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1.
Am J Hum Genet ; 105(5): 1005-1015, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31630790

RESUMO

Lissencephaly comprises a spectrum of malformations of cortical development. This spectrum includes agyria, pachygyria, and subcortical band heterotopia; each represents anatomical malformations of brain cortical development caused by neuronal migration defects. The molecular etiologies of neuronal migration anomalies are highly enriched for genes encoding microtubules and microtubule-associated proteins, and this enrichment highlights the critical role for these genes in cortical growth and gyrification. Using exome sequencing and family based rare variant analyses, we identified a homozygous variant (c.997C>T [p.Arg333Cys]) in TUBGCP2, encoding gamma-tubulin complex protein 2 (GCP2), in two individuals from a consanguineous family; both individuals presented with microcephaly and developmental delay. GCP2 forms the multiprotein γ-tubulin ring complex (γ-TuRC) together with γ-tubulin and other GCPs to regulate the assembly of microtubules. By querying clinical exome sequencing cases and through GeneMatcher-facilitated collaborations, we found three additional families with bi-allelic variation and similarly affected phenotypes including a homozygous variant (c.1843G>C [p.Ala615Pro]) in two families and compound heterozygous variants consisting of one missense variant (c.889C>T [p.Arg297Cys]) and one splice variant (c.2025-2A>G) in another family. Brain imaging from all five affected individuals revealed varying degrees of cortical malformations including pachygyria and subcortical band heterotopia, presumably caused by disruption of neuronal migration. Our data demonstrate that pathogenic variants in TUBGCP2 cause an autosomal recessive neurodevelopmental trait consisting of a neuronal migration disorder, and our data implicate GCP2 as a core component of γ-TuRC in neuronal migrating cells.

2.
Ann Clin Transl Neurol ; 6(8): 1395-1406, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31402629

RESUMO

OBJECTIVE: To characterize the molecular and clinical phenotypic basis of developmental and epileptic encephalopathies caused by rare biallelic variants in CACNA2D2. METHODS: Two affected individuals from a family with clinical features of early onset epileptic encephalopathy were recruited for exome sequencing at the Centers for Mendelian Genomics to identify their molecular diagnosis. GeneMatcher facilitated identification of a second family with a shared candidate disease gene identified through clinical gene panel-based testing. RESULTS: Rare biallelic CACNA2D2 variants have been previously reported in three families with developmental and epileptic encephalopathy, and one family with congenital ataxia. We identified three individuals in two unrelated families with novel homozygous rare variants in CACNA2D2 with clinical features of developmental and epileptic encephalopathy and cerebellar atrophy. Family 1 includes two affected siblings with a likely damaging homozygous rare missense variant c.1778G>C; p.(Arg593Pro) in CACNA2D2. Family 2 includes a proband with a homozygous rare nonsense variant c.485_486del; p.(Tyr162Ter) in CACNA2D2. We compared clinical and molecular findings from all nine individuals reported to date and note that cerebellar atrophy is shared among all. INTERPRETATION: Our study supports the candidacy of CACNA2D2 as a disease gene associated with a phenotypic spectrum of neurological disease that include features of developmental and epileptic encephalopathy, ataxia, and cerebellar atrophy. Age at presentation may affect apparent penetrance of neurogenetic trait manifestations and of a particular clinical neurological endophenotype, for example, seizures or ataxia.

3.
J Neurotrauma ; 36(22): 3164-3171, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31119974

RESUMO

Structural and functional connectivity (FC) after sports-related concussion (SRC) may remain altered in adolescent athletes despite symptom resolution. Little is known, however, about how alterations in structural connectivity and FC co-present in female athletes whose symptom recovery tends to be prolonged. Despite resolution of symptoms, one month after her second SRC, an 18-year-old female athlete had decreased structural connectivity in the corpus callosum and cingulum, with altered FC near those regions, compared with other SRC and orthopedically injured athletes. Findings show persistent effects of SRC on advanced brain imaging and the possibility of greater vulnerability of white matter tracts in females.

4.
Brain Imaging Behav ; 2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-31134584

RESUMO

Mediation analysis was used to investigate the role of white matter integrity in the relationship between injury severity and verbal memory performance in participants with chronic pediatric traumatic brain injury (TBI). DTI tractography was used to measure fractional anisotropy (FA) within the corpus callosum, fornix, cingulum bundles, perforant pathways, and uncinate fasciculi. Injury severity was indexed using Glasgow Coma Scale (GCS) scores obtained at the time of the injury. Verbal memory was measured by performance on the long-delay free recall (LDFR) trial of the California Verbal Learning Test-Children's version. Participants were between the ages of 10-18 and included 21 children with TBI (injured before age 9) and 19 typically-developing children (TDC). Children with TBI showed lower FA across all pathways and poorer LDFR performance relative to TDC. Within the TBI group, mediation analysis revealed neither a significant total effect of GCS on LDFR nor significant direct effects of GCS on LDFR across pathways; however, the indirect effects of GCS on LDFR through FA of the corpus callosum, left perforant pathway, and left uncinate fasciculus were significant and opposite in sign to their respective direct effects. These results suggests that the predictive validity of GCS for LDFR is initially suppressed by the substantial variance accounted for by FA, which is uncorrelated with GCS, and the predictive validity of GCS increases only when FA is considered, and the opposing path is controlled. These findings illustrate the complex associations between acute injury severity, white matter pathways, and verbal memory several years following pediatric TBI.

5.
Genet Med ; 21(8): 1797-1807, 2019 08.
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.

6.
Hum Mutat ; 2018 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-30520571

RESUMO

Next-generation sequencing has been instrumental in solving the genetic basis of rare inherited diseases, especially neurodevelopmental syndromes. However, functional workup is essential for precise phenotype definition and to understand the underlying disease mechanisms. Using whole exome and whole genome sequencing in 4 independent families with hypotonia, neurodevelopmental delay, facial dysmorphism, loss of white matter and thinning of the corpus callosum, we identified 4 previously unreported homozygous truncating PPP1R21 alleles: c.347delT p.(Ile116Lysfs*25), c.2170_2171insGGTA p.(Ile724Argfs*8), c.1607dupT p.(Leu536Phefs*7), c.2063delA p.(Lys688Serfs*26) and found that PPP1R21 was absent in fibroblasts of an affected individual, supporting the allele's loss of function effect. PPP1R21 function had not been studied except that a large scale affinity proteomics approach suggested an interaction with PIBF1 defective in Joubert syndrome. Our co-Immunoprecipitation studies did not confirm this but in contrast defined the localization of PPP1R21 to the early endosome. Consistent with the subcellular expression pattern and the clinical phenotype exhibiting features of storage diseases, we found patient fibroblasts exhibited a delay in clearance of transferrin-488 while uptake was normal. In summary, we delineate a novel neurodevelopmental syndrome caused by bi-allelic PPP1R21 loss of function variants, and suggest a role of PPP1R21 within the endosomal sorting process or endosome maturation pathway. This article is protected by copyright. All rights reserved.

7.
Brain Imaging Behav ; 2018 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-30565025

RESUMO

Microstructural neuropathology occurs in the corpus callosum (CC) after repetitive sports concussion in boxers and can be dose-dependent. However, the specificity and relation of CC changes to boxing exposure extent and post-career psychiatric and neuropsychological outcomes are largely unknown. Using deterministic diffusion tensor imaging (DTI) techniques, boxers and demographically-matched, noncontact sport athletes were compared to address literature gaps. Ten boxers and 9 comparison athletes between 26 and 59 years old (M = 44.63, SD = 9.24) completed neuropsychological testing and MRI. Quantitative DTI metrics were estimated for CC subregions. Group×Region interaction effects were observed on fractional anisotropy (FA; η2p ≥ .21). Follow-up indicated large effects of group (η2p ≥ .26) on splenium FA (boxerscomparisons), but not radial diffusivity (RD). The group of boxers had moderately elevated number of psychiatric symptoms and reduced neuropsychological scores relative to the comparison group. In boxers, years sparring, professional bouts, and knockout history correlated strongly (r > |.40|) with DTI metrics and fine motor dexterity. In the comparison group, splenium FA correlated positively with psychiatric symptoms. In the boxer group, neuropsychological scores correlated with DTI metrics in all CC subregions. Results suggested relative vulnerability of the splenium and, to a lesser extent, the genu to chronic, repetitive head injury from boxing. Dose-dependent associations of professional boxing history extent with DTI white matter structure indices as well as fine motor dexterity were supported. Results indicated that symptoms of depression and executive dysfunction may provide the strongest indicators of global CC disruption from boxing.

8.
Pediatr Radiol ; 2018 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-30402807

RESUMO

BACKGROUND: Therapeutic hypothermia is the standard-of-care treatment for infants diagnosed with moderate-to-severe hypoxic-ischemic encephalopathy (HIE). MRI for assessing brain injury is usually performed after hypothermia because of logistical challenges in bringing acutely sick infants receiving hypothermia from the neonatal intensive care unit (NICU) to the MRI suite. Perhaps examining and comparing early cerebral oxygen metabolism disturbances to those after rewarming will lead to a better understanding of the mechanisms of brain injury in HIE and the effects of therapeutic hypothermia. OBJECTIVE: The objectives were to assess the feasibility of performing a novel T2-relaxation under spin tagging (TRUST) MRI technique to measure venous oxygen saturation very early in the time course of treatment, 18-24 h after the initiation of therapeutic hypothermia, to provide a framework to measure neonatal cerebral oxygen metabolism noninvasively, and to compare parameters between early and post-hypothermia MRIs. MATERIALS AND METHODS: Early (18-24 h after initiating hypothermia) MRIs were performed during hypothermia treatment in nine infants with HIE (six with moderate and three with severe HIE). Six infants subsequently had an MRI after hypothermia. Mean values of cerebral blood flow, oxygen extraction fraction, and cerebral metabolic rate of oxygen from MRIs during hypothermia were compared between infants with moderate and severe HIE; and in those with moderate HIE, we compared cerebral oxygen metabolism parameters between MRIs performed during and after hypothermia. RESULTS: During the initial hypothermia MRI at 23.5±5.2 h after birth, infants with severe HIE had lower oxygen extraction fraction (P=0.04) and cerebral metabolic rate of oxygen (P=0.03) and a trend toward lower cerebral blood flow (P=0.33) compared to infants with moderate HIE. In infants with moderate HIE, cerebral blood flow decreased and oxygen extraction fraction increased between MRIs during and after hypothermia (although not significantly); cerebral metabolic rate of oxygen (P=0.93) was not different. CONCLUSION: Early MRIs were technically feasible while maintaining hypothermic goal temperatures in infants with HIE. Cerebral oxygen metabolism early during hypothermia is more disturbed in severe HIE. In infants with moderate HIE, cerebral blood flow decreased and oxygen extraction fraction increased between early and post-hypothermia scans. A comparison of cerebral oxygen metabolism parameters between early and post-hypothermia MRIs might improve our understanding of the evolution of HIE and the benefits of hypothermia. This approach could guide the use of adjunctive neuroprotective strategies in affected infants.

9.
Fetal Diagn Ther ; : 1-13, 2018 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-30223262

RESUMO

INTRODUCTION: In a pilot study of chronic maternal hyperoxygenation (CMH) in left heart hypoplasia (LHH), we sought to determine effect estimates of CMH on head size, vascular resistance indices, and neurodevelopment compared to controls. MATERIAL AND METHODS: Nine gravidae meeting the inclusion criteria (fetal LHH, ≥25.9 weeks' gestation, and ≥10% increase in percent aortic flow after acute hyperoxygenation) were prospectively enrolled. Controls were 9 contemporary gravidae with fetal LHH without CMH. Brain growth and Doppler-derived estimates of fetal cerebrovascular and placental resistance were blindly evaluated and compared using longitudinal regression. Postnatal anthropomorphic and neurodevelopmental assessments were compared. RESULTS: There was no difference in baseline fetal measures between groups. There was significantly slower biparietal diameter (BPD) growth in the CMH group (z-score change -0.03 ± 0.02 vs. +0.09 ± 0.05 units/week, p = 0.02). At 6 months postnatal age, the mean head circumference z-score in the CMH group was smaller than that of controls (-0.20 ± 0.58 vs. +0.85 ± 1.11, p = 0.048). There were no differences in neurodevelopmental testing at 6 and 12 months. DISCUSSION: In this pilot study, relatively diminished fetal BPD growth and smaller infant head circumference z-scores at 6 months were noted with in utero CMH exposure.

10.
J Neurotrauma ; 2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-29786476

RESUMO

To address controversy surrounding the most appropriate comparison group for mild traumatic brain injury (mTBI) research, mTBI patients 12-30 years of age were compared with an extracranial orthopedic injury (OI) patient group and an uninjured, typically developing (TD) participant group with comparable demographic backgrounds. Injured participants underwent subacute (within 96 h) and late (3 months) diffusion tensor imaging (DTI); TD controls underwent DTI once. Group differences in fractional anisotropy (FA) and mean diffusivity (MD) of commonly studied white matter tracts were assessed. For FA, subacute group differences occurred in the bilateral inferior frontal occipital fasciculus (IFOF) and right inferior longitudinal fasciculus (ILF), and for MD, differences were found in the total corpus callosum, right uncinate fasciculus, IFOF, ILF, and bilateral cingulum bundle (CB). In these analyses, differences (lower FA and higher MD) were generally observed between the mTBI and TD groups but not between the mTBI and OI groups. After a 3 month interval, groups significantly differed in left IFOF FA and in right IFOF and CB MD; the TD group had significantly higher FA and lower MD than both injury groups, which did not differ. There was one exception to this pattern, in which the OI group demonstrated significantly lower FA in the left ILF than the TD group, although neither group differed from the mTBI group. The mTBI and OI groups had generally similar longitudinal results. Findings suggest that different conclusions about group-level DTI analyses could be drawn, depending on the selected comparison group, highlighting the need for additional research in this area. Where possible, mTBI studies may benefit from the inclusion of both OI and TD controls.

11.
Am J Med Genet A ; 176(6): 1315-1326, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29696776

RESUMO

Xia-Gibbs syndrome (XGS: OMIM # 615829) results from de novo truncating mutations within the AT-Hook DNA Binding Motif Containing 1 gene (AHDC1). To further define the phenotypic and molecular spectrum of this disorder, we established an XGS Registry and recruited patients from a worldwide pool of approximately 60 probands. Additional de novo truncating mutations were observed among 25 individuals, extending both the known number of mutation sites and the range of positions within the coding region that were sensitive to alteration. Detailed phenotypic examination of 20 of these patients via clinical records review and data collection from additional surveys showed a wider age range than previously described. Data from developmental milestones showed evidence for delayed speech and that males were more severely affected. Neuroimaging from six available patients showed an associated thinning of the corpus callosum and posterior fossa cysts. An increased risk of both scoliosis and seizures relative to the population burden was also observed. Data from a modified autism screening tool revealed that XGS shares significant overlap with autism spectrum disorders. These details of the phenotypic heterogeneity of XGS implicate specific genotype/phenotype correlations and suggest potential clinical management guidelines.

12.
Brain Imaging Behav ; 12(4): 962-973, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28812290

RESUMO

Diffusion tensor imaging (DTI) has demonstrated its utility in detecting microscopic post-concussion cerebral white matter structural changes, which are not routinely evident on conventional neuroimaging modalities. In this study, we compared 10 adolescents with sports concussion (SC) to 12 orthopedically-injured (OI) individuals within 96 h and three months post injury to 12 typically-developing (TD) participants using DTI and volumetric analyses. In terms of volume, no group differences were noted between SC, OI and TD groups at both 96 h and three months post concussion. Results did not show significant differences between SC, OI, and TD groups for both fractional anisotropy (FA) and apparent diffusion coefficient (ADC) in all regions of interest within 96 h post concussion. However, at three months post-injury, the SC group exhibited significantly lower FA than the TD group in various regions of interest. In terms of ADC, significant group differences between SC and TD groups were found in some regions, with SC group having higher ADC than TD. No group differences for FA and ADC were noted between SC and OI groups at three months post-injury. However, several moderate effect sizes on between-group analyses were noted such that FA was lower and ADC was higher in SC relative to OI. Longitudinally, the SC group demonstrated decreased FA and increased ADC in some areas. The findings highlight the fact that the brain continues to change during the post-injury recovery period, and raises the possibility that adverse changes may result from the neurometabolic cascade that purportedly ensues following SC. DTI may potentially be used to characterize the nature of brain changes that occur following sports-related concussions.

13.
Radiology ; 286(1): 217-226, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28786752

RESUMO

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


Assuntos
Transtorno Autístico , Encéfalo/diagnóstico por imagem , Deleção Cromossômica , Transtornos Cromossômicos , Variações do Número de Cópias de DNA/genética , Deficiência Intelectual , Imagem por Ressonância Magnética/métodos , Adolescente , Adulto , Transtorno Autístico/diagnóstico por imagem , Transtorno Autístico/epidemiologia , Transtorno Autístico/genética , Encéfalo/patologia , Criança , Pré-Escolar , Transtornos Cromossômicos/diagnóstico por imagem , Transtornos Cromossômicos/epidemiologia , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 16/genética , Análise por Conglomerados , Estudos Transversais , Feminino , Deleção de Genes , Duplicação Gênica/genética , Humanos , Lactente , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/genética , Masculino , Pessoa de Meia-Idade , Adulto Jovem
14.
Pediatr Emerg Care ; 33(3): 161-165, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27918377

RESUMO

OBJECTIVE: The aim of the study was to evaluate the utility of the emergency department observation unit (EDOU) for neurologically intact children with closed head injuries (CHIs) and computed tomography (CT) abnormalities. METHODS: A retrospective cohort study of children aged 0 to 18 years with acute CHI, abnormal head CT, and a Glasgow Coma Scales score of 14 or higher admitted to the EDOU of a tertiary care children's hospital from 2007 to 2010. Children with multisystem trauma, nonaccidental trauma, and previous neurosurgical or coagulopathic conditions were excluded. Medical records were abstracted for demographic, clinical, and radiographic findings. Poor outcome was defined as death, intensive care unit admission, or medically/surgically treated increased intracranial pressure. RESULTS: Two hundred two children were included. Median (range) age was 14 (4 days-16 years) months; 51% were male. The most common CT findings were nondisplaced (136, 67%) or displaced (46, 23%) as well as skull fractures and subdural hematomas (38, 19%); 54 (27%) had less than 1 CT finding. The most common interventions included repeat CT (42, 21%), antiemetics (26, 13%), and pain medication (29, 14%). Eighty-nine percent were discharged in less than 24 hours. Inpatient admission from the EDOU occurred in 6 (3%); all were discharged in less than 3 days. One patient required additional intervention (corticosteroid therapy). She had a subdural hematoma, persistent vomiting, intractable headache, and a nonevolving CT. CONCLUSIONS: Neurologically intact patients on initial ED evaluation had a very low likelihood of requiring further interventions, irrespective of CT findings. Although prospective evidence is necessary, this supports reliance on clinical findings when evaluating a well-appearing child with an acute CHI.


Assuntos
Traumatismos Cranianos Fechados/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Conduta Expectante/estatística & dados numéricos , Adolescente , Criança , Pré-Escolar , Estudos Transversais , Gerenciamento Clínico , Feminino , Escala de Coma de Glasgow , Hospitalização , Humanos , Lactente , Recém-Nascido , Masculino , Neuroimagem/métodos , Estudos Retrospectivos
15.
Am J Hum Genet ; 99(4): 831-845, 2016 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-27640307

RESUMO

ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane protein implicated in mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. We identified a recurrent de novo ATAD3A c.1582C>T (p.Arg528Trp) variant by whole-exome sequencing (WES) in five unrelated individuals with a core phenotype of global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. We also describe two families with biallelic variants in ATAD3A, including a homozygous variant in two siblings, and biallelic ATAD3A deletions mediated by nonallelic homologous recombination (NAHR) between ATAD3A and gene family members ATAD3B and ATAD3C. Tissue-specific overexpression of borR534W, the Drosophila mutation homologous to the human c.1582C>T (p.Arg528Trp) variant, resulted in a dramatic decrease in mitochondrial content, aberrant mitochondrial morphology, and increased autophagy. Homozygous null bor larvae showed a significant decrease of mitochondria, while overexpression of borWT resulted in larger, elongated mitochondria. Finally, fibroblasts of an affected individual exhibited increased mitophagy. We conclude that the p.Arg528Trp variant functions through a dominant-negative mechanism that results in small mitochondria that trigger mitophagy, resulting in a reduction in mitochondrial content. ATAD3A variation represents an additional link between mitochondrial dynamics and recognizable neurological syndromes, as seen with MFN2, OPA1, DNM1L, and STAT2 mutations.


Assuntos
Adenosina Trifosfatases/genética , Alelos , Proteínas de Membrana/genética , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Proteínas Mitocondriais/genética , Mutação , Doenças do Sistema Nervoso/genética , ATPases Associadas a Diversas Atividades Celulares , Adulto , Animais , Axônios/patologia , Cardiomiopatias/genética , Criança , Pré-Escolar , Variações do Número de Cópias de DNA/genética , Deficiências do Desenvolvimento/genética , Drosophila melanogaster/genética , Feminino , Fibroblastos , Homozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Hipotonia Muscular/genética , Músculos/patologia , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/patologia , Neurônios/patologia , Atrofia Óptica/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Síndrome , Adulto Jovem
16.
Front Neurol ; 7: 116, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27504104

RESUMO

Recovery following sports-related concussion (SRC) is slower and often more complicated in young adolescent athletes than in collegiate players. Further, the clinical decision to return to play is currently based on symptoms and cognitive performance without direct knowledge of brain function. We tested the hypothesis that brain functional connectivity (FC) would be aberrant in recently concussed, asymptomatic athletes who had been cleared to return to play. A seed-based FC analysis measured the FC of the default mode network (DMN) (seeds = anterior cingulate cortex, posterior cingulate cortex (PCC), right lateral parietal cortex, and left lateral parietal cortex) 30 days after SRC in asymptomatic high school athletes cleared to return to play (n = 13) and was compared to the FC of high school athletes with orthopedic injury (OI) (n = 13). The SRC group demonstrated greater FC than the OI group between the PCC and the ventral lateral prefrontal cortex, as well as between the right lateral parietal cortex and lateral temporal cortex (with regions both outside of and within the DMN). Additionally, the OI group demonstrated greater FC than the SRC group between right lateral parietal cortex and supramarginal gyrus. When relating the FC results to verbal memory performance approximately 1 week and 1 month after injury, significantly different between-group relations were found for the posterior cingulate and right lateral parietal cortex seeds. However, the groups did not differ in verbal memory at 1 month. We suggest that changes in FC are apparent 1-month post-SRC despite resolution of post-concussion symptoms and recovery of cognitive performance in adolescent athletes cleared to return to play.

17.
Am J Med Genet A ; 170(11): 3028-3032, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27409069

RESUMO

Haploinsufficiency of SATB2 causes cleft palate, intellectual disability with deficient speech, facial and dental abnormalities, and other variable features known collectively as SATB2-associated syndrome. This phenotype was accompanied by osteoporosis, fractures, and tibial bowing in two previously reported adult patients; each possessed SATB2 mutations either predicted or demonstrated to escape nonsense-mediated decay, suggesting that the additional bone defects result from a dominant negative effect and/or age-dependent penetrance. These hypotheses remain to be confirmed, as do the specific downstream defects causing bone abnormalities. We report a SATB2 mutation (c.2018dupA; p.(H673fs)) in a 15-year-old patient whose SATB2-associated syndrome phenotype is accompanied by osteoporosis, fractures, progressive tibial bowing, and scoliosis. As this homeodomain-disrupting and predicted truncating mutation resides within the final exon of SATB2, escape from nonsense-mediated decay is likely. Thus, we provide further evidence of bone phenotypes beyond those typically associated with SATB2-associated syndrome in individuals with potential dominant-negative SATB2 alleles, as well as evidence for age-dependence of bone features. Elevations in alkaline phosphatase, urinary N-telopeptide/creatinine ratio, and osteocalcin in the patient indicate increased bone turnover. We propose surveillance and treatment with osteoclast inhibitors to prevent fractures and to slow progressive bone deformities. © 2016 Wiley Periodicals, Inc.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Éxons , Mutação da Fase de Leitura , Proteínas de Ligação à Região de Interação com a Matriz/genética , Fenótipo , Fatores de Transcrição/genética , Adolescente , Biomarcadores , Remodelação Óssea/genética , Encéfalo/patologia , Fraturas Ósseas/genética , Haploinsuficiência , Humanos , Imagem por Ressonância Magnética , Masculino , Osteoporose/genética , Radiografia , Escoliose/genética
18.
Handb Clin Neurol ; 136: 1173-98, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27430464

RESUMO

"Children are not little adults," and while this is a well-worn aphorism, it is especially true in the context of infection, where the same organism may evoke a different immune response in the pediatric central nervous system (CNS) and clinical presentation may be clouded by the lack of a good history or paucity of clinical information. The chronology and natural history of different organisms/infections will be laid out together with the preferred use of different imaging modalities. This chapter will use illustrative examples of some of the more common infections and their complications, in addition to several more rare conditions as well as mimics of childhood CNS infection. Challenges in the imaging of children, including strategies to minimize the use of radiation, are discussed. Some of the more recently voiced concerns regarding the use of anesthetic agents in children are also addressed, along with the contrast agents that are typically required for imaging. With a global increase in worldwide travel the anticipation is that pediatricians will increasingly see unusual organisms presenting with CNS infection while dealing with the ever-present risk of drug resistance with inappropriately treated common or garden infections.


Assuntos
Sistema Nervoso Central/diagnóstico por imagem , Infecção/patologia , Neuroimagem , Sistema Nervoso Central/efeitos dos fármacos , Humanos , Pediatria
19.
Am J Hum Genet ; 98(3): 562-570, 2016 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-26942288

RESUMO

The paradigm of a single gene associated with one specific phenotype and mode of inheritance has been repeatedly challenged. Genotype-phenotype correlations can often be traced to different mutation types, localization of the variants in distinct protein domains, or the trigger of or escape from nonsense-mediated decay. Using whole-exome sequencing, we identified homozygous variants in EMC1 that segregated with a phenotype of developmental delay, hypotonia, scoliosis, and cerebellar atrophy in three families. In addition, a de novo heterozygous EMC1 variant was seen in an individual with a similar clinical and MRI imaging phenotype. EMC1 encodes a member of the endoplasmic reticulum (ER)-membrane protein complex (EMC), an evolutionarily conserved complex that has been proposed to have multiple roles in ER-associated degradation, ER-mitochondria tethering, and proper assembly of multi-pass transmembrane proteins. Perturbations of protein folding and organelle crosstalk have been implicated in neurodegenerative processes including cerebellar atrophy. We propose EMC1 as a gene in which either biallelic or monoallelic variants might lead to a syndrome including intellectual disability and preferential degeneration of the cerebellum.


Assuntos
Atrofia/genética , Deficiências do Desenvolvimento/genética , Variação Genética , Hipotonia Muscular/genética , Proteínas/genética , Escoliose/genética , Adolescente , Alelos , Sequência de Aminoácidos , Atrofia/diagnóstico , Cerebelo/patologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico , Degradação Associada com o Retículo Endoplasmático , Feminino , Estudos de Associação Genética , Heterozigoto , Humanos , Imagem por Ressonância Magnética , Masculino , Dados de Sequência Molecular , Hipotonia Muscular/diagnóstico , Mutação , Linhagem , Dobramento de Proteína , Proteínas/metabolismo , Escoliose/diagnóstico
20.
J Neurotrauma ; 33(20): 1809-1817, 2016 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-26959810

RESUMO

Magnetic resonance imaging data were acquired at ∼24 h and ∼3 months post-injury on mild traumatic brain injury (mTBI; n = 75) and orthopedic injury (n = 60) cohorts. The mTBI subjects were randomly assigned to a treatment group with atorvastatin or a non-treatment mTBI group. The treatment group was further divided into drug and placebo subgroups. FreeSurfer software package was used to compute cortical thickness based on the three dimensional T1-weighted images at both time-points. Cross-sectional analysis was carried out to compare cortical thickness between the mTBI and control groups. Longitudinal unbiased templates were generated for all subjects and cortical thickness measurements were compared between baseline and follow-up scans in the mTBI group. At baseline, significant reduction in cortical thickness was observed in the left middle temporal and the right superior parietal regions in the mTBI group, relative to the control group (p = 0.01). At follow-up, significant cortical thinning was again observed in the left middle temporal cortex in the mTBI group. Further analysis revealed significant cortical thinning only in the non-treatment group relative to the control group. In the follow-up, small regions with significant but subtle cortical thinning and thickening were seen in the frontal, temporal, and parietal lobes in the left hemisphere in the non-treatment group only. Our results indicate that cortical thickness could serve as a useful measure in identifying subtle changes in mTBI patients.


Assuntos
Concussão Encefálica/diagnóstico por imagem , Concussão Encefálica/patologia , Córtex Cerebral/patologia , Adolescente , Adulto , Atorvastatina/uso terapêutico , Concussão Encefálica/tratamento farmacológico , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/efeitos dos fármacos , Estudos Transversais , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Adulto Jovem
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