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OBJECTIVES: This UK-wide study defines the natural history of argininosuccinic aciduria and compares long-term neurological outcomes in patients presenting clinically or treated prospectively from birth with ammonia-lowering drugs. METHODS: Retrospective analysis of medical records prior to March 2013, then prospective analysis until December 2015. Blinded review of brain MRIs. ASL genotyping. RESULTS: Fifty-six patients were defined as early-onset (n = 23) if symptomatic < 28 days of age, late-onset (n = 23) if symptomatic later, or selectively screened perinatally due to a familial proband (n = 10). The median follow-up was 12.4 years (range 0-53). Long-term outcomes in all groups showed a similar neurological phenotype including developmental delay (48/52), epilepsy (24/52), ataxia (9/52), myopathy-like symptoms (6/52) and abnormal neuroimaging (12/21). Neuroimaging findings included parenchymal infarcts (4/21), focal white matter hyperintensity (4/21), cortical or cerebral atrophy (4/21), nodular heterotopia (2/21) and reduced creatine levels in white matter (4/4). 4/21 adult patients went to mainstream school without the need of additional educational support and 1/21 lives independently. Early-onset patients had more severe involvement of visceral organs including liver, kidney and gut. All early-onset and half of late-onset patients presented with hyperammonaemia. Screened patients had normal ammonia at birth and received treatment preventing severe hyperammonaemia. ASL was sequenced (n = 19) and 20 mutations were found. Plasma argininosuccinate was higher in early-onset compared to late-onset patients. CONCLUSIONS: Our study further defines the natural history of argininosuccinic aciduria and genotype-phenotype correlations. The neurological phenotype does not correlate with the severity of hyperammonaemia and plasma argininosuccinic acid levels. The disturbance in nitric oxide synthesis may be a contributor to the neurological disease. Clinical trials providing nitric oxide to the brain merit consideration.
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Aciduria Argininosuccínica/patología , Aciduria Argininosuccínica/terapia , Adolescente , Adulto , Amoníaco/metabolismo , Ácido Argininosuccínico/sangre , Aciduria Argininosuccínica/sangre , Aciduria Argininosuccínica/genética , Niño , Preescolar , Femenino , Estudios de Seguimiento , Genotipo , Humanos , Hiperamonemia/metabolismo , Hiperamonemia/patología , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Mutación/genética , Fenotipo , Estudios Prospectivos , Estudios Retrospectivos , Adulto JovenRESUMEN
Neonates treated for acute respiratory failure experience episodes of hypoxia. The hippocampus, a structure essential for memory, is particularly vulnerable to such insults. Hence, some neonates undergoing treatment for acute respiratory failure might sustain bilateral hippocampal pathology early in life and memory problems later in childhood. We investigated this possibility in a cohort of 40 children who had been treated neonatally for acute respiratory failure but were free of overt neurological impairment. The cohort had mean hippocampal volumes (HVs) significantly below normal control values, memory scores significantly below the standard population means, and memory quotients significantly below those predicted by their full scale IQs. Brain white matter volume also fell below the volume of the controls, but brain gray matter volumes and scores on nonmnemonic neuropsychological tests were within the normal range. Stepwise linear regression models revealed that the cohort's HVs were predictive of degree of memory impairment, and gestational age at treatment was predictive of HVs: the younger the age, the greater the atrophy. We conclude that many neonates treated for acute respiratory failure sustain significant hippocampal atrophy as a result of the associated hypoxia and, consequently, show deficient memory later in life.
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Hipocampo/patología , Trastornos de la Memoria/etiología , Síndrome de Dificultad Respiratoria/complicaciones , Síndrome de Dificultad Respiratoria/patología , Adolescente , Atrofia/etiología , Lista de Verificación , Niño , Estudios de Cohortes , Demografía , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Pruebas de Inteligencia , Imagen por Resonancia Magnética , Masculino , Pruebas Neuropsicológicas , Área Pretectal , Estadística como Asunto , Aprendizaje VerbalRESUMEN
The first described patients with pyridox(am)ine 5'-phosphate oxidase deficiency all had neonatal onset seizures that did not respond to treatment with pyridoxine but responded to treatment with pyridoxal 5'-phosphate. Our data suggest, however, that the clinical spectrum of pyridox(am)ine 5'-phosphate oxidase deficiency is much broader than has been reported in the literature. Sequencing of the PNPO gene was undertaken for a cohort of 82 individuals who had shown a reduction in frequency and severity of seizures in response to pyridoxine or pyridoxal 5'-phosphate. Novel sequence changes were studied using a new cell-free expression system and a mass spectrometry-based assay for pyridoxamine phosphate oxidase. Three groups of patients with PNPO mutations that had reduced enzyme activity were identified: (i) patients with neonatal onset seizures responding to pyridoxal 5'-phosphate (n = 6); (ii) a patient with infantile spasms (onset 5 months) responsive to pyridoxal 5'-phosphate (n = 1); and (iii) patients with seizures starting under 3 months of age responding to pyridoxine (n = 8). Data suggest that certain genotypes (R225H/C and D33V) are more likely to result in seizures that to respond to treatment with pyridoxine. Other mutations seem to be associated with infertility, miscarriage and prematurity. However, the situation is clearly complex with the same combination of mutations being seen in patients who responded and did not respond to pyridoxine. It is possible that pyridoxine responsiveness in PNPO deficiency is affected by prematurity and age at the time of the therapeutic trial. Other additional factors that are likely to influence treatment response and outcome include riboflavin status and how well the foetus has been supplied with vitamin B6 by the mother. For some patients there was a worsening of symptoms on changing from pyridoxine to pyridoxal 5'-phosphate. Many of the mutations in PNPO affected residues involved in binding flavin mononucleotide or pyridoxal 5'-phosphate and many of them showed residual enzyme activity. One sequence change (R116Q), predicted to affect flavin mononucleotide binding and binding of the two PNPO dimers, and with high residual activity was found in Groups (ii) and (iii). This sequence change has been reported in the 1000 Genomes project suggesting it could be a polymorphism but alternatively it could be a common mutation, perhaps responsible for the susceptibility locus for genetic generalized epilepsy on 17q21.32 (close to rs72823592). We believe the reduction in PNPO activity and B6-responsive epilepsy in the patients reported here indicates that it contributes to the pathogenesis of epilepsy.
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Ambiente , Epilepsia/genética , Mutación/genética , Piridoxaminafosfato Oxidasa/genética , Anticonvulsivantes/uso terapéutico , Niño , Preescolar , Electroencefalografía , Epilepsia/terapia , Femenino , Células HeLa , Humanos , Lactante , Masculino , Mutagénesis Sitio-Dirigida/métodos , Fosfato de Piridoxal/uso terapéutico , Piridoxaminafosfato Oxidasa/metabolismo , Transfección , Adulto JovenRESUMEN
We describe a previously unreported syndrome characterized by secondary (post-natal) microcephaly with fronto-temporal lobe hypoplasia, multiple pituitary hormone deficiency, seizures, severe visual impairment and abnormalities of the kidneys and urinary tract in a highly consanguineous family with six affected children. Homozygosity mapping and exome sequencing revealed a novel homozygous frameshift mutation in the basic helix-loop-helix transcription factor gene ARNT2 (c.1373_1374dupTC) in affected individuals. This mutation results in absence of detectable levels of ARNT2 transcript and protein from patient fibroblasts compared with controls, consistent with nonsense-mediated decay of the mutant transcript and loss of ARNT2 function. We also show expression of ARNT2 within the central nervous system, including the hypothalamus, as well as the renal tract during human embryonic development. The progressive neurological abnormalities, congenital hypopituitarism and post-retinal visual pathway dysfunction in affected individuals demonstrates for the first time the essential role of ARNT2 in the development of the hypothalamo-pituitary axis, post-natal brain growth, and visual and renal function in humans.
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Translocador Nuclear del Receptor de Aril Hidrocarburo/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Hipopituitarismo/genética , Riñón/anomalías , Microcefalia/genética , Mutación/genética , Hormonas Hipofisarias/metabolismo , Percepción Visual , Niño , Preescolar , Femenino , Humanos , Hipopituitarismo/diagnóstico , Hipotálamo/metabolismo , Riñón/metabolismo , Masculino , Microcefalia/diagnóstico , Hormonas Hipofisarias/genética , Síndrome , Factores de TranscripciónRESUMEN
BACKGROUND: Premature birth may be associated with white matter injury later developing with widening of the ventricles. However, population-based data on normal ventricular size by age are sparse, making the evaluation of possible ventricular dilatation difficult. PURPOSE: To present the linear measurements of the ventricular system, to compare these to subjectively assessed ventricular size, and to examine differences in ventricular size between ex-prematures and controls. MATERIAL AND METHODS: Eligible survivors (n = 113) from the initial birth cohort (n = 217, born in 1986-1988, birth weight <2000 g) underwent MRI during 2006-2007. One hundred and three were ex-premature and included in the study. The ventricular size was subjectively judged by a pediatric neuroradiologist, and scored as normal, mildly, moderately, or severely dilated. Objective measurements, including width and depth of the frontal and occipital horns, were performed in a blinded fashion, by a pediatric radiologist. RESULTS: The normative standards for different parts of the ventricular system in ex-premature young adults varied considerably. We found significant associations between the objective measurements and the subjectively classification of ventricular dilatation. Ex-prematures had smaller heads than those born term (control group). After adjustment for head circumference, there were no significant group differences regarding the frontal horns, but the occipital horns were proportionately wider among ex-prematures. CONCLUSION: Young adults born prematurely, with a birth weight <2000 g, do not have larger lateral ventricles than healthy controls born term, even after correcting for a smaller head size. However, they do have larger occipital horns, confirming previous studies and strengthening our belief of a specific vulnerability of the occipital region.
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Ventrículos Cerebrales/patología , Imagen por Resonancia Magnética/métodos , Nacimiento Prematuro , Femenino , Humanos , Masculino , Noruega , Adulto JovenRESUMEN
There remains a misconception that arterial ischaemic stroke (AIS) is a rare childhood disorder. Approximately 2-6/100,000 children are affected annually, and it is one of the top ten causes of childhood death. Following the ictus, up to 25% of children will have a recurrence, and two thirds of children will have a long-term disability with considerable socio-economic burden. The established vascular risk factors seen in adult stroke are rare in children. Instead, childhood AIS is associated with a variety of underlying aetiologies, including cerebral arteriopathies, sickle cell disease, cardio-embolic disease, infection, head and neck trauma, genetic/metabolic disease and prothrombotic abnormalities. Approximately 50% of children will have another recognised medical condition, and many children will have multiple risk factors. Given the complexity of the presentation and the potential ambiguity of the clinical findings, imaging is often the most revealing aspect of the diagnostic workup during both an acute and chronic presentation. This review considers the practical issues related to imaging children and looks at some of the controversies pertaining to aetiology and its implication for stroke management. It aims to give an overview of childhood arterial ischaemic stroke and to highlight the importance of both acute and delayed vascular imaging in the diagnosis, management and stratification of further stroke risk.
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Isquemia Encefálica/diagnóstico , Isquemia Encefálica/etiología , Enfermedades Arteriales Intracraneales/complicaciones , Enfermedades Arteriales Intracraneales/diagnóstico , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/etiología , Adolescente , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Imagen por Resonancia Magnética/métodos , Masculino , Tomografía Computarizada por Rayos X/métodosRESUMEN
Bilateral basal ganglia abnormalities on MRI are observed in a wide variety of childhood disorders. MRI pattern recognition can enable rationalization of investigations and also complement clinical and molecular findings, particularly confirming genomic findings and also enabling new gene discovery. A pattern recognition approach in children with bilateral basal ganglia abnormalities on brain MRI was undertaken in this international multicentre cohort study. Three hundred and five MRI scans belonging to 201 children with 34 different disorders were rated using a standard radiological scoring proforma. In addition, literature review on MRI patterns was undertaken in these 34 disorders and 59 additional disorders reported with bilateral basal ganglia MRI abnormalities. Cluster analysis on first MRI findings from the study cohort grouped them into four clusters: Cluster 1-T2-weighted hyperintensities in the putamen; Cluster 2-T2-weighted hyperintensities or increased MRI susceptibility in the globus pallidus; Cluster 3-T2-weighted hyperintensities in the globus pallidus, brainstem and cerebellum with diffusion restriction; Cluster 4-T1-weighted hyperintensities in the basal ganglia. The 34 diagnostic categories included in this study showed dominant clustering in one of the above four clusters. Inflammatory disorders grouped together in Cluster 1. Mitochondrial and other neurometabolic disorders were distributed across clusters 1, 2 and 3, according to lesions dominantly affecting the striatum (Cluster 1: glutaric aciduria type 1, propionic acidaemia, 3-methylglutaconic aciduria with deafness, encephalopathy and Leigh-like syndrome and thiamine responsive basal ganglia disease associated with SLC19A3), pallidum (Cluster 2: methylmalonic acidaemia, Kearns Sayre syndrome, pyruvate dehydrogenase complex deficiency and succinic semialdehyde dehydrogenase deficiency) or pallidum, brainstem and cerebellum (Cluster 3: vigabatrin toxicity, Krabbe disease). The Cluster 4 pattern was exemplified by distinct T1-weighted hyperintensities in the basal ganglia and other brain regions in genetically determined hypermanganesemia due to SLC39A14 and SLC30A10. Within the clusters, distinctive basal ganglia MRI patterns were noted in acquired disorders such as cerebral palsy due to hypoxic ischaemic encephalopathy in full-term babies, kernicterus and vigabatrin toxicity and in rare genetic disorders such as 3-methylglutaconic aciduria with deafness, encephalopathy and Leigh-like syndrome, thiamine responsive basal ganglia disease, pantothenate kinase-associated neurodegeneration, TUBB4A and hypermanganesemia. Integrated findings from the study cohort and literature review were used to propose a diagnostic algorithm to approach bilateral basal ganglia abnormalities on MRI. After integrating clinical summaries and MRI findings from the literature review, we developed a prototypic decision-making electronic tool to be tested using further cohorts and clinical practice.
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The transcription factor SOX2 is expressed most notably in the developing CNS and placodes, where it plays critical roles in embryogenesis. Heterozygous de novo mutations in SOX2 have previously been associated with bilateral anophthalmia/microphthalmia, developmental delay, short stature, and male genital tract abnormalities. Here we investigated the role of Sox2 in murine pituitary development. Mice heterozygous for a targeted disruption of Sox2 did not manifest eye defects, but showed abnormal anterior pituitary development with reduced levels of growth hormone, luteinizing hormone, and thyroid-stimulating hormone. Consequently, we identified 8 individuals (from a cohort of 235 patients) with heterozygous sequence variations in SOX2. Six of these were de novo mutations, predicted to result in truncated protein products, that exhibited partial or complete loss of function (DNA binding, nuclear translocation, or transactivation). Clinical evaluation revealed that, in addition to bilateral eye defects, SOX2 mutations were associated with anterior pituitary hypoplasia and hypogonadotropic hypogonadism, variable defects affecting the corpus callosum and mesial temporal structures, hypothalamic hamartoma, sensorineural hearing loss, and esophageal atresia. Our data show that SOX2 is necessary for the normal development and function of the hypothalamo-pituitary and reproductive axes in both humans and mice.
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Proteínas de Unión al ADN/genética , Anomalías del Ojo/genética , Proteínas HMGB/genética , Hipotálamo/anomalías , Mutación , Hipófisis/anomalías , Transactivadores/genética , Factores de Transcripción/genética , Anomalías Múltiples/genética , Adulto , Animales , Niño , Femenino , Humanos , Lactante , Masculino , Ratones , Factores de Transcripción SOXB1RESUMEN
BACKGROUND: Advances in molecular genetic technologies have improved our understanding of genetic causes of rare neurological disorders with features of myoclonus. CASE REPORT: A family with two affected siblings, presenting with multifocal polymyoclonus and neurodevelopmental delay, was recruited for whole-exome sequencing following unyielding diagnostic neurometabolic investigations. Compound heterozygous mutations in TBC1D24, a gene previously associated with various epilepsy phenotypes and hearing loss, were identified in both siblings. The mutations included a missense change c.457G>A (p.Glu157Lys), and a novel frameshift mutation c.545del (p.Thr182Serfs*6). DISCUSSION: We propose that TBC1D24-related diseases should be in the differential diagnosis for children with polymyoclonus.
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BACKGROUND: TRNT1 (CCA-adding transfer RNA nucleotidyl transferase) enzyme deficiency is a new metabolic disease caused by defective post-transcriptional modification of mitochondrial and cytosolic transfer RNAs (tRNAs). RESULTS: We investigated four patients from two families with infantile-onset cyclical, aseptic febrile episodes with vomiting and diarrhoea, global electrolyte imbalance during these episodes, sideroblastic anaemia, B lymphocyte immunodeficiency, retinitis pigmentosa, hepatosplenomegaly, exocrine pancreatic insufficiency and renal tubulopathy. Other clinical features found in children include sensorineural deafness, cerebellar atrophy, brittle hair, partial villous atrophy and nephrocalcinosis. Whole exome sequencing and bioinformatic filtering were utilised to identify recessive compound heterozygous TRNT1 mutations (missense mutation c.668T>C, p.Ile223Thr and a novel splice mutation c.342+5G>T) segregating with disease in the first family. The second family was found to have a homozygous TRNT1 mutation (c.569G>T), p.Arg190Ile, (previously published). We found normal mitochondrial translation products using passage matched controls and functional perturbation of 3' CCA addition to mitochondrial tRNAs (tRNA(Cys), tRNA(LeuUUR) and tRNA(His)) in fibroblasts from two patients, demonstrating a pathomechanism affecting the CCA addition to mt-tRNAs. Acute management of these patients included transfusion for anaemia, fluid and electrolyte replacement and immunoglobulin therapy. We also describe three-year follow-up findings after treatment by bone marrow transplantation in one patient, with resolution of fever and reversal of the abnormal metabolic profile. CONCLUSIONS: Our report highlights that TRNT1 mutations cause a spectrum of disease ranging from a childhood-onset complex disease with manifestations in most organs to an adult-onset isolated retinitis pigmentosa presentation. Systematic review of all TRNT1 cases and mutations reported to date revealed a distinctive phenotypic spectrum and metabolic and other investigative findings, which will facilitate rapid clinical recognition of future cases.
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Enfermedades Mitocondriales/genética , Nucleotidiltransferasas/deficiencia , Anemia Sideroblástica/genética , Discapacidades del Desarrollo/genética , Humanos , Mutación/genética , Nucleotidiltransferasas/genética , Biosíntesis de Proteínas/genética , ARN de Transferencia/genéticaRESUMEN
Common birthmarks can be an indicator of underlying genetic disease but are often overlooked. Mongolian blue spots (dermal melanocytosis) are usually localized and transient, but they can be extensive, permanent, and associated with extracutaneous abnormalities. Co-occurrence with vascular birthmarks defines a subtype of phakomatosis pigmentovascularis, a group of syndromes associated with neurovascular, ophthalmological, overgrowth, and malignant complications. Here, we discover that extensive dermal melanocytosis and phakomatosis pigmentovascularis are associated with activating mutations in GNA11 and GNAQ, genes that encode Gα subunits of heterotrimeric G proteins. The mutations were detected at very low levels in affected tissues but were undetectable in the blood, indicating that these conditions are postzygotic mosaic disorders. In vitro expression of mutant GNA11(R183C) and GNA11(Q209L) in human cell lines demonstrated activation of the downstream p38 MAPK signaling pathway and the p38, JNK, and ERK pathways, respectively. Transgenic mosaic zebrafish models expressing mutant GNA11(R183C) under promoter mitfa developed extensive dermal melanocytosis recapitulating the human phenotype. Phakomatosis pigmentovascularis and extensive dermal melanocytosis are therefore diagnoses in the group of mosaic heterotrimeric G-protein disorders, joining McCune-Albright and Sturge-Weber syndromes. These findings will allow accurate clinical and molecular diagnosis of this subset of common birthmarks, thereby identifying infants at risk for serious complications, and provide novel therapeutic opportunities.
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Subunidades alfa de la Proteína de Unión al GTP/genética , Mancha Mongólica/genética , Mutación , Síndromes Neurocutáneos/genética , Enfermedades de la Piel/genética , Alelos , Animales , Animales Modificados Genéticamente , Secuencia de Bases , Análisis Mutacional de ADN , Subunidades alfa de la Proteína de Unión al GTP Gq-G11 , Células HEK293 , Humanos , Lactante , Datos de Secuencia Molecular , Mutación Missense , Fenotipo , Fosforilación , Transducción de Señal , Pez CebraRESUMEN
Synaptotagmin-1 (SYT1) is a calcium-binding synaptic vesicle protein that is required for both exocytosis and endocytosis. Here, we describe a human condition associated with a rare variant in SYT1. The individual harboring this variant presented with an early onset dyskinetic movement disorder, severe motor delay, and profound cognitive impairment. Structural MRI was normal, but EEG showed extensive neurophysiological disturbances that included the unusual features of low-frequency oscillatory bursts and enhanced paired-pulse depression of visual evoked potentials. Trio analysis of whole-exome sequence identified a de novo SYT1 missense variant (I368T). Expression of rat SYT1 containing the equivalent human variant in WT mouse primary hippocampal cultures revealed that the mutant form of SYT1 correctly localizes to nerve terminals and is expressed at levels that are approximately equal to levels of endogenous WT protein. The presence of the mutant SYT1 slowed synaptic vesicle fusion kinetics, a finding that agrees with the previously demonstrated role for I368 in calcium-dependent membrane penetration. Expression of the I368T variant also altered the kinetics of synaptic vesicle endocytosis. Together, the clinical features, electrophysiological phenotype, and in vitro neuronal phenotype associated with this dominant negative SYT1 mutation highlight presynaptic mechanisms that mediate human motor control and cognitive development.
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Discapacidad Intelectual/genética , Trastornos de la Destreza Motora/genética , Trastornos del Movimiento/genética , Mutación Missense , Mutación Puntual , Terminales Presinápticos/fisiología , Vesículas Sinápticas/fisiología , Sinaptotagmina I/fisiología , Secuencia de Aminoácidos , Animales , Calcio/metabolismo , Células Cultivadas , Niño , Endocitosis/genética , Endocitosis/fisiología , Potenciales Evocados Visuales , Exocitosis/genética , Exocitosis/fisiología , Genes Dominantes , Hipocampo/citología , Humanos , Cinética , Masculino , Fusión de Membrana , Ratones , Datos de Secuencia Molecular , Ratas , Proteínas Recombinantes de Fusión/metabolismo , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Sinaptotagmina I/genéticaRESUMEN
PURPOSE: To describe a case of ocular tilt reaction caused by vasculitic lesions in the midbrain in a child with polyarteritis nodosa. DESIGN: Observational case report. METHODS: A 5-year-old girl with a chronic illness developed diplopia associated with a left head tilt, right hypertropia, torsional nystagmus, slowed vertical saccades and poor convergence. Fundoscopic examination demonstrated conjugate leftward torsion of the eyes consistent with a sustained ocular tilt reaction.Renal angiography confirmed polyarteritis nodosa and cerebral magnetic resonance imaging demonstrated mesencephalic pathology. CONCLUSIONS: Polyarteritis nodosa is a difficult condition to diagnose in a child and can cause brainstem lesions. This rare case of ocular tilt reaction of midbrain origin highlights that a sustained head tilt in a child can be due to brainstem pathology, rather than a fourth nerve palsy.
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Encefalopatías/etiología , Diplopía/etiología , Nistagmo Patológico/etiología , Poliarteritis Nudosa/complicaciones , Estrabismo/etiología , Tegmento Mesencefálico/patología , Aspirina/uso terapéutico , Encefalopatías/diagnóstico , Encefalopatías/tratamiento farmacológico , Preescolar , Ciclofosfamida/uso terapéutico , Diplopía/tratamiento farmacológico , Quimioterapia Combinada , Femenino , Movimientos de la Cabeza , Humanos , Enfermedades Renales/diagnóstico por imagen , Enfermedades Renales/tratamiento farmacológico , Imagen por Resonancia Magnética , Nistagmo Patológico/tratamiento farmacológico , Poliarteritis Nudosa/tratamiento farmacológico , Prednisolona/uso terapéutico , Radiografía , Ranitidina/uso terapéutico , Movimientos Sacádicos , Estrabismo/tratamiento farmacológico , Tegmento Mesencefálico/efectos de los fármacosRESUMEN
Wernicke's encephalopathy is a triad of ophthalmoplegia, ataxia and confusion seen in alcoholics with dietary vitamin B1 (thiamine) deficiency. A rare genetic defect of thiamine transporter-2 may lead to similar clinical features, biotin-thiamine responsive basal ganglia disease (BTBGD). A 15-year-old girl developed rapid onset ptosis and ophthalmoplegia evolving into a subacute encephalopathy. Neuroimaging demonstrated symmetrical basal ganglia and mid-brain lesions reminiscent of Leigh's subacute necrotising encephalomyelopathy. Oral biotin and thiamine were started, and symptoms improved dramatically the next day. The therapeutic response suggested SLC19A3, encoding thiamine transporter-2, as a strong candidate gene and Sanger sequencing revealed a novel homozygous c.517A>G;p.Asn173Asp mutation, which segregated with disease within the family. BTBGD is a potentially treatable neurological disorder and should be considered in the differential diagnosis of Leigh syndrome and Wernicke's encephalopathy. Since delayed treatment results in permanent neurological dysfunction or death, prompt diagnosis and early initiation of biotin and thiamine therapy are essential.
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Biotina/uso terapéutico , Tiamina/uso terapéutico , Encefalopatía de Wernicke/diagnóstico , Encefalopatía de Wernicke/tratamiento farmacológico , Adolescente , Biopsia , Diagnóstico Diferencial , Diagnóstico por Imagen , Femenino , Humanos , Encefalopatía de Wernicke/genéticaRESUMEN
BACKGROUND: Over half of childhood intracranial ependymomas occur in children younger than 5 years. As an adjuvant treatment, radiotherapy can be effective, but has the potential to damage the child's developing nervous system at a crucial time-with a resultant reduction in IQ and cognitive impairment, endocrinopathy, and risk of second malignancy. We aimed to assess the role of a primary chemotherapy strategy in avoiding or delaying radiotherapy in children younger than 3 years with intracranial ependymoma. METHODS: Between December, 1992, and April, 2003, we enrolled 89 children with ependymoma who were aged 3 years or younger at diagnosis, of whom nine had metastatic disease on pre-operative imaging. After maximal surgical resection, children received alternating blocks of myelosuppressive and non-myelosuppressive chemotherapy every 14 days for an intended duration of 1 year. Radiotherapy was withheld unless local imaging (ie, from the child's treatment centre) showed progressive disease. FINDINGS: 50 of the 80 patients with non-metastatic disease progressed, 34 of whom were irradiated for progression. The 5-year cumulative incidence of freedom from radiotherapy for the 80 non-metastatic patients was 42% (95% CI 32-53). With a median follow-up of 6 years (range 1.5-11.3), overall survival for the non-metastatic patients at 3 years was 79.3% (95% CI 68.5-86.8) and at 5 years 63.4% (51.2-73.4). The corresponding values for event-free survival were 47.6% (36.2-58.1) and 41.8% (30.7-52.6). There was no significant difference in event-free or overall survival between complete and incomplete surgical resection, nor did survival differ according to histological grade, age at diagnosis, or site of disease. In 47 of 59 (80%) patients who progressed, relapse resulted from local control only. The median time to progression for the 59 patients who progressed was 1.6 years (range 0.1-10.2 years). The median age at irradiation of the whole group was 3.6 years (range 1.5-11.9). For the 80 non-metastatic patients, the 23 who achieved the highest relative dose intensity of chemotherapy had the highest post-chemotherapy 5-year overall survival of 76% (95% CI 46.6-91.2), compared with 52% (33.3-68.1) for the 32 patients who achieved the lowest relative dose intensity of chemotherapy. INTERPRETATION: This protocol avoided or delayed radiotherapy in a substantial proportion of children younger than 3 years without compromising survival. These results suggest, therefore, that primary chemotherapy strategies have an important role in the treatment of very young children with intracranial ependymoma.