RESUMEN
Alexander disease (AxD) is a genetic leukodystrophy caused by GFAP mutations leading to astrocyte dysfunction. Neonatal AxD is a rare phenotype with onset in the first month of life. The proband, belonging to a large pedigree with dominantly inherited benign familial neonatal epilepsy (BFNE), had a phenotype distinct from the rest of the family, with hypotonia and macrocephaly in addition to drug-resistant neonatal seizures. The patient deteriorated and passed away at 6 weeks of age. The pathological and neuroimaging data were consistent with the diagnosis of AxD. Genetic analysis of the proband identified a novel de novo GFAP missense mutation and a KCNQ2 splice site mutation segregating with the BFNE phenotype in the family. The GFAP mutation was located in the coil 2B region of GFAP protein, similar to most neonatal-onset AxD cases with an early death. The clinical and neuroradiological features of the previously published neonatal AxD patients are presented. This study further supports the classification of neonatal-onset AxD as a distinct phenotype based on the age of onset.
Asunto(s)
Enfermedad de Alexander/genética , Proteína Ácida Fibrilar de la Glía/genética , Mutación , Enfermedad de Alexander/diagnóstico por imagen , Enfermedad de Alexander/patología , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Resultado Fatal , Humanos , Lactante , Masculino , FenotipoRESUMEN
The hereditary spastic paraplegias (HSPs) are heterogeneous neurodegenerative disorders with over 50 known causative genes. We identified a recurrent mutation in KCNA2 (c.881G>A, p.R294H), encoding the voltage-gated K(+) -channel, KV 1.2, in two unrelated families with HSP, intellectual disability (ID), and ataxia. Follow-up analysis of > 2,000 patients with various neurological phenotypes identified a de novo p.R294H mutation in a proband with ataxia and ID. Two-electrode voltage-clamp recordings of Xenopus laevis oocytes expressing mutant KV 1.2 channels showed loss of function with a dominant-negative effect. Our findings highlight the phenotypic spectrum of a recurrent KCNA2 mutation, implicating ion channel dysfunction as a novel HSP disease mechanism. Ann Neurol 2016.
Asunto(s)
Ataxia/genética , Discapacidad Intelectual/genética , Canal de Potasio Kv.1.2/genética , Paraplejía Espástica Hereditaria/genética , Adulto , Animales , Ataxia/fisiopatología , Niño , Exoma , Femenino , Humanos , Discapacidad Intelectual/fisiopatología , Masculino , Persona de Mediana Edad , Mutación , Oocitos/metabolismo , Linaje , Paraplejía Espástica Hereditaria/fisiopatología , Xenopus laevis , Adulto JovenRESUMEN
Cerebroretinal microangiopathy with calcifications and cysts (CRMCC) is a rare multisystem disorder characterized by extensive intracranial calcifications and cysts, leukoencephalopathy, and retinal vascular abnormalities. Additional features include poor growth, skeletal and hematological abnormalities, and recurrent gastrointestinal bleedings. Autosomal-recessive inheritance has been postulated. The pathogenesis of CRMCC is unknown, but its phenotype has key similarities with Revesz syndrome, which is caused by mutations in TINF2, a gene encoding a member of the telomere protecting shelterin complex. After a whole-exome sequencing approach in four unrelated individuals with CRMCC, we observed four recessively inherited compound heterozygous mutations in CTC1, which encodes the CTS telomere maintenance complex component 1. Sanger sequencing revealed seven more compound heterozygous mutations in eight more unrelated affected individuals. Two individuals who displayed late-onset cerebral findings, a normal fundus appearance, and no systemic findings did not have CTC1 mutations, implying that systemic findings are an important indication for CTC1 sequencing. Of the 11 mutations identified, four were missense, one was nonsense, two resulted in in-frame amino acid deletions, and four were short frameshift-creating deletions. All but two affected individuals were compound heterozygous for a missense mutation and a frameshift or nonsense mutation. No individuals with two frameshift or nonsense mutations were identified, which implies that severe disturbance of CTC1 function from both alleles might not be compatible with survival. Our preliminary functional experiments did not show evidence of severely affected telomere integrity in the affected individuals. Therefore, determining the underlying pathomechanisms associated with deficient CTC1 function will require further studies.
Asunto(s)
Calcificación Fisiológica/genética , Enfermedades de los Pequeños Vasos Cerebrales/genética , Quistes/genética , Mutación , Proteínas de Unión a Telómeros/genética , Telómero/genética , Adolescente , Adulto , Edad de Inicio , Secuencia de Aminoácidos , Enfermedades de los Pequeños Vasos Cerebrales/metabolismo , Enfermedades de los Pequeños Vasos Cerebrales/patología , Niño , Preescolar , Quistes/metabolismo , Quistes/patología , Exoma , Exones , Femenino , Heterocigoto , Humanos , Lactante , Recién Nacido , Masculino , Datos de Secuencia Molecular , Linaje , Fenotipo , Análisis de Secuencia de ADN/métodos , Adulto JovenRESUMEN
OBJECTIVE: The aim of this follow-up study was to evaluate the development of object naming ability and auditory processing in prematurely born children. Furthermore, we investigated whether the mismatch negativity (MMN) parameters at the age of 4 years correlate with the MMN parameters and naming ability at the age of 6 years. METHODS: Twelve very low birth weight (VLBW) preterm children (mean age 5 years 7 months) and matched controls were studied. Object naming was measured by the Boston naming test. Auditory event-related potentials (ERPs), especially the MMN, were recorded for Finnish syllables (standard /taa/; deviants /ta/ and /kaa/) in an oddball paradigm. RESULTS: VLBW preterm children scored significantly lower in the object naming test than their controls. The MMN amplitude for consonant change was significantly smaller in the preterm group compared to the controls. The MMN amplitude at the age of 4 years correlated with the MMN amplitude at the age of 6 years. Furthermore, absence of the MMN at the age of 4 years predicted naming difficulties at the age of 6 years. CONCLUSIONS: VLBW preterm children with a difficulty to preattentively discriminate changes in syllables, as indexed by the diminished change detection response, MMN, seem to have sustained naming difficulty. Therefore, it is reasonable to record the MMN along with the language development from infancy, in order to identify the children at risk for language deficiencies and to provide appropriate rehabilitation.
Asunto(s)
Percepción Auditiva/fisiología , Recien Nacido Prematuro/psicología , Trastornos del Lenguaje/fisiopatología , Trastornos del Lenguaje/psicología , Niño , Preescolar , Potenciales Evocados Auditivos/fisiología , Femenino , Estudios de Seguimiento , Humanos , Recién Nacido , Recién Nacido de muy Bajo Peso/psicología , Desarrollo del Lenguaje , Masculino , Pruebas Neuropsicológicas , Habla/fisiología , Percepción del Habla/fisiología , VocabularioRESUMEN
Very low birth weight (VLBW, <1500 g) preterm birth has been associated with anatomic abnormalities in brain development and cognitive and language disorders. We examined object naming ability, and an electrophysiologic index of auditory sensory discrimination of speech sounds (the mismatch negativity, MMN) in 4-year-old VLBW prematurely born children. We found that half of the VLBW children were inferior to their controls in the object naming ability. Also the MMN amplitudes were smaller in the preterm group as compared with the controls. Further, the MMN amplitude varied as a function of children's performance on object naming, such that the weaker object-naming performance of the preterm group was paralleled by the diminished MMN amplitudes. Therefore, difficulties in auditory discrimination seem to be implicated in language difficulties encountered in VLBW prematurely born children.
Asunto(s)
Encéfalo/fisiopatología , Trastornos del Conocimiento/etiología , Trastornos del Desarrollo del Lenguaje/etiología , Trabajo de Parto Prematuro/fisiopatología , Fonética , Estimulación Acústica , Trastornos de la Percepción Auditiva/etiología , Encéfalo/anomalías , Mapeo Encefálico , Estudios de Casos y Controles , Preescolar , Discriminación en Psicología , Electroencefalografía , Electrofisiología , Potenciales Evocados Auditivos/fisiología , Femenino , Humanos , Recién Nacido de Bajo Peso/fisiología , Recién Nacido , Pruebas del Lenguaje , Masculino , Embarazo , Percepción del Habla/fisiologíaRESUMEN
BACKGROUND: New imaging techniques allow a detailed visualization of the brain and the findings possibly correlate with neurophysiologic measurements and neurosensory and motor outcomes. Postnatal clinical factors known to associate with neurologic disabilities may contribute to brain abnormalities not visible to the naked eye. OBJECTIVES: We evaluated whether quantitative measurement of organized water diffusion on MR imaging, apparent diffusion coefficient (ADC), relates to neurophysiologic function and to clinical risk factors and motor outcome in preterm infants. METHODS: Diffusion-weighted imaging was successfully performed at term age on 30 infants born <32 weeks of gestation, birth weight <1,000 g. Infants with major destructive brain lesions were excluded from the final analysis (n = 2). ADC was calculated within regions of interest placed in pons and in white matter regions known to contain motor fibers. Brain stem auditory evoked potentials (BAEP) were registered at term age. Gross motor outcome was assessed using Griffiths Scales at 2 years of corrected age. RESULTS: A positive correlation was found between ADC in the pons and the latency of wave III in BAEP (r = 0.619, p = 0.024). Need for inotrope support during the postnatal period and bronchopulmonary dysplasia associated with high ADC values in the pons and in the corona radiata. Infants with poor gross motor outcome had higher ADC in the corona radiata than infants with better outcome (mean = 1.343 vs. 1.197, p = 0.004). CONCLUSIONS: This is the first study to report a relationship between ADC and BAEP measurements in the pons. The study may add to the current knowledge about the relation between postnatal clinical factors and diffusion-weighted imaging when evaluating the high-risk infants.
Asunto(s)
Corteza Cerebral/patología , Imagen de Difusión por Resonancia Magnética/métodos , Potenciales Evocados Auditivos del Tronco Encefálico/fisiología , Recien Nacido Prematuro/fisiología , Tractos Piramidales/patología , Peso al Nacer , Mapeo Encefálico , Displasia Broncopulmonar/patología , Displasia Broncopulmonar/fisiopatología , Corteza Cerebral/fisiopatología , Femenino , Edad Gestacional , Humanos , Recién Nacido , Masculino , Actividad Motora , Puente , Tractos Piramidales/fisiopatología , Síndrome de Dificultad Respiratoria del Recién Nacido/patología , Síndrome de Dificultad Respiratoria del Recién Nacido/fisiopatologíaRESUMEN
OBJECTIVE: We studied the prevalence, segregation, and phenotype of the mitochondrial DNA 3243A>G mutation in children in a defined population in Northern Ostrobothnia, Finland. METHODS: Children with diagnoses commonly associated with mitochondrial diseases were ascertained. Blood DNA from 522 selected children was analyzed for 3243A>G. Children with the mutation were clinically examined. Information on health history before the age of 18 years was collected from previously identified adult patients with 3243A>G. Mutation segregation analysis in buccal epithelial cells was performed in mothers with 3243A>G and their children whose samples were analyzed anonymously. RESULTS: Eighteen children were found to harbor 3243A>G in a population of 97,609. A minimum estimate for the prevalence of 3243A>G was 18.4 in 100,000 (95% confidence interval, 10.9-29.1/100,000). Information on health in childhood was obtained from 37 adult patients with 3243A>G. The first clinical manifestations appearing in childhood were sensorineural hearing impairment, short stature or delayed maturation, migraine, learning difficulties, and exercise intolerance. Mutation analysis from 13 mothers with 3243A>G and their 41 children gave a segregation rate of 0.80. The mothers with heteroplasmy greater than 50% tended to have offspring with lower or equal heteroplasmy, whereas the opposite was true for mothers with heteroplasmy less than or equal to 50% (p = 0.0016). INTERPRETATION: The prevalence of 3243A>G is relatively high in the pediatric population, but the morbidity in children is relatively low. The random genetic drift model may be inappropriate for the transmission of the 3243A>G mutation.
Asunto(s)
ADN Mitocondrial/genética , Enfermedades Mitocondriales/genética , Mutación/genética , Adulto , Estatura/genética , Niño , Segregación Cromosómica/genética , Estudios de Cohortes , ADN Mitocondrial/sangre , Células Epiteliales , Tolerancia al Ejercicio/genética , Femenino , Finlandia/epidemiología , Frecuencia de los Genes , Flujo Genético , Crecimiento/genética , Crecimiento/fisiología , Haplotipos , Pérdida Auditiva Sensorineural/genética , Humanos , Discapacidades para el Aprendizaje/genética , Síndrome MELAS/genética , Masculino , Trastornos Migrañosos/genética , Mucosa Bucal/citología , Mutación/fisiología , FenotipoRESUMEN
Intrauterine inflammation may relate to neurologic disability among preterm children. We investigated the relationship between chorioamnionitis, cord serum cytokines, and neurologic outcome. Sixty-one consecutively born very preterm extremely low birth weight (ELBW) infants were prospectively enrolled. Histologic inflammation in placenta and umbilical cord and vascular pathology were evaluated. Cord sera were analyzed for five proinflammatory cytokines. Serial brain ultrasound and magnetic resonance imaging were performed for evaluation of intraventricular hemorrhage (IVH grade I-III) and white matter damage (WMD: cystic periventricular leukomalacia or IVH grade IV). Neurologic and neurocognitive outcomes were assessed at the corrected age of 2 y. The incidences of HCA, WMD, and abnormal neurologic outcome were 48%, 13% and 19%, respectively. HCA or high IL-6 in cord serum predicted spontaneous preterm labor with high accuracy. HCA increased the risk of IVH grade II-III. In HCA, without either clinical chorioamnionitis or histologic placental perfusion defect, the children had a low risk of WMD (0%) and a low risk of abnormal neurologic outcome (6%). In HCA, the concentration of IL-6 in cord serum was lower in children with abnormal neurologic outcome than in children with normal neurologic outcome. In HCA and placental perfusion defect (compound defect) the risk of abnormal neurologic outcome was high. Compound placental defect and WMD additively predicted abnormal neurologic outcome. We propose that HCA together with other insults (placental perfusion defect or maternal systemic infection) increases the risk of poor neurologic outcome in very preterm ELBW infants.
Asunto(s)
Corioamnionitis , Citocinas/inmunología , Discapacidades del Desarrollo , Sangre Fetal/inmunología , Recien Nacido Prematuro , Recién Nacido de muy Bajo Peso , Encéfalo/anatomía & histología , Encéfalo/patología , Encéfalo/fisiología , Corioamnionitis/inmunología , Corioamnionitis/fisiopatología , Estudios de Cohortes , Discapacidades del Desarrollo/inmunología , Discapacidades del Desarrollo/fisiopatología , Femenino , Humanos , Recién Nacido , Leucomalacia Periventricular/inmunología , Masculino , Embarazo , Complicaciones del Embarazo , Resultado del EmbarazoRESUMEN
PURPOSE: To assess growth and the serum lipid profile in girls with epilepsy receiving monotherapy at a mean age of 12.6 years and approximately 6 years later. METHODS: A population-based cohort of 77 girls with epilepsy and 49 healthy controls participated in this follow-up study including two cross-sectional evaluations (age range, 8-18.5 years on the first evaluation, and 12.5-25.8 years on the second evaluation). Forty of the patients were initially taking valproate (VPA), 19, carbamazepine (CBZ), and 18, oxcarbazepine (OXC). Growth data were compiled, body mass index (BMI) was calculated, and serum total (TC), and high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C) cholesterol and triglyceride concentrations were analyzed. RESULTS: Linear growth and final height did not differ between the patients and the controls. At follow-up, the mean BMI of the patients who were off medication (61%) was similar to that of the controls, whereas the patients initially treated with VPA who were still taking any medication had a higher BMI. On the first evaluation, the patients taking VPA had low serum HDL-C, and those taking CBZ or OXC had high serum TC and LDL-C concentrations. At follow-up, serum lipid levels were similar in the patients off medication and the controls. CONCLUSIONS: Neither epilepsy nor antiepileptic therapy affects linear growth or final height, but they may have unfavorable effects on body weight and serum lipid concentrations. Lipid-profile impairment seems to be transient if the medication is discontinued. Overweight is common in patients treated with VPA during puberty if epilepsy and medication continue into adulthood.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Crecimiento/fisiología , Lípidos/sangre , Pubertad/fisiología , Adolescente , Adulto , Anticonvulsivantes/efectos adversos , Estatura/efectos de los fármacos , Estatura/fisiología , Índice de Masa Corporal , Peso Corporal/efectos de los fármacos , Peso Corporal/fisiología , Niño , Epilepsia/metabolismo , Epilepsia/fisiopatología , Femenino , Estudios de Seguimiento , Crecimiento/efectos de los fármacos , Humanos , Metabolismo de los Lípidos , Estudios Longitudinales , Pubertad/efectos de los fármacos , Factores SexualesRESUMEN
BACKGROUND: The objective of the current study was to determine whether therapy for childhood acute lymphoblastic leukemia (ALL) results in long-lasting neurologic signs or electrophysiologic injuries within the motor tracts. METHODS: Twenty-seven children who were treated for ALL were studied clinically 5 years after the cessation of therapy by means of motor-evoked potentials (MEPs) elicited by magnetic stimulation transcranially and peripherally. An equal number of healthy children matched with regard to age, gender, and height served as the control group. RESULTS: The MEP latencies to the hands and legs elicited by stimulation at the cortex were prolonged significantly in the children treated for ALL compared with the control group, with the differences being 2.2 milliseconds [ms] (P < 0.001) from the cortex to the thenar on the right side and 2.0 ms (P < 0.001) on the left, and 1.4 ms (P = 0.004) from the cortex to the leg on the right side and 1.3 ms (P = 0.004) on the left. Correspondingly, the MEP latency from the fifth lumbar vertebrae (LV) level to the leg also was prolonged, by 1.0 ms (P = 0.005) on the right side and 0.8 ms (P = 0.005) on the left side. The calculated latency between the cortex and the LV level was not found to be significantly longer in those patients treated for ALL compared with the healthy controls. Neurologic signs, in the form of depressed deep tendon reflexes, were observed in 8% of the patients, whereas approximately 33% of the patients were found to have fine or gross motor difficulties and dysdiadochokinesia. CONCLUSIONS: Neurologic signs still persisted 5 years after therapy for ALL. Approximately 33% of the patients had fine or gross motor difficulties and dysdiadochokinesia, and demyelinative injuries to the peripheral nerve tracts were found proximally but not within the central nervous system.
Asunto(s)
Enfermedad de la Neurona Motora/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Adolescente , Adulto , Brazo/inervación , Niño , Potenciales Evocados Motores , Femenino , Estudios de Seguimiento , Humanos , Pierna/inervación , Masculino , Enfermedad de la Neurona Motora/fisiopatología , Factores de TiempoRESUMEN
OBJECTIVE: Cytochrome c oxidase (COX) deficiency has been demonstrated in some patients with Alpers-Huttenlocher disease, but no genetic background has been identified. Our objective was to determine the molecular defect underlying the mitochondrial respiratory chain deficiency in a child with Alpers-Huttenlocher-like progressive cerebrohepatic disease. METHODS: The entire coding region of mitochondrial DNA was analyzed by conformation-sensitive gel electrophoresis and sequencing. Biochemical and morphologic investigations were performed on tissue biopsy material, including oximetric and spectrophotometric analyses of oxidative phosphorylation, histochemistry, and electron microscopy. RESULTS: Postmortem histologic examination revealed a marked loss of neurons in the olivary nuclei and a spongy change in the calcarine cortex, fatty infiltration and micronodular cirrhosis of the liver, and atrophic ovaries. A novel heteroplasmic 7706G>A mutation was found in the COX II gene. The median degree of the mutant heteroplasmy was 90% in 5 tissues examined but was lower in the blood of asymptomatic maternal relatives. The distribution of the mutant heteroplasmy was skewed to the left in single muscle fibers of the proband and her mother. The 7706G>A mutation converts a hydrophobic alanine in a conserved transmembrane segment to hydrophilic threonine. CONCLUSIONS: The 7706G>A mutation is pathogenic and may lead to impaired dioxygen transfer to the active site of COX. The clinical phenotype of this patient resembled that in Alpers-Huttenlocher disease, suggesting that analysis of mitochondrial DNA is worthwhile in patients with a progressive cerebrohepatic disease.
Asunto(s)
Deficiencia de Citocromo-c Oxidasa/genética , ADN Mitocondrial/genética , Esclerosis Cerebral Difusa de Schilder/genética , Complejo IV de Transporte de Electrones/genética , Mutación , Encéfalo/patología , Niño , Deficiencia de Citocromo-c Oxidasa/metabolismo , Deficiencia de Citocromo-c Oxidasa/patología , Esclerosis Cerebral Difusa de Schilder/metabolismo , Esclerosis Cerebral Difusa de Schilder/patología , Metabolismo Energético/genética , Femenino , Humanos , Hígado/patología , Núcleo Olivar/patología , Fenotipo , Reacción en Cadena de la PolimerasaRESUMEN
PURPOSE: To evaluate reproductive endocrine function in boys and young men with epilepsy taking an antiepileptic drug in a population-based, controlled study. METHODS: Seventy patients and 70 controls matched for age and pubertal stage participated in this study. Twenty-eight patients were taking carbamazepine (CBZ); five, lamotrigine (LTG); 12, oxcarbazepine (OXC); and 25, valproate (VPA) as monotherapy for epilepsy. All subjects were examined clinically, and their medical histories were obtained. Serum reproductive hormone and sex hormone-binding globulin concentrations were measured, and testicular ultrasonography was performed. RESULTS: Serum testosterone levels were within the normal range in young male patients with epilepsy. However, the patients taking VPA had high serum androstenedione levels at all pubertal stages. In prepuberty, their serum androstenedione values were already approximately fivefold compared with the values of the controls (8.7 nM; SD, 4.0 vs. 1.8 nM, SD, 1.0; p < 0.0003), and they were elevated in 64% of the VPA-treated patients compared with none of the other patients, p = 0.0006. Serum sex hormone-binding globulin levels were increased, and serum dehydroepiandrosterone sulfate concentrations decreased in the pubertal patients taking CBZ. The mean testicular volumes did not differ between the patients and the controls. CONCLUSIONS: CBZ and VPA, but not LTG and OXC, are associated with changes in serum sex-hormone levels in boys and young men with epilepsy. However, the long-term health consequences of these reproductive endocrine changes during pubertal development remain to be established.
Asunto(s)
Andrógenos/sangre , Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Pubertad/sangre , Pubertad/fisiología , Testículo/anatomía & histología , Testículo/efectos de los fármacos , Adolescente , Adulto , Androstenodiona/sangre , Carbamazepina/análogos & derivados , Carbamazepina/farmacología , Carbamazepina/uso terapéutico , Niño , Epilepsia/sangre , Humanos , Lamotrigina , Masculino , Oxcarbazepina , Análisis de Regresión , Globulina de Unión a Hormona Sexual/análisis , Testículo/crecimiento & desarrollo , Testosterona/sangre , Triazinas/farmacología , Triazinas/uso terapéutico , Ácido Valproico/farmacología , Ácido Valproico/uso terapéuticoRESUMEN
OBJECTIVES: Many heteroplasmic point mutations in tRNA genes of mitochondrial DNA (mtDNA) have been associated with human diseases. We recently reported on a prospective 7-year study in which we enrolled 116 consecutive children with undefined encephalomyopathy. Seventeen of them were found to have both a defect in the mitochondrial respiratory chain and abnormal ultrastructure of muscle mitochondria, suggesting a clinically probable mitochondrial encephalopathy. METHODS: We determined the frequency of mtDNA mutations in these 17 children by analyzing the entire sequence of mtDNA by conformation-sensitive gel electrophoresis and sequencing. RESULTS: Three heteroplasmic tRNA mutations that were considered to be pathogenic were detected. Two of the mutations were novel transitions, 10438A>G in the tRNA(Arg) gene and 14696A>G in the tRNA(Glu) gene, whereas the third one was 3243A>G, the common MELAS mutation. The mutant load was very high in the blood and skeletal muscle of the patients and markedly lower in the blood of asymptomatic maternal relatives. The 10438A>G mutation changes the nucleotide flanking the anticodon, whereas 14696A>G changes a nucleotide in the stem of the pseudouridine loop, creating a novel base pair and reducing the wobble. CONCLUSIONS: Our results emphasize that the analysis of the entire sequence of mtDNA is worthwhile in the diagnostic evaluation of patients with clinically probable mitochondrial encephalomyopathy. The frequency of pathogenic mtDNA mutations was found to be 18% among children with biochemically and histologically defined mitochondrial disease, suggesting that the likelihood of nuclear DNA mutations in such a group is several times higher than that of mtDNA mutations.
Asunto(s)
ADN Mitocondrial/genética , Encefalomiopatías Mitocondriales/genética , ARN de Transferencia/genética , Secuencia de Bases , Niño , Femenino , Humanos , Discapacidad Intelectual/genética , Masculino , Epidemiología Molecular , Datos de Secuencia Molecular , Análisis de Secuencia de ADN , Trastornos del Habla/genéticaRESUMEN
PURPOSE: Antiepileptic drugs may affect the serum thyroid hormone concentrations. The aim of this study was to evaluate thyroid function in 78 girls taking carbamazepine (CBZ), oxcarbazepine (OXC), or valproate (VPA) monotherapy for epilepsy and after withdrawal of the treatment. METHODS: Forty-one girls taking VPA, 19 taking CBZ, and 18 taking OXC for epilepsy, as well as 54 healthy age-matched controls, aged 8 to 18 years, participated in the study. All the girls were examined clinically, and their pubertal stage was assessed. Blood samples were obtained for thyroid hormone and antibody assays. These examinations were repeated after a mean follow-up of 5.8 years to assess thyroid function, and 64 (82%) of 78 patients and 42 (78%) of 54 controls agreed to participate in the second evaluation. RESULTS: In the first evaluation, the mean serum thyroid hormone concentrations were lower in the girls taking CBZ [thyroxine (T4), 70.2; SD, 10.9 nM; and free thyroxine (FT4), 11.5; SD, 1.8 pM] or OXC (T4, 74.9; SD, 16.4 nM; and FT4, 11.3; SD, 1.8 pM) than in the control girls (T4, 96.6; SD, 15.1 nM, and FT4, 14.4; SD, 1.5 pM; p < 0.001, all comparisons). However, thyrotropin (TSH) concentrations were normal in the girls taking CBZ or OXC. Sixty-three% of the girls taking CBZ and 67% of the girls taking OXC had serum T4 and/or FT4 levels below the lower limit of the reference range. The VPA-treated girls with epilepsy had normal serum T4 and FT4 concentrations, but slightly increased TSH levels (3.3; SD, 1.5 mU/L; p < 0.01) compared with the control girls (2.5; SD, 1.0 mU/L). Normal serum hormone concentrations were restored in the patients who discontinued the medication. CONCLUSIONS: Both CBZ and OXC reduce serum thyroid hormone concentrations in girls with epilepsy. Conversely, VPA is associated with normal serum thyroid hormone and increased thyrotropin levels. However, our results suggest that the changes in serum thyroid hormone and thyrotropin levels are reversible after withdrawal of the medication.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Carbamazepina/análogos & derivados , Carbamazepina/uso terapéutico , Epilepsia/tratamiento farmacológico , Glándula Tiroides/efectos de los fármacos , Glándula Tiroides/fisiopatología , Tirotropina/sangre , Tiroxina/sangre , Ácido Valproico/uso terapéutico , Adolescente , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/efectos adversos , Carbamazepina/administración & dosificación , Carbamazepina/efectos adversos , Niño , Estudios Transversales , Esquema de Medicación , Epilepsia/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Oxcarbazepina , Tirotropina/metabolismo , Tiroxina/metabolismo , Ácido Valproico/administración & dosificación , Ácido Valproico/efectos adversos , Privación de Tratamiento , gamma-Glutamiltransferasa/sangreRESUMEN
Cerebral palsy (CP) is a major neurodevelopmental disability in childhood. An association between intrauterine infection and CP has been reported. We examined the relationship between inflammatory mediators in cord serum and CP in term and preterm children. Regional multicenter study was conducted on 19 CP children and 19 gestation-matched paired controls. CP children (n = 27) were further compared with controls of similar gestation at birth (n = 25). Serum levels of 78 protein mediators were analyzed. Eleven analytes correlated with the length of gestation both in cases and controls. In paired analysis, B-lymphocyte chemoattractant, ciliary neurotrophic factor, epidermal growth factor, interleukin (IL)-5, IL-12, IL-13, IL-15, macrophage migration inhibitory factor, monocyte chemoattractant protein-3, monokine induced by interferon gamma, and tumor necrosis factor-related apoptosis-inducing ligand were higher in children with CP (p < or = 0.05). Preterm infants with CP showed higher epidermal growth factor and lower levels of granulocyte-macrophage colony-stimulating factor, IL-2, macrophage-derived chemokine, and pulmonary and activation-regulated chemokine than their paired controls. Inflammatory mediators and growth factors serve as a footprint of the fetal response to an insult manifesting after birth as a permanent brain damage. The cytokine patterns at birth differ between premature and term infants who develop CP.
Asunto(s)
Biomarcadores/sangre , Parálisis Cerebral/sangre , Sangre Fetal/química , Recien Nacido Prematuro , Citocinas/sangre , Femenino , Edad Gestacional , Sustancias de Crecimiento/sangre , Humanos , Recién Nacido , Masculino , Trabajo de Parto Prematuro , Embarazo , Análisis por Matrices de Proteínas , Factores de RiesgoRESUMEN
PURPOSE: To study the prevalence and features of visual field constrictions (VFCs) associated with vigabatrin (VGB) in children. METHODS: A systematic collection of all children with any history of VGB treatment in fifteen Finnish neuropediatric units was performed, and children were included after being able to cooperate reliably in repeated visual field tests by Goldmann kinetic perimetry. This inclusion criterion yielded 91 children (45 boys; 46 girls) between ages 5.6 and 17.9 years. Visual field extent <70 degrees in the temporal meridian was considered abnormal VFC. RESULTS: There was a notable variation in visual field extents between successive test sessions and between different individuals. VFCs <70 degrees were found in repeated test sessions in 17 (18.7%) of 91 children. There was no difference in the ages at the study, the ages at the beginning of treatment, the total duration of the treatment, general cognitive performance, or neuroradiologic findings between the patients with normal visual fields and those with VFC, but the patients with VFC had received a higher total dose of VGB. In linear regression analysis, there were statistically significant inverse correlations between the temporal extent of the visual fields and the total dose and the duration of VGB treatment. The shortest duration of VGB treatment associated with VFC was 15 months, and the lowest total dose 914 g. CONCLUSIONS: Because of a wide variation in normal visual-field test results in children, the prevalence figures of VFCs are highly dependent on the definition of normality. Although our results confirm the previous findings that VFC may occur in children treated with VGB, our study points out the need to reevaluate critically any suspected VFC to avoid misdiagnosis. Nevertheless, our study suggests that the prevalence of VFC may be lower in children than in adults, and that the cumulative dose of VGB or length of VGB therapy may add to the personal predisposition for developing VFC.