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1.
Nat Genet ; 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31570889

RESUMO

Hypopigmentation along Blaschko's lines is a hallmark of a poorly defined group of mosaic syndromes whose genetic causes are unknown. Here we show that postzygotic inactivating mutations of RHOA cause a neuroectodermal syndrome combining linear hypopigmentation, alopecia, apparently asymptomatic leukoencephalopathy, and facial, ocular, dental and acral anomalies. Our findings pave the way toward elucidating the etiology of pigmentary mosaicism and highlight the role of RHOA in human development and disease.

2.
J Biol Chem ; 294(18): 7445-7459, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-30898877

RESUMO

RNA polymerase III (Pol III) is an essential enzyme responsible for the synthesis of several small noncoding RNAs, a number of which are involved in mRNA translation. Recessive mutations in POLR3A, encoding the largest subunit of Pol III, cause POLR3-related hypomyelinating leukodystrophy (POLR3-HLD), characterized by deficient central nervous system myelination. Identification of the downstream effectors of pathogenic POLR3A mutations has so far been elusive. Here, we used CRISPR-Cas9 to introduce the POLR3A mutation c.2554A→G (p.M852V) into human cell lines and assessed its impact on Pol III biogenesis, nuclear import, DNA occupancy, transcription, and protein levels. Transcriptomic profiling uncovered a subset of transcripts vulnerable to Pol III hypofunction, including a global reduction in tRNA levels. The brain cytoplasmic BC200 RNA (BCYRN1), involved in translation regulation, was consistently affected in all our cellular models, including patient-derived fibroblasts. Genomic BC200 deletion in an oligodendroglial cell line led to major transcriptomic and proteomic changes, having a larger impact than those of POLR3A mutations. Upon differentiation, mRNA levels of the MBP gene, encoding myelin basic protein, were significantly decreased in POLR3A-mutant cells. Our findings provide the first evidence for impaired Pol III transcription in cellular models of POLR3-HLD and identify several candidate effectors, including BC200 RNA, having a potential role in oligodendrocyte biology and involvement in the disease.

3.
BMC Cancer ; 19(1): 137, 2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-30744595

RESUMO

BACKGROUND: Cancer-associated fibroblasts (CAFs), activated by tumour cells, are the predominant type of stromal cells in cancer tissue and play an important role in interacting with neoplastic cells to promote cancer progression. Epithelial-mesenchymal transition (EMT) is a key feature of metastatic cells. However, the mechanism by which CAFs induce EMT program in bladder cancer cells remains unclear. METHODS: To investigate the role of CAFs in bladder cancer progression, healthy primary bladder fibroblasts (HFs) were induced into CAFs (iCAFs) by bladder cancer-derived exosomes. Effect of conditioned medium from iCAFs (CM iCAF) on EMT markers expression of non-invasive RT4 bladder cancer cell line was determined by qPCR and Western blot. IL6 expression in iCAFs was evaluated by ELISA and Western blot. RT4 cell proliferation, migration and invasion were assessed in CM iCAF +/- anti-IL6 neutralizing antibody using cyQUANT assay, scratch test and transwell chamber respectively. We investigated IL6 expression relevance for bladder cancer progression by querying gene expression datasets of human bladder cancer specimens from TCGA and GEO genomic data platforms. RESULTS: Cancer exosome-treated HFs showed CAFs characteristics with high expression levels of αSMA and FAP. We showed that the CM iCAF induces the upregulation of mesenchymal markers, such as N-cadherin and vimentin, while repressing epithelial markers E-cadherin and p-ß-catenin expression in non-invasive RT4 cells. Moreover, EMT transcription factors SNAIL1, TWIST1 and ZEB1 were upregulated in CM iCAF-cultured RT4 cells compared to control. We also showed that the IL-6 cytokine was highly expressed by CAFs, and its receptor IL-6R was found on RT4 bladder cancer cells. The culture of RT4 bladder cancer cells with CM iCAF resulted in markedly promoted cell growth, migration and invasion. Importantly, inhibition of CAFs-secreted IL-6 by neutralizing antibody significantly reversed the IL-6-induced EMT phenotype, suggesting that this cytokine is necessary for CAF-induced EMT in the progression of human bladder cancer. Finally, we observed that IL6 expression is up-regulated in aggressive bladder cancer and correlate with CAF marker ACTA2. CONCLUSIONS: We conclude that CAFs promote aggressive phenotypes of non-invasive bladder cancer cells through an EMT induced by the secretion of IL-6.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Transição Epitelial-Mesenquimal , Interleucina-6/metabolismo , Comunicação Parácrina , Transdução de Sinais , Biomarcadores , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Exossomos/metabolismo , Humanos , Mitomicina/farmacologia , Comunicação Parácrina/efeitos dos fármacos , Prognóstico , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologia
4.
Nat Commun ; 10(1): 707, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30755602

RESUMO

Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. To date, biallelic mutations in 31 ARS genes are known to cause recessive, early-onset severe multi-organ diseases. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. Here, we report seven patients from five unrelated families with five different biallelic missense variants in VARS. Subjects present with a range of global developmental delay, epileptic encephalopathy and primary or progressive microcephaly. Longitudinal assessment demonstrates progressive cortical atrophy and white matter volume loss. Variants map to the VARS tRNA binding domain and adjacent to the anticodon domain, and disrupt highly conserved residues. Patient primary cells show intact VARS protein but reduced enzymatic activity, suggesting partial loss of function. The implication of VARS in pediatric neurodegeneration broadens the spectrum of human diseases due to mutations in tRNA synthetase genes.


Assuntos
Epilepsia/genética , Mutação , Valina-tRNA Ligase/genética , Alelos , Anticódon , Criança , Pré-Escolar , Progressão da Doença , Epilepsia/enzimologia , Epilepsia/patologia , Feminino , Predisposição Genética para Doença , Humanos , Estudos Longitudinais , Mutação com Perda de Função , Masculino , Microcefalia/enzimologia , Microcefalia/genética , Modelos Moleculares , Transtornos do Neurodesenvolvimento/enzimologia , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Linhagem , Biossíntese de Proteínas , Domínios e Motivos de Interação entre Proteínas , RNA de Transferência/genética , Sequenciamento Completo do Exoma , Sequenciamento Completo do Genoma
5.
J Child Neurol ; : 883073818811223, 2018 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-30486714

RESUMO

AIMP1/p43, is a noncatalytic component of the mammalian multi-tRNA synthetase complex that catalyzes the ligation of amino acids to their cognate tRNAs. AIMP1 is largely expressed in the central nervous system, where it is part of the regulatory machine of the neurofilament assembly, playing a crucial role in neuronal development and function. To date, nonsense mutations in AIMP1 have been associated with a primary neurodegenerative disorder consisting of cerebral atrophy, hypomyelination, microcephaly and epilepsy, whereas missense mutations have recently been linked to intellectual disability without neurodegeneration. Here, we report the first French-Canadian patient with a novel frameshift AIMP1 homozygous mutation (c.191_192delAA, p.Gln64Argfs*25), resulting in a severe neurodegenerative phenotype. We review and discuss the phenotypic spectrum associated with AIMP1 pathogenic variants.

6.
Pediatr Neurol ; 84: 21-26, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29859719

RESUMO

BACKGROUND: We attempted to characterize the health-related quality of life in patients with genetically determined leukoencephalopathies as it relates to the severity of clinical features and the presence or absence of a precise molecular diagnosis. METHODS: Health-related quality of life was assessed using the Pediatric Quality of Life Inventory model (Pediatric Quality of Life Inventory 4.0 Self- and Proxy-reports) on 59 patients diagnosed with genetically determined leukoencephalopathies. In total, 38 male and 21 female patients ranging from one to 32 years of age (mean nine years), as well as their parents, completed the Pediatric Quality of Life Inventory health-related quality of life measures. In addition, participants completed detailed standardized clinical assessments or questionnaires. The correlation between health-related quality of life results and the severity of the clinical features, as well as the presence or absence of a molecular diagnosis, were analyzed. RESULTS: Patients with more severe clinical features showed statistically significant lower total Pediatric Quality of Life Inventory scores. More specifically, lower health-related quality of life was noted in children with sialorrhea, gastrostomy, and dystonia and in children who use a wheelchair. CONCLUSIONS: Patients with more severe clinical features experience a lower quality of life. Our study further highlights the importance of addressing both physical and psychosocial issues and discussing perception of quality of life with both parents and children. A larger multicenter prospective study will be needed to further define the burden of these diseases and to identify modifiable factors.

7.
Mol Cancer Res ; 16(7): 1196-1204, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29636362

RESUMO

A particularly important tumor microenvironment relationship exists between cancer cells and surrounding stromal cells. Fibroblasts, in response to cancer cells, become activated and exhibit myofibroblastic characteristics that favor invasive growth and metastasis. However, the mechanism by which cancer cells promote activation of healthy fibroblasts into cancer-associated fibroblasts (CAF) is still not well understood. Exosomes are nanometer-sized vesicles that shuttle proteins and nucleic acids between cells to establish intercellular communication. Here, bladder cancer-derived exosomes were investigated to determine their role in the activation of healthy primary vesical fibroblasts. Exosomes released by bladder cancer cells are internalized by fibroblasts and promoted the proliferation and expression of CAF markers. In addition, cancer cell-derived exosomes contain TGFß and in exosome-induced CAFs SMAD-dependent signaling is activated. Furthermore, TGFß inhibitors attenuated CAF marker expression in healthy fibroblasts. Therefore, these data demonstrate that bladder cancer cells trigger the differentiation of fibroblasts to CAFs by exosomes-mediated TGFß transfer and SMAD pathway activation. Finally, exosomal TGFß localized inside the vesicle and contributes 53.4% to 86.3% of the total TGFß present in the cancer cell supernatant. This study highlights a new function for bladder cancer exosomes as novel modulators of stromal cell differentiation.Implication: This study identifies exosomal TGFß as new molecular mechanism involved in cancer-associated fibroblast activation. Mol Cancer Res; 16(7); 1196-204. ©2018 AACR.

8.
Am J Hum Genet ; 102(4): 676-684, 2018 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-29576217

RESUMO

Hypomyelinating leukodystrophies are genetic disorders characterized by insufficient myelin deposition during development. They are diagnosed on the basis of both clinical and MRI features followed by genetic confirmation. Here, we report on four unrelated affected individuals with hypomyelination and bi-allelic pathogenic variants in EPRS, the gene encoding cytoplasmic glutamyl-prolyl-aminoacyl-tRNA synthetase. EPRS is a bifunctional aminoacyl-tRNA synthetase that catalyzes the aminoacylation of glutamic acid and proline tRNA species. It is a subunit of a large multisynthetase complex composed of eight aminoacyl-tRNA synthetases and its three interacting proteins. In total, five different EPRS mutations were identified. The p.Pro1115Arg variation did not affect the assembly of the multisynthetase complex (MSC) as monitored by affinity purification-mass spectrometry. However, immunoblot analyses on protein extracts from fibroblasts of the two affected individuals sharing the p.Pro1115Arg variant showed reduced EPRS amounts. EPRS activity was reduced in one affected individual's lymphoblasts and in a purified recombinant protein model. Interestingly, two other cytoplasmic aminoacyl-tRNA synthetases have previously been implicated in hypomyelinating leukodystrophies bearing clinical and radiological similarities to those in the individuals we studied. We therefore hypothesized that leukodystrophies caused by mutations in genes encoding cytoplasmic aminoacyl-tRNA synthetases share a common underlying mechanism, such as reduced protein availability, abnormal assembly of the multisynthetase complex, and/or abnormal aminoacylation, all resulting in reduced translation capacity and insufficient myelin deposition in the developing brain.

10.
Neuropediatrics ; 49(2): 112-117, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29179231

RESUMO

4H leukodystrophy is characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism. With its variability in clinical symptoms, application of pattern recognition to identify specific magnetic resonance imaging (MRI) features proved useful for the diagnosis. We collected 3T MR imaging data of 12 patients with mutations in POLR3A (n = 8), POLR3B (n = 3), and POLR1C (n = 1), all obtained at the same scanner. We assessed these images and compared them with previously obtained 1.5T images in 8 patients. Novel MRI findings were myelin islets, closed eye sign, and a cyst-like lesion in the splenium. Myelin islets were variable numbers of small T1 hyperintense and T2 hypointense dots, mostly in the frontal and parietal white matter, and present in all patients. This interpretation was supported with perivascular staining of myelin protein in the hypomyelinated white matter of a deceased 4H patient. All patients had better myelination of the medial lemniscus with a relatively hypointense signal of this structure on axial T2-weighted (T2W) images ("closed eye sign"). Five patients had a small cyst-like lesion in the splenium. In 10 patients with sagittal T2W images, we also found spinal cord hypomyelination. In conclusion, imaging at 3T identified additional features in 4H leukodystrophy, aiding the MRI diagnosis of this entity.

12.
Int J Pediatr Otorhinolaryngol ; 101: 141-144, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28964285

RESUMO

BACKGROUND: Leukodystrophies consist of degenerative neurogenetic diseases often associated with comorbidities that extend beyond the neurological system. Despite their impacts on patients' quality of life and risks of complications, head and neck symptomology is poorly reported in the literature. The objective of this study was to identify and quantify the main head and neck complaints among a cohort of patients diagnosed with leukodystrophies and define the role of the otolaryngologist as part of a multidisciplinary team for treating these patients. METHODS: During the First Canadian National Conference on Leukodystrophies held at the Montreal's Children Hospital, a cohort of 12 patients diagnosed with leukodystrophies were recruited and evaluated by a multidisciplinary team. An otolaryngology-focused assessment was done through history and physical examination, and included a screening questionnaire for 23 common otolaryngology issues. If families reported a history of sialorrhea, a validated questionnaire (Drool Quality of Life Assessment Questionnaire (DroolQoL)) was subsequently distributed. Results from the questionnaires were then compiled and analyzed. RESULTS: Of the 12 recruited patients, 83% (10/12) were known to an otolaryngologist. Drooling affected 67% (8/12) of patients although only 37.5% (3/8) of patients had undergone medical or surgical therapies for this issue. Four patients experienced at least one aspiration pneumonia. 58% (7/12) of the patients had dysphagia, of whom 43% (3/12) were fed exclusively via gastrostomy tube and 28% (2/7) required thickening of feeds. Two patients, despite suspicion of dysphagia and aspiration, had never undergone evaluation. As for otologic issues, it was noted that 25% (3/12) of patients had a history of pressure equalizing tubes (PETs) and one patient had a history of hearing loss. CONCLUSION: Head and neck comorbidities affect children with leukodystrophies. Therefore, the otolaryngologist should be part of the multidisciplinary team, specifically for the management of dysphagia and sialorrhea.


Assuntos
Transtornos de Deglutição/etiologia , Doenças Neurodegenerativas/complicações , Doenças Neurodegenerativas/terapia , Sialorreia/etiologia , Adolescente , Canadá , Criança , Pré-Escolar , Feminino , Gastrostomia , Hospitais Pediátricos , Humanos , Lactente , Masculino , Otorrinolaringologistas , Qualidade de Vida , Estudos Retrospectivos , Sialorreia/complicações , Inquéritos e Questionários , Adulto Jovem
13.
Biomaterials ; 145: 233-241, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28888113

RESUMO

The tumour microenvironment is critical to both the initiation and maintenance of tumorigenesis. Reconstitution of the microenvironment is a major challenge for in vitro cancer models. Indeed, conventional 2D culture systems cannot replicate the complexity, diversity and dynamic nature of the tumour microenvironment. In this study, we have developed a 3D endotheliazed vesical equivalent by using tissue engineering from primary human cells in which non-invasive or invasive bladder cancer (BCa) cell lines, cultured as compact spheroids, were incorporated. Invasive BCa cells cross the basement membrane and invade the stromal compartment whereas non-invasive BCa cells are confined to the urothelium. Our 3D BCa model could be used as a reliable model for assessing drug responses, potentially reducing or partially replacing animal experiments, and thus should have applications in the identification of novel targets as well as toxicological evaluation of anti-cancer therapies.


Assuntos
Descoberta de Drogas , Modelos Biológicos , Engenharia Tecidual/métodos , Neoplasias da Bexiga Urinária/patologia , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Células Endoteliais da Veia Umbilical Humana , Humanos , Mitomicina/farmacologia , Invasividade Neoplásica , Reprodutibilidade dos Testes , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/patologia , Microambiente Tumoral/efeitos dos fármacos
14.
Mol Genet Metab ; 122(1-2): 18-32, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28863857

RESUMO

Leukodystrophies are a broad class of genetic disorders that result in disruption or destruction of central myelination. Although the mechanisms underlying these disorders are heterogeneous, there are many common symptoms that affect patients irrespective of the genetic diagnosis. The comfort and quality of life of these children is a primary goal that can complement efforts directed at curative therapies. Contained within this report is a systems-based approach to management of complications that result from leukodystrophies. We discuss the initial evaluation, identification of common medical issues, and management options to establish a comprehensive, standardized care approach. We will also address clinical topics relevant to select leukodystrophies, such as gallbladder pathology and adrenal insufficiency. The recommendations within this review rely on existing studies and consensus opinions and underscore the need for future research on evidence-based outcomes to better treat the manifestations of this unique set of genetic disorders.


Assuntos
Doenças Desmielinizantes/terapia , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/terapia , Leucoencefalopatias/terapia , Doenças por Armazenamento dos Lisossomos/prevenção & controle , Doenças por Armazenamento dos Lisossomos/terapia , Insuficiência Adrenal/terapia , Adulto , Criança , Doenças Desmielinizantes/congênito , Feminino , Vesícula Biliar/patologia , Predisposição Genética para Doença , Humanos , Leucoencefalopatias/congênito , Masculino , Qualidade de Vida
15.
Neuropediatrics ; 48(3): 152-160, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28561206

RESUMO

4H (hypomyelination, hypodontia and hypogonadotropic hypogonadism) leukodystrophy (4H) is an autosomal recessive hypomyelinating white matter (WM) disorder with neurologic, dental, and endocrine abnormalities. The aim of this study was to develop and validate a magnetic resonance imaging (MRI) scoring system for 4H. A scoring system (0-54) was developed to quantify hypomyelination and atrophy of different brain regions. Pons diameter and bicaudate ratio were included as measures of cerebral and brainstem atrophy, and reference values were determined using controls. Five independent raters completed the scoring system in 40 brain MRI scans collected from 36 patients with genetically proven 4H. Interrater reliability (IRR) and correlations between MRI scores, age, gross motor function, gender, and mutated gene were assessed. IRR for total MRI severity was found to be excellent (intraclass correlation coefficient: 0.87; 95% confidence interval: 0.80-0.92) but varied between different items with some (e.g., myelination of the cerebellar WM) showing poor IRR. Atrophy increased with age in contrast to hypomyelination scores. MRI scores (global, hypomyelination, and atrophy scores) significantly correlated with clinical handicap (p < 0.01 for all three items) and differed between the different genotypes. Our 4H MRI scoring system reliably quantifies hypomyelination and atrophy in patients with 4H, and MRI scores reflect clinical disease severity.


Assuntos
Anodontia/diagnóstico por imagem , Ataxia/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Hipogonadismo/diagnóstico por imagem , Leucoencefalopatias/diagnóstico por imagem , Imagem por Ressonância Magnética , Índice de Gravidade de Doença , Adolescente , Adulto , Atrofia , Criança , Pré-Escolar , Avaliação da Deficiência , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Imagem por Ressonância Magnética/métodos , Masculino , Atividade Motora , Bainha de Mielina , Tamanho do Órgão , Reprodutibilidade dos Testes , Estudos Retrospectivos , Adulto Jovem
16.
Mol Brain ; 10(1): 13, 2017 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-28407788

RESUMO

Recessive mutations in the ubiquitously expressed POLR3A gene cause one of the most frequent forms of childhood-onset hypomyelinating leukodystrophy (HLD): POLR3-HLD. POLR3A encodes the largest subunit of RNA Polymerase III (Pol III), which is responsible for the transcription of transfer RNAs (tRNAs) and a large array of other small non-coding RNAs. In order to study the central nervous system pathophysiology of the disease, we introduced the French Canadian founder Polr3a mutation c.2015G > A (p.G672E) in mice, generating homozygous knock-in (KI/KI) as well as compound heterozygous mice for one Polr3a KI and one null allele (KI/KO). Both KI/KI and KI/KO mice are viable and are able to reproduce. To establish if they manifest a motor phenotype, WT, KI/KI and KI/KO mice were submitted to a battery of behavioral tests over one year. The KI/KI and KI/KO mice have overall normal balance, muscle strength and general locomotion. Cerebral and cerebellar Luxol Fast Blue staining and measurement of levels of myelin proteins showed no significant differences between the three groups, suggesting that myelination is not overtly impaired in Polr3a KI/KI and KI/KO mice. Finally, expression levels of several Pol III transcripts in the brain showed no statistically significant differences. We conclude that the first transgenic mice with a leukodystrophy-causing Polr3a mutation do not recapitulate the childhood-onset HLD observed in the majority of human patients with POLR3A mutations, and provide essential information to guide selection of Polr3a mutations for developing future mouse models of the disease.


Assuntos
Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Mutação/genética , Bainha de Mielina/metabolismo , RNA Polimerase III/genética , Animais , Cerebelo/patologia , Cerebelo/fisiopatologia , Técnicas de Introdução de Genes , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/fisiopatologia , Homozigoto , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora , Células de Purkinje/metabolismo , Células de Purkinje/patologia , RNA Polimerase III/metabolismo , Transcrição Genética
17.
Hum Mutat ; 38(5): 511-516, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28185376

RESUMO

Deleterious variants in the same gene present in two or more families with overlapping clinical features provide convincing evidence of a disease-gene association; this can be a challenge in the study of ultrarare diseases. To facilitate the identification of additional families, several groups have created "matching" platforms. We describe four individuals from three unrelated families "matched" by GeneMatcher and MatchMakerExchange. Individuals had microcephaly, developmental delay, epilepsy, and recessive mutations in TRIT1. A single homozygous mutation in TRIT1 associated with similar features had previously been reported in one family. The identification of these individuals provides additional evidence to support TRIT1 as the disease-causing gene and interprets the variants as "pathogenic." TRIT1 functions to modify mitochondrial tRNAs and is necessary for protein translation. We show that dysfunctional TRIT1 results in decreased levels of select mitochondrial proteins. Our findings confirm the TRIT1 disease association and advance the phenotypic and molecular understanding of this disorder.


Assuntos
Alquil e Aril Transferases/genética , Alelos , Genes Recessivos , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Mutação , Adolescente , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Criança , Pré-Escolar , Facies , Feminino , Testes Genéticos , Homozigoto , Humanos , Imagem por Ressonância Magnética , Masculino , Fenótipo
18.
J Child Neurol ; 32(3): 301-307, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28193112

RESUMO

We describe the presenting features and long-term outcome of an unusual cluster of pediatric acute flaccid paralysis cases that occurred in Canada during the 2014 enterovirus D68 outbreak. Children (n = 25; median age 7.8 years) presenting to Canadian centers between July 1 and October 31, 2014, and who met diagnostic criteria for acute flaccid paralysis were evaluated retrospectively. The predominant presenting features included prodromal respiratory illness (n = 22), cerebrospinal fluid lymphocytic pleocytosis (n = 18), pain in neck/back (n = 14) and extremities (n = 10), bowel/bladder dysfunction (n = 9), focal central gray matter lesions found in all regions of the spinal cord within the cohort (n = 16), brain stem lesions (n = 8), and bulbar symptoms (n = 5). Enterovirus D68 was detectable in nasopharyngeal specimens (n = 7) but not in cerebrospinal fluid. Acute therapies (corticosteroids, intravenous immunoglobulins, plasmapheresis) were well tolerated with few side effects. Fourteen of 16 patients who were followed beyond 12 months post onset had neurologic deficits but showed ongoing clinical improvement and motor recovery.


Assuntos
Encéfalo/diagnóstico por imagem , Enterovirus Humano D , Infecções por Enterovirus/complicações , Paraplegia/terapia , Potenciais de Ação/fisiologia , Adolescente , Corticosteroides/uso terapêutico , Canadá , Criança , Pré-Escolar , Eletromiografia , Infecções por Enterovirus/fisiopatologia , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Lactente , Masculino , Músculo Esquelético/fisiopatologia , Condução Nervosa/fisiologia , Paraplegia/diagnóstico por imagem , Paraplegia/tratamento farmacológico , Paraplegia/virologia , Plasmaferese , Estudos Retrospectivos , Resultado do Tratamento
19.
Pediatr Neurol ; 66: 59-62, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27843092

RESUMO

BACKGROUND: Leukoencephalopathy with temporal lobe cysts may be associated with monogenetic conditions such as Aicardi-Goutières syndrome or RNASET2 mutations and with congenital infections such as cytomegalovirus. In view of the fact that congenital cytomegalovirus is difficult to confirm outside the neonatal period, excluding a Mendelian disorder is extremely relevant, changing family planning and medical management in affected families. We performed diagnostic testing in individuals with leukoencephalopathy with temporal lobe cysts without a definitive diagnosis of congenital cytomegalovirus infection. METHODS: We reviewed a large-scale biorepository of patients with unsolved leukodystrophies and identified two individuals with required for meiotic nuclear division 1 (RMND1) mutations and similar magnetic resonance imaging (MRI) features, including temporal lobe cysts. Ten additional subjects with confirmed RMND1 mutations were identified as part of a separate disease specific cohort. Brain MRIs from all 12 individuals were reviewed for common neuroradiological features. RESULTS: MRI features in RMND1 mutations included temporal lobe swelling, with rarefaction and cystic evolution, enlarged tips of the temporal lobes, and multifocal subcortical white matter changes with confluent periatrial T2 signal hyperintensity. A combination of these features was present in ten of the 12 individuals reviewed. CONCLUSIONS: Despite the small number of reported individuals with RMND1 mutations, a clinically recognizable phenotype of leukoencephalopathy with temporal lobe swelling, rarefaction, and cystic changes has emerged in a subset of individuals. Careful clinical phenotyping, including for lactic acidosis, deafness, and severe muscle involvement seen in RMND1 mutation positive individuals, and MRI pattern recognition will be important in differentiating these patients from children with congenital infections like cytomegalovirus.


Assuntos
Neoplasias Encefálicas/genética , Proteínas de Ciclo Celular/genética , Infecções por Citomegalovirus/congênito , Surdez/genética , Leucoencefalopatias/genética , Neoplasias Encefálicas/diagnóstico por imagem , Criança , Pré-Escolar , Estudos de Coortes , Cistos/diagnóstico por imagem , Infecções por Citomegalovirus/diagnóstico por imagem , Infecções por Citomegalovirus/genética , Surdez/diagnóstico por imagem , Diagnóstico Diferencial , Humanos , Lactente , Leucoencefalopatias/diagnóstico por imagem , Mutação , Fenótipo , Lobo Temporal/diagnóstico por imagem
20.
Brain ; 139(Pt 12): 3163-3169, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27797806

RESUMO

We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.


Assuntos
Tremor Essencial/genética , Estudo de Associação Genômica Ampla , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Proteínas Serina-Treonina Quinases/genética , alfa Catenina/genética , Humanos , Polimorfismo de Nucleotídeo Único
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