RESUMEN
Three missense variants of ST3GAL3 are known to be responsible for a congenital disorder of glycosylation determining a neurodevelopmental disorder (intellectual disability/epileptic encephalopathy). Here we report a novel nonsense variant, p.Y220*, in two dichorionic infant twins presenting a picture of epileptic encephalopathy with impaired neuromotor development. Upon expression in HEK-293T cells, the variant appears totally devoid of enzymatic activity in vitro, apparently accumulated with respect to the wild-type or the missense variants, as detected by western blot, and in large part properly localized in the Golgi apparatus, as assessed by confocal microscopy. Both patients were found to efficiently express the CA19.9 antigen in the serum despite the total loss of ST3GAL3 activity, which thus appears replaceable from other ST3GALs in the synthesis of the sialyl-Lewis a epitope. Kinetic studies of ST3GAL3 revealed a strong preference for lactotetraosylceramide as acceptor and gangliotetraosylceramide was also efficiently utilized in vitro. Moreover, the p.A13D missense variant, the one maintaining residual sialyltransferase activity, was found to have much lower affinity for all suitable substrates than the wild-type enzyme with an overall catalytic efficiency almost negligible. Altogether the present data suggest that the apparent redundancy of ST3GALs deduced from knock-out mouse models only partially exists in humans. In fact, our patients lacking ST3GAL3 activity synthesize the CA19.9 epitope sialyl-Lewis a, but not all glycans necessary for fine brain functions, where the role of minor gangliosides deserves further attention.
Asunto(s)
Antígenos de Carbohidratos Asociados a Tumores , Errores Innatos del Metabolismo de los Carbohidratos , Epilepsia , Regulación de la Expresión Génica , Mutación Missense , Sialiltransferasas , Gemelos Dicigóticos , Antígenos de Carbohidratos Asociados a Tumores/biosíntesis , Antígenos de Carbohidratos Asociados a Tumores/genética , Errores Innatos del Metabolismo de los Carbohidratos/genética , Errores Innatos del Metabolismo de los Carbohidratos/metabolismo , Epilepsia/genética , Epilepsia/metabolismo , Femenino , Humanos , Lactante , Masculino , Sialiltransferasas/genética , Sialiltransferasas/metabolismoRESUMEN
We report a 9-year-old girl with hypotonia, severe motor delay, absent speech, and facial dysmorphism who developed acute encephalopathy with severe neurological outcome. Trio-based whole exome sequencing (WES) analysis detected a de novo heterozygous mutation in the BRAF gene leading to the diagnosis of an atypical presentation of cardiofaciocutaneous (CFC) syndrome. This is the second case of CFC syndrome complicated with acute encephalopathy reported in the literature and supports the hypothesis that acute encephalopathy might be one of the complications of the syndrome due to an intrinsic susceptibility to this acute event. The report furthermore highlights the role of WES in providing a fast diagnosis in patients in critical conditions with atypical presentation of rare genetic syndromes.
Asunto(s)
Genes ras , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Mutación , Fenotipo , Proteínas Proto-Oncogénicas B-raf/genética , Encéfalo/anomalías , Encéfalo/diagnóstico por imagen , Niño , Hibridación Genómica Comparativa , Egipto , Electroencefalografía , Facies , Femenino , Estudios de Asociación Genética/métodos , Humanos , Cariotipificación , Imagen por Resonancia Magnética , Secuenciación del ExomaRESUMEN
To facilitate an integrated and rational approach to the care of women with epilepsy of childbearing potential, a group of experts appointed by Italian scientific societies in the fields of epileptology, neonatology, pediatrics, neuropediatrics, child neuropsychiatry, obstetrics, and gynecology held a joint meeting in Santa Trada di Cannitello, Reggio Calabria, Italy, on October 15-16, 2004, with the aim of reaching consensus on the optimal management of these women. An ad hoc system for the classification of available published evidence and the opinions of experts was developed and used to grade recommendations on different aspects related to counseling, diagnostic, and treatment issues. The present document summarizes available evidence on the reciprocal interactions between epilepsy, antiepileptic drugs, fertility, contraception, pregnancy, delivery, breastfeeding, and the offspring. Recommendations are made concerning the information and counseling that should be provided to women with epilepsy with respect to issues related to contraception, conception, pregnancy, labour, and puerperium. More detailed recommendations on the same issues are provided to physicians and other healthcare professionals involved in the care of these women, with special reference to choice of effective contraception, optimization of antiepileptic drug therapy, use of prenatal diagnostic tests and other monitoring procedures, and appropriate management practices in relation to childbirth, puerperium, and the care of the child.
Asunto(s)
Epilepsia/terapia , Trabajo de Parto/fisiología , Periodo Posparto/fisiología , Complicaciones del Embarazo/fisiopatología , Complicaciones del Embarazo/terapia , Epilepsia/fisiopatología , Femenino , Humanos , Italia , EmbarazoRESUMEN
PURPOSE: To evaluate the influence of aging on the pharmacokinetics of valproic acid (VPA) at steady-state and on the susceptibility of VPA metabolism to enzyme induction by antiepileptic comedication. METHODS: The database of the therapeutic drug monitoring service of a large neurological hospital was searched to identify patients aged > or = 65 years stabilized on VPA therapy. Apparent VPA oral clearance (CL/F) calculated for each elderly patient was compared with that determined in an equal number of VPA-treated controls aged 20-50 years and matched for gender, body weight and antiepileptic drug (AED) comedication. RESULTS: A total of 71 elderly patients aged 70.0+/-4.4 years, including 20 receiving enzyme inducing AEDs, was included in the main evaluation. In the absence of enzyme inducing comedication, VPA CL/F in the elderly was similar to that found in non-elderly controls (9.7+/-4.6 versus 10.2+/-4.6mlh(-1)kg(-1)). Elderly patients on enzyme inducing comedication, on the other hand, had lower CL/F values than enzyme induced younger controls (11.7+/-5.4 versus 16.0+/-6.3mlh(-1)kg(-1), p<0.05). Since VPA CL/F is known to increase with increasing dosage, a lower VPA dosage in elderly patients comedicated with enzyme inducers compared with controls may have contributed to differences in CL/F between the two groups. CONCLUSIONS: In the absence of enzyme inducing comedication, VPA clearance in the elderly was comparable to that observed in controls. VPA clearance in elderly patients receiving enzyme inducing AEDs was lower than in controls, the difference being probably due to an influence of age as well as to the fact that mean VPA dosage was lower in these patients than in controls. Since our measurements of clearance were based on total serum VPA concentrations and VPA binding to plasma proteins is known to be reduced in old age, it is likely that the clearance of unbound, pharmacologically active, VPA was decreased to an important extent in the elderly, presumably as a result of a decline in drug metabolizing capacity.
Asunto(s)
Envejecimiento/fisiología , Anticonvulsivantes/farmacocinética , Inducción Enzimática , Ácido Valproico/farmacocinética , Adulto , Anciano , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/sangre , Estudios de Casos y Controles , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Monitoreo de Drogas , Quimioterapia Combinada , Epilepsia/tratamiento farmacológico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis de Regresión , Ácido Valproico/efectos adversos , Ácido Valproico/sangreRESUMEN
OBJECTIVE: To compare the steady-state pharmacokinetics of topiramate in a large population of children and adults with epilepsy in a therapeutic drug monitoring setting. STUDY DESIGN: Retrospective, case-matched pharmacokinetic evaluation. PATIENTS: Seventy children (aged 1-17 years) with epilepsy and 70 adult controls (aged 18-65 years) with epilepsy, matched for sex and comedication. METHODS: Topiramate apparent oral clearance (CL/F) values were calculated from steady-state serum concentrations in children and compared with those determined in controls. Comparisons were made by means of the Mann-Whitney's U-test, or the Kruskal-Wallis test in the case of multiple comparisons. A linear regression model was used to assess potential correlation of CL/F values with age. To investigate the influence of different variables on the variability in topiramate CL/F values, a multiple regression model was developed. RESULTS: In the absence of enzyme-inducing comedication, mean topiramate CL/F was 42% higher in children than in adults (40.3 +/- 21.0 vs 28.4 +/- 15.3 mL/h/kg; p < 0.01). In children and adults comedicated with enzyme-inducing antiepileptic drugs (AEDs), topiramate CL/F values were approximately 1.5- to 2-fold higher than those observed in the absence of enzyme inducers, and the elevation in topiramate CL/F in children compared with adults was also present in the subgroups receiving enzyme inducers (66%; 76.6 +/- 35.1 vs 46.1 +/- 16.7 mL/h/kg; p < 0.0001). In the paediatric population, a negative correlation between CL/F and age was demonstrated, both in the absence (p < 0.01) and in the presence (p < 0.001) of enzyme induction. The independent influence of age and enzyme-inducing AEDs on topiramate CL/F was confirmed by multiple regression analysis. CONCLUSION: Topiramate CL/F is highest in young children and decreases progressively with age until puberty, presumably due to age-dependent changes in the rate of drug metabolism. As a result of this, younger patients require higher dosages to achieve serum topiramate concentrations comparable with those found in older children and adults. Enzyme-inducing comedication decreases serum topiramate concentration by approximately one-half and one-third in children and adults, respectively.
Asunto(s)
Anticonvulsivantes/farmacocinética , Epilepsia/tratamiento farmacológico , Fructosa/análogos & derivados , Fructosa/farmacocinética , Administración Oral , Adolescente , Adulto , Factores de Edad , Anciano , Anticonvulsivantes/sangre , Anticonvulsivantes/uso terapéutico , Niño , Preescolar , Interacciones Farmacológicas , Monitoreo de Drogas , Inducción Enzimática , Femenino , Fructosa/sangre , Fructosa/uso terapéutico , Humanos , Lactante , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Estudios Retrospectivos , TopiramatoRESUMEN
PURPOSE: To assess the influence of aging on the pharmacokinetics of phenobarbital (PB) at steady state in patients receiving long-term therapy. METHODS: Serum PB concentrations from the database of the therapeutic drug monitoring service of a large neurological hospital were used to calculate apparent clearance values (CL/F) in 224 patients aged 65 years and older (mean, 73 +/- 6.1 years). CL/F values in these patients were compared with those determined in an equal number of controls aged 20 to 50 years (mean, 35.7 +/- 7.9 years) and matched for gender, body weight, and type of anticonvulsant comedication. Correlations of CL/F with age, body weight, gender, and comedication also were explored within each age group. RESULTS: PB CL/F values were significantly lower in elderly patients than in controls (3.2 +/- 0.8 vs. 4.1 +/- 1.2 ml/h/kg; p < 0.0001). Age was identified as a statistically significant predictor of CL/F at multiple regression analysis, but it accounted for only a modest component of the interindividual pharmacokinetic variation. Comedication with carbamazepine (CBZ) and phenytoin (PHT) was associated with a moderate decrease in PB CL/F, which reached statistical significance in the elderly group (p < 0.01 for CBZ comedication; p < 0.001 for PHT comedication). CONCLUSIONS: Aging is associated with a significant decrease in PB clearance, which might be related to a reduction in glomerular filtration rate or diminished drug-metabolizing capacity in the liver or both. Because of this, older patients will require lower dosages to achieve serum PB concentrations comparable with those found in nonelderly adults.
Asunto(s)
Envejecimiento/metabolismo , Anticonvulsivantes/farmacocinética , Epilepsia/metabolismo , Fenobarbital/farmacocinética , Adulto , Distribución por Edad , Factores de Edad , Anciano , Anciano de 80 o más Años , Algoritmos , Anticonvulsivantes/sangre , Anticonvulsivantes/uso terapéutico , Disponibilidad Biológica , Carbamazepina/sangre , Carbamazepina/farmacocinética , Carbamazepina/uso terapéutico , Esquema de Medicación , Monitoreo de Drogas , Quimioterapia Combinada , Epilepsia/sangre , Epilepsia/tratamiento farmacológico , Femenino , Humanos , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Fenobarbital/sangre , Fenobarbital/uso terapéutico , Análisis de RegresiónRESUMEN
The influence of aging on the pharmacokinetics of phenytoin at steady-state was evaluated retrospectically by comparing apparent oral clearance values (CL/F) in 75 patients aged 65-90 years (mean, 71.7 +/- 5.3 years) receiving phenytoin alone (n = 58) or in combination with phenobarbital (n = 17) and in an equal number of control patients aged 20-50 years (mean, 36.7 +/- 8.5 years) matched for gender, body weight, and comedication. All data were derived from the database of the therapeutic drug monitoring service (TDMS) of an academic neurological hospital. On average, elderly patients were found to exhibit slightly higher CL/F values compared with controls (14.6 +/- 4.7 ml h(-1) kg(-1) versus 13.1 +/- 4.2 ml h(-1) kg(-1), P < 0.05), the difference being probably related to the dose-dependent nature of phenytoin metabolism and the fact that elderly patients received lower dosages (4.4 +/- 1.1 mg kg(-1)day(-1) versus 5.3 +/- 1.1 mg kg(-1) day(-1), P < 0.001) and had lower serum phenytoin concentrations (14.1 +/- 5.7 microg ml(-1) versus 18.6 +/- 6.8 microg ml(-1), P < 0.0001). Gender and phenobarbital comedication were not found to exert any statistically significant influence on phenytoin CL/F. By contrast, in the elderly group, CL/F values were negatively correlated with age. On average, CL/F values decreased by about one-third between 65 and 85 years of age, but interindividual variability was considerable and age explained only 7.8% of the variation in CL/F in the elderly group. Overall, these findings indicate that aging is associated with a progressive decline in phenytoin clearance, presumably as a result of decreased drug metabolizing capacity. Because assessment was based on total serum phenytoin concentrations and the unbound fraction of phenytoin is known to decrease in old age, the influence of aging as quantified in this study may underestimate the magnitude of changes in the clearance of unbound, pharmacologically active drug. Based on these data, it is prudent to utilize initially smaller phenytoin dosages in old patients, and to make subsequent dose adjustments based on clinical response and serum drug level measurements. Interpretation of the latter, however, should take into account the possibility of an increase in the fraction of unbound drug.
Asunto(s)
Envejecimiento/fisiología , Fenitoína/sangre , Fenitoína/farmacocinética , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/sangre , Análisis de Varianza , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Tasa de Depuración Metabólica/fisiología , Persona de Mediana Edad , Monitoreo Fisiológico/métodos , Monitoreo Fisiológico/estadística & datos numéricos , Estudios Retrospectivos , Estadísticas no ParamétricasRESUMEN
PURPOSE: To assess the influence of aging on the steady-state pharmacokinetics of carbamazepine (CBZ) in a large population of patients evaluated in a therapeutic drug monitoring (TDM) setting. METHODS: The database of a large TDM service was used to identify retrospectively steady-state serum CBZ concentrations in 157 elderly patients with epilepsy (65 years and older) treated with CBZ alone or in combination with phenobarbital (PB). CBZ apparent oral clearance (CL/F) values were calculated and compared with those determined in an equal number of controls aged 20 to 50 years, and matched for gender, body weight, and comedication. RESULTS: Compared with corresponding controls, mean CBZ CL/F values were 23% and 24% lower, respectively, in the groups of elderly patients receiving monotherapy (57.1 +/- 20.6 vs. 74.6 +/- 28.3 ml/h/kg; p < 0.0001) and PB comedication (74.7 +/- 25.5 vs. 98.7 +/- 34.9 ml/h/kg; p < 0.01). Within each age group, patients comedicated with PB showed significantly higher CBZ CL/F values than those on monotherapy. A negative correlation between CL/F and age was found both within the monotherapy and the PB comedicated groups. In addition, CL/F values showed a positive relation with the administered daily dosage, which persisted within subgroups homogeneous for age and comedication. The independent influence of age, CBZ dosage, and comedication on CBZ CL/F was confirmed by multiple regression analysis. CONCLUSIONS: CBZ CL/F is decreased in an age-dependent manner in elderly patients compared with younger subjects, presumably because a reduction in the rate of CYP3A4-mediated drug metabolism. Elderly patients retain their sensitivity to dose-dependent autoinduction and to heteroinduction by enzyme-inducing AEDs, but their metabolic rates remain considerably below those observed in matched controls. As a result of this, patients in old age will require lower CBZ dosages to achieve serum concentrations comparable with those found in nonelderly adults.