RESUMO
Malonyl-CoA-acyl carrier protein transacylase (MCAT) is an enzyme involved in mitochondrial fatty acid synthesis (mtFAS) and catalyzes the transfer of the malonyl moiety of malonyl-CoA to the mitochondrial acyl carrier protein (ACP). Previously, we showed that loss-of-function of mtFAS genes, including Mcat, is associated with severe loss of electron transport chain (ETC) complexes in mouse immortalized skeletal myoblasts (Nowinski et al., 2020). Here, we report a proband presenting with hypotonia, failure to thrive, nystagmus, and abnormal brain MRI findings. Using whole exome sequencing, we identified biallelic variants in MCAT. Protein levels for NDUFB8 and COXII, subunits of complex I and IV respectively, were markedly reduced in lymphoblasts and fibroblasts, as well as SDHB for complex II in fibroblasts. ETC enzyme activities were decreased in parallel. Re-expression of wild-type MCAT rescued the phenotype in patient fibroblasts. This is the first report of a patient with MCAT pathogenic variants and combined oxidative phosphorylation deficiency.
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Proteína de Transporte de Acila S-Maloniltransferase , Doenças Mitocondriais , Animais , Camundongos , Adipogenia , Encéfalo , Mitocôndrias , Doenças Mitocondriais/genética , Proteína de Transporte de Acila S-Maloniltransferase/genéticaRESUMO
BACKGROUND: Flexion-extension magnetic resonance imaging (MRI) has potential to identify cervical pathology not detectable on conventional static MRI. Our study evaluated standard quantitative and novel subjective grading scales for assessing the severity of cervical spondylotic myelopathy in dynamic sagittal MRI as well as in static axial and sagittal images. METHODS: Forty-five patients underwent both conventional and flexion-extension MRI prior to anterior cervical discectomy and fusion from C4 through C7. In addition to measuring Cobb angles and cervical canal diameter, grading scales were developed for assessment of vertebral body translation, loss of disc height, change in disc contour, deformation of cord contour, and cord edema. Data were collected at all levels from C2-C3 through C7-T1. Variations in measurements between cervical levels and from flexion through neutral to extension were assessed using Mann-Whitney, Kruskal-Wallis, and two-way ANOVA tests. RESULTS: Cervical canal diameter, vertebral translation, and posterior disc opening changed significantly from flexion to neutral to extension positions (P < 0.01). When comparing operative versus nonoperative cervical levels, significant differences were found when measuring sagittal cervical canal dimensions, vertebral translation, and posterior disc opening (P < 0.01). Degenerative loss of disc height, disc dehydration, deformation of ventral cord contour, and cord edema were all significantly increased at operative levels versus nonoperative levels (P < 0.01). CONCLUSIONS: Flexion-extension MRI demonstrated significant changes not available from conventional MRI. Subjective scales for assessing degenerative changes were significantly more severe at levels with operative cervical spondylotic myelopathy. The utility of these scales for planning surgical intervention at specific and adjacent levels is currently under investigation.
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Doenças da Medula Espinal , Humanos , Doenças da Medula Espinal/diagnóstico por imagem , Doenças da Medula Espinal/cirurgia , Doenças da Medula Espinal/patologia , Imageamento por Ressonância Magnética/métodos , Vértebras Cervicais/diagnóstico por imagem , Vértebras Cervicais/cirurgia , Vértebras Cervicais/patologia , Pescoço/cirurgia , DiscotomiaRESUMO
BACKGROUND: Intracranial chondrosarcomas are slowly growing malignant cartilaginous tumors that are especially rare in adolescents. CASE DESCRIPTION: A 19-year-old woman with no medical history presented with symptoms of intermittent facial twitching and progressive generalized weakness for 6 months. The patient's physical examination was unremarkable. Imaging revealed a large bifrontal mass arising from the falx cerebri, with significant compression of both cerebral hemispheres and downward displacement of the corpus callosum. The patient underwent a bifrontal craniotomy for gross total resection of tumor. Neuropathologic examination revealed a bland cartilaginous lesion most consistent with low-grade chondrosarcoma. Her postoperative course was uneventful, and she was discharged to home on postoperative day 3. CONCLUSION: This is an unusual case of an extra-axial, non-skull base, low-grade chondrosarcoma presenting as facial spasm in an adolescent patient.
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Chordoid glioma (CG) is a rare WHO Grade II neoplasm of the anterior third ventricle. We report two cases of CG with new presentation in terms of histopathology and location: a case of CG with osseous metaplasia evident on imaging, and another CG, unusually located in the posterior portion of the third ventricle.
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Neoplasias do Ventrículo Cerebral , Glioma , Terceiro Ventrículo , Neoplasias do Ventrículo Cerebral/diagnóstico por imagem , Neoplasias do Ventrículo Cerebral/cirurgia , Glioma/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Radiografia , Terceiro Ventrículo/diagnóstico por imagemRESUMO
De novo, heterozygous, loss-of-function variants were identified in Pou domain, class 4, transcription factor 1 (POU4F1) via whole-exome sequencing in four independent probands presenting with ataxia, intention tremor, and hypotonia. POU4F1 is expressed in the developing nervous system, and mice homozygous for null alleles of Pou4f1 exhibit uncoordinated movements with newborns being unable to successfully right themselves to feed. Head magnetic resonance imaging of the four probands was reviewed and multiple abnormalities were noted, including significant cerebellar vermian atrophy and hypertrophic olivary degeneration in one proband. Transcriptional activation of the POU4F1 p.Gln306Arg protein was noted to be decreased when compared with wild type. These findings suggest that heterozygous, loss-of-function variants in POU4F1 are causative of a novel ataxia syndrome.
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Ataxia/genética , Hipotonia Muscular/genética , Fator de Transcrição Brn-3A/genética , Tremor/genética , Adulto , Ataxia/complicações , Ataxia/diagnóstico , Ataxia/patologia , Criança , Pré-Escolar , Feminino , Haploinsuficiência , Humanos , Imageamento por Ressonância Magnética , Masculino , Hipotonia Muscular/complicações , Hipotonia Muscular/diagnóstico , Mutação de Sentido Incorreto , Estudos Retrospectivos , Síndrome , Tremor/complicações , Tremor/diagnóstico , Estados Unidos , Sequenciamento do Exoma , Adulto JovemRESUMO
The locus coeruleus (LC) has a long-established role in the attentional and arousal response to threat, and in the emergence of pathological anxiety in pre-clinical models. However, human evidence of links between LC function and pathological anxiety has been restricted by limitations in discerning LC with current neuroimaging techniques. We combined ultra-high field 7-Tesla and 0.4 × 0.4 × 0.5 mm quantitative MR imaging with a computational LC localization and segmentation algorithm to delineate the LC in 29 human subjects including subjects with and without an anxiety or stress-related disorder. Our automated, data-driven LC segmentation algorithm provided LC delineations that corresponded well with postmortem anatomic definitions of the LC. There was variation of LC size in healthy subjects (125.7 +/- 59.3 mm3), which recapitulates histological reports. Patients with an anxiety or stress-related disorder had larger LC compared to controls (Cohen's d = 1.08, p = 0.024). Larger LC was additionally associated with poorer attentional and inhibitory control and higher anxious arousal (FDR-corrected p's<0.025), trans-diagnostically across the full sample. This study combined high-resolution and quantitative MR with a mixture of supervised and unsupervised computational techniques to provide robust, sub-millimeter measurements of the LC in vivo, which were additionally related to common psychopathology. This work has wide-reaching applications for a range of neurological and psychiatric disorders characterized by expected LC dysfunction.
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Transtornos de Ansiedade , Interpretação de Imagem Assistida por Computador/métodos , Locus Cerúleo/anatomia & histologia , Aprendizado de Máquina , Imageamento por Ressonância Magnética/métodos , Neuroimagem/métodos , Transtornos de Estresse Pós-Traumáticos , Adulto , Transtornos de Ansiedade/diagnóstico por imagem , Transtornos de Ansiedade/patologia , Transtornos de Ansiedade/fisiopatologia , Feminino , Humanos , Locus Cerúleo/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Transtornos de Estresse Pós-Traumáticos/diagnóstico por imagem , Transtornos de Estresse Pós-Traumáticos/patologia , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Adulto JovemRESUMO
Fucosidosis is a lysosomal storage disease, resulting from a deficiency of the enzyme alpha-L-fucosidase. We present the case of an affected female with numerous manifestations, clinically and radiographically. In fucosidosis, advanced interventions are not always necessary to have rewarding outcomes. In fact, early diagnosis and management of the symptoms with a multi-systemic supportive care approach can improve the quality of life and may also prolong the life of those patients diagnosed with fucosidosis.
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The spine and spinal cord are composed of multiple segments initiated by different embryologic mechanisms and advanced under different systems of control. In humans, the upper central nervous system is formed by primary neurulation, the lower by secondary neurulation, and the intervening segment by junctional neurulation. This article focuses on the distal spine and spinal cord to address their embryogenesis and the molecular derangements that lead to some distal spinal malformations.
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Desenvolvimento Embrionário , Coluna Vertebral/anormalidades , Coluna Vertebral/anatomia & histologia , Humanos , Coluna Vertebral/embriologiaRESUMO
Plastic surgeons are frequently consulted to evaluate concerns about a patient's skull. Imaging studies often reveal abnormalities in bone morphology, from increased porosity to sclerotic changes. While focal findings imply a benign or malignant neoplasm, the etiology of more diffuse findings can be more varied, making the correct diagnosis challenging. The present review summarizes the differential diagnosis of osseous lesions of the calvarium that affect the bone and contribute to changes seen on imaging studies.
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Osteólise/diagnóstico por imagem , Osteoporose/diagnóstico por imagem , Osteosclerose/diagnóstico por imagem , Crânio/diagnóstico por imagem , Doenças Ósseas Metabólicas/diagnóstico por imagem , Diagnóstico Diferencial , Humanos , Imageamento por Ressonância Magnética , Osteólise/etiologia , Osteoporose/etiologia , Osteosclerose/etiologia , Tomografia Computadorizada por Raios XRESUMO
In vivo morphological study of the human habenula, a pair of small epithalamic nuclei adjacent to the dorsomedial thalamus, has recently gained significant interest for its role in reward and aversion processing. However, segmenting the habenula from in vivo magnetic resonance imaging (MRI) is challenging due to the habenula's small size and low anatomical contrast. Although manual and semi-automated habenula segmentation methods have been reported, the test-retest reproducibility of the segmented habenula volume and the consistency of the boundaries of habenula segmentation have not been investigated. In this study, we evaluated the intra- and inter-site reproducibility of in vivo human habenula segmentation from 3T MRI (0.7-0.8 mm isotropic resolution) using our previously proposed semi-automated myelin contrast-based method and its fully-automated version, as well as a previously published manual geometry-based method. The habenula segmentation using our semi-automated method showed consistent boundary definition (high Dice coefficient, low mean distance, and moderate Hausdorff distance) and reproducible volume measurement (low coefficient of variation). Furthermore, the habenula boundary in our semi-automated segmentation from 3T MRI agreed well with that in the manual segmentation from 7T MRI (0.5 mm isotropic resolution) of the same subjects. Overall, our proposed semi-automated habenula segmentation showed reliable and reproducible habenula localization, while its fully-automated version offers an efficient way for large sample analysis.
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Habenula/anatomia & histologia , Imageamento por Ressonância Magnética/métodos , Neuroimagem/métodos , Adulto , Feminino , Habenula/diagnóstico por imagem , Humanos , Masculino , Adulto JovemRESUMO
OBJECTIVE: Posterior inferior cerebellar artery (PICA) aneurysms are heterogeneous, uncommon lesions that can be treated in many fashions. Many previous series have focused on a specific aneurysm subset or treatment paradigm. The aim of this study was to present a comprehensive approach for all PICA aneurysms and analyze outcomes by PICA location. METHODS: All PICA aneurysms treated from 2012 until present were reviewed retrospectively and classified by location. Angiographic and clinical outcome were assessed. RESULTS: We identified 30 patients (average age 56 years, female 76.7%, subarachnoid hemorrhage 83.3%) with 30 aneurysms (saccular 50.0%) who underwent 36 treatments. Locations included the vertebral artery-PICA junction: 8; anterior medullary (AM): 7; lateral medullary: 3; tonsillomedullary: 1; telovelotonsillar: 5; and cortical: 6. Treatments included clipping: 6; trapping: 2; coiling: 13; balloon-assisted coiling: 1; stent-assisted coiling: 1; flow diversion: 1; and endovascular parent vessel occlusion: 6. There were 3 procedural complications. Recurrence and retreatment rates were 23.3% and 20.0%, respectively. Retreatments included coiling: 1; clipping: 4; and bypass: 1. Seven patients had an associated cerebellar arteriovenous malformation, of whom 5 have undergone resection. Good clinical outcome was achieved in 43.3% at discharge and 84.6% at follow-up (average 10.7 months). Aneurysms distal to the AM segment were more likely to occur in older patients (P = 0.007), with cerebellar arteriovenous malformations (P = 0.031), and to be treated with parent vessel occlusion (P = 0.001). Recurrences were more common for AM segment aneurysms (P = 0.016). Poor outcome was associated with poor SAH grade (P = 0.010), not aneurysm morphology (P = 0.356), location (P = 0.867), or treatment type (P = 0.365). CONCLUSIONS: Our 5-year modern experience highlights the diversity of PICA aneurysms and the need for multimodality paradigms to treat them successfully. The AM segment has the greatest rate of recurrence. Aggressive management is warranted given that the majority of patients can have a good neurologic outcome.
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Doenças Cerebelares/terapia , Cerebelo/irrigação sanguínea , Aneurisma Intracraniano/terapia , Angiografia Digital/métodos , Oclusão com Balão/métodos , Doenças Cerebelares/diagnóstico por imagem , Cerebelo/diagnóstico por imagem , Angiografia Cerebral/métodos , Artérias Cerebrais/diagnóstico por imagem , Terapia Combinada , Feminino , Humanos , Aneurisma Intracraniano/diagnóstico por imagem , Malformações Arteriovenosas Intracranianas/terapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Stents , Hemorragia Subaracnóidea/terapia , Resultado do TratamentoAssuntos
Analgésicos Opioides/efeitos adversos , Perda Auditiva/diagnóstico , Oxicodona/efeitos adversos , Paraplegia/diagnóstico , Uso Excessivo de Medicamentos Prescritos/efeitos adversos , Insuficiência Respiratória/diagnóstico , Adulto , Analgésicos Opioides/urina , Feminino , Perda Auditiva/induzido quimicamente , Perda Auditiva/urina , Humanos , Hipóxia/induzido quimicamente , Hipóxia/diagnóstico , Hipóxia/urina , Oxicodona/urina , Paraplegia/induzido quimicamente , Paraplegia/urina , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/urinaRESUMO
Key differences exist in the epidemiology, pathophysiology, and clinical presentation of vascular lesions of the cerebellum in children versus adults. An understanding of these differences and an appreciation of the distinct imaging features of these lesions aid in distinguishing normal vascular variations from pathology, in predicting lesion etiology, and in directing effective treatment strategies. This paper reviews the embryogenesis of the normal vascular system of the cerebellum and brainstem and then discusses the clinical and imaging features of the common vascular lesions affecting these structures in the pediatric population.
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Doenças Cerebelares/diagnóstico por imagem , Malformações Arteriovenosas Intracranianas/diagnóstico por imagem , Adolescente , Cerebelo/diagnóstico por imagem , Criança , Angiografia por Tomografia Computadorizada , Feminino , Humanos , Angiografia por Ressonância Magnética , Imageamento por Ressonância Magnética , Masculino , Tomografia Computadorizada por Raios XRESUMO
Human BK polyomavirus (BKV) is reactivated under conditions of immunosuppression leading most commonly to nephropathy or cystitis; its tropism for the brain is rare and poorly understood. We present a unique case of BKV-associated encephalopathy in a man with hypohidrotic ectodermal dysplasia and immunodeficiency (HED-ID) due to IKK-gamma (NEMO) mutation, who developed progressive neurological symptoms. Brain biopsy demonstrated polyomavirus infection of gray and white matter, with predominant involvement of cortex and distinct neuronal tropism, in addition to limited demyelination and oligodendroglial inclusions. Immunohistochemistry demonstrated polyoma T-antigen in neurons and glia, but expression of VP1 capsid protein only in glia. PCR analysis on both brain biopsy tissue and cerebrospinal fluid detected high levels of BKV DNA. Sequencing studies further identified novel BKV variant and disclosed unique rearrangements in the noncoding control region of the viral DNA (BKVN NCCR). Neuropathological analysis also demonstrated an unusual form of obliterative fibrosing vasculopathy in the subcortical white matter with abnormal lysosomal accumulations, possibly related to the patient's underlying ectodermal dysplasia. Our report provides the first neuropathological description of HED-ID due to NEMO mutation, and expands the diversity of neurological presentations of BKV infection in brain, underscoring the importance of its consideration in immunodeficient patients with unexplained encephalopathy. We also document novel BKVN NCCR rearrangements that may be associated with the unique neuronal tropism in this patient.
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Vírus BK , Encefalopatias/complicações , Displasia Ectodérmica Anidrótica Tipo 1/complicações , Síndromes de Imunodeficiência/complicações , Infecções por Polyomavirus/complicações , Adulto , Vírus BK/genética , Encéfalo/irrigação sanguínea , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encefalopatias/imunologia , Encefalopatias/patologia , Displasia Ectodérmica Anidrótica Tipo 1/genética , Displasia Ectodérmica Anidrótica Tipo 1/imunologia , Displasia Ectodérmica Anidrótica Tipo 1/patologia , Humanos , Quinase I-kappa B/genética , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/patologia , Masculino , Infecções por Polyomavirus/imunologia , Infecções por Polyomavirus/patologiaRESUMO
BACKGROUND: Early infantile Krabbe disease is rapidly fatal, but hematopoietic stem cell transplantation (HSCT) may improve outcomes if performed soon after birth. New York State began screening all newborns for Krabbe disease in 2006. METHODS: Infants with abnormal newborn screen results for Krabbe disease were referred to specialty-care centers. Newborns found to be at high risk for Krabbe disease underwent a neurodiagnostic battery to determine the need for emergent HSCT. RESULTS: Almost 2 million infants were screened. Five infants were diagnosed with early infantile Krabbe disease. Three died, two from HSCT-related complications and one from untreated disease. Two children who received HSCT have moderate to severe developmental delays. Forty-six currently asymptomatic children are considered to be at moderate or high risk for development of later-onset Krabbe disease. CONCLUSIONS: These results show significant HSCT-associated morbidity and mortality in early infantile Krabbe disease and raise questions about its efficacy when performed in newborns diagnosed through newborn screening. The unanticipated identification of "at risk" children introduces unique ethical and medicolegal issues. New York's experience raises questions about the risks, benefits, and practicality of screening newborns for Krabbe disease. It is imperative that objective assessments be made on an ongoing basis as additional states begin screening for this disorder.Genet Med 18 12, 1235-1243.
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Leucodistrofia de Células Globoides/genética , Leucodistrofia de Células Globoides/terapia , Programas de Rastreamento , Triagem Neonatal , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Lactente , Recém-Nascido , Leucodistrofia de Células Globoides/diagnóstico , Leucodistrofia de Células Globoides/mortalidade , New York , Fatores de RiscoRESUMO
The habenula consists of a pair of small epithalamic nuclei located adjacent to the dorsomedial thalamus. Despite increasing interest in imaging the habenula due to its critical role in mediating subcortical reward circuitry, in vivo neuroimaging research targeting the human habenula has been limited by its small size and low anatomical contrast. In this work, we have developed an objective semi-automated habenula segmentation scheme consisting of histogram-based thresholding, region growing, geometric constraints, and partial volume estimation steps. This segmentation scheme was designed around in vivo 3 T myelin-sensitive images, generated by taking the ratio of high-resolution T1w over T2w images. Due to the high myelin content of the habenula, the contrast-to-noise ratio with the thalamus in the in vivo 3T myelin-sensitive images was significantly higher than the T1w or T2w images alone. In addition, in vivo 7 T myelin-sensitive images (T1w over T2*w ratio images) and ex vivo proton density-weighted images, along with histological evidence from the literature, strongly corroborated the in vivo 3 T habenula myelin contrast used in the proposed segmentation scheme. The proposed segmentation scheme represents a step toward a scalable approach for objective segmentation of the habenula suitable for both morphological evaluation and habenula seed region selection in functional and diffusion MRI applications.
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Mapeamento Encefálico/métodos , Habenula/anatomia & histologia , Processamento de Imagem Assistida por Computador/métodos , Bainha de Mielina , Adulto , Feminino , Humanos , Aumento da Imagem/métodos , Imageamento por Ressonância Magnética , MasculinoRESUMO
This report discusses the syndrome of amnionic bands, anencephaly, schizencephaly and hydranencephaly, four entities whose pathogenesis includes significant injury to the fetus in utero.