RESUMO
Isolated complex I deficiency is a common biochemical phenotype observed in pediatric mitochondrial disease and often arises as a consequence of pathogenic variants affecting one of the â¼65 genes encoding the complex I structural subunits or assembly factors. Such genetic heterogeneity means that application of next-generation sequencing technologies to undiagnosed cohorts has been a catalyst for genetic diagnosis and gene-disease associations. We describe the clinical and molecular genetic investigations of four unrelated children who presented with neuroradiological findings and/or elevated lactate levels, highly suggestive of an underlying mitochondrial diagnosis. Next-generation sequencing identified bi-allelic variants in NDUFA6, encoding a 15 kDa LYR-motif-containing complex I subunit that forms part of the Q-module. Functional investigations using subjects' fibroblast cell lines demonstrated complex I assembly defects, which were characterized in detail by mass-spectrometry-based complexome profiling. This confirmed a marked reduction in incorporated NDUFA6 and a concomitant reduction in other Q-module subunits, including NDUFAB1, NDUFA7, and NDUFA12. Lentiviral transduction of subjects' fibroblasts showed normalization of complex I. These data also support supercomplex formation, whereby the â¼830 kDa complex I intermediate (consisting of the P- and Q-modules) is in complex with assembled complex III and IV holoenzymes despite lacking the N-module. Interestingly, RNA-sequencing data provided evidence that the consensus RefSeq accession number does not correspond to the predominant transcript in clinically relevant tissues, prompting revision of the NDUFA6 RefSeq transcript and highlighting not only the importance of thorough variant interpretation but also the assessment of appropriate transcripts for analysis.
Assuntos
Complexo I de Transporte de Elétrons/deficiência , Doenças Mitocondriais/genética , Proteínas Mitocondriais/genética , Mutação/genética , Alelos , Sequência de Aminoácidos , Complexo I de Transporte de Elétrons/genética , Feminino , Fibroblastos/patologia , Heterogeneidade Genética , Humanos , Lactente , Masculino , Mitocôndrias/genética , Fenótipo , Alinhamento de SequênciaRESUMO
Polymicrogyria (PMG) is a structural brain abnormality involving the cerebral cortex that results from impaired neuronal migration and although several genes have been implicated, many cases remain unsolved. In this study, exome sequencing in a family where three fetuses had all been diagnosed with PMG and cerebellar hypoplasia allowed us to identify regions of the genome for which both chromosomes were shared identical-by-descent, reducing the search space for causative variants to 8.6% of the genome. In these regions, the only plausibly pathogenic mutations were compound heterozygous variants in PI4KA, which Sanger sequencing confirmed segregated consistent with autosomal recessive inheritance. The paternally transmitted variant predicted a premature stop mutation (c.2386C>T; p.R796X), whereas the maternally transmitted variant predicted a missense substitution (c.5560G>A; p.D1854N) at a conserved residue within the catalytic domain. Functional studies using expressed wild-type or mutant PI4KA enzyme confirmed the importance of p.D1854 for kinase activity. Our results emphasize the importance of phosphoinositide signalling in early brain development.
Assuntos
Artrogripose/enzimologia , Cerebelo/anormalidades , Doenças Fetais/enzimologia , Mutação em Linhagem Germinativa , Malformações do Sistema Nervoso/enzimologia , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Polimicrogiria/enzimologia , Sequência de Aminoácidos , Artrogripose/embriologia , Artrogripose/genética , Sequência de Bases , Encéfalo/embriologia , Encéfalo/enzimologia , Cerebelo/embriologia , Cerebelo/enzimologia , Deficiências do Desenvolvimento/enzimologia , Deficiências do Desenvolvimento/genética , Exoma , Feminino , Doenças Fetais/genética , Humanos , Lactente , Masculino , Antígenos de Histocompatibilidade Menor , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Malformações do Sistema Nervoso/embriologia , Malformações do Sistema Nervoso/genética , Linhagem , Fosfotransferases (Aceptor do Grupo Álcool)/química , Polimicrogiria/embriologia , Polimicrogiria/genética , Polimorfismo de Nucleotídeo Único , Alinhamento de SequênciaRESUMO
ß-III spectrin is present in the brain and is known to be important in the function of the cerebellum. Heterozygous mutations in SPTBN2, the gene encoding ß-III spectrin, cause Spinocerebellar Ataxia Type 5 (SCA5), an adult-onset, slowly progressive, autosomal-dominant pure cerebellar ataxia. SCA5 is sometimes known as "Lincoln ataxia," because the largest known family is descended from relatives of the United States President Abraham Lincoln. Using targeted capture and next-generation sequencing, we identified a homozygous stop codon in SPTBN2 in a consanguineous family in which childhood developmental ataxia co-segregates with cognitive impairment. The cognitive impairment could result from mutations in a second gene, but further analysis using whole-genome sequencing combined with SNP array analysis did not reveal any evidence of other mutations. We also examined a mouse knockout of ß-III spectrin in which ataxia and progressive degeneration of cerebellar Purkinje cells has been previously reported and found morphological abnormalities in neurons from prefrontal cortex and deficits in object recognition tasks, consistent with the human cognitive phenotype. These data provide the first evidence that ß-III spectrin plays an important role in cortical brain development and cognition, in addition to its function in the cerebellum; and we conclude that cognitive impairment is an integral part of this novel recessive ataxic syndrome, Spectrin-associated Autosomal Recessive Cerebellar Ataxia type 1 (SPARCA1). In addition, the identification of SPARCA1 and normal heterozygous carriers of the stop codon in SPTBN2 provides insights into the mechanism of molecular dominance in SCA5 and demonstrates that the cell-specific repertoire of spectrin subunits underlies a novel group of disorders, the neuronal spectrinopathies, which includes SCA5, SPARCA1, and a form of West syndrome.
Assuntos
Cerebelo , Espectrina/genética , Ataxias Espinocerebelares , Adulto , Animais , Cerebelo/crescimento & desenvolvimento , Cerebelo/patologia , Mapeamento Cromossômico , Transtornos Cognitivos/genética , Humanos , Camundongos , Camundongos Knockout , Mutação , Neurônios/metabolismo , Neurônios/patologia , Células de Purkinje/patologia , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/fisiopatologiaRESUMO
The development of next generation sequencing (NGS) has radically transformed the scientific landscape, making it possible to sequence the exome of any given individual in a cost-effective way. The power of this approach has been demonstrated by a number of groups who have identified pathogenic mutations in small pedigrees that have been resistant to traditional genetic mapping. Recently it has become clear that exome sequencing has great potential with respect to sporadic disease and the identification of de novo mutations. This is highlighted by studies reporting whole-exome sequencing of patient-parental trios affected by learning disability, autism and schizophrenia. It is widely anticipated that the introduction of this technique into a clinical setting will revolutionise genetic diagnosis. However, the sensitivity of NGS exome sequencing is currently unclear. Here, we describe the exome sequencing of DNA samples from a patient with double cortex syndrome and her parents, resulting in the detection of a mosaic splicing mutation in LIS1. This variant was found at an allele frequency of just 18%, demonstrating that NGS methods have the capacity to identify pathogenic mosaic mutations present at a low level.
Assuntos
Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/genética , Exoma/genética , Frequência do Gene/genética , Mosaicismo , Análise de Sequência de DNA/métodos , 1-Alquil-2-acetilglicerofosfocolina Esterase/química , 1-Alquil-2-acetilglicerofosfocolina Esterase/genética , Sequência de Aminoácidos , Sequência de Bases , Criança , Feminino , Humanos , Imageamento por Ressonância Magnética , Proteínas Associadas aos Microtúbulos/química , Proteínas Associadas aos Microtúbulos/genética , Dados de Sequência MolecularRESUMO
INTRODUCTION: Neuromyelitis optica (NMO) is a severe demyelinating disease that preferentially involves spinal cord and optic nerve. It is part of a spectrum of neurological conditions associated with antibodies to aquaporin-4 (AQP4). This study investigates the role of MRI where novel, more sensitive AQP4 antibody immunoassay techniques are being used. METHODS: Retrospective review of neuroimaging in 69 patients (25 antibody positive, 44 antibody negative), investigated in the context of suspected NMO or NMO spectrum disorder, was performed independently by two consultant neuroradiologists. RESULTS: Longitudinally extensive, central spinal cord lesions were more frequent in AQP4 positive patients (95.2% vs 35.5%, p < 0.0001; 85.7% vs 45.2%, p = 0.015). Multiple sclerosis diagnostic criteria were less frequently fulfilled on brain MRI in antibody positive patients (5.6% vs 33.3%, p = 0.035). Juxtacortical and corpus callosal lesions were also less common in this group (16.7% vs 46.7%, p = 0.063; 5.6% vs 46.7%, p = 0.0034). Hypothalamic and periependymal disease related to the aqueduct was not seen in antibody negative patients. T1 hypointensity was more common in cord lesions of antibody positive patients (75.0% vs 35.3%, p = 0.037). However, this characteristic did not discriminate antibody positive and negative longitudinally extensive cord lesions (73.3% vs 62.5%, p = 0.66). CONCLUSION: The NMO spectrum of diseases are among an increasing number of neurological conditions defined by serological tests. However, despite improved immunoassay techniques, MRI of the brain and spinal cord continues to be among the first-line investigations in these patients, providing valuable diagnostic information that will help guide patient management.
Assuntos
Imageamento por Ressonância Magnética/métodos , Neuromielite Óptica/diagnóstico , Adulto , Meios de Contraste , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Masculino , Neuromielite Óptica/patologia , Estudos Retrospectivos , Sensibilidade e Especificidade , Estatísticas não ParamétricasRESUMO
Superficial intracranial siderosis is a degenerative condition secondary to recurrent occult subarachnoid hemorrhage. Progressive sensorineural deafness, cerebellar ataxia, and pyramidal signs are well-documented clinical manifestations, but optic neuropathy is not a recognized feature. We describe 2 patients with clinical and electrophysiological evidence of optic nerve/chiasm dysfunction and MRI signal abnormalities consistent with hemosiderin staining of the anterior visual pathway. In a third case, neuropathological examination of the optic chiasm showed demyelination attributed to hemosiderin deposition. We suggest that anterior visual pathway damage may be underrecognized in this condition.
Assuntos
Doenças do Nervo Óptico/etiologia , Doenças do Nervo Óptico/patologia , Nervo Óptico/patologia , Siderose/complicações , Siderose/patologia , Idoso , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/patologiaRESUMO
BACKGROUND: A 44-year-old male presented to a general neurology clinic with a 6-month history of progressive right-sided spastic hemiparesis without sensory symptoms or signs. The thigh muscle in the affected leg showed signs of wasting. The patient had a remote family history of celiac disease. INVESTIGATIONS: Neurological examination, neurophysiological studies, brain MRI scan, routine blood tests, duodenal biopsy, cerebrospinal fluid analysis including polymerase chain reaction test for JC virus DNA, serological testing for HIV and for the presence of serum antibodies to endomysium, gliadin and tissue transglutaminase. DIAGNOSIS: Celiac disease with neurological involvement, mimicking amyotrophic lateral sclerosis. MANAGEMENT: Strict gluten-free diet.
Assuntos
Esclerose Lateral Amiotrófica/diagnóstico , Doença Celíaca/diagnóstico , Adulto , Encéfalo/patologia , Doença Celíaca/sangue , Doença Celíaca/líquido cefalorraquidiano , Doença Celíaca/dietoterapia , Dieta com Restrição de Proteínas , Glutens , Humanos , Imageamento por Ressonância Magnética , Masculino , Exame Neurológico/métodos , Sensibilidade e Especificidade , Testes SorológicosRESUMO
OBJECTIVE: To investigate mitophagy in 5 patients with severe dominantly inherited optic atrophy (DOA), caused by depletion of OPA1 (a protein that is essential for mitochondrial fusion), compared with healthy controls. METHODS: Patients with severe DOA (DOA plus) had peripheral neuropathy, cognitive regression, and epilepsy in addition to loss of vision. We quantified mitophagy in dermal fibroblasts, using 2 high throughput imaging systems, by visualizing colocalization of mitochondrial fragments with engulfing autophagosomes. RESULTS: Fibroblasts from 3 biallelic OPA1(-/-) patients with severe DOA had increased mitochondrial fragmentation and mitochondrial DNA (mtDNA)-depleted cells due to decreased levels of OPA1 protein. Similarly, in siRNA-treated control fibroblasts, profound OPA1 knockdown caused mitochondrial fragmentation, loss of mtDNA, impaired mitochondrial function, and mitochondrial mislocalization. Compared to controls, basal mitophagy (abundance of autophagosomes colocalizing with mitochondria) was increased in (1) biallelic patients, (2) monoallelic patients with DOA plus, and (3) OPA1 siRNA-treated control cultures. Mitophagic flux was also increased. Genetic knockdown of the mitophagy protein ATG7 confirmed this by eliminating differences between patient and control fibroblasts. CONCLUSIONS: We demonstrated increased mitophagy and excessive mitochondrial fragmentation in primary human cultures associated with DOA plus due to biallelic OPA1 mutations. We previously found that increased mitophagy (mitochondrial recycling) was associated with visual loss in another mitochondrial optic neuropathy, Leber hereditary optic neuropathy (LHON). Combined with our LHON findings, this implicates excessive mitochondrial fragmentation, dysregulated mitophagy, and impaired response to energetic stress in the pathogenesis of mitochondrial optic neuropathies, potentially linked with mitochondrial mislocalization and mtDNA depletion.
Assuntos
GTP Fosfo-Hidrolases/genética , Mitofagia/genética , Mutação/genética , Atrofia Óptica/genética , Antioxidantes/farmacologia , Células Cultivadas , Transtornos Cognitivos/etiologia , Análise Mutacional de DNA , DNA Mitocondrial/genética , Saúde da Família , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Fibroblastos/ultraestrutura , Humanos , Masculino , Potencial da Membrana Mitocondrial/genética , Proteínas Mitocondriais/genética , Atrofia Óptica/complicações , Atrofia Óptica/patologia , Linhagem , Proteínas Quinases/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transfecção , Ubiquinona/análogos & derivados , Ubiquinona/farmacologia , Ubiquitina-Proteína Ligases/genéticaRESUMO
Transverse myelitis is defined as inflammation of the spinal cord, named because of its typical clinical presentation with bandlike symptoms of altered sensation or pain in a horizontal fashion-at a specific dermatome level. Radiographic patterns might vary but the idiopathic form is more frequent to present as involvement of 3-4 vertebral segments and both sides of the cord. It is now recognized that there are numerous other causes as well as the idiopathic type, with often atypical features and geographic variation. There is also increasing recognition of other forms of myelitis, particularly the longitudinally extensive manifestation with involvement of 3 or more vertebral segments. Neuromyelitis optica, one of these subtypes can be diagnosed by means of an antibody assessment. The picture is more complicated with the expansion of the description to involve neuromyelitis optica spectrum disorders, new antibodies such as myelin oligodendrocyte glycoprotein and the inclusion of an antibody-negative variant. This article describes the different entities of transverse myelitis, with a particular focus on neuromyelitis optica spectrum disorders.
Assuntos
Imageamento por Ressonância Magnética/métodos , Mielite Transversa/diagnóstico por imagem , Neuroimagem/métodos , Neuromielite Óptica/diagnóstico por imagem , Meios de Contraste , Diagnóstico Diferencial , HumanosRESUMO
This report constitutes the first report of a cryptic exonic splice-donor site in CDK5RAP2, highlights the importance of evaluating novel splice mutations, and suggests that the phenotypic range associated with CDK5RAP2 mutations may include skin pigmentary abnormalities.
RESUMO
Mitochondrial DNA disease is one of the most common groups of inherited neuromuscular disorders and frequently associated with marked phenotypic and genotypic heterogeneity. We describe an adult patient who initially presented with childhood-onset ataxia without a family history and an unremarkable diagnostic muscle biopsy. Subsequent multi-system manifestations included basal ganglia calcification, proteinuria, cataract and retinitis pigmentosa, prompting a repeat muscle biopsy that showed features consistent with mitochondrial myopathy 13 years later. She had a stroke with restricted diffusion change in the basal ganglia and internal capsule at age 44 years. Molecular genetic testing identified a previously-reported pathogenic, heteroplasmic mutation in the mitochondrial-encoded transfer RNA tryptophan (MT-TW) gene which based on family studies was likely to have arisen de novo in our patient. Interestingly, we documented an increase in the mutant mtDNA heteroplasmy level in her second biopsy (72% compared to 56%), reflecting the progression of clinical disease.
Assuntos
Ataxia/genética , DNA Mitocondrial , Doenças Mitocondriais/genética , Mutação , Ataxia/diagnóstico por imagem , Ataxia/patologia , Ataxia/fisiopatologia , Encéfalo/diagnóstico por imagem , Progressão da Doença , Feminino , Humanos , Pessoa de Meia-Idade , Doenças Mitocondriais/diagnóstico por imagem , Doenças Mitocondriais/patologia , Doenças Mitocondriais/fisiopatologia , Músculo Esquelético/patologia , FenótipoRESUMO
BACKGROUND: Deep brain stimulation (DBS) of the anterior cingulate cortex (ACC) is a new treatment for alleviating intractable neuropathic pain. However, it fails to help some patients. The large size of the ACC and the intersubject variability make it difficult to determine the optimal site to position DBS electrodes. The aim of this work was therefore to compare the ACC connectivity of patients with successful versus unsuccessful DBS outcomes to help guide future electrode placement. METHODS: Diffusion magnetic resonance imaging (dMRI) and probabilistic tractography were performed preoperatively in 8 chronic pain patients (age 53.4 ± 6.1 years, 2 females) with ACC DBS, of whom 6 had successful (SO) and 2 unsuccessful outcomes (UOs) during a period of trialing. RESULTS: The number of patients was too small to demonstrate any statistically significant differences. Nevertheless, we observed differences between patients with successful and unsuccessful outcomes in the fiber tract projections emanating from the volume of activated tissue around the electrodes. A strong connectivity to the precuneus area seems to predict unsuccessful outcomes in our patients (UO: 160n/SO: 27n), with (n), the number of streamlines per nonzero voxel. On the other hand, connectivity to the thalamus and brainstem through the medial forebrain bundle (MFB) was only observed in SO patients. CONCLUSIONS: These findings could help improve presurgical planning by optimizing electrode placement, to selectively target the tracts that help to relieve patients' pain and to avoid those leading to unwanted effects.
Assuntos
Dor Crônica/cirurgia , Estimulação Encefálica Profunda/métodos , Imagem de Tensor de Difusão/métodos , Giro do Cíngulo/anatomia & histologia , Giro do Cíngulo/cirurgia , Procedimentos Neurocirúrgicos/métodos , Eletrodos , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Feixe Prosencefálico Mediano/anatomia & histologia , Feixe Prosencefálico Mediano/cirurgia , Pessoa de Meia-Idade , Medição da Dor , Tálamo/anatomia & histologia , Tálamo/cirurgia , Resultado do TratamentoRESUMO
Although ribosomes are ubiquitous and essential for life, recent data indicate that monogenic causes of ribosomal dysfunction can confer a remarkable degree of specificity in terms of human disease phenotype. Box C/D small nucleolar RNAs (snoRNAs) are evolutionarily conserved non-protein-coding RNAs involved in ribosome biogenesis. Here we show that biallelic mutations in the gene SNORD118, encoding the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts (LCC), presenting at any age from early childhood to late adulthood. These mutations affect U8 expression, processing and protein binding and thus implicate U8 as essential in cerebral vascular homeostasis.
Assuntos
Doenças de Pequenos Vasos Cerebrais/genética , Leucoencefalopatias/genética , Mutação , RNA Nucleolar Pequeno/genética , Adolescente , Adulto , Calcinose/genética , Calcinose/patologia , Linhagem Celular , Doenças de Pequenos Vasos Cerebrais/patologia , Criança , Pré-Escolar , Cromossomos Humanos Par 17 , Estudos de Coortes , Cistos/genética , Cistos/patologia , Exoma , Feminino , Ligação Genética , Genoma Humano , Humanos , Lactente , Leucoencefalopatias/patologia , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNA , Adulto JovemRESUMO
IMPORTANCE: Aquaporin 4 antibody (AQP4-Ab)-negative patients with longitudinally extensive transverse myelitis (LETM) behave differently from those with AQP4-Ab. Aquaporin 4 antibody-negative neuromyelitis optica (NMO) is rare when good assays are used. OBJECTIVE: To assess if AQP4-Ab-negative patients with LETM share similar disease characteristics with AQP4-Ab-positive patients or whether they have distinct features and alternative diagnoses. DESIGN We collated clinical and paraclinical data on patients with LETM identified through the Oxford NMO clinical database. Aquaporin 4 antibodies were tested using 2 sensitive assays. We describe the features of patients with LETM, compare findings between patients with and without AQP4-Ab, and describe alternative diagnoses in AQP4-Ab-negative patients. SETTING: Single specialist UK center for NMO. PARTICIPANTS: Seventy-six adult patients with LETM. MAIN OUTCOMES AND MEASURES: Comparison of clinical and paraclinical data. RESULTS: Fifty-eight percent of patients were AQP4-Ab positive. Alternative diagnoses could usually be identified in AQP4-Ab-negative patients, including those fulfilling NMO diagnostic criteria. Only 6.5% of patients had "true" seronegative NMO and 6.5% had idiopathic LETM. There were some important differences between AQP4-Ab-positive and -negative cases, including older onset age, higher proportion of females, lower incidence of simultaneous optic neuritis, lower frequency of conus involvement, and higher prevalence of coexisting autoimmune disorders in AQP4-Ab-positive cases. Attack severity and degree of recovery were similar in the 2 groups. CONCLUSIONS AND RELEVANCE: Patients with LETM without AQP4-Ab include a number of different diagnostic categories and it is not surprising therefore that they show important differences compared with AQP4-Ab-positive patients, even when considering only those fulfilling current NMO diagnostic criteria. Thus, we suggest that diagnoses such as myelin-oligodendrocyte glycoprotein antibody disease, multiple sclerosis, acute disseminated encephalomyelitis, and postinfectious disorders should be exclusions in the NMO diagnostic criteria and AQP4-Ab-positive and antibody-negative NMO/NMO spectrum disorder cohorts should be analyzed separately.
Assuntos
Aquaporina 4/imunologia , Autoanticorpos/sangue , Mielite Transversa/sangue , Mielite Transversa/diagnóstico , Neuromielite Óptica/sangue , Adulto , Idoso , Feminino , Células HEK293 , Humanos , Estimativa de Kaplan-Meier , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mielite Transversa/complicações , Mielite Transversa/fisiopatologia , Neuromielite Óptica/complicações , Neuromielite Óptica/diagnóstico , Estudos Retrospectivos , Estatísticas não Paramétricas , TransfecçãoRESUMO
We propose a method for registration of 3D fetal brain ultrasound with a reconstructed magnetic resonance fetal brain volume. This method, for the first time, allows the alignment of models of the fetal brain built from magnetic resonance images with 3D fetal brain ultrasound, opening possibilities to develop new, prior information based image analysis methods for 3D fetal neurosonography. The reconstructed magnetic resonance volume is first segmented using a probabilistic atlas and a pseudo ultrasound image volume is simulated from the segmentation. This pseudo ultrasound image is then affinely aligned with clinical ultrasound fetal brain volumes using a robust block-matching approach that can deal with intensity artefacts and missing features in the ultrasound images. A qualitative and quantitative evaluation demonstrates good performance of the method for our application, in comparison with other tested approaches. The intensity average of 27 ultrasound images co-aligned with the pseudo ultrasound template shows good correlation with anatomy of the fetal brain as seen in the reconstructed magnetic resonance image.
Assuntos
Encéfalo/anatomia & histologia , Ecoencefalografia/métodos , Imageamento Tridimensional/métodos , Imageamento por Ressonância Magnética/métodos , Reconhecimento Automatizado de Padrão/métodos , Técnica de Subtração , Ultrassonografia Pré-Natal/métodos , Algoritmos , Humanos , Aumento da Imagem/métodos , Interpretação de Imagem Assistida por Computador/métodos , Tamanho do Órgão , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Isolated paediatric neurosarcoidosis (IPN) is exceptionally rare and only seven cases have been reported so far in the literature. We report the clinical and radiological profile of a 7 year-old boy with epilepsia partialis continua (EPC) who was initially thought to have Acute Disseminated Encephalomyelitis (ADEM), but was subsequently found to have isolated neurosarcoidosis. Additionally, we performed a literature search on Medline and Embase and secondary sources of data such as reference list of articles reviewed. Whilst cranial neuropathy is the commonest presenting feature in adults with neurosarcoidosis, paediatric patients are more likely to present with seizures. Diagnosis presents a clinical challenge as a result of its protean manifestations. Due to its rarity, there remains a lack of evidence base to inform the best choice of treatment for these children. Our patient was successfully treated with a combination of various immunomodulants.
Assuntos
Doenças do Sistema Nervoso Central/diagnóstico , Doenças do Sistema Nervoso Central/terapia , Encefalomielite Aguda Disseminada/diagnóstico , Epilepsia Parcial Contínua/diagnóstico , Sarcoidose/diagnóstico , Sarcoidose/terapia , Convulsões/diagnóstico , Doenças do Sistema Nervoso Central/complicações , Criança , Diagnóstico Diferencial , Encefalomielite Aguda Disseminada/complicações , Epilepsia Parcial Contínua/fisiopatologia , Humanos , Imunomodulação/imunologia , Masculino , Sarcoidose/complicações , Convulsões/complicações , Resultado do TratamentoRESUMO
Mutations in the recently described RARS2 gene encoding for mitochondrial arginyl-transfer RNA synthetase give rise to a disorder characterised by early onset seizures, progressive microcephaly and developmental delay. The disorder was named pontocerebellar hypoplasia type 6 (PCH6) based on the corresponding radiological findings observed in the original cases. We report two siblings with the RARS2 mutation who displayed typical clinical features of PCH6, but who had distinct neuroimaging features. Early scans showed marked supratentorial, rather than infratentorial, atrophy, and the pons remained preserved throughout. One sibling also had bilateral subdural effusions at presentation. The deceleration in head growth pointed to an evolving genetic/metabolic process giving rise to cerebral atrophy and secondary subdural effusions. RARS2 mutations should be considered in infants presenting with seizures, subdural effusions, decelerating head growth and evidence of cerebral atrophy even in the absence of pontocerebellar hypoplasia on imaging.
Assuntos
Arginina-tRNA Ligase/genética , Cerebelo/anormalidades , Atrofias Olivopontocerebelares/genética , Ponte/anormalidades , Derrame Subdural/genética , Cerebelo/patologia , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Masculino , Mutação , Atrofias Olivopontocerebelares/diagnóstico , Ponte/patologia , Irmãos , Derrame Subdural/diagnóstico , Derrame Subdural/patologiaRESUMO
We propose a method for the reconstruction of volumetric fetal MRI from 2D slices, comprising super-resolution reconstruction of the volume interleaved with slice-to-volume registration to correct for the motion. The method incorporates novel intensity matching of acquired 2D slices and robust statistics which completely excludes identified misregistered or corrupted voxels and slices. The reconstruction method is applied to motion-corrupted data simulated from MRI of a preterm neonate, as well as 10 clinically acquired thick-slice fetal MRI scans and three scan-sequence optimized thin-slice fetal datasets. The proposed method produced high quality reconstruction results from all the datasets to which it was applied. Quantitative analysis performed on simulated and clinical data shows that both intensity matching and robust statistics result in statistically significant improvement of super-resolution reconstruction. The proposed novel EM-based robust statistics also improves the reconstruction when compared to previously proposed Huber robust statistics. The best results are obtained when thin-slice data and the correct approximation of the point spread function is used. This paper addresses the need for a comprehensive reconstruction algorithm of 3D fetal MRI, so far lacking in the scientific literature.
Assuntos
Encéfalo/embriologia , Imageamento por Ressonância Magnética/métodos , Feto , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imageamento Tridimensional , Movimento (Física)RESUMO
We propose a novel method for registration of 3D fetal brain ultrasound and a reconstructed magnetic resonance fetal brain volumes. The reconstructed MR volume is first segmented using a probabilistic atlas and an ultrasound-like image volume is simulated from the segmentation of the MR image. This ultrasound-like image volume is then affinely aligned with real ultrasound volumes of 27 fetal brains using a robust block-matching approach which can deal with intensity artefacts and missing features in ultrasound images. We show that this approach results in good overlap of four small structures. The average of the co-aligned US images shows good correlation with anatomy of the fetal brain as seen in the MR reconstruction.