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Cerebellar atrophy (CA) is a frequent neuroimaging finding in paediatric neurology, usually associated with cerebellar ataxia. The list of genes involved in hereditary forms of CA is continuously growing and reveals its genetic complexity. We investigated ten cases with early-onset cerebellar involvement with and without ataxia by exome sequencing or by a targeted panel with 363 genes involved in ataxia or spastic paraplegia. Novel variants were investigated by in silico or experimental approaches. Seven probands carry causative variants in well-known genes associated with CA or cerebellar hypoplasia: SETX, CACNA1G, CACNA1A, CLN6, CPLANE1, and TBCD. The remaining three cases deserve special attention; they harbour variants in MAST1, PI4KA and CLK2 genes. MAST1 is responsible for an ultrarare condition characterised by global developmental delay and cognitive decline; our index case added ataxia to the list of concomitant associated symptoms. PIK4A is mainly related to hypomyelinating leukodystrophy; our proband presented with pure spastic paraplegia and normal intellectual capacity. Finally, in a patient who suffers from mild ataxia with oculomotor apraxia, the de novo novel CLK2 c.1120T>C variant was found. The protein expression of the mutated protein was reduced, which may indicate instability that would affect its kinase activity.
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Ataxia Cerebelar , Doenças Cerebelares , Doenças Neurodegenerativas , Paraplegia Espástica Hereditária , Criança , Humanos , Heterogeneidade Genética , Mutação , Ataxia Cerebelar/genética , Ataxia Cerebelar/diagnóstico , Ataxia , Fenótipo , Paraplegia Espástica Hereditária/genética , Paraplegia , Linhagem , Atrofia , Proteínas Associadas aos Microtúbulos/genética , Proteínas de Membrana/genéticaRESUMO
AIMS: We aim to present data obtained from three patients belonging to three unrelated families with an infantile onset demyelinating neuropathy associated to somatic and neurodevelopmental delay and to describe the underlying genetic changes. METHODS: We performed whole-exome sequencing on genomic DNA from the patients and their parents and reviewed the clinical, muscle and nerve data, the serial neurophysiological studies, brain and muscle MRIs, as well as the respiratory chain complex activity in the muscle of the three index patients. Computer modelling was used to characterise the new missense variant detected. RESULTS: All three patients had a short stature, delayed motor milestone acquisition, intellectual disability and cerebellar abnormalities associated with a severe demyelinating neuropathy, with distinct morphological features. Despite the proliferation of giant mitochondria, the mitochondrial respiratory chain complex activity in skeletal muscle was normal, except in one patient in whom there was a mild decrease in complex I enzyme activity. All three patients carried the same two compound heterozygous variants of the TRMT5 (tRNA Methyltransferase 5) gene, one known pathogenic frameshift mutation [c.312_315del (p.Ile105Serfs*4)] and a second rare missense change [c.665 T > C (p.Ile222Thr)]. TRMT5 is a nuclear-encoded protein involved in the post-transcriptional maturation of mitochondrial tRNA. Computer modelling of the human TRMT5 protein structure suggests that the rare p.Ile222Thr mutation could affect the stability of tRNA binding. CONCLUSIONS: Our study expands the phenotype of mitochondrial disorders caused by TRTM5 mutations and defines a new form of recessive demyelinating peripheral neuropathy.
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Doenças Mitocondriais , Doenças do Sistema Nervoso Periférico , tRNA Metiltransferases , Humanos , Doenças Mitocondriais/patologia , Mutação , Fenótipo , RNA de Transferência , Síndrome , tRNA Metiltransferases/genéticaRESUMO
IMMT gene codes for mitofilin, a mitochondrial inner membrane protein that regulates the morphology of mitochondrial cristae. The phenotype associated with mutations in this gene has not been yet established, but functional studies carried out show that its loss causes a mitochondrial alteration, both in the morphology of the mitochondrial crests and in their function. We present two cousins from an extended highly consanguineous family with developmental encephalopathy, hypotonia, nystagmus due to optic neuropathy. The likely pathogenic homozygous c.895A>G (p.Lys299Glu) variant in the IMMT gene co-segregates with the disease and associates altered mitochondrial cristae observed by electron microscopy.
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Homozigoto , Encefalomiopatias Mitocondriais/diagnóstico , Encefalomiopatias Mitocondriais/genética , Proteínas Mitocondriais , Proteínas Musculares , Mutação , Doenças do Nervo Óptico/diagnóstico , Doenças do Nervo Óptico/genética , Alelos , Substituição de Aminoácidos , Biópsia , Consanguinidade , Diagnóstico por Imagem , Predisposição Genética para Doença , Humanos , Lactente , Fenótipo , Avaliação de SintomasRESUMO
Mutations in SPTAN1 gene, encoding the nonerythrocyte αII-spectrin, are responsible for a severe developmental and epileptic encephalopathy (DEE5) and a wide spectrum of neurodevelopmental disorders, as epilepsy with or without intellectual disability (ID) or ID with cerebellar syndrome. A certain genotype-phenotype correlation has been proposed according to the type and location of the mutation. Herein, we report three novel cases with de novo SPTAN1 mutations, one of them associated to a mild phenotype not previously described. They range from (1) severe developmental encephalopathy with ataxia and a mild cerebellar atrophy, without epilepsy; (2) moderate intellectual disability, severe language delay, ataxia and tremor; (3) normal intelligence, chronic migraine, and generalized tonic-clonic seizures. Remarkably, all these patients showed brain MRI abnormalities, being of special interest the subependymal heterotopias detected in the latter patient. Thus we extend the SPTAN1-related phenotypic spectrum, both in its radiological and clinical involvement. Furthermore, after systematic analysis of all the patients so far reported, we noted an excess of male versus female patients (20:9, p = 0.04), more pronounced among the milder phenotypes. Consequently, some protection factor might be suspected among female carriers, which if confirmed should be considered when establishing the pathogenicity of milder genetic variants in this gene.
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Encefalopatias , Epilepsia , Deficiência Intelectual , Transtornos de Enxaqueca , Encefalopatias/genética , Epilepsia/diagnóstico , Epilepsia/genética , Feminino , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Masculino , Mutação , FenótipoRESUMO
BACKGROUND: Norrie disease (ND) is a rare X-linked disorder characterized by bilateral congenital blindness. ND is caused by a mutation in the Norrie disease pseudoglioma (NDP) gene, which encodes a 133-amino acid protein called norrin. Intragenic deletions including NDP and adjacent genes have been identified in ND patients with a more severe neurologic phenotype. We report the biochemical, molecular, clinical and radiological features of two unrelated affected males with a deletion including NDP and MAO genes. METHODS: Biochemical and genetic analyses were performed to understand the atypical phenotype and radiological findings. Biogenic amines in cerebrospinal fluid (CSF) were measured by high-performance liquid chromatography. The coding exons of NDP gene were amplified by polymerase chain reaction. Multiplex ligation-dependent probe amplification and chromosomal microarray were carried out on both affected males. Computed tomography and magnetic resonance imaging were performed on the two patients. RESULTS: In one patient, the serotonin and catecholamine metabolite levels in CSF were virtually undetectable. In both patients, genetic studies revealed microdeletions in the Xp11.3 region, involving the NDP, MAOA and MAOB genes. Radiological examination demonstrated brain and cerebellar atrophy. CONCLUSIONS: We suggest that alterations caused by MAO deficit may remain during the first years of life. Clinical phenotype, biochemical findings and neuroimaging can guide the genetic study in patients with atypical ND and help us to a better understanding of this disease.
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Cegueira/congênito , Proteínas do Olho/genética , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Monoaminoxidase/genética , Proteínas do Tecido Nervoso/genética , Doenças do Sistema Nervoso/diagnóstico , Degeneração Retiniana/diagnóstico , Espasmos Infantis/diagnóstico , Adolescente , Aminas Biogênicas/líquido cefalorraquidiano , Cegueira/diagnóstico , Cegueira/diagnóstico por imagem , Cegueira/genética , Cegueira/patologia , Cerebelo/patologia , Córtex Cerebral/patologia , Pré-Escolar , Olho/patologia , Deleção de Genes , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico por imagem , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Masculino , Doenças do Sistema Nervoso/diagnóstico por imagem , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/patologia , Neurotransmissores/líquido cefalorraquidiano , Degeneração Retiniana/diagnóstico por imagem , Degeneração Retiniana/genética , Degeneração Retiniana/patologia , Espasmos Infantis/diagnóstico por imagem , Espasmos Infantis/genética , Espasmos Infantis/patologiaRESUMO
BACKGROUND: Pantothenate kinase-associated neurodegeneration is a progressive neurological disorder occurring in both childhood and adulthood. The objective of this study was to design and pilot-test a disease-specific clinical rating scale for the assessment of patients with pantothenate kinase-associated neurodegeneration. METHODS: In this international cross-sectional study, patients were examined at the referral centers following a standardized protocol. The motor examination was filmed, allowing 3 independent specialists in movement disorders to analyze 28 patients for interrater reliability assessment. The scale included 34 items (maximal score, 135) encompassing 6 subscales for cognition, behavior, disability, parkinsonism, dystonia, and other neurological signs. RESULTS: Forty-seven genetically confirmed patients (30 ± 17 years; range, 6-77 years) were examined with the scale (mean score, 62 ± 21; range, 20-106). Dystonia with prominent cranial involvement and atypical parkinsonian features were present in all patients. Other common signs were cognitive impairment, psychiatric features, and slow and hypometric saccades. Dystonia, parkinsonism, and other neurological features had a moderate to strong correlation with disability. The scale showed good internal consistency for the total scale (Cronbach's α = 0.87). On interrater analysis, weighted kappa values (0.30-0.93) showed substantial or excellent agreement in 85% of the items. The scale also discriminated a subgroup of homozygous c.1583C>T patients with lower scores, supporting construct validity for the scale. CONCLUSIONS: The proposed scale seems to be a reliable and valid instrument for the assessment of pediatric and adult patients with pantothenate kinase-associated neurodegeneration. Additional validation studies with a larger sample size will be required to confirm the present results and to complete the scale validation testing. © 2017 International Parkinson and Movement Disorder Society.
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Pessoas com Deficiência , Distonia/diagnóstico , Neurodegeneração Associada a Pantotenato-Quinase/diagnóstico , Transtornos Parkinsonianos/diagnóstico , Índice de Gravidade de Doença , Adolescente , Adulto , Idoso , Criança , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/etiologia , Estudos Transversais , Distonia/etiologia , Humanos , Transtornos Mentais/diagnóstico , Transtornos Mentais/etiologia , Pessoa de Meia-Idade , Transtornos da Motilidade Ocular/diagnóstico , Transtornos da Motilidade Ocular/etiologia , Neurodegeneração Associada a Pantotenato-Quinase/complicações , Neurodegeneração Associada a Pantotenato-Quinase/genética , Transtornos Parkinsonianos/etiologia , Projetos Piloto , Reprodutibilidade dos Testes , Adulto JovemRESUMO
Mutations in SCN2A genes have been described in patients with epilepsy, finding a large phenotypic variability, from benign familial epilepsy to epileptic encephalopathy. To explain this variability, it was proposed the existence of dominant modifier alleles at one or more loci that contribute to determine the severity of the epilepsy phenotype. One example of modifier factor may be the CACNA1G gene, as proved in animal models. We present a 6-day-old male newborn with recurrent seizures in which a mutation in the SCN2A gene is observed, in addition to a variant in CACNA1G gene. Our patient suffered in the first days of life myoclonic seizures, with pathologic intercritical electroencephalogram pattern, requiring multiple drugs to achieve adequate control of them. During the next weeks, the patient progressively improved until complete remission at the second month of life, being possible to withdraw the antiepileptic treatment. We propose that the variant in CACNA1G gene could have acted as a modifier of the epilepsy syndrome produced by the mutation in SCN2A gene in our patient.
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BACKGROUND: Whole-exome sequencing (WES) and whole-genome sequencing (WGS) have become indispensable tools to solve rare Mendelian genetic conditions. Nevertheless, there is still an urgent need for sensitive, fast algorithms to maximise WES/WGS diagnostic yield in rare disease patients. Most tools devoted to this aim take advantage of patient phenotype information for prioritization of genomic data, although are often limited by incomplete gene-phenotype knowledge stored in biomedical databases and a lack of proper benchmarking on real-world patient cohorts. METHODS: We developed ClinPrior, a novel method for the analysis of WES/WGS data that ranks candidate causal variants based on the patient's standardized phenotypic features (in Human Phenotype Ontology (HPO) terms). The algorithm propagates the data through an interactome network-based prioritization approach. This algorithm was thoroughly benchmarked using a synthetic patient cohort and was subsequently tested on a heterogeneous prospective, real-world series of 135 families affected by hereditary spastic paraplegia (HSP) and/or cerebellar ataxia (CA). RESULTS: ClinPrior successfully identified causative variants achieving a final positive diagnostic yield of 70% in our real-world cohort. This includes 10 novel candidate genes not previously associated with disease, 7 of which were functionally validated within this project. We used the knowledge generated by ClinPrior to create a specific interactome for HSP/CA disorders thus enabling future diagnoses as well as the discovery of novel disease genes. CONCLUSIONS: ClinPrior is an algorithm that uses standardized phenotype information and interactome data to improve clinical genomic diagnosis. It helps in identifying atypical cases and efficiently predicts novel disease-causing genes. This leads to increasing diagnostic yield, shortening of the diagnostic Odysseys and advancing our understanding of human illnesses.
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Algoritmos , Genômica , Humanos , Estudos Prospectivos , Bases de Dados Factuais , Estudos de Associação GenéticaRESUMO
BACKGROUND: Expand the knowledge about the clinical phenotypes associated with pathogenic or likely pathogenic variants in the SCN1A gene. METHODS: The study was carried out in 15 patients with SCN1A variants. The complete phenotype of the patients was evaluated. A systematic search was carried out in the scientific literature for those unexpected symptoms. RESULTS: Ten patients showed a missense variant, whereas the remaining showed different loss-of-function variants. Twelve (80%) had Dravet syndrome. Two (13.3%) had Epilepsy with febrile seizures plus. Three (20%) presented an atypical phenotype. One of them was developmental and epileptic encephalopathy with arthrogryposis, the other Dravet syndrome and movement disorder, and lastly one patient had Dravet syndrome and malformations of the cortical development. CONCLUSION: The exhaustive assessment of patients with pathogenic alterations detected in massive sequencing can help us to expand the phenotype, understand the etiopathogenesis associated with each genetic abnormality, and thus improve the prognosis and management of future patients.
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Artrogripose , Epilepsias Mioclônicas , Malformações do Desenvolvimento Cortical , Transtornos dos Movimentos , Espasmos Infantis , Artrogripose/genética , Epilepsias Mioclônicas/genética , Síndromes Epilépticas , Humanos , Transtornos dos Movimentos/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , FenótipoRESUMO
Dominant pathogenic variations in the SCN1A gene are associated with several neuro developmental disorders with or without epilepsy, including Dravet syndrome (DS). Conversely, there are few published cases with homozygous or compound heterozygous variations in the SCN1A gene. Here, we describe two siblings from a consanguineous pedigree with epilepsy phenotype compatible with genetic epilepsy with febrile seizures plus (GEFS+) associated with the homozygous likely pathogenic variant (NM_001165963.1): c.4513A > C (p.Lys1505Gln). Clinical and genetic data were compared to those of other 10 previously published patients with epilepsy and variants in compound heterozygosity or homozygosity in the SCN1A gene. Most patients (11/12) had missense variants. Patients in whom the variants were located at the cytoplasmic or the extracellular domains frequently presented a less severe phenotype than those in whom they are located at the pore-forming domains. Five of the patients (41.7%) meet clinical criteria for Dravet syndrome (DS), one of them associated acute encephalopathy. Other five patients (41.7%) had a phenotype of epilepsy with febrile seizures plus familial origin, while the two remaining (17%) presented focal epileptic seizures. SCN1A-related epilepsies present in most cases an autosomal dominant inheritance; however, there is growing evidence that some genetic variants only manifest clinical symptoms when they are present in both alleles, following an autosomal recessive inheritance.
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INTRODUCTION: Venous sinus thrombosis (VST) is a rare entity in pediatrics, probably under-diagnosed and poten tially serious, described as a cause of stroke in childhood. OBJECTIVE: To describe the clinical presenta tion, risk factors, treatment, and evolution of pediatric patients with VST. PATIENTS AND METHOD: Re trospective study of patients admitted to a referral hospital, diagnosed with VST, aged between one month and seventeen years, from January 2011 to December 2019. The following data were re viewed: age at diagnosis, sex, signs and symptoms of presentation, predisposing mechanisms, study of thrombophilias, treatment and duration of treatment, follow-up protocol, long-term sequelae, and mortality. Due to their differences in clinical presentation, the sample was divided into two age groups: young children between 1 month and 5 years and older children and adolescents between 6 and 17 years. RESULTS: 17 patients were diagnosed with VST, 45% were women, with a median age of 4.5 years. The most frequent symptoms in older children (6-17 years old) were headache (80%) and diplopia (60%). In children under 5 years old, the most frequent clinical presentation was cerebellar ataxia (42%), asymptomatic (34%), and headache (25%). In 23.5% of the total, VST was a casual fin ding in neuroimaging. 13 patients presented relevant histories such as complicated otitis media with mastoiditis (53%), severe traumatic head injury (6%), and resection of a space-occupying lesion of the brain (6%). 23% of the cases were idiopathic and in 23% there were prothrombotic factors. The treatment of choice in all patients was low-molecular-weight heparin. During the short-term follow- up, 11.8% presented self-limited neurological symptoms. One patient presented long-term paresis of the sixth paired cranial nerve. There were no deaths or recurrences of the episode in our series. CONCLUSIONS: VST is a rare entity and it usually appears with signs and symptoms of intracranial hy pertension. It is a potentially serious condition and early diagnosis and treatment can help minimize long-term sequelae.
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Trombose dos Seios Intracranianos , Trombose Venosa , Adolescente , Anticoagulantes/uso terapêutico , Criança , Pré-Escolar , Feminino , Seguimentos , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Estudos Retrospectivos , Fatores de Risco , Trombose dos Seios Intracranianos/diagnóstico , Trombose dos Seios Intracranianos/tratamento farmacológico , Trombose dos Seios Intracranianos/etiologia , Trombose dos Seios Intracranianos/mortalidade , Centros de Atenção Terciária , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Trombose Venosa/diagnóstico , Trombose Venosa/tratamento farmacológico , Trombose Venosa/etiologia , Trombose Venosa/mortalidadeRESUMO
BACKGROUND: Single-center clinical series provide important information on genetic distribution that can guide genetic testing. However, there are few such studies on pediatric populations with inherited peripheral neuropathies (IPNs). METHODS: Thorough genetic testing was performed on IPN patients under 20 years of age from a geographically well-defined Mediterranean area (Valencian Community, Spain), annually assessed with the Charcot-Marie-Tooth disease Pediatric Scale (CMTPedS). RESULTS: From 86 families with IPNs, 99 patients (59 males) were identified, 85 with sensorimotor neuropathy or CMT (2/3 demyelinating form) and 14 with distal hereditary motor neuropathy (dHMN). Genetic diagnosis was achieved in 79.5% families, with a similar mutation detection rate in the demyelinating (88.7%) and axonal (89.5%) forms, significantly higher than in the dHMN families (27.3%). CMT1A was the most common subtype, followed by those carrying heterozygous mutations in either the GDAP1 or GJB1 genes. Mutations in 15 other genes were identified, including a new pathogenic variant in the ATP1A gene. The CMTPedS detected significant disease progression in all genetic subtypes of CMT, at a rate of 1.84 (±3.7) over 1 year (p < 0.0005, n = 62) and a 2-year rate of 3.6 (±4.4: p < 0.0005, n = 45). Significant disease worsening was also detected for CMT1A over 1 (1.7 ± 3.6, p < 0.05) and 2 years (4.2 ± 4.3, p < 0.0005). CONCLUSIONS: This study highlights the unique spectrum of IPN gene frequencies among pediatric patients in this specific geographic region, identifying the CMTPedS as a sensitive tool to detect significant disease worsening over 1 year that could help optimize the design of clinical trials.
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Neuropatia Hereditária Motora e Sensorial , Doenças do Sistema Nervoso Periférico , Adolescente , Adulto , Idade de Início , Doença de Charcot-Marie-Tooth/diagnóstico , Doença de Charcot-Marie-Tooth/epidemiologia , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/fisiopatologia , Criança , Pré-Escolar , Feminino , Neuropatia Hereditária Motora e Sensorial/diagnóstico , Neuropatia Hereditária Motora e Sensorial/epidemiologia , Neuropatia Hereditária Motora e Sensorial/genética , Neuropatia Hereditária Motora e Sensorial/fisiopatologia , Humanos , Estudos Longitudinais , Masculino , Região do Mediterrâneo/epidemiologia , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/epidemiologia , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/fisiopatologia , Encaminhamento e Consulta , Espanha/epidemiologia , Adulto JovemRESUMO
INTRODUCTION: The infection due to cytomegalovirus is the most common congenital infection in developed countries, and on of the main causes of psychomotor impairment and neurosensory hearing loss of infectious origin. The present study has its objectives to describe the clinical-analytical and neuroimaging of patients with secondary neurological sequelae secondary to the congenital cytomegalovirus infection and then compare them with the group of patients with a congenital cytomegalovirus infection that did not have neurological symptoms during their follow-up. MATERIAL AND METHODS: A retrospective, observational, cohort study was conducted that included all the cases of congenital cytomegalovirus infection from 2003 until 2018 and the short-medium term neurological sequelae were evaluated. Prenatal, perinatal, and postnatal data of patients with neurological sequelae were compared against those that did not present with any. RESULTS: A total of 60 patients with congenital cytomegalovirus infection were recorded during the study period, with 65% having neurological involvement during their follow-up period (62.2% with psychomotor impairment, 61.5% with microcephaly, 46.2% loss of hearing, 27.8% motor disorders, 20.5% epilepsy, and 5.6% with chorioretinitis). In the patient group that had sequelae, the presence of clinical symptoms during the neonatal period, as well as changes in the neuroimaging study, were the most common, with both being statistically significant compared to the asymptomatic group. The patients with neurological involvement also had a higher score on the Noyola et al. neuroimaging scale. CONCLUSIONS: The symptoms at birth, and certain findings in the neuroimaging, like the changes in the white matter or neuronal migration disorders, could predict neurocognitive sequelae in patients with congenital cytomegalovirus infection.
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Infecções por Citomegalovirus/complicações , Perda Auditiva Neurossensorial/virologia , Microcefalia/virologia , Doenças do Sistema Nervoso/virologia , Pré-Escolar , Estudos de Coortes , Infecções por Citomegalovirus/congênito , Feminino , Seguimentos , Perda Auditiva Neurossensorial/epidemiologia , Humanos , Lactente , Recém-Nascido , Masculino , Microcefalia/epidemiologia , Doenças do Sistema Nervoso/diagnóstico por imagem , Doenças do Sistema Nervoso/epidemiologia , Neuroimagem , Gravidez , Transtornos Psicomotores/epidemiologia , Transtornos Psicomotores/virologia , Estudos Retrospectivos , Substância Branca/diagnóstico por imagemRESUMO
BACKGROUND: Investigations of myelin oligodendrocyte glycoprotein (MOG) antibodies are usually focused on demyelinating syndromes, but the entire spectrum of MOG antibody-associated syndromes in children is unknown. In this study, we aimed to determine the frequency and distribution of paediatric demyelinating and encephalitic syndromes with MOG antibodies, their response to treatment, and the phenotypes associated with poor prognosis. METHODS: In this prospective observational study, children with demyelinating syndromes and with encephalitis other than acute disseminated encephalomyelitis (ADEM) recruited from 40 secondary and tertiary centres in Spain were investigated for MOG antibodies. All MOG antibody-positive cases were included in our study, which assessed syndromes, treatment and response to treatment (ie, number of relapses), outcomes (measured with the modified Rankin scale [mRS]), and phenotypes associated with poor prognosis. We used Fisher's exact and Wilcoxon rank sum tests to analyse clinical features, and survival Cox regression to analyse time to antibody negativity. FINDINGS: Between June 1, 2013, and Dec 31, 2018, 239 children with demyelinating syndromes (cohort A) and 296 with encephalitis other than ADEM (cohort B) were recruited. 116 patients had MOG antibodies, including 94 (39%) from cohort A and 22 (7%) from cohort B; 57 (49%) were female, with a median age of 6·2 years (IQR 3·7-10·0). Presenting syndromes in these 116 patients included ADEM (46 [68%]), encephalitis other than ADEM (22 [19%]), optic neuritis (20 [17%]), myelitis (13 [11%]), neuromyelitis optica spectrum disorders (six [5%]), and other disorders (nine [8%]). Among the patients with autoimmune encephalitis in cohort B (n=64), MOG antibodies were more common than all neuronal antibodies combined (22 [34%] vs 21 [33%]). After a median follow-up of 42 months (IQR 22-67), 33 (28%) of the 116 patients had relapses, including 17 (17%) of 100 diagnosed at first episode. Steroids, intravenous immunoglobulin, or plasma exchange were used in 100 (86%) patients at diagnosis, and 32 (97%) of 33 at relapses. Rituximab was mainly used at relapses (11 [33%]). 99 (85%) of 116 patients had substantial recovery (mRS <2) and 17 (15%) moderate to severe deficits (mRS >2; one died). Phenotypes of poor prognosis included ADEM-like relapses progressing to leukodystrophy-like features, and extensive cortical encephalitis evolving to atrophy. Time to antibody negativity was longer in patients with relapses (HR 0·18, 95% CI 0·05-0·59). INTERPRETATION: The spectrum of paediatric MOG antibody-associated syndromes is wider than previously reported and includes demyelinating syndromes and encephalitis. Recognition of these disorders has important clinical and prognostic implications. FUNDING: Mutua Madrileña Foundation; ISCIII-Subdirección General de Evaluación y Fomento de la Investigación Sanitaria; Fondo Europeo de Desarrollo Regional; Pediatrics Spanish Society; Departament de Salut, Generalitat de Catalunya; Marato TV3 Foundation; Red Española de Esclerosis Múltiple; La Caixa Foundation; and Fundació CELLEX.
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Doenças Desmielinizantes/imunologia , Encefalite/imunologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Autoanticorpos/sangue , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulinas Intravenosas , Imageamento por Ressonância Magnética , Masculino , Glicoproteína Mielina-Oligodendrócito/análise , Neuromielite Óptica/sangue , Neuromielite Óptica/diagnóstico , Neuromielite Óptica/imunologia , Pediatria , Estudos Prospectivos , Espanha , SíndromeRESUMO
INTRODUCTION: Schaaf-Yang syndrome (SYS) is caused by truncating point mutations of the paternal allele of MAGEL2, an imprinted gene located in the critical region of Prader-Willi syndrome (PWS). These patients present a phenotype with neurodevelopmental delay, hypotonia, joint contractures, and a particularly high prevalence of autism (up to 75% in affected individuals). The loss of function of MAGEL2 is suggested to contribute to endocrine hypothalamic dysfunction in individuals with PWS. CASE PRESENTATION: The current study presented the case of a patient with SYS and a novel de novo truncating mutation of MAGEL2 and phenotypic characteristics typical of this Prader-Willi-like syndrome and also including partial hypopituitarism, hypothyroidism, growth hormone deficiency, and hyperprolactinemia. CONCLUSIONS: The clinical and molecular similarities between SYS and PWS suggested the need for a thorough endocrinological follow-up to improve the prognosis and long-term quality of life for patients with SYS.
RESUMO
INTRODUCTION: Psychotic manifestations in childhood are not infrequent, yet the existing literature dealing with the neurological appraisal of children and adolescents with a clinical picture of psychosis is very scant. AIM: To conduct a non-systematic review of the literature that provides an answer to these three questions: When must a neurological appraisal be performed in a child with psychotic traits? What medical conditions can include signs and symptoms of psychosis in their development? And, what diagnostic procedure should be followed? DEVELOPMENT: The diseases that can present psychotic symptoms at onset or during their course are reviewed and grouped by pathologies: inborn errors of metabolism, genetic diseases, autoimmune and infectious diseases, malformations of the central nervous system, epilepsy, vascular pathology, rheumatologic processes, brain tumours, and psychoactive substances and drugs. A diagnostic regimen is proposed in which both the information obtained from the anamnesis and examination and the findings from each of the diagnostic tests are evaluated. CONCLUSIONS: A huge number of processes can display psychotic symptoms during their course and the key information offered by the anamnesis and examination must be taken into account. This review can help neuropaediatricians and other specialists perform a more systematised appraisal of children and adolescents with psychotic signs and symptoms.
TITLE: Valoracion neurologica de niños y adolescentes con sintomas psicoticos.Introduccion. Las manifestaciones psicoticas en la infancia no son infrecuentes; sin embargo, la bibliografia existente acerca de la valoracion neurologica de niños y adolescentes con cuadros psicoticos es muy escasa. Objetivo. Realizar una revision bibliografica no sistematica que permita responder a estas tres cuestiones: cuando debe llevarse a cabo una valoracion neurologica en un niño con rasgos psicoticos?, cuales son las condiciones medicas que pueden incluir un cuadro psicotico en su evolucion? y cual debe ser el procedimiento diagnostico? Desarrollo. Se revisan las enfermedades que pueden presentar sintomatologia psicotica al inicio o durante la evolucion, y se agrupan por patologias: errores congenitos del metabolismo, enfermedades geneticas, enfermedades autoinmunes e infecciosas, malformaciones del sistema nervioso central, epilepsia, patologia vascular, procesos reumatologicos, tumores cerebrales, y farmacos y sustancias psicoactivas. Se propone una pauta diagnostica en la que se valora la informacion obtenida a partir de la anamnesis y la exploracion y la aportacion de cada prueba diagnostica. Conclusiones. El numero de procesos que pueden manifestar sintomatologia psicotica a lo largo de su evolucion es muy elevado, y hay que considerar las claves que ofrecen la anamnesis y la exploracion. Esta revision puede ayudar a neuropediatras y otros especialistas a realizar una valoracion mas sistematizada de niños y adolescentes con cuadros psicoticos.
Assuntos
Neuroimagem , Exame Neurológico , Transtornos Psicóticos/diagnóstico , Adolescente , Idade de Início , Doenças Autoimunes do Sistema Nervoso/psicologia , Neoplasias Encefálicas/psicologia , Criança , Pré-Escolar , Encefalite/psicologia , Epilepsia/psicologia , Doenças Genéticas Inatas/psicologia , Humanos , Lactente , Recém-Nascido , Lúpus Eritematoso Sistêmico/psicologia , Erros Inatos do Metabolismo/psicologia , Malformações do Sistema Nervoso/psicologia , Psicoses Induzidas por Substâncias/diagnóstico , Transtornos Psicóticos/epidemiologia , Transtornos Psicóticos/metabolismo , Adulto JovemAssuntos
Bevacizumab/farmacologia , Calcinose/diagnóstico por imagem , Calcinose/tratamento farmacológico , Cistos do Sistema Nervoso Central/diagnóstico por imagem , Cistos do Sistema Nervoso Central/tratamento farmacológico , Fatores Imunológicos/farmacologia , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/tratamento farmacológico , Bevacizumab/administração & dosagem , Humanos , Fatores Imunológicos/administração & dosagem , Lactente , Imageamento por Ressonância Magnética , Masculino , RNA Nucleolar PequenoRESUMO
INTRODUCTION: Acute disseminated encephalomyelitis (ADE) is an inflammatory disorder of the central nervous system that is mediated immunologically and of unknown pathogenesis. It can present at any age, but is much more frequent in children. ADE has no specific biological marker and diagnosis is based on findings from clinical and neuroimaging studies. AIM: To enhance our knowledge of the clinico-radiological profile of this disease. PATIENTS AND METHODS: This retrospective study involved patients under 14 years of age who were admitted to a tertiary hospital over the last 15 years with a diagnosis of ADE. History, clinical presenting symptoms, lab findings from blood/cerebrospinal fluid analyses and radiological semiology were reviewed. In 16 cases an average follow-up of 25 months was performed. RESULTS: The study examined 20 patients, 70% children, with a mean age of 4.4 years. Forty per cent had a previous febrile episode. Eighty-five per cent presented fever or vomiting, and 70% had altered states of mind. Motor deficits (45%), convulsions (35%) and involvement of the cranial nerves (30%) were predominant. Three children progressed with relapses and three others were left with motor sequelae. Magnetic resonance imaging showed hyperintense lesions in T2, with a pattern of scarce/no enhancement, which were predominantly located in the thalamus (70%), the spinal cord (67%) and the white matter of the sub-cortex (50%). Haemorrhagic ADE was diagnosed in two patients. CONCLUSIONS: ADE is a condition with an important degree of general involvement and neurological repercussions, as well as considerable potential to leave the patient with sequelae. Clinico-analytical data and magnetic resonance scans of the head and spinal cord are relevant for the initial diagnosis and follow-up of patients with ADE.
TITLE: Perfil clinicorradiologico de la encefalomielitis aguda diseminada en la poblacion infantil. Analisis retrospectivo de una serie de 20 pacientes de un hospital terciario.Introduccion. La encefalomielitis aguda diseminada (EAD) es un trastorno inflamatorio del sistema nervioso central mediado inmunologicamente y de patogenia desconocida. Puede presentarse en cualquier edad, pero es mucho mas frecuente en niños. La EAD no tiene marcador biologico especifico y el diagnostico se basa en hallazgos clinicos y neurorradiologicos. Objetivo. Mejorar el conocimiento del perfil clinicorradiologico de esta enfermedad. Pacientes y metodos. Estudio retrospectivo con inclusion de pacientes menores de 14 años ingresados en un hospital terciario en los ultimos 15 años con el diagnostico de EAD. Se revisaron antecedentes, signos clinicos de presentacion, datos analiticos en sangre/liquido cefalorraquideo y la semiologia radiologica. En 16 casos se realizo un seguimiento medio de 25 meses. Resultados. Se revisaron 20 pacientes, un 70% niños, con una edad media de 4,4 años. El 40% tuvo un episodio febril previo. El 85% presento fiebre o vomitos, y el 70%, afectacion del estado de consciencia. Predominaron los deficits motores (45%), las convulsiones (35%) y la afectacion de pares craneales (30%). Tres niños presentaron una evolucion recidivante, y otros tres, secuelas motoras. Los estudios de resonancia magnetica mostraron lesiones hiperintensas en secuencias T2, con patron de realce escaso o nulo, que predominaron en los talamos (70%), la medula (67%) y la sustancia blanca subcortical (50%). En dos pacientes se diagnostico EAD hemorragica. Conclusiones. La EAD representa una entidad con importante afectacion general y repercusion neurologica, que muestra un potencial secuelar considerable. Los datos clinicoanaliticos y la resonancia magnetica cerebral y medular son relevantes para el diagnostico inicial y seguimiento de pacientes con EAD.
Assuntos
Encefalomielite Aguda Disseminada/diagnóstico , Aciclovir/uso terapêutico , Adolescente , Corticosteroides/uso terapêutico , Encéfalo/patologia , Proteínas do Líquido Cefalorraquidiano/análise , Criança , Pré-Escolar , Comorbidade , Transtornos da Consciência/etiologia , Doenças dos Nervos Cranianos/etiologia , Diagnóstico Diferencial , Encefalomielite Aguda Disseminada/epidemiologia , Encefalomielite Aguda Disseminada/metabolismo , Encefalomielite Aguda Disseminada/patologia , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Lactente , Imageamento por Ressonância Magnética , Masculino , Meningite Viral/diagnóstico , Plasmaferese , Estudos Retrospectivos , Convulsões/etiologia , Espanha/epidemiologia , Avaliação de Sintomas , Centros de Atenção Terciária/estatística & dados numéricosRESUMO
INTRODUCTION: Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a rare condition that has only recently been reported. Here we present two new cases belonging to the same family. CASE REPORTS: Case 1: 17-month-old boy with severe underdevelopment in all areas, absence of language and eye contact. The examination revealed microcephaly with spastic tetraparesis. A magnetic resonance imaging scan showed predominantly vermian atrophy of the cerebellum with loss of volume of both nuclei of the putamen and the head of the caudate, and a pattern of hypomyelination of the white matter. Electromyography recording highlighted the presence of a predominantly motor pattern of chronic polyneuropathy. Homovallinic acid and 5-hydroxyindoleacetic acid values were lower than usual. Treatment with levodopa/carbidopa was not effective. Case 2: 11-month-old girl, the sister of the boy in the previous case. The patient presented severe underdevelopment in all areas and microcephaly with spastic tetraparesis was detected in the clinical examination. Magnetic resonance imaging of the head showed findings that could be superimposed upon those of the brother, with hypomyelination, cerebellar atrophy and involvement of the putamen and both caudates; electromyography findings were consistent with motor polyneuropathy of a demyelinating nature. Homovallinic acid and 5-hydroxyindoleacetic acid values in cerebrospinal fluid were lower than usual. Treatment with levodopa/carbidopa was ineffective. CONCLUSIONS: These two new cases help characterise this condition better and reinforce the hypothesis of the genetic origin of the syndrome, given that the two cases occurred in the same family.
TITLE: Hipomielinizacion con atrofia de ganglios basales y de cerebelo. Aportacion de dos nuevos casos a una entidad de descripcion reciente.Introduccion. La hipomielinizacion con atrofia de ganglios basales y de cerebelo (H-ABC) es una rara entidad descrita recientemente. Se presentan dos nuevos casos pertenecientes a una misma familia. Casos clinicos. Caso 1: niño de 17 meses con retraso grave en todas las areas, ausencia de lenguaje y de contacto visual. En la exploracion destacaba una microcefalia con tetraparesia espastica. En la resonancia magnetica cerebral se apreciaba atrofia cerebelosa de predominio vermiano con perdida de volumen de ambos nucleos del putamen y la cabeza del caudado, y patron de hipomielinizacion de la sustancia blanca. En la electromiografia se objetivo un patron de polineuropatia cronica de predominio motor. Presento un descenso de los valores de acido homovalinico y de acido 5-hidroxindolacetico. El tratamiento con levodopa/carbidopa no fue efectivo. Caso 2: niña de 11 meses, hermana del caso anterior. Presentaba un retraso grave en todas las areas y en la exploracion clinica se detecto una microcefalia con tetraparesia espastica. La resonancia magnetica cerebral mostro hallazgos superponibles a los del hermano, con hipomielinizacion, atrofia cerebelosa y afectacion putaminal y de ambos caudados; en la electromiografia, hallazgos compatibles con polineuropatia motora de caracter desmielinizante. Presento un descenso de los valores de acido homovalinico y acido 5-hidroxindolacetico en el liquido cefalorraquideo. El tratamiento con levodopa/carbidopa resulto ineficaz. Conclusiones. Estos dos nuevos casos ayudan a caracterizar mejor esta entidad y refuerzan la hipotesis del origen genetico del sindrome, dado que se trata de dos casos pertenecientes a una misma familia.