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Two-thirds of patients with mucopolysaccharidosis II (MPS II; Hunter syndrome) have cognitive impairment. This phase 2/3, randomized, controlled, open-label, multicenter study (NCT02055118) investigated the effects of intrathecally administered idursulfase-IT on cognitive function in patients with MPS II. Children older than 3 years with MPS II and mild-to-moderate cognitive impairment (assessed by Differential Ability Scales-II [DAS-II], General Conceptual Ability [GCA] score) who had tolerated intravenous idursulfase for at least 4 months were randomly assigned (2:1) to monthly idursulfase-IT 10 mg (n = 34) via an intrathecal drug delivery device (IDDD; or by lumbar puncture) or no idursulfase-IT treatment (n = 15) for 52 weeks. All patients continued to receive weekly intravenous idursulfase 0.5 mg/kg as standard of care. Of 49 randomized patients, 47 completed the study (two patients receiving idursulfase-IT discontinued). The primary endpoint (change from baseline in DAS-II GCA score at week 52 in a linear mixed-effects model for repeated measures analysis) was not met: although there was a smaller decrease in DAS-II GCA scores with idursulfase-IT than with no idursulfase-IT at week 52, this was not significant (least-squares mean treatment difference [95% confidence interval], 3.0 [-7.3, 13.3]; p = 0.5669). Changes from baseline in Vineland Adaptive Behavioral Scales-II Adaptive Behavior Composite scores at week 52 (key secondary endpoint) were similar in the idursulfase-IT (n = 31) and no idursulfase-IT (n = 14) groups. There were trends towards a potential positive effect of idursulfase-IT across DAS-II composite, cluster, and subtest scores, notably in patients younger than 6 years at baseline. In a post hoc analysis, there was a significant (p = 0.0174), clinically meaningful difference in change from baseline in DAS-II GCA scores at week 52 with idursulfase-IT (n = 13) versus no idursulfase-IT (n = 6) among those younger than 6 years with missense iduronate-2-sulfatase gene variants. Overall, idursulfase-IT reduced cerebrospinal glycosaminoglycan levels from baseline by 72.0% at week 52. Idursulfase-IT was generally well tolerated. These data suggest potential benefits of idursulfase-IT in the treatment of cognitive impairment in some patients with neuronopathic MPS II. After many years of extensive review and regulatory discussions, the data were found to be insufficient to meet the evidentiary standard to support regulatory filings.
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Iduronato Sulfatasa , Mucopolisacaridosis II , Mieloma Múltiple , Niño , Preescolar , Humanos , Terapia de Reemplazo Enzimático/métodos , Glicosaminoglicanos , Iduronato Sulfatasa/genética , Ácido Idurónico , Mucopolisacaridosis II/tratamiento farmacológico , Mucopolisacaridosis II/genéticaRESUMEN
Enzyme replacement therapy with weekly infused intravenous (IV) idursulfase is effective in treating somatic symptoms of mucopolysaccharidosis II (MPS II; Hunter syndrome). A formulation of idursulfase for intrathecal administration (idursulfase-IT) is under investigation for the treatment of neuronopathic MPS II. Here, we report 36-month data from the open-label extension (NCT02412787) of a phase 2/3, randomized, controlled study (HGT-HIT-094; NCT02055118) that assessed the safety and efficacy of monthly idursulfase-IT 10 mg in addition to weekly IV idursulfase on cognitive function in children older than 3 years with MPS II and mild-to-moderate cognitive impairment. Participants were also enrolled in this extension from a linked non-randomized sub-study of children younger than 3 years at the start of idursulfase-IT therapy. The extension safety population comprised 56 patients who received idursulfase-IT 10 mg once a month (or age-adjusted dose for sub-study patients) plus IV idursulfase (0.5 mg/kg) once a week. Idursulfase-IT was generally well tolerated over the cumulative treatment period of up to 36 months. Overall, 25.0% of patients had at least one adverse event (AE) related to idursulfase-IT; most treatment-emergent AEs were mild in severity. Of serious AEs (reported by 76.8% patients), none were considered related to idursulfase-IT treatment. There were no deaths or discontinuations owing to AEs. Secondary efficacy analyses (in patients younger than 6 years at phase 2/3 study baseline; n = 40) indicated a trend for improved Differential Ability Scale-II (DAS-II) General Conceptual Ability (GCA) scores in the early idursulfase-IT versus delayed idursulfase-IT group (treatment difference over 36 months from phase 2/3 study baseline: least-squares mean, 6.8 [90% confidence interval: -2.1, 15.8; p = 0.2064]). Post hoc analyses of DAS-II GCA scores by genotype revealed a clinically meaningful treatment effect in patients younger than 6 years with missense variants of the iduronate-2-sulfatase gene (IDS) (least-squares mean [standard error] treatment difference over 36 months, 12.3 [7.24]). These long-term data further suggest the benefits of idursulfase-IT in the treatment of neurocognitive dysfunction in some patients with MPS II. After many years of extensive review and regulatory discussions, the data were found to be insufficient to meet the evidentiary standard to support regulatory filings.
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Iduronato Sulfatasa , Mucopolisacaridosis II , Niño , Preescolar , Humanos , Recién Nacido , Terapia de Reemplazo Enzimático/efectos adversos , Iduronato Sulfatasa/efectos adversos , Iduronato Sulfatasa/genética , Ácido Idurónico , Mucopolisacaridosis II/tratamiento farmacológico , Mucopolisacaridosis II/genéticaRESUMEN
PURPOSE: To describe the temporal association of specific acute neurological symptoms in pediatric patients with confirmed SARS-CoV-2 infection between May and August 2020. METHODS: We performed a recollection of all the clinical and laboratory data of patients having acute neurological symptoms temporally associated with SARS-CoV-2 infection at a third-level referral hospital in Mexico City (Instituto Nacional de Pediatría). Patients in an age group of 0-17 years with acute neurological signs (including ascending weakness with areflexia, diminished visual acuity, encephalopathy, ataxia, stroke, or weakness with plasma creatinine kinase (CK) elevation) were evaluated. RESULTS: Out of 23 patients with neurological manifestations, 10 (43%) had a confirmed SARS-CoV-2 infection. Among the infected patients, 5 (50%) were males aged 2-16 years old (median age 11.8 years old). Four (40%) patients confirmed a close contact with a relative positive for SARS-CoV-2, while 6 (60%) cases had a history of SARS-CoV-2-related symptoms over the previous 2 weeks. The following diagnoses were established: 3 cases of GBS, 2 of ON, 2 of AIS, one of myositis with rhabdomyolysis, one ACA, and one of anti-NMDA-R encephalitis. CONCLUSIONS: Neurological manifestations temporally associated with SARS-CoV-2 infection were noticed in the pediatric population even without respiratory symptoms. In this study, 2 of 6 symptomatic patients had mild respiratory symptoms and 4 had unspecific symptoms. During this pandemic, SARS-CoV-2 infection should be considered as etiology in patients with acute neurological symptoms, with or without previous respiratory manifestations, particularly in teenagers.
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COVID-19 , Accidente Cerebrovascular , Adolescente , Niño , Preescolar , Humanos , Lactante , Recién Nacido , Masculino , México/epidemiología , Pandemias , SARS-CoV-2RESUMEN
In the pediatric population, epilepsy is one of the most common neurological disorders that often results in cognitive dysfunction. It affects patients' life quality by limiting academic performance and self-esteem and increasing social rejection. There are several interventions for the neurohabilitation of cognitive impairment, including LEGO®-based therapy (LEGO® B-T), which promotes neuronal connectivity and cortical plasticity through the use of assembly sets and robotic programming. Therefore, the aim of this study was to analyze the effect of LEGO® B-T on cognitive processes in pediatric patients with epilepsy. Eligible patients were identified; in the treatment group, an initial evaluation was performed with the NEUROPSI and BANFE-2 neuropsychological tests. Then, the interventions were performed once a week, and a final test was performed. In the control group, after the initial evaluation, the final evaluation was performed. An overall improvement was observed in the LEGO® B-T patients, with a significant increase in BANFE-2 scores in the orbitomedial, anterior prefrontal, and dorsolateral areas. In addition, in the gain score analysis, the orbitomedial and memory scores were significantly different from the control group. LEGO® B-T neurohabilitation is a remarkable option for epilepsy patients, who are motivated when they observe improvements.
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BACKGROUND: Mucopolysaccharidosis (MPS) II is a rare, X-linked lysosomal storage disease. Approximately two-thirds of patients have central nervous system involvement with some demonstrating progressive cognitive impairment (neuronopathic disease). The natural history of cognitive and adaptive function in patients with MPS II is not well-defined. This 2-year, prospective, observational study evaluated the neurodevelopmental trajectories of boys with MPS II aged ≥ 2 years and < 18 years. RESULTS: Overall, 55 patients were enrolled. At baseline, mean (standard deviation [SD]) age was 5.60 (3.32) years; all patients were receiving intravenous idursulfase. Cognitive and adaptive function were assessed using the Differential Ability Scales, Second Edition (DAS-II) General Conceptual Ability (GCA) and the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) Adaptive Behavior Composite (ABC) scores, respectively. Baseline mean (SD) DAS-II GCA and VABS-II ABC scores were 78.4 (19.11) and 83.7 (14.22), respectively, indicating low cognitive function and moderately low adaptive behavior. Over 24 months, modest deteriorations in mean (SD) scores were observed for DAS-II GCA (-3.8 [12.7]) and VABS-II ABC (-2.0 [8.07]). Changes in DAS-II GCA scores varied considerably, and data suggested the existence of four potential patient subgroups: (1) patients with marked early impairment and rapid subsequent decline, (2) patients with marked early impairment then stabilization, (3) patients with mild early impairment then stabilization, and (4) patients without impairment who remained stable. Subgroup analyses revealed numerically greater DAS-II GCA score reductions from baseline in patients aged < 7 years at baseline (vs. those aged ≥ 7 years) and in patients with DAS-II GCA scores ≤ 70 at baseline (vs. those with scores > 70); between-group differences were nonsignificant. No clear subgroups or patterns were identified for individual changes in VABS-II ABC scores. In total, 49 patients (89.1%) reported ≥ 1 adverse event (AE) and nine patients (16.4%) reported serious AEs. CONCLUSIONS: Some patients with MPS II had rapid declines in cognitive ability, whereas others remained relatively stable after an initial decline. These insights provide a basis for more detailed analyses of different patient subgroups, which may enhance the definition and understanding of factors that influence cognitive and adaptive function in MPS II. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01822184. Registered retrospectively: April 2, 2013.
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Mucopolisacaridosis II , Masculino , Niño , Humanos , Estudios Prospectivos , Estudios Retrospectivos , Estudios Longitudinales , Adaptación PsicológicaRESUMEN
Epilepsy is a chronic neurological disease characterized by the presence of spontaneous seizures, with a higher incidence in the pediatric population. Anti-seizure medication (ASM) may produce adverse drug reactions (ADRs) with an elevated frequency and a high severity. Thus, the objective of the present study was to analyze, through intensive pharmacovigilance over 112 months, the ADRs produced by valproic acid (VPA), oxcarbazepine (OXC), phenytoin (PHT), and levetiracetam (LEV), among others, administered to monotherapy or polytherapy for Mexican hospitalized pediatric epilepsy patients. A total of 1034 patients were interviewed; 315 met the inclusion criteria, 211 patients presented ADRs, and 104 did not. A total of 548 ASM-ADRs were identified, and VPA, LEV, and PHT were the main culprit drugs. The most frequent ADRs were drowsiness, irritability, and thrombocytopenia, and the main systems affected were hematologic, nervous, and dermatologic. LEV and OXC caused more nonsevere ADRs, and PHT caused more severe ADRs. The risk analysis showed an association between belonging to the younger groups and polytherapy with ADR presence and between polytherapy and malnutrition with severe ADRs. In addition, most of the severe ADRs were preventable, and most of the nonsevere ADRs were nonpreventable.
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OBJECTIVE: To present a case series of encephalitis patients with anti-N-methyl-D-aspartate receptor antibodies, attending two neurological referral centers in a three-year period. METHODS: A retrospective, descriptive, comparative study included child and adult patients in two neurological populations, positive for antibodies against the NR1 and NR2 subunits of the glutamate (NMDA) receptor in serum and CSF, as determined during a three-year period. RESULTS: Sixty-six patients were included (40 children and 26 adults). Male patients were more affected (M: F ratio was 1:0.6). No differences in progression or hospitalization time were observed between groups. In children, 35% of patients showed herpetic infection before autoimmune encephalitis (P = 0.01). Among viral prodromal symptoms, upper respiratory tract infection (P = 0.02) and fever (P = 0.001) predominated in children, while infectious gastroenteritis was more frequent in adults (P = 0.03). Among neuropsychiatric signs, mental confusion (P = 0.0001) and orofacial dyskinesia/oromandibular dystonia (P = 0.0001) were frequent in children, while emotional lability (P = 0.03), catatonia (P = 0.0001), and headache (P = 0.005) predominated in adults. The score in the modified Rankin scale on admission was higher in children (4.3 ± 0.8 vs. 2.2 ± 1.3, P = 0.0001), but at one-year of clinical follow up no significant differences were found. CONCLUSIONS: Male patients were predominantly affected in our population. One-third of all patients developed prodromal infection. Neuropsychiatric clinical complaints were different in children and adults. However, post-hospitalization recovery was similar between groups.
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Encefalitis Antirreceptor N-Metil-D-Aspartato/líquido cefalorraquídeo , Encefalitis Antirreceptor N-Metil-D-Aspartato/diagnóstico por imagen , Síntomas Prodrómicos , Adolescente , Adulto , Factores de Edad , Encefalitis Antirreceptor N-Metil-D-Aspartato/epidemiología , Niño , Preescolar , Electroencefalografía/métodos , Femenino , Estudios de Seguimiento , Células HEK293 , Humanos , Masculino , México/epidemiología , Factores Sexuales , Adulto JovenRESUMEN
This study reports on a Mexican mestizo patient with a multi-systemic syndrome including neurological involvement and a type I serum transferrin profile. Clinical exome sequencing revealed complex alleles in ALG1, the encoding gene for the chitobiosyldiphosphodolichol beta-mannosyltransferase that participates in the formation of the dolichol-pyrophosphate-GlcNAc2Man5, a lipid-linked glycan intermediate during N-glycan synthesis. The identified complex alleles were NM_019109.5(ALG1): c.[208 + 16_208 + 19dup; 208 + 25G > T] and NM_019109.5(ALG1): c.[208 + 16_208 + 19dup; 1312C > T]. Although both alleles carried the benign variant c.208 + 16_208 + 19dup, one allele carried a known ALG1 pathogenic variant (c.1312C > T), while the other carried a new uncharacterized variant (c.208 + 25G > T) causing non-functional alternative splicing that, in conjunction with the benign variant, defines the pathogenic protein effect (p.N70S_S71ins9). The presence in the patient's serum of the pathognomonic N-linked mannose-deprived tetrasaccharide marker for ALG1-CDG (Neu5Acα2,6Galß1,4-GlcNAcß1,4GlcNAc) further supported this diagnosis. This is the first report of an ALG1-CDG patient from Latin America.
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[This corrects the article DOI: 10.3389/fgene.2021.744884.].
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BACKGROUND: Most of bayesian pharmacokinetic studies and the influence of clinical variables have been carried out in adults. PURPOSE: The aim was to estimate population-based pharmacokinetic of valproic acid (VPA) and to determine the effect of treatment and additional disease on its performance in children with epilepsy. MATERIAL AND METHODS: For the study steady-state serum concentrations of VPA were determined from 108 epileptic patients (44 females and 64 males) who were receiving the anticonvulsant as main drug of treatment with age range since 1 to 16 years (median 4y, 6m) and weight since 5.2 to 50 kg (median 17.5 kg). All patients had their renal, hepatic and nutritional functions normal. One compartment model using interactive two-stage Bayesian approach was employed in the analysis. RESULTS; Population estimates of CL/F and V/F for VPA were 0.022 +/- 0.013 L/h and 0.217 +/- 0.134 L/kg, respectively. These estimates were significantly affected by weight, age, carbamazepine (CBZ) and gastroesophageal reflux (GER). The final regression models were: CL/F (L/h) = 0.0696 + 0.0031 (Age) + 0.0075 (Weight); and V/F (L) = 0.674 + 0.0308 (Age) + 0.0756 (Weight). Prediction of VPA serum concentration in other validation group revealed an important improvement in the predictive performance of VPA concentrations in comparison with the basic model that did not include any co-variables. CONCLUSIONS: Based on a population model of children with epilepsy, the pharmacokinetic of VPA could be altered by weight, age and the administration of CBZ and additional GER to epilepsy.
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Anticonvulsivantes/farmacocinética , Epilepsia/tratamiento farmacológico , Ácido Valproico/farmacocinética , Adolescente , Factores de Edad , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/sangre , Anticonvulsivantes/uso terapéutico , Teorema de Bayes , Peso Corporal , Lesiones Encefálicas/complicaciones , Lesiones Encefálicas/metabolismo , Carbamazepina/administración & dosificación , Carbamazepina/farmacocinética , Carbamazepina/uso terapéutico , Niño , Preescolar , Interacciones Farmacológicas , Quimioterapia Combinada , Epilepsia/complicaciones , Epilepsia/metabolismo , Femenino , Reflujo Gastroesofágico/complicaciones , Reflujo Gastroesofágico/metabolismo , Humanos , Lactante , Masculino , Meningitis/complicaciones , Meningitis/metabolismo , Modelos Biológicos , Infecciones del Sistema Respiratorio/complicaciones , Infecciones del Sistema Respiratorio/metabolismo , Ácido Valproico/administración & dosificación , Ácido Valproico/sangre , Ácido Valproico/uso terapéuticoRESUMEN
Introduction Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is one of the most common autoimmune encephalitides. The frequency of anti-NMDAR encephalitis is known to exceed the frequency of any individual viral encephalitis in young subjects. Epileptic seizures are a cardinal symptom in anti-NMDAR encephalitis; a significant amount of pediatric patients exhibit seizures as the first symptom of the disease, and most of them will develop them during the acute phase. The use of antiepileptic drugs (AEDs) is a cornerstone of the treatment of these patients, but the choice of agent and duration of treatment is currently unknown. Materials and methods This was a single-center retrospective review case series of all pediatric patients with a confirmed diagnosis of anti-NMDAR encephalitis and epileptic seizures admitted to the National Institute of Pediatrics in Mexico City from January 2012 to July 2019. Results We included a total of 31 patients (males 64.5%, median age: 10 years). No patient showed evidence of teratoma; only 38% of cases had a viral prodrome. Most patients initially exhibited psychiatric symptoms (51%), but the leading cause in soliciting medical assistance was the presence of epileptic seizures (71%). About 85% of patients presented epileptic seizures during the course of the illness, predominantly focal onset seizures (42% focal to bilateral tonic-clonic seizures, 32% focal seizures with impaired awareness). Electroencephalogram (EEG) was abnormal in 97% of patients; the characteristic extreme delta brush pattern was found in 9% of patients. Two AEDs on average were required to control seizures during the acute stage. In six (19%) patients, human herpesvirus (HHV) was detected in cerebrospinal fluid (CSF); all of them had epileptic seizures, which were more resistant to pharmacological treatment during the acute phase, requiring a higher number of AED (median 2.5 vs. 2). The development of epilepsy after acute encephalitis was uncommon; at 24 months, only one patient continued to have epileptic seizures. One of the factors most closely related to the persistence of epileptic seizures was the inadequate response to immunotherapy after four weeks. The functional prognosis was generally good; at a two-year follow-up, only two (10%) patients had a significant disability [modified Rankin Scale (mRS) score: 3-5]; both patients had seizures at a one-year follow-up. Conclusions Sustained use of AEDs after the acute phase of anti-NMDAR encephalitis is controversial. We found that the continuation of AEDs after the acute phase could be considered in the following scenarios: status epilepticus (SE), inadequate response to immunotherapy at four weeks, and a high mRS score at discharge and during follow-up. In other cases, discontinuation of AED may be warranted. More studies are needed in our country to replicate these results.
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Ketogenic diet, a high fat and low carbohydrate diet, has been used as a non-pharmacological treatment in refractory epilepsy since 1920. In recent years, it has demonstrated to be effective in the treatment of numerous neurological and non-neurological diseases. Some neurological and neuropsychiatric disorders are known to be caused by gamma-aminobutyric acid (GABA)-mediated neurotransmission dysfunction. The strength and polarity of GABA-mediated neurotransmission are determined by the intracellular chloride concentration, which in turn is regulated by cation-chloride cotransporters NKCC1 and KCC2. Currently, it is unknown if the effect of ketogenic diet is due to the modulation of these cotransporters. Thus, we analyzed the effect of a ketogenic diet on the cation-chloride cotransporters expression in the dentate gyrus. We estimated the total number of NKCC1 immunoreactive (NKCC1-IR) neuronal and glial cells by stereology and determined KCC2 labeling intensity by densitometry in the molecular and granule layers as well as in the hilus of dentate gyrus of rats fed with normal or ketogenic diet for 3 months. The results indicated that ketogenic diet provided during 3 months increased KCC2 expression, but not NKCC1 in the dentate gyrus of the rat. The significant increase of KCC2 expression could explain, at least in part, the beneficial effect of ketogenic diet in the diseases where the GABAergic system is altered by increasing its inhibitory efficiency.
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The complete mutational spectrum of dystrophinopathies and limb-girdle muscular dystrophy (LGMD) remains unknown in Mexican population. Seventy-two unrelated Mexican male patients (73% of pediatric age) with clinical suspicion of muscular dystrophy and no evidence of DMD gene deletion on multiplex polymerase chain reaction (mPCR) analysis were analyzed by multiplex ligation-dependent probe amplification (MLPA). Those with a normal result were subjected to Sanger sequencing or to next-generation sequencing for DMD plus 10 selected LGMD-related genes. We achieved a diagnostic genotype in 80.5% (n = 58/72) of patients with predominance of dystrophinopathy-linked genotypes (68%, n = 49/72), followed by autosomal recessive LGMD-related genotypes (types 2A-R1, 2C-R5, 2E-R4, 2D-R3 and 2I-R9; 12.5%, n = 9/72). MLPA showed 4.2% of false-negatives for DMD deletions assessed by mPCR. Among the small DMD variants, 96.5% (n = 28/29) corresponded to null-alleles, most of which (72%) were inherited through a carrier mother. The FKRP p.[Leu276Ile]; [Asn463Asp] genotype is reported for the first time in Mexican patients as being associated with dilated cardiomyopathy. Absence of dysferlinopathies could be related to the small sample size and/or the predominantly pediatric age of patients. The employed strategy seems to be an affordable diagnosis approach for Mexican muscular dystrophy male patients and their families.
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Distrofina/genética , Pruebas Genéticas/normas , Distrofia Muscular de Duchenne/genética , Mutación , Adolescente , Adulto , Niño , Preescolar , Reacciones Falso Negativas , Pruebas Genéticas/métodos , Genotipo , Humanos , Masculino , México , Reacción en Cadena de la Polimerasa Multiplex/métodos , Reacción en Cadena de la Polimerasa Multiplex/normas , Distrofia Muscular de Duchenne/patología , Pentosiltransferasa/genéticaRESUMEN
BACKGROUND: Tetrahydrobiopterin (BH4) is the cofactor for 6-pyruvoyl-tetrahydropterin synthase (PTPS); it is involved in BH4 biosynthesis and is encoded by PTS gene. Its deficiency (PTPSD) is characterized by hyperphenylalaninemia (HPA) and deficit in central monoamine neurotransmitters. We describe the clinical and mutational spectrum of five patients with PTPSD, from four unrelated Mexican families. All patients had symptomatic diagnosis and presented severe early neurological manifestations and HPA. METHODS: Clinical and biochemical data from studied patients were recorded. Responsible PTPSD genotypes was determined by direct and bidirectional Sanger DNA sequencing of the six PTS coding exons and their exon-intron borders, and these were directly searched in the available relatives. The novel PTS missense variant [NM_3000317.2:331Gâ¯>â¯T, p.(Ala111Ser)] was subjected to in silico, to predict a possible deleterious effect. RESULTS: Diminished fetal movements were perceived as a uniform characteristic in the studied group. DNA sequencing showed two known p.(Arg25∗) and p.(Val132TyrFs∗19) and the novel missense p.(Ala111Ser) PTS variants, the latter representing potentially a frequent PTPSD-responsible allele (50%, 4/8) in Mexican patients. In silico protein modeling analysis of the p.(Ala111Ser) variant revealed loss of hydrophobic interactions between the alanine and neighboring valines, suggesting that these changes in polarity may be detrimental for enzyme function, structure and/or stability. CONCLUSIONS: This work contributes to the knowledge of PTPS molecular spectrum. The delayed diagnosis of these patients emphasizes the importance of considering BH4 metabolism defects in the differential diagnosis of HPA, especially for countries that are beginning their HPA newborn screening programs.
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Mutación , Liasas de Fósforo-Oxígeno/deficiencia , Liasas de Fósforo-Oxígeno/genética , Preescolar , Simulación por Computador , Exones , Familia , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Lactante , México , Modelos Moleculares , Fenotipo , Liasas de Fósforo-Oxígeno/metabolismoRESUMEN
BACKGROUND: Human neurocysticercosis (NC) is caused by Taenia solium larvae lodged in the central nervous system. NC is clinically heterogeneous, ranging from asymptomatic infection to severely incapacitating and even fatal presentations. Although NC affects adults and children, age-related factors have not been thoroughly studied. METHODS: We describe and compare the clinical, radiologic, and inflammatory features of pediatric and adult Mexican NC cases. Two hundred six NC cases (92 pediatric and 114 adult) diagnosed by computed tomography or magnetic resonance imaging were included. RESULTS: Seizures were more frequent in children (80.4% versus 56.1%), and intracranial hypertension and headaches were more frequent in adults (27.2% versus 15.2% and 35.1% versus 21.7%, respectively). Different causes underlie the different distribution of seizures and intracranial hypertension in the 2 patient groups. In pediatric NC patients, single colloidal parenchymal cysts were the most common radiologic findings compared with adults in whom multiple viable parasites in the basal subarachnoidal cisterns or in the ventricles were seen. Cerebrospinal fluid inflammation was greater in adults than in children (P = 0.02). CONCLUSIONS: This study documents significant age-related radiologic, clinical, and inflammatory differences in Mexican NC patients. Possible causes and relevance of these age-associated findings are discussed.
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Neurocisticercosis/patología , Taenia solium/crecimiento & desarrollo , Adolescente , Adulto , Factores de Edad , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Neurocisticercosis/diagnóstico por imagen , Neurocisticercosis/inmunología , RadiografíaRESUMEN
Congenital toxoplasmosis is an obstetric problem in Mexico, but its actual frequency is unknown. Using a network for screening of non-infectious disorders, we performed a pilot study to determine the frequency of IgM antibodies to Toxoplasma gondii in 1,003 infants (53.1% male, mean +/- SD age = 18.3 +/- 13.0 days, birth weight = 3.116 +/- 0.453 kg) in Mexico City from March to April 2003. Blood samples embedded in filter paper were assayed for IgM antibodies using a capture enzyme-linked immunosorbent assay and results were confirmed by Western blot. Two asymptomatic newborns, one of them premature, had IgM and IgG antibodies in a serum sample taken from both the infant and the mother and were clinically followed. Our data suggest a frequency of approximately two cases of congenital T. gondii infection per 1,000 newborns in Mexico City.
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Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Toxoplasmosis Congénita/epidemiología , Toxoplasmosis Congénita/prevención & control , Adulto , Animales , Anticuerpos Antiprotozoarios/sangre , Western Blotting , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Recién Nacido , Masculino , México/epidemiología , Proyectos Piloto , Prevalencia , Factores de Riesgo , Toxoplasma/inmunología , Toxoplasmosis Congénita/etiología , Toxoplasmosis Congénita/transmisiónRESUMEN
Tilia genus is commonly used around the world for its central nervous system properties; it is prepared as tea and used as tranquilizing, anticonvulsant, and analgesic. In this study, anticonvulsant activity of the Tilia americana var. mexicana inflorescences and leaves was investigated by evaluating organic and aqueous extracts (100, 300, and 600 mg/kg, i.p.) and some flavonoids in the pentylenetetrazole-induced seizures in mice. Moreover, antioxidant effect of these extracts and flavonoids was examined in an in vitro study by using spectrophotometric technique. Significant activity was observed in the methanol extract from inflorescences. An HPLC analysis of the methanol extract from inflorescences and leaves of Tilia allowed demonstrating the respective presence of some partial responsible flavonoid constituents: quercetin (20.09 ± 1.20 µg/mg and 3.39 ± 0.10 µg/mg), rutin (3.52 ± 0.21 µg/mg and 8.94 ± 0.45 µg/mg), and isoquercitrin (1.74 ± 0.01 µg/mg and 1.24 ± 0.13 µg/mg). In addition, significant but different antioxidant properties were obtained among the flavonoids and the extracts investigated. Our results provide evidence of the anticonvulsant activity of Tilia reinforcing its utility for central nervous system diseases whose mechanism of action might involve partial antioxidant effects due to the presence of flavonoids.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Antioxidantes/uso terapéutico , Flavonoides/uso terapéutico , Convulsiones/tratamiento farmacológico , Tilia/química , Animales , Antioxidantes/química , Cromatografía Líquida de Alta Presión , Femenino , Flavonoides/análisis , Flores/química , Flores/metabolismo , Ratones , Pentilenotetrazol/toxicidad , Extractos Vegetales/química , Extractos Vegetales/uso terapéutico , Hojas de la Planta/química , Hojas de la Planta/metabolismo , Quercetina/análogos & derivados , Quercetina/análisis , Quercetina/aislamiento & purificación , Especies Reactivas de Oxígeno/análisis , Rutina/análisis , Rutina/aislamiento & purificación , Convulsiones/inducido químicamente , Convulsiones/patología , Tilia/metabolismoRESUMEN
Introducción. El ácido valproico (VPA) es un antiepiléptico útil para controlar diferentes tipos de epilepsia. Tiene efectos colaterales y se asocia a incremento del peso corporal y a alteraciones metabólicas y endocrinas, entre ellas síndrome metabólico. Objetivo. Conocer la prevalencia de la obesidad y el síndrome metabólico en pacientes pediátricos con epilepsia tratados en monoterapia con VPA. Pacientes y métodos. Estudio transversal, observacional, analítico. Se estudiaron pacientes tratados con VPA entre 2010- 2014, y se midió el índice de masa corporal (IMC), el perímetro abdominal, la presión arterial, la glucosa, los triglicéridos y las lipoproteínas de alta densidad (HDL), en búsqueda de obesidad y síndrome metabólico. La obesidad se definió con un IMC mayor del percentil 95; el síndrome metabólico, con al menos tres de los siguientes criterios: perímetro abdominal mayor del percentil 90, presión arterial sistémica mayor del percentil 90, triglicéridos mayores de 110 mg/dL y HDL menor de 40 mg/dL. Resultados. Se estudiaron 47 pacientes con una edad media de 10,1 ± 4 años; el 51,06% eran varones. Ocho (17%) desarrollaron obesidad y, de ellos, dos (25%), síndrome metabólico. Tres pacientes desarrollaron sobrepeso (6%). Observamos diferencias estadísticamente significativas de media de edad comparados con los grupos de IMC, donde los pacientes obesos eran adolescentes (ANOVA; p = 0,0001), y aquellos que tomaban más VPA al día eran los obesos (ANOVA; p = 0,024). Conclusiones. Los pacientes tratados con VPA que se convierten en obesos pueden desarrollar síndrome metabólico. Requieren una monitorización cuidadosa y, ante la presencia de ganancia de peso, se deberá valorar la retirada del fármaco (AU)
Introduction. Valproic acid (VPA) is a useful antiepileptic drug for controlling different types of epilepsy. It has several side effects and is associated to increased body weight, as well as metabolic and endocrine disorders, including metabolic syndrome. Aim. To determine the prevalence of obesity and metabolic syndrome among paediatric patients with epilepsy treated in monotherapy with VPA. Patients and methods. The study was cross-sectional, observational and analytical. A sample of patients treated with VPA between 2010-2014 were studied and the body mass index (BMI), abdominal perimeter, arterial blood pressure, glucose, triglycerides and high density lipoproteins (HDL) were studied in search of obesity and metabolic syndrome. Obesity was defined as a BMI above the 95th percentile, and metabolic syndrome was considered if at least three of the following criteria were fulfilled: abdominal perimeter above the 90th percentile, systolic arterial pressure above the 90th percentile, triglycerides above 110 mg/dL and HDL below 40 mg/dL. Results. A total of 47 patients with a mean age of 10.1 ± 4 years were studied; 51.06% were males. Eight (17%) of them developed obesity and, of those, two (25%) had metabolic syndrome. Three patients went on to become overweight (6%). Statistically significant differences were observed in the mean age in comparison to the BMI groups, where the obese patients were adolescents (ANOVA, p = 0.0001) and those who took more VPA per day were the obese (ANOVA, p = 0.024). Conclusions. Patients treated with VPA who become obese may go on to develop metabolic syndrome. They require careful monitoring and, if they are seen to put on weight, withdrawal of the drug should be considered (AU)