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1.
Clin Genet ; 95(5): 601-606, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30790272

RESUMO

The GTPBP2 gene encodes a guanosine triphosphate (GTP)-binding protein of unknown function. Biallelic loss-of-function variants in the GTPBP2 gene have been previously reported in association with a neuro-ectodermal clinical presentation in six individuals from four unrelated families. Here, we provide detailed descriptions of three additional individuals from two unrelated families in the context of the previous literature. Both families carry nonsense variants in GTPBP2: homozygous p.(Arg470*) and compound heterozygous p.(Arg432*)/p.(Arg131*). Key features of this clinically recognizable condition include prenatal onset microcephaly, tone abnormalities, and movement disorders, epilepsy, dysmorphic features, retinal dysfunction, ectodermal dysplasia, and brain iron accumulation. Our findings suggest that some aspects of the clinical presentation appear to be age-related; brain iron accumulation may appear only after childhood, and the ectodermal findings and peripheral neuropathy are most prominent in older individuals. In addition, we present prenatal and neonatal findings as well as the first Caucasian and black African families with GTPBP2 biallelic variants. The individuals described herein provide valuable additional phenotypic information about this rare, novel, and progressive neuroectodermal condition.

2.
Genet Med ; 21(8): 1797-1807, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30679821

RESUMO

PURPOSE: Haploinsufficiency of USP7, located at chromosome 16p13.2, has recently been reported in seven individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), seizures, and hypogonadism. Further, USP7 was identified to critically incorporate into the MAGEL2-USP7-TRIM27 (MUST), such that pathogenic variants in USP7 lead to altered endosomal F-actin polymerization and dysregulated protein recycling. METHODS: We report 16 newly identified individuals with heterozygous USP7 variants, identified by genome or exome sequencing or by chromosome microarray analysis. Clinical features were evaluated by review of medical records. Additional clinical information was obtained on the seven previously reported individuals to fully elucidate the phenotypic expression associated with USP7 haploinsufficiency. RESULTS: The clinical manifestations of these 23 individuals suggest a syndrome characterized by DD/ID, hypotonia, eye anomalies,feeding difficulties, GERD, behavioral anomalies, and ASD, and more specific phenotypes of speech delays including a nonverbal phenotype and abnormal brain magnetic resonance image findings including white matter changes based on neuroradiologic examination. CONCLUSION: The consistency of clinical features among all individuals presented regardless of de novo USP7 variant type supports haploinsufficiency as a mechanism for pathogenesis and refines the clinical impact faced by affected individuals and caregivers.

3.
Artigo em Inglês | MEDLINE | ID: mdl-30476126

RESUMO

Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a rare hypomyelinating leukodystrophy characterized by infantile or childhood onset of motor developmental delay, progressive rigidity and spasticity, with hypomyelination and progressive atrophy of the basal ganglia and cerebellum due to a genetic mutation of the TUBB4A gene. It has only been recognized since 2002 and the full spectrum of the disorder is still being delineated. Here, we review a case report of a severely affected girl with a thorough neuropathological evaluation demonstrating novel clinical and pathological findings. Clinically, our patient demonstrated visual dysfunction and hypodontia in addition to the typical phenotype. Morphologically, more severe and widespread changes in the white matter were observed, including to the optic tracts; in gray structures such as the caudate nucleus, thalamus, globus pallidus, and substantia nigra; as well as an area of focal cortical dysplasia. Overall this case offers further insight into the broad range of clinical and neuropathological findings that may be associated with H-ABC and related TUBB4A gene mutations.

4.
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.

5.
Handb Clin Neurol ; 148: 669-692, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29478607

RESUMO

Unique clinical presentations and magnetic resonance imaging patterns can help differentiate the various adult presentations of leukodystrophies and leukoencephalopathies. White-matter disorders are genetically based disorders affecting the central nervous system white matter, with or without peripheral nervous system involvement. These disorders predominantly affect patients in the pediatric population; however, a number of classic leukodystrophies can present in adulthood. Disease progression can be of variable onset with a broad range of symptoms, usually progressing from cognitive dysfunction. Recognition of specific disorders can have important implications for treatment, involvement of multidisciplinary services, and important conversations surrounding social issues the families may face. The focus of this chapter is to highlight the adult presentations of the classic childhood-onset leukodystrophies as well as to describe leukodystrophies which predominantly present in adulthood.


Assuntos
Encéfalo/patologia , Leucoencefalopatias , Imagem por Ressonância Magnética , Adulto , Encéfalo/diagnóstico por imagem , Humanos , Processamento de Imagem Assistida por Computador , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Leucoencefalopatias/patologia
6.
PLoS One ; 13(1): e0190247, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29320539

RESUMO

BACKGROUND: Champlain BASE™ (Building Access to Specialists through eConsultation) is a web-based asynchronous electronic communication service that allows primary-care- practitioners (PCPs) to submit "elective" clinical questions to a specialist. For adults, PCPs have reported improved access and timeliness to specialist advice, averted face-to-face specialist referrals in up to 40% of cases and high provider satisfaction. OBJECTIVE: To determine whether the expansion of eConsult to a pediatric setting would result in similar measures of improved healthcare system process and high provider acceptance reported in adults. DESIGN: Prospective observational cohort study. SETTING: Single Canadian tertiary-care academic pediatric hospital (June 2014-16) servicing 1.2 million people. PARTICIPANTS: 1. PCPs already using eConsult. 2.Volunteer pediatric specialists provided services in addition to their regular workload. 3.Pediatric patients (< 18 years-old) referred for none-acute care conditions. MAIN OUTCOMES AND MEASURES: Specialty service utilization and access, impact on PCP course-of-action and referral-patterns and survey-based provider satisfaction data were collected. RESULTS: 1064 eConsult requests from 367 PCPs were answered by 23 pediatric specialists representing 14 specialty-services. The top three specialties represented were: General Pediatrics 393 cases (36.9%), Orthopedics 162 (15.2%) and Psychiatry 123 (11.6%). Median specialist response time was 0.9 days (range <1 hour-27 days), most consults (63.2%) required <10minutes to complete and 21/21(100%) specialist survey-respondents reported minimal workload burden. For 515/1064(48.4%) referrals, PCPs received advice for a new or additional course of action; 391/1064(36.7%) referrals resulted in an averted face-to-face specialist visit. In 9 specialties with complete data, the median wait-time was significantly less (p<0.001) for an eConsult (1 day, 95%CI:0.9-1.2) compared with a face-to-face referral (132 days; 95%CI:127-136). The majority (>93.3%) of PCPs rated eConsult as very good/excellent value for both patients and themselves. All specialist survey-respondents indicated eConsult should be a continued service. CONCLUSIONS AND RELEVANCE: Similar to adults, eConsult improves PCP access and timeliness to elective pediatric specialist advice and influences their care decisions, while reporting high end-user satisfaction. Further study is warranted to assess impact on resource utilization and clinical outcomes.


Assuntos
Pediatria , Encaminhamento e Consulta , Consulta Remota , Centros de Atenção Terciária/organização & administração , Canadá , Cuidadores , Redução de Custos , Humanos , Pais , Satisfação do Paciente , Estudos Prospectivos , Centros de Atenção Terciária/economia
7.
Brain ; 140(12): 3105-3111, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29186371

RESUMO

Hypomyelinating leukodystrophies are a heterogeneous group of disorders with a clinical presentation that often includes early-onset nystagmus, ataxia and spasticity and a wide range of severity. Using next-generation sequencing techniques and GeneMatcher, we identified four unrelated patients with brain hypomyelination, all with the same recurrent dominant mutation, c.754G>A p.(Asp252Asn), in TMEM106B. The mutation was confirmed as de novo in three of the cases, and the mildly affected father of the fourth affected individual was confirmed as mosaic for this variant. The protein encoded by TMEM106B is poorly characterized but is reported to have a role in regulation of lysosomal trafficking. Polymorphisms in TMEM106B are thought to modify disease onset in frontotemporal dementia, but its relation to myelination is not understood. Clinical presentation in three of the four patients is remarkably benign compared to other hypomyelinating disorders, with congenital nystagmus and mild motor delay. These findings add TMEM106B to the growing list of genes causing hypomyelinating disorders and emphasize the essential role lysosomes play in myelination.

9.
Eur J Hum Genet ; 25(9): 1049-1054, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28635952

RESUMO

Yunis-Varón syndrome (YVS) is an autosomal recessive disorder comprising skeletal anomalies, dysmorphism, global developmental delay and intracytoplasmic vacuolation in brain and other tissues. All hitherto-reported pathogenic variants affect FIG4, a lipid phosphatase involved in phosphatidylinositol (3,5)-bisphosphate [PtdIns(3,5)P2] metabolism. FIG4 interacts with PIKfyve, a lipid kinase, via the adapter protein VAC14; all subunits of the resulting complex are essential for PtdIns(3,5)P2 synthesis in the endolysosomal membrane compartment. Here, we present the case of a female neonate with clinical features of YVS and normal FIG4 sequencing; exome sequencing identified biallelic rare coding variants in VAC14. Cultured patient fibroblasts exhibited a YVS-like vacuolation phenotype ameliorated in a dose-dependent fashion by ML-SA1, a pharmacological activator of the lysosomal PtdIns(3,5)P2 effector TRPML1. The patient developed a diffuse leukoencephalopathy with loss of the normal N-acetylaspartate spectrographic peak and presence of a large abnormal peak consistent with myoinositol. We report that VAC14 is a second gene for Yunis-Varón syndrome.


Assuntos
Displasia Cleidocraniana/genética , Displasia Ectodérmica/genética , Deformidades Congênitas dos Membros/genética , Proteínas de Membrana/genética , Micrognatismo/genética , Mutação , Alelos , Células Cultivadas , Displasia Cleidocraniana/diagnóstico , Displasia Ectodérmica/diagnóstico , Feminino , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Recém-Nascido , Inositol/metabolismo , Deformidades Congênitas dos Membros/diagnóstico , Proteínas de Membrana/metabolismo , Micrognatismo/diagnóstico , Fenótipo , Ftalimidas/farmacologia , Quinolinas/farmacologia , Vacúolos/metabolismo
10.
Am J Med Genet A ; 173(6): 1593-1600, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28440577

RESUMO

Isolated 7p22.3p22.2 deletions are rarely described with only two reports in the literature. Most other reported cases either involve a much larger region of the 7p arm or have an additional copy number variation. Here, we report five patients with overlapping microdeletions at 7p22.3p22.2. The patients presented with variable developmental delays, exhibiting relative weaknesses in expressive language skills and relative strengths in gross, and fine motor skills. The most consistent facial features seen in these patients included a broad nasal root, a prominent forehead a prominent glabella and arched eyebrows. Additional variable features amongst the patients included microcephaly, metopic ridging or craniosynostosis, cleft palate, cardiac defects, and mild hypotonia. Although the patients' deletions varied in size, there was a 0.47 Mb region of overlap which contained 7 OMIM genes: EIP3B, CHST12, LFNG, BRAT1, TTYH3, AMZ1, and GNA12. We propose that monosomy of this region represents a novel microdeletion syndrome. We recommend that individuals with 7p22.3p22.2 deletions should receive a developmental assessment and a thorough cardiac exam, with consideration of an echocardiogram, as part of their initial evaluation.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 7/genética , Deficiências do Desenvolvimento/genética , Pré-Escolar , Variações do Número de Cópias de DNA/genética , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Humanos , Lactente , Masculino , Monossomia
11.
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
12.
Neurology ; 87(9 Suppl 2): S28-37, 2016 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-27572858

RESUMO

Major advances have been made in the clinical and radiologic characterization of children presenting with the different forms of an acquired inflammatory demyelinating syndrome (ADS) such as acute disseminating encephalomyelitis, neuromyelitis optica spectrum disorders, and clinically isolated syndromes. Nevertheless, a proportion of cases that present with similar symptoms are due to a broad spectrum of other inflammatory disorders affecting the white matter, primary CNS tumors, or neurometabolic diseases. The clinician therefore has to be aware of the different forms of ADS, the risk factors for a chronic-relapsing course, and features that indicate an alternative diagnosis. The goal of this article is therefore to provide an outline of a pathway for evaluating pediatric patients with a presumed inflammatory demyelinating disorder and discussing the spectrum of the more common differential diagnoses.


Assuntos
Doenças Desmielinizantes/diagnóstico , Diagnóstico Diferencial , Sistema Nervoso Central/diagnóstico por imagem , Sistema Nervoso Central/patologia , Criança , Doenças Desmielinizantes/classificação , Humanos , Imagem por Ressonância Magnética , Pediatria
13.
Neuropediatrics ; 47(4): 245-52, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27128728

RESUMO

Under the umbrella of pediatric-acquired demyelinating syndromes, there is a multitude of disorders, including optic neuritis, transverse myelitis, acute disseminated encephalomyelitis (ADEM), multiple sclerosis (MS), and neuromyelitis optica spectrum disorders (NMOSD). Due to overlapping clinical and magnetic resonance imaging (MRI) features, it can be challenging to provide an accurate diagnosis. In view of therapeutic and prognostic implications, an early and reliable diagnosis is however of utmost importance. Recent studies of myelin oligodendrocyte glycoprotein (MOG) identify MOG, as a promising target for antibody-mediated demyelination and a biomarker for a relatively benign and non-MS disease course. We describe the clinical and MRI presentation of five children presenting with an acute, severe central nervous system inflammatory disease involving the brain and spinal cord, all of whom were positive for MOG-IgG antibody. Encephalopathy was uncommon at presentation and all had quick resolution of symptoms with intravenous steroid and intravenous immunoglobulin (IVIG) treatment. All patients recovered well, and have been treated with IVIG to potentially prevent relapses.


Assuntos
Autoanticorpos/imunologia , Encéfalo/diagnóstico por imagem , Doenças Desmielinizantes/fisiopatologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Medula Espinal/diagnóstico por imagem , Criança , Pré-Escolar , Doenças Desmielinizantes/diagnóstico por imagem , Doenças Desmielinizantes/tratamento farmacológico , Doenças Desmielinizantes/imunologia , Encefalomielite Aguda Disseminada/diagnóstico por imagem , Encefalomielite Aguda Disseminada/tratamento farmacológico , Encefalomielite Aguda Disseminada/imunologia , Encefalomielite Aguda Disseminada/fisiopatologia , Feminino , Glucocorticoides/uso terapêutico , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Imagem por Ressonância Magnética , Masculino , Metilprednisolona/uso terapêutico , Mielite Transversa/diagnóstico por imagem , Mielite Transversa/tratamento farmacológico , Mielite Transversa/imunologia , Mielite Transversa/fisiopatologia , Neuromielite Óptica/diagnóstico por imagem , Neuromielite Óptica/tratamento farmacológico , Neuromielite Óptica/imunologia , Neuromielite Óptica/fisiopatologia , Estudos Retrospectivos , Resultado do Tratamento
14.
J Neurol Neurosurg Psychiatry ; 87(8): 897-905, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26645082

RESUMO

OBJECTIVE: To determine the frequency and clinical-radiological associations of antibodies to myelin oligodendrocyte glycoprotein (MOG) and aquaporin-4 (AQP4) in children presenting with neuromyelitis optica (NMO) and limited forms. METHODS: Children with a first event of NMO, recurrent (RON), bilateral ON (BON), longitudinally extensive transverse myelitis (LETM) or brainstem syndrome (BS) with a clinical follow-up of more than 12 months were enrolled. Serum samples were tested for MOG- and AQP4-antibodies using live cell-based assays. RESULTS: 45 children with NMO (n=12), LETM (n=14), BON (n=6), RON (n=12) and BS (n=1) were included. 25/45 (56%) children had MOG-antibodies at initial presentation (7 NMO, 4 BON, 8 ON, 6 LETM). 5/45 (11%) children showed AQP4-antibodies (3 NMO, 1 LETM, 1 BS) and 15/45 (33%) were seronegative for both antibodies (2 NMO, 2 BON, 4 RON, 7 LETM). No differences were found in the age at presentation, sex ratio, frequency of oligoclonal bands or median EDSS at last follow-up between the three groups. Children with MOG-antibodies more frequently (1) had a monophasic course (p=0.018) after one year, (2) presented with simultaneous ON and LETM (p=0.004) and (3) were less likely to receive immunosuppressive therapies (p=0.0002). MRI in MOG-antibody positive patients (4) less frequently demonstrated periependymal lesions (p=0.001), (5) more often were unspecific (p=0.004) and (6) resolved more frequently (p=0.016). CONCLUSIONS: 67% of all children presenting with NMO or limited forms tested positive for MOG- or AQP4-antibodies. MOG-antibody positivity was associated with distinct features. We therefore recommend to measure both antibodies in children with demyelinating syndromes.


Assuntos
Aquaporina 4/imunologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Mielite Transversa/imunologia , Neuromielite Óptica/imunologia , Adolescente , Aquaporina 4/sangue , Autoanticorpos/sangue , Autoanticorpos/imunologia , Tronco Encefálico/diagnóstico por imagem , Tronco Encefálico/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Leucocitose/líquido cefalorraquidiano , Imagem por Ressonância Magnética , Masculino , Glicoproteína Mielina-Oligodendrócito/sangue , Mielite Transversa/sangue , Mielite Transversa/líquido cefalorraquidiano , Mielite Transversa/diagnóstico por imagem , Neuroimagem , Neuromielite Óptica/sangue , Neuromielite Óptica/líquido cefalorraquidiano , Neuromielite Óptica/diagnóstico por imagem , Bandas Oligoclonais/líquido cefalorraquidiano , Fatores de Risco , Síndrome
15.
Hum Mol Genet ; 24(22): 6293-300, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26307080

RESUMO

Protein translation is an essential cellular process initiated by the association of a methionyl-tRNA with the translation initiation factor eIF2. The Met-tRNA/eIF2 complex then associates with the small ribosomal subunit, other translation factors and mRNA, which together comprise the translational initiation complex. This process is regulated by the phosphorylation status of the α subunit of eIF2 (eIF2α); phosphorylated eIF2α attenuates protein translation. Here, we report a consanguineous family with severe microcephaly, short stature, hypoplastic brainstem and cord, delayed myelination and intellectual disability in two siblings. Whole-exome sequencing identified a homozygous missense mutation, c.1972G>A; p.Arg658Cys, in protein phosphatase 1, regulatory subunit 15b (PPP1R15B), a protein which functions with the PPP1C phosphatase to maintain dephosphorylated eIF2α in unstressed cells. The p.R658C PPP1R15B mutation is located within the PPP1C binding site. We show that patient cells have greatly diminished levels of PPP1R15B-PPP1C interaction, which results in increased eIF2α phosphorylation and resistance to cellular stress. Finally, we find that patient cells have elevated levels of PPP1R15B mRNA and protein, suggesting activation of a compensatory program aimed at restoring cellular homeostasis which is ineffective due to PPP1R15B alteration. PPP1R15B now joins the expanding list of translation-associated proteins which when mutated cause rare genetic diseases.


Assuntos
Nanismo/genética , Fator de Iniciação 2 em Eucariotos/genética , Deficiência Intelectual/genética , Proteína Fosfatase 1/genética , Sítios de Ligação , Estatura/genética , Proteínas de Ciclo Celular/genética , Pré-Escolar , Consanguinidade , Nanismo/enzimologia , Fator de Iniciação 2 em Eucariotos/metabolismo , Feminino , Homozigoto , Humanos , Deficiência Intelectual/enzimologia , Masculino , Microcefalia/enzimologia , Microcefalia/genética , Mutação , Mutação de Sentido Incorreto , Fosforilação , Biossíntese de Proteínas , Proteína Fosfatase 1/metabolismo , Subunidades Proteicas , Análise de Sequência de DNA
16.
Pediatrics ; 136(3): e714-7, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26240209

RESUMO

ß-propeller protein-associated neurodegeneration (BPAN) is a recently identified X-linked dominant form of neurodegeneration with brain iron accumulation caused by mutations in the WDR45 gene. BPAN commonly presents as global developmental delay in childhood with rapid onset of parkinsonism and dementia in early adulthood and associated pathognomonic changes seen on brain MRI. In this case report, we present a pediatric patient with mild cognitive delay and pathognomonic MRI changes indicative of BPAN preceding neurologic deterioration who is found to have a novel de novo mutation in the WDR45 gene.


Assuntos
Proteínas de Transporte/genética , Transtornos Cognitivos/genética , Distúrbios do Metabolismo do Ferro/genética , Mutação , Distrofias Neuroaxonais/genética , Adolescente , Encéfalo/patologia , Transtornos Cognitivos/etiologia , Feminino , Humanos , Distúrbios do Metabolismo do Ferro/patologia , Imagem por Ressonância Magnética , Distrofias Neuroaxonais/patologia
17.
Pediatrics ; 136(1): e115-23, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26034241

RESUMO

BACKGROUND: Few prospective studies have systematically evaluated the extent of recovery from incident acquired demyelinating syndromes (ADS) of the central nervous system in children. METHODS: In a national cohort study of pediatric ADS, severity of the incident attack and extent of recovery by 12 months were evaluated. Annual evaluations were used to determine current diagnoses (monophasic ADS or multiple sclerosis [MS]) and new deficits. RESULTS: Of 283 children, 244 (86%) required hospitalization for a median (interquartile range [IQR]) of 6 (3-10) days, and 184 had moderate or severe deficits; 41 children were profoundly encephalopathic, 129 were unable to ambulate independently, and 59 with optic neuritis (ON) had moderately or severely impaired vision. Those with transverse myelitis (TM) and patients with monophasic disease were more likely to have moderate or severe deficits at onset. Twenty-seven children (10%) did not experience full neurologic recovery from their incident attack; 12 have severe residual deficits. Monophasic illness, TM, and moderate or severe deficits at onset were associated with poor recovery. After a median (IQR) follow-up of 5.06 (3.41-6.97) years, 59 children (21%) were diagnosed with MS; all recovered fully from their incident ADS attacks, although 6 subsequently acquired irreversible deficits after a median (IQR) observation period of 5.93 (4.01-7.02) years. CONCLUSIONS: ADS is a serious illness, with 86% of affected Canadian children requiring hospitalization. More than 90% of children recovered physically from their ADS event, including those children experiencing onset of MS. However, permanent visual or spinal cord impairment occurred in some children with ON or TM.


Assuntos
Sistema Nervoso Central/fisiologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/diagnóstico , Recuperação de Função Fisiológica , Criança , Pré-Escolar , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/fisiopatologia , Diagnóstico Diferencial , Feminino , Seguimentos , Humanos , Masculino , Prognóstico , Estudos Retrospectivos
18.
Childs Nerv Syst ; 31(3): 487-91, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25293530

RESUMO

INTRODUCTION: Spinal cord infarction is extremely rare in childhood and can result from a wide range of causes. Fibrocartilaginous embolism can give rise to spinal stroke and mimic non-vascular disease such as acute transverse myelitis. CASE: We report two children who suffered an asymmetrical spinal cord infarction due to fibrocartilaginous embolism. The clinical presentation, radiological findings, and pathophysiology of fibrocartilaginous embolism are described. Each patient demonstrated marked clinical improvement after receiving extensive physical therapy and rehabilitation. One child demonstrated complete clinical recovery. The other had persistent asymmetrical foot weakness and distal sensory deficits. CONCLUSION: We outline the key clinical and radiographic features that enable spinal cord infarction to be differentiated from transverse myelitis. Prognosis depends on many factors such as extent and type of injury, level of the cord affected, and age at the time of spinal cord infarction.


Assuntos
Doenças das Cartilagens/complicações , Embolia/complicações , Infarto/etiologia , Medula Espinal/patologia , Adolescente , Criança , Feminino , Humanos , Masculino
19.
PLoS Genet ; 10(10): e1004772, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25356899

RESUMO

Genetics is believed to have an important role in intellectual disability (ID). Recent studies have emphasized the involvement of de novo mutations (DNMs) in ID but the extent to which they contribute to its pathogenesis and the identity of the corresponding genes remain largely unknown. Here, we report a screen for DNMs in subjects with moderate or severe ID. We sequenced the exomes of 41 probands and their parents, and confirmed 81 DNMs affecting the coding sequence or consensus splice sites (1.98 DNMs/proband). We observed a significant excess of de novo single nucleotide substitutions and loss-of-function mutations in these cases compared to control subjects, suggesting that at least a subset of these variations are pathogenic. A total of 12 likely pathogenic DNMs were identified in genes previously associated with ID (ARID1B, CHD2, FOXG1, GABRB3, GATAD2B, GRIN2B, MBD5, MED13L, SETBP1, TBR1, TCF4, WDR45), resulting in a diagnostic yield of ∼29%. We also identified 12 possibly pathogenic DNMs in genes (HNRNPU, WAC, RYR2, SET, EGR1, MYH10, EIF2C1, COL4A3BP, CHMP2A, PPP1CB, VPS4A, PPP2R2B) that have not previously been causally linked to ID. Interestingly, no case was explained by inherited mutations. Protein network analysis indicated that the products of many of these known and candidate genes interact with each other or with products of other ID-associated genes further supporting their involvement in ID. We conclude that DNMs represent a major cause of moderate or severe ID.


Assuntos
Epilepsia/genética , Deficiência Intelectual/genética , Códon sem Sentido , Epilepsia/patologia , Exoma/genética , Mutação da Fase de Leitura , Humanos , Deficiência Intelectual/patologia , Mutação de Sentido Incorreto , Mutação Puntual , Processamento de RNA/genética , Deleção de Sequência
20.
Epilepsia ; 55(7): e75-9, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24903190

RESUMO

We present a 4-year-old girl with profound global developmental delay and refractory epilepsy characterized by multiple seizure types (partial complex with secondary generalization, tonic, myoclonic, and atypical absence). Her seizure semiology did not fit within a specific epileptic syndrome. Despite a broad metabolic and genetic workup, a diagnosis was not forthcoming. Whole-exome sequencing with a trio analysis (affected child compared to unaffected parents) was performed and identified a novel de novo missense mutation in GRIN2A, c.2449A>G, p.Met817Val, as the likely cause of the refractory epilepsy and global developmental delay. GRIN2A encodes a subunit of N-methyl-d-aspartate (NMDA) receptor that mediates excitatory transmission in the central nervous system. A significant reduction in the frequency and the duration of her seizures was observed after the addition of topiramate over a 10-month period. Further prospective studies in additional patients with mutations in GRIN2A will be required to optimize seizure management for this rare disorder. This report expands the current phenotype associated with GRIN2A mutations.


Assuntos
Deficiências do Desenvolvimento/genética , Epilepsia/genética , Exoma/genética , Mutação de Sentido Incorreto/genética , Receptores de N-Metil-D-Aspartato/genética , Índice de Gravidade de Doença , Pré-Escolar , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/diagnóstico , Epilepsia/complicações , Epilepsia/diagnóstico , Feminino , Humanos , Linhagem
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