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1.
Int J Mol Sci ; 19(7)2018 07 06.
Artículo en Inglés | MEDLINE | ID: mdl-29986434

RESUMEN

Early infantile epileptic encephalopathies (EIEEs) are a group of neurological disorders characterized by early-onset refractory seizures, severe electroencephalographic abnormalities, and developmental delay or intellectual disability. Recently, genetic studies have indicated that a significant portion of previously cryptogenic EIEEs are single-gene disorders. SPTAN1 is among the genes whose mutations are associated with EIEE development (OMIM# 613477). Here, a case of the c.6923_6928dup (p.Arg2308_Met2309dup) SPTAN1 mutation associated with a severe EIEE is reported. This case shows that mutations in the α20 repeat in the C-terminal of αII spectrin can be associated with EIEE. Duplication seems essential to cause EIEE. This causation is not demonstrated for amino acid deletions in the same spectrin residues. Reportedly, children with p.(Asp2303_Leu2305del) and p.(Gln2304_Gly2306del) deletions have childhood-onset epilepsy and no or marginal magnetic resonance imaging abnormalities, suggesting that not only the location but also the type of mutation plays a role in conditioning nervous system damage. Further studies are needed for a better understanding of the phenotype/genotype correlation in SPTAN1-related encephalopathies.


Asunto(s)
Proteínas Portadoras/genética , Proteínas de Microfilamentos/genética , Mutación , Espasmos Infantiles/genética , Encéfalo/fisiopatología , Preescolar , Electroencefalografía , Estudios de Asociación Genética , Tamización de Portadores Genéticos , Genotipo , Humanos , Imagen por Resonancia Magnética , Masculino , Fenotipo , Espasmos Infantiles/sangre , Espasmos Infantiles/diagnóstico por imagen
2.
J Child Neurol ; 33(12): 767-771, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30032694

RESUMEN

There have been few case reports showing association of vitamin B12 deficiency with infantile spasms. We planned this study to see if there was an association of serum vitamin B12 deficiency in children with development of infantile spasms. Cases included children with infantile spasms of ages 6 months to 3 years. The controls were children in the same age group who had global developmental delay but no history of epileptic spasms. Mean serum vitamin B12, serum homocysteine, and urinary methylmalonic acid levels were measured in both groups and compared. Children with infantile spasms had lower mean serum vitamin B12 levels (354.1 pg/mL; standard deviation 234.1 pg/mL) as compared to children with global developmental delay without spasms (466.7 pg/mL; standard deviation 285.5 pg/mL) ( P value < .05). Mean serum homocysteine level (13.9 vs 7.8 µmol/L, P = .02) and mean urinary methylmalonic acid level (68.1 mmol/mol of creatinine vs 26.1 mmol/mol of creatinine, P = .03) were elevated in children with infantile spasms than in controls. Fourteen children (35.0%) with infantile spasms were vitamin B12 deficient compared with 3 (7.50%) controls ( P = .005). Thus, vitamin B12 deficiency may have an association with infantile spasms. More studies are needed before recommending routine measurement of serum B12 levels in children with infantile spasms.


Asunto(s)
Espasmos Infantiles/complicaciones , Deficiencia de Vitamina B 12/complicaciones , Asfixia Neonatal/complicaciones , Estudios de Casos y Controles , Preescolar , Discapacidades del Desarrollo/sangre , Discapacidades del Desarrollo/etiología , Discapacidades del Desarrollo/orina , Femenino , Homocisteína/sangre , Humanos , Lactante , Masculino , Ácido Metilmalónico/orina , Estudios Retrospectivos , Espasmos Infantiles/sangre , Espasmos Infantiles/etiología , Espasmos Infantiles/orina , Vitamina B 12/sangre , Deficiencia de Vitamina B 12/sangre , Deficiencia de Vitamina B 12/etiología , Deficiencia de Vitamina B 12/orina
3.
J Child Neurol ; 33(8): 528-533, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29724126

RESUMEN

Adrenocorticotropic hormone (ACTH) therapy is effective for West syndrome; however, the underlying mechanism of action remains unknown. This study explored this mechanism in 5 Japanese patients with West syndrome, injected with ACTH for 28 days. Serum samples were obtained before and 30, 120, and 720 minutes after ACTH injection divided into an "early" (1-4 days) and a "late" (10-28 days) group. Responses to ACTH over time were analyzed by measuring the levels of 27 cytokines. In the early group, serum levels of interleukins-5, -9, and -17, basic fibroblast growth factor, interferon (IFN-γ), IFN-γ-inducible protein 10, chemokine ligand (CCL) 3 and 4, and platelet-derived growth factor were higher in all patients before ACTH administration than in the 720-minute time point. In the late group, no definite trend was observed except for decreased CCL2 levels after ACTH administration. These changes may correlate with mechanisms underlying the anticonvulsant effects of ACTH.


Asunto(s)
Hormona Adrenocorticotrópica/uso terapéutico , Anticonvulsivantes/uso terapéutico , Citocinas/sangre , Espasmos Infantiles/sangre , Espasmos Infantiles/tratamiento farmacológico , Biomarcadores/sangre , Humanos , Lactante , Espasmos Infantiles/inmunología , Resultado del Tratamiento
4.
Metab Brain Dis ; 32(6): 2131-2137, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28900819

RESUMEN

We describe two sisters from a consanguineous Arab family with global developmental delay, dystrophy, axial hypotonia, epileptic encephalopathy dominated by intractable complex partial seizures that were resistant to various anti-epileptic treatments. Dysmorphic features comprised low set ears, hypertelorism, upslanting palpebral fissures, a broad nasal bridge, and blue sclera with elongated eyelashes. Brain MRI in both children showed a corpus callosum hypoplasia that was evident already in utero and evolving cortical atrophy. Autozygosity mapping in combination with Whole Exome Sequencing revealed a homozygous missense mutation in the PIGO gene [c.765G > A, NM_032634.3] that affected a highly conserved methionine in the alkaline phosphatase-like core domain of the protein [p.(Met255Ile), NP_116023.2]. PIGO encodes the GPI-ethanolamine phosphate transferase 3, which is crucial for the final synthetic step of the glycosylphosphatidylinositol-anchor that attaches many enzymes to their cell surfaces, such as the alkaline phosphatase and granulocyte surface markers. Interestingly, measurement of serum alkaline phosphatase activities in both children was normal or only slightly elevated. Quantification of granulocyte surface antigens CD16/24/59 yielded reduced levels only for CD59. Phenotype analysis of our and other published patients with PIGO mutations reveals a more severe affectation and predominantly neurological presentation in individuals carrying a mutation in the alkaline phosphatase-like core domain thereby hinting towards a genotype-phenotype relation for PIGO gene mutations.


Asunto(s)
Agenesia del Cuerpo Calloso/genética , Fosfatasa Alcalina/sangre , Encéfalo/diagnóstico por imagen , Proteínas de la Membrana/genética , Mutación , Espasmos Infantiles/genética , Agenesia del Cuerpo Calloso/sangre , Agenesia del Cuerpo Calloso/diagnóstico por imagen , Preescolar , Femenino , Homocigoto , Humanos , Lactante , Espasmos Infantiles/sangre , Espasmos Infantiles/diagnóstico por imagen , Ultrasonografía
5.
Seizure ; 41: 112-5, 2016 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-27525580

RESUMEN

PURPOSE: Infantile spasm is an age-dependent epileptic syndrome seen in infancy or early childhood. Although studies have investigated the epilepsy-cytokine relationship, there has been insufficient research into the relation between cytokines and infantile spasm. The purpose of this study was to examine the role of cytokines in the pathogenesis of infantile spasm by investigating cytokine levels before and 1month after adrenocorticotropic hormone (ACTH) therapy in patients diagnosed with the condition. METHOD: Twenty patients aged between 1month and 2years and diagnosed with infantile spasm at the Karadeniz Technical University Medical Faculty Department of Child Health and Diseases Pediatric Neurology Clinic, Turkey, and 20 healthy children were included in the study. Patients received 11 doses of ACTH on 2days a week. Levels of TNF-alpha and IL-2, the main cytokines involved in inflammation and recently associated with infantile spasm, and of IL-1beta, IL-6 and IL-17A, associated with epileptic seizures, and serum levels of the IL-17A activator IL-23 were investigated in all patients at the start of treatment and 1month after completion of treatment. RESULTS: No statistically significant difference was observed between pre- and post-treatment patient group and control group IL-1beta, IL-2, IL-23 or TNF-alpha levels. Pre-treatment IL-6 and IL-17A levels were significantly higher in the untreated patient group compared to the healthy control group (p<0.001 and p=0.002). CONCLUSION: Our study supports the recent idea that IL-6 and IL-17A are cytokines involved in the pathogenesis of infantile spasm.


Asunto(s)
Hormona Adrenocorticotrópica/uso terapéutico , Citocinas/sangre , Hormonas/uso terapéutico , Espasmos Infantiles/sangre , Espasmos Infantiles/tratamiento farmacológico , Preescolar , Femenino , Humanos , Lactante , Masculino , Turquia
6.
J Inherit Metab Dis ; 39(5): 733-741, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27342130

RESUMEN

BACKGROUND: Recent decades have unravelled the molecular background of a number of inborn errors of metabolism (IEM) causing vitamin B6-dependent epilepsy. As these defects interfere with vitamin B6 metabolism by different mechanisms, the plasma vitamin B6 profile can give important clues for further molecular work-up. This has so far been investigated in only a small number of patients. METHODS: We evaluated the vitamin B6 vitamers pyridoxal 5'-phosphate (PLP), pyridoxal (PL), pyridoxamine (PM), pyridoxine (PN) and the catabolite pyridoxic acid (PA) in the so far largest patient cohort: reference (n = 50); pyridox(am)ine 5'-phosphate oxidase (PNPO) deficiency (n = 6); antiquitin (ATQ) deficiency (n = 21); tissue non-specific alkaline phosphatase (TNSALP) deficiency (n = 2) and epileptic encephalopathy (EE) of unknown etiology tested negative for ATQ and PNPO deficiency (n = 64). RESULTS: High plasma PM concentration was found in all patients with PNPO deficiency irrespective of vitamin B6 supplementation. Their PM concentration and the PM/PA ratio was significantly higher (p < 0.0001), compared to any other patients analysed. One patient with TNSALP deficiency and sampling prior to PN supplementation had markedly elevated plasma PLP concentration. On PN supplementation, patients with TNSALP deficiency, ATQ deficiency and patients of the EE cohort had similar plasma vitamin B6 profiles that merely reflect the intake of supra-physiological doses of vitamin B6. The interval of sampling to the last PN intake strongly affected the plasma concentrations of PN, PL and PA. CONCLUSIONS: PM concentrations and the PM/PA ratio clearly separated PNPO-deficient patients from the other cohorts. The plasma PM/PA ratio thus represents a robust biomarker for the selective screening of PNPO deficiency.


Asunto(s)
Plasma/química , Espasmos Infantiles/sangre , Adolescente , Adulto , Biomarcadores/sangre , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Errores Innatos del Metabolismo/sangre , Piridoxal/sangre , Fosfato de Piridoxal/análogos & derivados , Fosfato de Piridoxal/sangre , Piridoxamina/sangre , Ácido Piridóxico/sangre , Piridoxina/sangre , Vitamina B 6/sangre , Adulto Joven
7.
Brain Dev ; 38(8): 750-4, 2016 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26923721

RESUMEN

Early-onset epileptic encephalopathies (EOEEs) are severe and intractable infantile-onset epilepsies with progressive intellectual disability and other associated neurologic comorbidities. Whole-exome sequencing (WES) was recently used to determine the causative gene mutations in individuals with unclassified EOEEs. The present study used WES to determine the causative variant in a family with X-linked, EOEE. One potential variant (c. 427A>G, NM_002641.3; p.Lys143Glu, NP_002632.1) of the gene encoding phosphatidylinositol glycan biosynthesis class A protein (PIGA; PIGA) was found, which was verified by Sanger sequencing. The functional effect of this PIGA mutation was assessed by the surface expression levels of glycosylphosphatidylinositol-anchored proteins on blood cells: CD16 on red blood cells was significantly decreased in the proband (by 11.0%) and his mother (by 15.6%). This is the second report of a less-severe form of PIGA deficiency.


Asunto(s)
Proteínas de la Membrana/genética , Mutación , Espasmos Infantiles/genética , Niño , Epilepsias Mioclónicas/genética , Familia , Resultado Fatal , Proteínas Ligadas a GPI/sangre , Técnicas de Genotipaje , Humanos , Lactante , Masculino , Proteínas de la Membrana/deficiencia , Linaje , Receptores de IgG/sangre , Espasmos Infantiles/sangre , Espasmos Infantiles/terapia
8.
Am J Hum Genet ; 97(6): 894-903, 2015 Dec 03.
Artículo en Inglés | MEDLINE | ID: mdl-26637979

RESUMEN

SLC39A8 is a membrane transporter responsible for manganese uptake into the cell. Via whole-exome sequencing, we studied a child that presented with cranial asymmetry, severe infantile spasms with hypsarrhythmia, and dysproportionate dwarfism. Analysis of transferrin glycosylation revealed severe dysglycosylation corresponding to a type II congenital disorder of glycosylation (CDG) and the blood manganese levels were below the detection limit. The variants c.112G>C (p.Gly38Arg) and c.1019T>A (p.Ile340Asn) were identified in SLC39A8. A second individual with the variants c.97G>A (p.Val33Met) and c.1004G>C (p.Ser335Thr) on the paternal allele and c.610G>T (p.Gly204Cys) on the maternal allele was identified among a group of unresolved case subjects with CDG. These data demonstrate that variants in SLC39A8 impair the function of manganese-dependent enzymes, most notably ß-1,4-galactosyltransferase, a Golgi enzyme essential for biosynthesis of the carbohydrate part of glycoproteins. Impaired galactosylation leads to a severe disorder with deformed skull, severe seizures, short limbs, profound psychomotor retardation, and hearing loss. Oral galactose supplementation is a treatment option and results in complete normalization of glycosylation. SLC39A8 deficiency links a trace element deficiency with inherited glycosylation disorders.


Asunto(s)
Proteínas de Transporte de Catión/genética , Trastornos Congénitos de Glicosilación/genética , Enanismo/genética , Manganeso/sangre , Espasmos Infantiles/genética , Secuencia de Aminoácidos , Secuencia de Carbohidratos , Proteínas de Transporte de Catión/deficiencia , Cationes Bivalentes , Trastornos Congénitos de Glicosilación/sangre , Trastornos Congénitos de Glicosilación/complicaciones , Trastornos Congénitos de Glicosilación/dietoterapia , Enanismo/sangre , Enanismo/complicaciones , Enanismo/dietoterapia , Femenino , Galactosa/uso terapéutico , Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Transporte Iónico , Manganeso/deficiencia , Datos de Secuencia Molecular , Mutación , Linaje , Alineación de Secuencia , Espasmos Infantiles/sangre , Espasmos Infantiles/complicaciones , Espasmos Infantiles/dietoterapia
9.
Free Radic Biol Med ; 86: 156-65, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26006105

RESUMEN

CDKL5 mutation is associated with an atypical Rett syndrome (RTT) variant. Recently, cholesterol homeostasis perturbation and oxidative-mediated loss of the high-density lipoprotein receptor SRB1 in typical RTT have been suggested. Here, we demonstrate an altered lipid serum profile also in CDKL5 patients with decreased levels of SRB1 and impaired activation of the defensive system Nrf2. In addition, CDKL5 fibroblasts showed an increase in 4-hydroxy-2-nonenal- and nitrotyrosine-SRB1 adducts that lead to its ubiquitination and probable degradation. This study highlights a possible common denominator between two different RTT variants (MECP2 and CDKL5) and a possible common future therapeutic target.


Asunto(s)
Lípidos/sangre , Factor 2 Relacionado con NF-E2/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Síndrome de Rett/genética , Receptores Depuradores de Clase B/genética , Espasmos Infantiles/genética , Adolescente , Células Cultivadas , Niño , Preescolar , Síndromes Epilépticos , Femenino , Fibroblastos/metabolismo , Expresión Génica , Humanos , Masculino , Óxido Nítrico Sintasa de Tipo II/metabolismo , Estrés Oxidativo , Síndrome de Rett/sangre , Receptores Depuradores de Clase B/metabolismo , Espasmos Infantiles/sangre , Regulación hacia Arriba
10.
Epilepsy Res ; 109: 28-33, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25524839

RESUMEN

The pathogenesis of infantile spasms remains unclear. DNA methylation may play a pivotal role in the development of some types of neurological diseases, such as epilepsy. In this study, we aimed to investigate the relationship between global DNA methylation of peripheral blood leukocytes and cryptogenic infantile spasms. DNA from peripheral blood leukocytes was extracted from 20 patients with cryptogenic infantile spasms and 20 gender and age matched healthy controls. Global DNA methylation percentage of peripheral blood leukocytes was measured using a global DNA methylation quantification kit. Global DNA methylation levels of peripheral blood lymphocytes in patients with cryptogenic infantile spasms (23.4 ± 20.0%) were significantly lower than those in healthy controls (46.8 ± 8.4%). Furthermore, we did not find any association between the levels of DNA methylation and effectiveness of Adrenocorticotropic hormone treatment. Our study demonstrates that global DNA hypomethylation of peripheral blood lymphocytes is correlated with infantile spasms. This finding provides information for better understanding of the pathogenesis of infantile spasms.


Asunto(s)
Metilación de ADN , Linfocitos/metabolismo , Espasmos Infantiles/sangre , Espasmos Infantiles/genética , Hormona Adrenocorticotrópica/uso terapéutico , Anticonvulsivantes/uso terapéutico , Femenino , Humanos , Lactante , Masculino , Espasmos Infantiles/tratamiento farmacológico , Resultado del Tratamiento
11.
Clin Pharmacokinet ; 53(11): 1019-31, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25172554

RESUMEN

BACKGROUND AND OBJECTIVES: Vigabatrin is an inhibitor of γ-aminobutyric acid transaminase. The purpose of these analyses was to develop a population pharmacokinetics model to characterize the vigabatrin concentration-time profile for adults and children with refractory complex partial seizures (rCPS) and for children with infantile spasms (IS); to identify covariates that affect its disposition, and to enable predictions of systemic vigabatrin exposure for patients 1-12 months of age. METHODS: Vigabatrin pharmacokinetic data from six randomized controlled clinical trials and one open-label study were analyzed using nonlinear mixed-effects modeling. Data collected from 349 adults with rCPS and 119 pediatric patients with rCPS or IS were used in the analyses. RESULTS: A two-compartment model with first-order elimination and transit-compartment absorption consisting of five transit compartments adequately described the vigabatrin concentration-time data for these adult and pediatric patient populations. An exponential error model was used to estimate inter-individual variability for the transit-rate constant (k tr) (24.2 %), elimination rate constant (k) (14.7 %) and apparent central volume of distribution (V c/F) (18 %). For the study of children with IS, inter-occasion variability was estimated for k tr (58.1 %) and relative bioavailability (F) (26.9 %). Covariate analysis indicated that age, creatinine clearance (CLCR), and body weight were important predictors of vigabatrin pharmacokinetic parameters. Vigabatrin apparent clearance increased with increasing CLCR, consistent with renal excretion (primary pathway of vigabatrin elimination). Rate of vigabatrin absorption was dependent on age. The rate was slower in younger patients, which resulted in a smaller predicted maximum concentration and longer predicted time to maximum concentrations. Vigabatrin V c/F, apparent inter-compartmental clearance between the central and peripheral compartment, and apparent peripheral volume of distribution were increased with greater patient body weights. Sex did not contribute significantly to vigabatrin pharmacokinetic variability. CONCLUSION: The model adequately described vigabatrin pharmacokinetic and enabled predictions of systemic exposures in pediatric patients 1-12 months of age.


Asunto(s)
Inhibidores Enzimáticos/farmacocinética , Epilepsia/sangre , Convulsiones/sangre , Espasmos Infantiles/sangre , Vigabatrin/farmacocinética , Adulto , Peso Corporal , Niño , Preescolar , Inhibidores Enzimáticos/administración & dosificación , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Modelos Biológicos , Dinámicas no Lineales , Ensayos Clínicos Controlados Aleatorios como Asunto , Vigabatrin/administración & dosificación , Adulto Joven , Ácido gamma-Aminobutírico/sangre
12.
Neonatal Netw ; 32(4): 285-8, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23835548

RESUMEN

The incidence of neonatal seizures varies according to gestational age, weight, and cause. Seizures occur in an estimated 1.0-3.5 per 1,000 term infants1 with an increased incidence of 10-130/1,000 in preterm infants.2 Most neonatal seizures have a specific cause.3 Hypoxic-ischemic encephalopathy has been identified as the most common etiology associated with neonatal seizures, accounting for 50-60 percent of the cases.4 Table 1 outlines common causes of neonatal seizures. Early recognition of seizures and appropriate treatment is vital in preventing multiorgan dysfunction and permanent brain damage.


Asunto(s)
Anticonvulsivantes/uso terapéutico , Piracetam/análogos & derivados , Espasmos Infantiles/tratamiento farmacológico , Espasmos Infantiles/enfermería , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/farmacocinética , Quimioterapia Combinada , Electroencefalografía/efectos de los fármacos , Humanos , Recién Nacido , Levetiracetam , Fenobarbital/efectos adversos , Fenobarbital/farmacocinética , Fenobarbital/uso terapéutico , Piracetam/efectos adversos , Piracetam/farmacocinética , Piracetam/uso terapéutico , Espasmos Infantiles/sangre , Espasmos Infantiles/etiología , Resultado del Tratamiento
13.
Pharmacology ; 91(5-6): 275-80, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23711937

RESUMEN

AIM: To evaluate the relationship between the pharmacokinetic (PK) parameters and therapeutic and adverse effects of rufinamide (RUF) in children with epileptic encephalopathies (EE) aged <4 years. METHODS: PK analysis was conducted at the steady state using a previously validated liquid chromatography tandem-mass spectrometric method in 15 children aged 6-42 months treated with RUF in add-on. Responders were defined as patients who achieved >50% decrease of seizures. Tolerability was evaluated by analysis of a parental report of adverse effects, a clinical examination and laboratory tests. RESULTS: Maximum plasma concentration (47.40 ± 35.36 mg/l), average plasma concentration (39.94 ± 24.53 mg/l) and half-life (13.66 ± 4.43 h) were extremely variable and considerably higher than those reported in older children treated with the same dose regimen. At the last evaluation, 9 patients (60%) were responders. CONCLUSION: RUF is efficacious and is well tolerated in children with EE. Nonetheless, a correlation between dose, serum concentration and efficacy could not be demonstrated. The variability in measured concentrations may be related to polytherapy that is necessary for controlling seizures in this very severe form of epilepsy, in which the off-label use of RUF is justified.


Asunto(s)
Anticonvulsivantes/farmacocinética , Discapacidad Intelectual/sangre , Espasmos Infantiles/sangre , Triazoles/farmacocinética , Anticonvulsivantes/sangre , Anticonvulsivantes/uso terapéutico , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Discapacidad Intelectual/tratamiento farmacológico , Síndrome de Lennox Gastaut , Masculino , Espasmos Infantiles/tratamiento farmacológico , Triazoles/sangre , Triazoles/uso terapéutico
14.
J Child Neurol ; 28(2): 251-4, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22532538

RESUMEN

Nonketotic hyperglycinemia is a rare metabolic disorder with severe, frequently fatal, neurologic manifestations. Reliable and accurate diagnosis depends on careful interpretation of laboratory findings. The clinical suspicion should lead to determination of glycine in plasma and cerebrospinal fluid. Amino acid analysis presents diagnostic values for classic nonketotic hyperglycinemia, but it also should be performed in suspected cases of atypical nonketotic hyperglycinemia and in children with seizures, failure to thrive, behavior problems, and uncoordinated movements. Clinical assessment should be reinforced by demonstration of elevated cerebrospinal fluid-to-plasma glycine ratio. Confirmatory diagnosis requires enzymatic and genetic investigation of glycine cleavage system. An early diagnosis, though not affecting clinical outcome, allows proper genetic counseling, with the possibility of prenatal diagnosis. We report 3 cases of nonketotic hyperglycinemia, 2 typical neonatal and 1 atypical, diagnosed in Pediatric Hospital of Coimbra, Portugal, and investigated at Laboratory of Biochemical Genetics in 2004 to 2010 (incidence 1:47 455; prevalence 1:782 951).


Asunto(s)
Hiperglicinemia no Cetósica/complicaciones , Discapacidad Intelectual/etiología , Espasmos Infantiles/etiología , Niño , Femenino , Glicina/sangre , Glicina/líquido cefalorraquídeo , Humanos , Hiperglicinemia no Cetósica/sangre , Hiperglicinemia no Cetósica/líquido cefalorraquídeo , Discapacidad Intelectual/sangre , Discapacidad Intelectual/líquido cefalorraquídeo , Síndrome de Lennox Gastaut , Masculino , Espasmos Infantiles/sangre , Espasmos Infantiles/líquido cefalorraquídeo
15.
Int J Neurosci ; 123(1): 17-23, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22900512

RESUMEN

Many reports in the field of childhood brain disorders have documented that brain-derived neurotrophic factor (BDNF) affects central nervous system (CNS) functions. In this clinical study, BDNF levels were evaluated in association with pediatric CNS infections. BDNF levels in the serum and cerebrospinal fluid (CSF) of 42 patients admitted during 5-year period, due to CNS infections, were measured by enzyme-linked immunosorbent assays (ELISAs). Control samples were collected from 108 patients with non-CNS infections (urinary tract infection, acute upper respiratory infection, acute gastroenteritis, etc.). Mean values of BDNF levels, at various ages, were determined and compared. BDNF levels were below the sensitivity of the ELISA in most CSF samples from the control group, but were significantly elevated in the patients with bacterial meningitis. The serum BDNF levels were elevated in all subgroups of patients with CNS infections, and the elevation was particularly notable in those with bacterial meningitis. BDNF expression in the CSF was correlated with CSF interleukin (IL)-6 levels as well as with blood platelet counts and neurological prognoses in those with bacterial meningitis. No correlation was found between BDNF levels and serum leukocyte numbers or C-reactive protein (CRP) levels. BDNF levels were found to be elevated in the serum and CSF of pediatric patients with CNS infections, particularly those with bacterial meningitis. Monitoring the changes in serum and CSF levels of BDNF may facilitate the diagnosis of acute meningitis and acute encephalopathy and allow the differential diagnosis of specific CNS infections.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/sangre , Factor Neurotrófico Derivado del Encéfalo/líquido cefalorraquídeo , Discapacidad Intelectual/sangre , Discapacidad Intelectual/líquido cefalorraquídeo , Meningitis/sangre , Meningitis/líquido cefalorraquídeo , Espasmos Infantiles/sangre , Espasmos Infantiles/líquido cefalorraquídeo , Plaquetas/metabolismo , Proteína C-Reactiva/metabolismo , Niño , Preescolar , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Lactante , Discapacidad Intelectual/complicaciones , Interleucina-6/líquido cefalorraquídeo , Síndrome de Lennox Gastaut , Leucocitos/patología , Masculino , Meningitis/complicaciones , Estudios Retrospectivos , Espasmos Infantiles/complicaciones , Estadística como Asunto
16.
J Inherit Metab Dis ; 36(1): 43-53, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22569581

RESUMEN

Recessive mutations in the mitochondrial arginyl-transfer RNA synthetase (RARS2) gene have been associated with early onset encephalopathy with signs of oxidative phosphorylation defects classified as pontocerebellar hypoplasia 6. We describe clinical, neuroimaging and molecular features on five patients from three unrelated families who displayed mutations in RARS2. All patients rapidly developed a neonatal or early-infantile epileptic encephalopathy with intractable seizures. The long-term follow-up revealed a virtual absence of psychomotor development, progressive microcephaly, and feeding difficulties. Mitochondrial respiratory chain enzymes in muscle and fibroblasts were normal in two. Blood and CSF lactate was abnormally elevated in all five patients at early stages while appearing only occasionally abnormal with the progression of the disease. Cerebellar vermis hypoplasia with normal aspect of the cerebral and cerebellar hemispheres appeared within the first months of life at brain MRI. In three patients follow-up neuroimaging revealed a progressive pontocerebellar and cerebral cortical atrophy. Molecular investigations of RARS2 disclosed the c.25A>G/p.I9V and the c.1586+3A>T in family A, the c.734G>A/p.R245Q and the c.1406G>A/p.R469H in family B, and the c.721T>A/p.W241R and c.35A>G/p.Q12R in family C. Functional complementation studies in Saccharomyces cerevisiae showed that mutation MSR1-R531H (equivalent to human p.R469H) abolished respiration whereas the MSR1-R306Q strain (corresponding to p.R245Q) displayed a reduced growth on non-fermentable YPG medium. Although mutations functionally disrupted yeast we found a relatively well preserved arginine aminoacylation of mitochondrial tRNA. Clinical and neuroimaging findings are important clues to raise suspicion and to reach diagnostic accuracy for RARS2 mutations considering that biochemical abnormalities may be absent in muscle biopsy.


Asunto(s)
Arginino-ARNt Ligasa/genética , Mutación , Atrofias Olivopontocerebelosas/enzimología , Atrofias Olivopontocerebelosas/genética , Cerebelo/enzimología , Cerebelo/patología , Cerebelo/fisiología , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Discapacidad Intelectual/sangre , Discapacidad Intelectual/líquido cefalorraquídeo , Discapacidad Intelectual/genética , Ácido Láctico/sangre , Ácido Láctico/líquido cefalorraquídeo , Síndrome de Lennox Gastaut , Imagen por Resonancia Magnética/métodos , Masculino , Microcefalia/sangre , Microcefalia/líquido cefalorraquídeo , Microcefalia/genética , Mitocondrias/genética , Neuroimagen/métodos , Atrofias Olivopontocerebelosas/diagnóstico , Atrofias Olivopontocerebelosas/metabolismo , Trastornos Psicomotores/genética , Convulsiones/sangre , Convulsiones/líquido cefalorraquídeo , Convulsiones/genética , Espasmos Infantiles/sangre , Espasmos Infantiles/líquido cefalorraquídeo , Espasmos Infantiles/genética
18.
Dev Med Child Neurol ; 53(11): 1053-7, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-21592118

RESUMEN

Fever-induced refractory epileptic encephalopathy in school-age children (FIRES) is a clinically recognized epileptic encephalopathy of unknown aetiology. Presentation in previously healthy children is characterized by febrile status epilepticus. A pharmacoresistant epilepsy ensues, occurring in parallel with dramatic cognitive decline and behavioural difficulties. We describe a case of FIRES in a 4-year-old boy that was associated with elevated voltage-gated potassium channel (VGKC) complex antibodies and a significant clinical and immunological response to immunomodulation. This case, therefore, potentially expands the clinical phenotype of VGKC antibody-associated disease to include that of FIRES. Prior to immunomodulation, neuropsychology assessment highlighted significant attention, memory, and word-finding difficulties. The UK version of the Wechsler Preschool and Primary Scale of Intelligence assessment indicated particular difficulties with verbal skills (9th centile). Immunomodulation was initially administered as intravenous methylprednisolone (followed by maintenance oral prednisolone) and later in the disease course as regular monthly intravenous immunoglobulin infusions and low-dose azathioprine. Now aged 6 years, the seizure burden in this child is much reduced, although increased seizure frequency is observed in the few days before his monthly immunoglobulin infusions. Formal IQ assessment has not been repeated but there is no clinical suggestion of further cognitive regression. VGKC complex antibodies have been reported in a range of central and peripheral neurological disorders (predominantly presenting in adulthood), and the identification of elevated VGKC complex antibodies, combined with the response to immunotherapies in this child, supports an autoimmune pathogenesis in FIRES with potential diagnostic and therapeutic implications.


Asunto(s)
Anticuerpos/sangre , Fiebre/complicaciones , Discapacidad Intelectual/sangre , Discapacidad Intelectual/etiología , Canales de Potasio con Entrada de Voltaje/inmunología , Espasmos Infantiles/sangre , Espasmos Infantiles/etiología , Preescolar , Electroencefalografía , Humanos , Inmunoterapia/métodos , Discapacidad Intelectual/inmunología , Discapacidad Intelectual/terapia , Síndrome de Lennox Gastaut , Masculino , Espasmos Infantiles/inmunología , Espasmos Infantiles/terapia
19.
Ther Drug Monit ; 33(2): 214-21, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21383651

RESUMEN

Rufinamide (RUF) is an orphan drug for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in persons aged 4 years and older. Several studies have investigated the pharmaconkinetics of RUF, but information about interactions is still limited and the results are in part inconsistent. The aim of our study was to analyze the effect of age, gender, daily RUF dose per body weight (mg/kg), valproic acid (VPA), and enzyme-inducing antiepileptic drugs (EIAEDs) on RUF concentration-to-dose ratio (RUF serum concentration/RUF dose per body weight), RUF clearance (RUF dose/RUF serum concentration), and RUF trough concentrations. Different statistical methods were used to evaluate 292 blood samples from 119 patients who fulfilled the inclusion criteria. In summary, the results using generalized estimating equation regression models confirm a moderate but statistically significant nonlinear RUF concentration-dose relationship. At steady state, the trough concentrations of RUF increase in a less than dose proportional manner. Children (younger than 12 years) had significantly lower RUF concentrations (19.0%, P < 0.001) than adults (18 years or older) on comparable RUF doses per body weight. VPA was the most frequent comedication (51%) in our patient group. Mean RUF concentrations were 86.6% higher when VPA concentrations were greater than 90 µg/mL (P < 0.001) and 45.4% higher when VPA concentrations were between 50 and 90 µg/mL (P < 0.001) but not significantly different at VPA concentrations less than 50 µg/mL (4.4%, P > 0.1) compared with combinations without VPA. In combination with EIAEDs, mean RUF concentrations were 21.8% lower (P = 0.002) compared with combinations without EIAEDs. However, the group of AEDs classified as EIAEDs was heterogeneous and the number of patients, especially of children with EIAEDs, was relatively small. Our data indicate that oxcarbazepine and, especially, methsuximide decrease RUF concentrations as well. Therapeutic drug monitoring might be helpful because RUF concentrations differ markedly in patients on comparable RUF doses.


Asunto(s)
Anticonvulsivantes/sangre , Monitoreo de Drogas , Discapacidad Intelectual/tratamiento farmacológico , Espasmos Infantiles/tratamiento farmacológico , Triazoles/sangre , Ácido Valproico/sangre , Adolescente , Adulto , Factores de Edad , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapéutico , Peso Corporal , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Quimioterapia Combinada , Femenino , Humanos , Discapacidad Intelectual/sangre , Síndrome de Lennox Gastaut , Masculino , Persona de Mediana Edad , Convulsiones/tratamiento farmacológico , Espasmos Infantiles/sangre , Triazoles/administración & dosificación , Triazoles/farmacocinética , Triazoles/uso terapéutico , Ácido Valproico/administración & dosificación , Ácido Valproico/farmacocinética , Ácido Valproico/uso terapéutico , Adulto Joven
20.
J Neurol Sci ; 298(1-2): 106-9, 2010 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-20807663

RESUMEN

The aim of this study was to evaluate whether proconvulsive interleukin-1ß (IL-1ß) and anticonvulsive IL-1 receptor antagonist (IL-1Ra) are markers of the effectiveness of treatment in patients with West syndrome (WS). We analyzed serum and cerebrospinal fluid (CSF) levels of IL-1ß and IL-1Ra in 13 patients with WS. The serum IL-1Ra levels postimprovement (average, 384.6 pg/ml) in clinical and electroencephalographic (EEG) findings were significantly higher than the preimprovement values (average, 240.6 pg/ml). No significant difference in the preimprovement serum IL-1Ra levels was noted between the anticonvulsant (AED)-response and adrenocorticotropic hormone (ACTH)-response groups (260.0 pg/ml, n=7 vs. 218.0 pg/m, n=6) and the cryptogenic and symptomatic groups (290.1 pg/ml, n=4 vs. 218.3 pg/m, n=9), respectively; as for the preimprovement CSF levels, the AED-response group (114.5 pg/m; n=3) and ACTH-response groups (138.0 pg/m; n=6) and the cryptogenic (59.3 pg/m; n=3) and symptomatic groups (165.6 pg/m; n=6), respectively. Serum and CSF IL-1ß levels were detected only in 3 patients preimprovement. Serum IL-1Ra levels were elevated subsequent to resolution of clinical and EEG findings in WS patients. A larger study should be conducted to clarify whether an immunological processes are concerned with the pathophysiology of WS.


Asunto(s)
Proteína Antagonista del Receptor de Interleucina 1/sangre , Espasmos Infantiles/sangre , Espasmos Infantiles/tratamiento farmacológico , Hormona Adrenocorticotrópica/uso terapéutico , Anticonvulsivantes/uso terapéutico , Electroencefalografía , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Lactante , Proteína Antagonista del Receptor de Interleucina 1/líquido cefalorraquídeo , Interleucina-1beta/sangre , Interleucina-1beta/líquido cefalorraquídeo , Masculino , Espasmos Infantiles/líquido cefalorraquídeo
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