640) against the agent, which remained high until the end of the experimental period. Microscopically, no noticeable changes were observed. Macroscopically, 29.5% of the total piglets euthanized, from both inoculation groups, were born with a low cerebellar:brain ratio. Nevertheless, some piglets had a high cerebellar:brain ratio, indicating the need for standardizing this value. Thus, it was concluded that BVDV is not an etiological agent for congenital swine tremor.


Assuntos
Doença das Mucosas por Vírus da Diarreia Viral Bovina/virologia , Cerebelo/anormalidades , Malformações do Sistema Nervoso/veterinária , Doenças dos Suínos/congênito , Tremor/congênito , Tremor/etiologia , Animais , Animais Lactentes , Anticorpos Antivirais/sangue , Encéfalo/virologia , Bovinos , Cerebelo/virologia , Deficiências do Desenvolvimento/virologia , Vírus da Diarreia Viral Bovina Tipo 2/genética , Vírus da Diarreia Viral Bovina Tipo 2/isolamento & purificação , Feminino , Feto/virologia , Malformações do Sistema Nervoso/virologia , Placenta/virologia , Gravidez , Complicações Infecciosas na Gravidez/virologia , RNA Viral/genética , Reação em Cadeia da Polimerase em Tempo Real , Suínos , Doenças dos Suínos/virologia , Tremor/virologia
14.
Dev Biol ; 440(2): 152-166, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29792854

RESUMO

Neuronal-glial relationships play a critical role in the maintenance of central nervous system architecture and neuronal specification. A deeper understanding of these relationships can elucidate cellular cross-talk capable of sustaining proper development of neural tissues. In the cerebellum, cerebellar granule neuron precursors (CGNPs) proliferate in response to Purkinje neuron-derived Sonic hedgehog (Shh) before ultimately exiting the cell cycle and migrating radially along Bergmann glial fibers. However, the function of Bergmann glia in CGNP proliferation remains not well defined. Interestingly, the Hh pathway is also activated in Bergmann glia, but the role of Shh signaling in these cells is unknown. In this study, we show that specific ablation of Shh signaling using the tamoxifen-inducible TNCYFP-CreER line to eliminate Shh pathway activator Smoothened in Bergmann glia is sufficient to cause severe cerebellar hypoplasia and a significant reduction in CGNP proliferation. TNCYFP-CreER; SmoF/- (SmoCKO) mice demonstrate an obvious reduction in cerebellar size within two days of ablation of Shh signaling. Mutant cerebella have severely reduced proliferation and increased differentiation of CGNPs due to a significant decrease in Shh activity and concomitant activation of Wnt signaling in SmoCKO CGNPs, suggesting that this pathway is involved in cross-talk with the Shh pathway in regulating CGNP proliferation. In addition, Purkinje cells are ectopically located, their dendrites stunted, and the Bergmann glial network disorganized. Collectively, these data demonstrate a previously unappreciated role for Bergmann glial Shh signaling activity in the proliferation of CGNPs and proper maintenance of cerebellar architecture.


Assuntos
Córtex Cerebelar/embriologia , Proteínas Hedgehog/fisiologia , Neuroglia/fisiologia , Animais , Astrócitos/metabolismo , Diferenciação Celular , Divisão Celular , Proliferação de Células/fisiologia , Células Cultivadas , Córtex Cerebelar/fisiologia , Neoplasias Cerebelares/metabolismo , Cerebelo/anormalidades , Cerebelo/embriologia , Deficiências do Desenvolvimento/genética , Proteínas Hedgehog/metabolismo , Camundongos , Malformações do Sistema Nervoso/embriologia , Malformações do Sistema Nervoso/genética , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Neurônios/metabolismo , Células de Purkinje/metabolismo , Transdução de Sinais , Via de Sinalização Wnt/genética
15.
J Hum Genet ; 63(8): 935-939, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29695797

RESUMO

Biallelic pathogenic variants in PIBF1 have been identified as one of the genetic etiologies of Joubert syndrome. We report a two-year-old girl with global developmental delay, facial dysmorphism, hypotonia, enlarged cystic kidneys, molar tooth sign, and thinning of corpus callosum. A novel homozygous 36-bp insertion in PIBF1 (c.1181_1182ins36) was identified by exome sequencing as the likely cause of her condition. This is the second publication demonstrating the cause and effect relationship between PIBF1 and Joubert syndrome.


Assuntos
Anormalidades Múltiplas/genética , Alelos , Pareamento de Bases/genética , Cerebelo/anormalidades , Anormalidades do Olho/genética , Doenças Renais Císticas/genética , Mutagênese Insercional/genética , Proteínas da Gravidez/genética , Retina/anormalidades , Fatores Supressores Imunológicos/genética , Anormalidades Múltiplas/diagnóstico por imagem , Sequência de Bases , Cerebelo/diagnóstico por imagem , Pré-Escolar , Anormalidades do Olho/diagnóstico por imagem , Feminino , Humanos , Doenças Renais Císticas/diagnóstico por imagem , Imagem por Ressonância Magnética , Masculino , Mutação/genética , Linhagem , Retina/diagnóstico por imagem
16.
Rev Chil Pediatr ; 89(1): 92-97, 2018 Feb.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-29664509

RESUMO

INTRODUCTION: Hydrocephalus is defined as complex conditions influenced by genetic and environmental factors. Excluding hydrocephalus acquired from infection or brain tumors, congenital hydrocephalus with a genetic cause may occur isolated (hydrocephalus isolated, pure or non-syndromatic) or as a component of a genetic syndrome (syndromic hydrocephalus). OBJECTIVE: To present a syndromic congenital hydrocephalus with a known diagnosis, in order to be considered in the study of this pathology and to perform a review of hydrocephaly with a genetic cause. CLINICAL CASE: Preschool with a prenatal diagnosis of hydrocephalus and rhombencephalosynapsis, karyotype and study of TORCH was normal. At the moment of birth, the prenatal diagnoses were confirmed and a malformation of cerebral cortical development was excluded. During the first week of life, perito neal ventricle shunt was performed. A reevaluation at age 4, the absence of corneal reflexes bilate ral parietal and congenital focal alopecia associated with rhombencephalosynapsis, meet definitive criteria for cerebello-trigeminal-dermal displasia or Gómez-López-Hernández syndrome (GLHS). CONCLUSIONS: GLHS is an uncommon neurocutaneous syndrome, possibly a sporadic condition that is underdiagnosed. Due to the new imaging and genetic technologies pre and post-natal, today it is possible to achieve a better and more accurate diagnosis of hydrocephalus with a genetic origin, in which the high suspicion of teams of clinical specialists is essential. Without accurate diagnosis, we can not access to a long-term prognosis, prevention of aggregate morbidity or an adequate genetic counseling, which are required in today's pediatrics.


Assuntos
Anormalidades Múltiplas/diagnóstico , Alopecia/diagnóstico , Cerebelo/anormalidades , Anormalidades Craniofaciais/diagnóstico , Transtornos do Crescimento/diagnóstico , Hidrocefalia/congênito , Síndromes Neurocutâneas/diagnóstico , Pré-Escolar , Humanos , Hidrocefalia/diagnóstico , Recém-Nascido , Masculino , Rombencéfalo
17.
J Obstet Gynaecol Res ; 44(6): 1031-1035, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29517144

RESUMO

AIM: This study was aimed to determine reference ranges for fetal cerebellar hemisphere biometry, including the transverse cerebellar diameter (TCD), anteroposterior cerebellar diameter (APCD) and APCD/TCD ratio in normal fetuses. In addition, we investigated which parameter would be useful for cerebellar hypoplasia in trisomy 18. METHODS: This retrospective study included 340 normal singleton pregnancies and 15 cases of trisomy 18, in all of which fetal cerebellar biometry was performed between 14 and 40 weeks of gestational age (GA). The TCD, APCD and APCD/TCD ratio were assessed ultrasonographically. RESULTS: In normal fetuses, the TCD (rs = 0.876, P < 0.001) and APCD (rs = 0.791, P < 0.001) were strongly correlated with GA. However, the APCD/TCD ratio was not correlated with GA (rs = 0.058, P = 0.289), with median values of 0.52. Low TCD, APCD and APCD/TCD ratio values were detected in 53%, 100% and 100% of trisomy 18 cases, respectively. The median APCD/TCD ratio for trisomy 18 was 0.39 (range, 0.30-0.43), which was significantly lower than that of normal fetuses (P < 0.001). A cut-off APCD/TCD ratio of 0.44 served as a good predictor for trisomy 18 (sensitivity 100%, specificity 95.3% and negative predictive value 100%). CONCLUSION: This study shows that TCD and APCD are correlated with GA, while the APCD/TCD ratio is a fixed value throughout gestation. Using the APCD/TCD ratio to assess cerebellar hypoplasia in trisomy 18 is useful because it does not require the individual evaluation of the TCD and APCD.


Assuntos
Cerebelo/anormalidades , Cerebelo/diagnóstico por imagem , Malformações do Sistema Nervoso/diagnóstico por imagem , Síndrome da Trissomía do Cromossomo 18/diagnóstico por imagem , Ultrassonografia Pré-Natal/normas , Cerebelo/patologia , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/etiologia , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Malformações do Sistema Nervoso/etiologia , Malformações do Sistema Nervoso/patologia , Gravidez , Sensibilidade e Especificidade , Síndrome da Trissomía do Cromossomo 18/complicações , Síndrome da Trissomía do Cromossomo 18/patologia
18.
Taiwan J Obstet Gynecol ; 57(1): 119-122, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29458880

RESUMO

OBJECTIVE: We present prenatal diagnosis of hydrancephaly and enlarged cerebellum and cisterna magna in a fetus with thanatophoric dysplasia type II (TD2) and a review of prenatal diagnosis of brain anomalies associated with TD. CASE REPORT: A 33-year-old woman was referred for genetic counseling at 25 weeks of gestation because of fetal ultrasound abnormalities. Prenatal ultrasound at 14 weeks of gestation revealed an increased nuchal translucency (NT) and hydrocephalus. Level II ultrasound examination at 25 weeks of gestation revealed hydrancephaly, macrocephaly, a cloverleaf skull, frontal bossing, enlarged cerebellum and cisterna magna, a narrow chest, small ribs, short straight limbs. Amniocentesis revealed a karyotype of 46,XX. FGFR3 mutation analysis using the DNA extracted from uncultured amniocytes revealed a genotype of WT/c.1948A>G (p.Lys650Glu). The result was consistent with a K650E mutation in FGFR3 and TD2. The pregnancy was subsequently terminated. CONCLUSION: Fetuses with TD2 may present increased NT, early onset hydrocephalus, enlarged cerebellum and cisterna magna, and hydrancephaly on prenatal ultrasound.


Assuntos
Cerebelo/anormalidades , Cisterna Magna/diagnóstico por imagem , Hidranencefalia/diagnóstico por imagem , Crânio/anormalidades , Displasia Tanatofórica/diagnóstico por imagem , Ultrassonografia Pré-Natal/métodos , Amniocentese/métodos , Cerebelo/diagnóstico por imagem , Análise Mutacional de DNA , Feminino , Humanos , Cariótipo , Mutação , Gravidez , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Crânio/diagnóstico por imagem
19.
Brain Dev ; 40(4): 259-267, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29217415

RESUMO

OBJECTIVE: Arima syndrome (AS) is a rare disease and its clinical features mimic those of Joubert syndrome or Joubert syndrome-related diseases (JSRD). Recently, we clarified the AS diagnostic criteria and its severe phenotype. However, genetic evidence of AS remains unknown. We explored causative genes of AS and compared the clinical and genetic features of AS with the other JSRD. PATIENTS AND METHODS: We performed genetic analyses of 4 AS patients of 3 families with combination of whole-exome sequencing and Sanger sequencing. Furthermore, we studied cell biology with the cultured fibroblasts of 3 AS patients. RESULTS: All patients had a specific homozygous variant (c.6012-12T>A, p.Arg2004Serfs*7) or compound heterozygous variants (c.1711+1G>A; c.6012-12T>A, p.Gly570Aspfs*19;Arg2004Serfs*7) in centrosomal protein 290 kDa (CEP290) gene. These unique variants lead to abnormal splicing and premature termination. Morphological analysis of cultured fibroblasts from AS patients revealed a marked decrease of the CEP290-positive cell number with significantly longer cilium and naked and protruded ciliary axoneme without ciliary membrane into the cytoplasm. CONCLUSION: AS resulted in cilia dysfunction from centrosome disruption. The unique variant of CEP290 could be strongly linked to AS pathology. Here, we provided AS specific genetic evidence, which steers the structure and functions of centrosome that is responsible for normal ciliogenesis. This is the first report that has demonstrated the molecular basis of Arima syndrome.


Assuntos
Antígenos de Neoplasias/genética , Doenças Cerebelares/genética , Doenças Cerebelares/patologia , Coloboma/genética , Coloboma/patologia , Fibroblastos/patologia , Proteínas de Neoplasias/genética , Doenças Renais Policísticas/genética , Doenças Renais Policísticas/patologia , Anormalidades Múltiplas/patologia , Anormalidades Múltiplas/fisiopatologia , Adolescente , Adulto , Antígenos de Neoplasias/metabolismo , Células Cultivadas , Centrossomo/metabolismo , Centrossomo/patologia , Doenças Cerebelares/fisiopatologia , Cerebelo/anormalidades , Cerebelo/patologia , Cerebelo/fisiopatologia , Cílios/metabolismo , Cílios/patologia , Coloboma/fisiopatologia , Anormalidades do Olho/patologia , Anormalidades do Olho/fisiopatologia , Família , Feminino , Fibroblastos/metabolismo , Humanos , Imuno-Histoquímica , Doenças Renais Císticas/patologia , Doenças Renais Císticas/fisiopatologia , Microscopia Eletrônica de Transmissão , Peso Molecular , Mutação , Proteínas de Neoplasias/metabolismo , Doenças Renais Policísticas/fisiopatologia , Retina/anormalidades , Retina/patologia , Retina/fisiopatologia , Sequenciamento Completo do Exoma , Adulto Jovem
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