RESUMO
BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) comprises various age-dependent clinical phenotypes and may be monophasic, multiphasic, or chronic. Optic neuritis (ON) is a common manifestation and frequently appears in combination with other MOGAD phenotypes, particularly in young children. Despite permanent structural damage to the retinal nerve fiber layer (RNFL), children often experience complete visual recovery. AIMS: To analyze the progression and impact of MOGAD on the visual system of pediatric patients independently of the history of ON. METHODS: This retrospective study included children who met specific criteria: myelin oligodendrocyte glycoprotein (MOG) immunoglobulin G (IgG) seropositivity, acute presentation of MOGAD, and written general consent. Main outcome measures were global peripapillary retinal nerve fiber layer (pRNFL) thickness, and near and distance visual acuity, analyzed using descriptive statistics. RESULTS: We identified 10 patients with median age of 7.7 years at first event: 7 patients manifested with acute disseminated encephalomyelitis (ADEM) (with ON 5/7, ADEM only 1/7, with transverse myelitis (TM) 1/7), 2 with isolated ON, and 1 patient with neuromyelitis optica spectrum disorder (NMOSD)-like phenotype with ON. Among ON patients, 5/8 were affected bilaterally, with 3 initially diagnosed with unilateral ON but experiencing subsequent involvement of the fellow eye. None of the patients without previous ON showed a deterioration of visual acuity and, if evaluated, a reduction of the pRNFL. CONCLUSION: Most pediatric MOGAD-ON patients in our cohort presented with acute vison loss and optic disc edema. All patients achieved complete visual recovery, independent of number of relapses or initial visual loss. The pRNFL thickness decreased for several months and stabilized at reduced levels after 12 months in the absence of further relapses. MOGAD may not have subclinical/'silent' effects on the visual system, as visual acuity and pRNFL were not affected in patients without ON.
Assuntos
Encefalomielite Aguda Disseminada , Neuromielite Óptica , Neurite Óptica , Humanos , Criança , Pré-Escolar , Glicoproteína Mielina-Oligodendrócito , Estudos Retrospectivos , Autoanticorpos , Recidiva Local de Neoplasia , Avaliação de Resultados em Cuidados de Saúde , RecidivaRESUMO
Spina bifida affects spinal cord and cerebral development, leading to motor and cognitive delay. We investigated whether there are associations between thalamocortical connectivity topography, neurological function, and developmental outcomes in open spina bifida. Diffusion tensor MRI was used to assess thalamocortical connectivity in 44 newborns with open spina bifida who underwent prenatal surgical repair. We quantified the volume of clusters formed based on the strongest probabilistic connectivity to the frontal, parietal, and temporal cortex. Developmental outcomes were assessed using the Bayley III Scales, while the functional level of the lesion was assessed by neurological examination at 2 years of age. Higher functional level was associated with smaller thalamo-parietal, while lower functional level was associated with smaller thalamo-temporal connectivity clusters (Bonferroni-corrected P < 0.05). Lower functional levels were associated with weaker thalamic temporal connectivity, particularly in the ventrolateral and ventral anterior nuclei. No associations were found between thalamocortical connectivity and developmental outcomes. Our findings suggest that altered thalamocortical circuitry development in open spina bifida may contribute to impaired lower extremity function, impacting motor function and independent ambulation. We hypothesize that the neurologic function might not merely be caused by the spinal cord lesion, but further impacted by the disruption of cerebral neuronal circuitry.
Assuntos
Espinha Bífida Cística , Disrafismo Espinal , Gravidez , Feminino , Recém-Nascido , Humanos , Espinha Bífida Cística/complicações , Disrafismo Espinal/diagnóstico por imagem , Disrafismo Espinal/complicações , Disrafismo Espinal/psicologia , Medula Espinal/patologia , Imagem de Tensor de Difusão , Tálamo/patologiaRESUMO
BACKGROUND AND OBJECTIVE: The spectrum of myelin oligodendrocyte glycoprotein (MOG) antibody-associated disorder (MOGAD) comprises monophasic diseases such as acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), and transverse myelitis and relapsing courses of these presentations. Persistently high MOG antibodies (MOG immunoglobulin G [IgG]) are found in patients with a relapsing disease course. Prognostic factors to determine the clinical course of children with a first MOGAD are still lacking. The objective of the study is to assess the clinical and laboratory prognostic parameters for a risk of relapse and the temporal dynamics of MOG-IgG titers in children with MOGAD in correlation with clinical presentation and disease course. METHODS: In this prospective multicenter hospital-based study, children with a first demyelinating attack and complete data set comprising clinical and radiologic findings, MOG-IgG titer at onset, and clinical and serologic follow-up data were included. Serum samples were analyzed by live cell-based assay, and a titer level of ≥1:160 was classified as MOG-IgG-positive. RESULTS: One hundred sixteen children (f:m = 57:59) with MOGAD were included and initially diagnosed with ADEM (n = 59), unilateral ON (n = 12), bilateral ON (n = 16), myelitis (n = 6), neuromyelitis optica spectrum disorder (n = 8) or encephalitis (n = 6). The median follow-up time was 3 years in monophasic and 5 years in relapsing patients. There was no significant association between disease course and MOG-IgG titers at onset, sex, age at presentation, or clinical phenotype. Seroconversion to MOG-IgG-negative within 2 years of the initial event showed a significant risk reduction for a relapsing disease course. Forty-two/one hundred sixteen patients (monophasic n = 26, relapsing n = 16) had serial MOG-IgG testing in years 1 and 2 after the initial event. In contrast to relapsing patients, monophasic patients showed a significant decrease of MOG-IgG titers during the first and second years, often with seroconversion to negative titers. During the follow-up, MOG-IgG titers were persistently higher in relapsing than in monophasic patients. Decrease in MOG-IgG of ≥3 dilution steps after the first and second years was shown to be associated with a decreased risk of relapses. In our cohort, no patient experienced a relapse after seroconversion to MOG-IgG-negative. DISCUSSION: In this study, patients with declining MOG-IgG titers, particularly those with seroconversion to MOG-IgG-negative, are shown to have a significantly reduced relapse risk.
Assuntos
Encefalomielite Aguda Disseminada , Neuromielite Óptica , Neurite Óptica , Humanos , Imunoglobulina G , Glicoproteína Mielina-Oligodendrócito , Recidiva Local de Neoplasia , Estudos Prospectivos , SíndromeRESUMO
Early infantile epileptic encephalopathy (EIEE) is a severe neurologic and neurodevelopmental disease that manifests in the first year of life. It shows a high degree of genetic heterogeneity, but the genetic origin is only identified in half of the cases. We report the case of a female child initially diagnosed with Leber congenital amaurosis (LCA), an early-onset retinal dystrophy due to photoreceptor cell degeneration in the retina. The first examination at 9 months of age revealed no reaction to light or objects and showed wandering eye movements. Ophthalmological examination did not show any ocular abnormalities. The patient displayed mildly dysmorphic features and a global developmental delay. Brain MRI demonstrated pontine hypo-/dysplasia. The patient developed myoclonic epileptic seizures and epileptic spasms with focal and generalized epileptiform discharges on electroencephalogram (EEG) at the age of 16 months. Genetic screening for a potentially pathogenic DNA sequence variant by whole-exome sequencing (WES) revealed a novel, conserved, homozygous frameshift variant (c.5391delA, p.(Ala1798LeufsTer59)) in exon 42 of the DOCK7 gene (NM_001271999.1). Further analysis by SNP array (Karyomapping) showed loss of heterozygosity (LOH) in four segments of chromosome 1. WES data of the parents and the index patient (trio analysis) demonstrated that chromosome 1 was exclusively inherited from the mother. Four LOH segments of chromosome 1 alternately showed isodisomy (UPiD) and heterodisomy (UPhD). In WES data, the father was a noncarrier, and the mother was heterozygous for this DOCK7 variant. The DOCK7 gene is located in 1p31.3, a region situated in one of the four isodisomic segments of chromosome 1, explaining the homozygosity seen in the affected child. Finally, Sanger sequencing confirmed maternal UPiD for the DOCK7 variant. Homozygous or compound heterozygous pathogenic variants in the DOCK7 (dedicator of cytokinesis 7) gene are associated with autosomal recessive, early infantile epileptic encephalopathy 23 (EIEE23; OMIM #615,859), a rare and heterogeneous group of neurodevelopmental disorders diagnosed during early childhood. To our knowledge, this is the first report of segmental uniparental iso- and heterodisomy of chromosome 1, leading to homozygosity of the DOCK7 frameshift variant in the affected patient.
Assuntos
Cromossomos Humanos Par 1 , Dissomia Uniparental , Feminino , Proteínas Ativadoras de GTPase/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Lactente , Polimorfismo de Nucleotídeo Único , Espasmos Infantis , Transtornos da VisãoRESUMO
Primrose syndrome (PS) is a rare disorder characterized by macrocephaly, tall stature, intellectual disability, autistic traits, and disturbances of glucose metabolism with insulin-resistant diabetes and distal muscle wasting occurring in adulthood. The disorder is caused by functional dysregulation of ZBTB20, a transcriptional repressor controlling energetic metabolism and developmental programs. ZBTB20 maps in a genomic region that is deleted in the 3q13.31 microdeletion syndrome, which explains the clinical overlap between the two disorders. A narrow spectrum of amino acid substitutions in a restricted region of ZBTB20 encompassing the first and second zinc-finger motifs have been reported thus far. Here, we characterize clinically and functionally the first truncating mutation [(c.1024delC; p.(Gln342Serfs*42)] and a missense change affecting the third zinc-finger motif of the protein [(c.1931C > T; p.(Thr644Ile)]. Our data document that both mutations have dominant negative impact on wild-type ZBTB20, providing further evidence of the specific behavior of PS-causing mutations on ZBTB20 function.
Assuntos
Anormalidades Múltiplas/genética , Calcinose/genética , Otopatias/genética , Predisposição Genética para Doença , Deficiência Intelectual/genética , Atrofia Muscular/genética , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição/genética , Anormalidades Múltiplas/fisiopatologia , Calcinose/fisiopatologia , Criança , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 3/genética , Hibridização Genômica Comparativa , Otopatias/fisiopatologia , Feminino , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Atrofia Muscular/fisiopatologia , Mutação de Sentido Incorreto/genética , Dedos de Zinco/genéticaRESUMO
OBJECTIVE: To determine the neuroimaging pattern of cerebellar dysplasia (CD) and other posterior fossa morphological anomalies associated with mutations in tubulin genes and to perform clinical and genetic correlations. METHODS: Twenty-eight patients harbouring 23 heterozygous pathogenic variants (ten novel) in tubulin genes TUBA1A (n = 10), TUBB2B (n = 8) or TUBB3 (n = 5) were studied by a brain MRI scan performed either on a 1.5 T (n = 10) or 3 T (n = 18) MR scanner with focus on the posterior fossa. RESULTS: Cerebellar anomalies were detected in 24/28 patients (86%). CD was recognised in 19/28 (68%) including cortical cerebellar dysplasia (CCD) in 18/28, either involving only the cerebellar hemispheres (12/28) or associated with vermis dysplasia (6/28). CCD was located only in the right hemisphere in 13/18 (72%), including four TUBB2B-, four TUBB3- and five TUBA1A-mutated patients, while in the other five TUBA1A cases it was located only in the left hemisphere or in both hemispheres. The postero-superior region of the cerebellar hemispheres was most frequently affected. CONCLUSIONS: The cerebellar involvement in tubulinopathies shows specific features that may be labelled as 'tubulin-related CD'. This pattern is unique and differs from other genetic causes of cerebellar dysplasia. KEY POINTS: ⢠Cortical cerebellar dysplasia without cysts is suggestive of tubulin-related disorder. ⢠Cerebellar dysplasia in tubulinopathies shows specific features labelled as 'tubulin-related CD'. ⢠Focal and unilateral involvement of cerebellar hemispheres has important implications for counselling.
Assuntos
Cerebelo/anormalidades , Mutação , Malformações do Sistema Nervoso/diagnóstico por imagem , Neuroimagem/métodos , Tubulina (Proteína)/genética , Adulto , Tronco Encefálico/diagnóstico por imagem , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/patologia , Adulto JovemAssuntos
Cateteres de Demora/microbiologia , Cateteres Venosos Centrais/microbiologia , Neoplasias Cerebelares/tratamento farmacológico , Sistemas de Liberação de Medicamentos/efeitos adversos , Meduloblastoma/tratamento farmacológico , Cateteres de Demora/efeitos adversos , Neoplasias Cerebelares/líquido cefalorraquidiano , Neoplasias Cerebelares/microbiologia , Neoplasias Cerebelares/cirurgia , Ventriculite Cerebral/líquido cefalorraquidiano , Ventriculite Cerebral/etiologia , Ventriculite Cerebral/microbiologia , Feminino , Humanos , Lactente , Injeções Intraventriculares , Meduloblastoma/líquido cefalorraquidiano , Meduloblastoma/microbiologia , Meduloblastoma/cirurgia , Meningites Bacterianas/líquido cefalorraquidiano , Meningites Bacterianas/etiologia , Meningites Bacterianas/microbiologia , Infecções Estafilocócicas/etiologia , Infecções Estafilocócicas/microbiologia , Staphylococcus epidermidis/isolamento & purificaçãoRESUMO
Rhino-orbito-cerebral mucormycosis is a rare fulminant opportunistic fungal infection that particularly occurs in immunocompromised patients. We present a case of fatal invasive rhino-orbito-cerebral mucormycosis complicated by bilateral thrombotic occlusion of the internal carotid artery with consequent cerebral infarction in a 5-year-old boy after hematopoietic stem cell transplantation for acute pre-B-cell lymphoblastic leukemia.