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1.
Genet Med ; 23(2): 352-362, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33106617

RESUMEN

PURPOSE: Neurodevelopmental disorders (NDD) caused by protein phosphatase 2A (PP2A) dysfunction have mainly been associated with de novo variants in PPP2R5D and PPP2CA, and more rarely in PPP2R1A. Here, we aimed to better understand the latter by characterizing 30 individuals with de novo and often recurrent variants in this PP2A scaffolding Aα subunit. METHODS: Most cases were identified through routine clinical diagnostics. Variants were biochemically characterized for phosphatase activity and interaction with other PP2A subunits. RESULTS: We describe 30 individuals with 16 different variants in PPP2R1A, 21 of whom had variants not previously reported. The severity of developmental delay ranged from mild learning problems to severe intellectual disability (ID) with or without epilepsy. Common features were language delay, hypotonia, and hypermobile joints. Macrocephaly was only seen in individuals without B55α subunit-binding deficit, and these patients had less severe ID and no seizures. Biochemically more disruptive variants with impaired B55α but increased striatin binding were associated with profound ID, epilepsy, corpus callosum hypoplasia, and sometimes microcephaly. CONCLUSION: We significantly expand the phenotypic spectrum of PPP2R1A-related NDD, revealing a broader clinical presentation of the patients and that the functional consequences of the variants are more diverse than previously reported.


Asunto(s)
Discapacidad Intelectual , Microcefalia , Trastornos del Neurodesarrollo , Humanos , Discapacidad Intelectual/genética , Hipotonía Muscular , Trastornos del Neurodesarrollo/epidemiología , Trastornos del Neurodesarrollo/genética , Proteína Fosfatasa 2/genética , Factores de Transcripción
2.
Glob Pediatr Health ; 7: 2333794X20968718, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33225022

RESUMEN

Introduction. The developing world continues to face challenges in closing the large treatment gap for epilepsy, due to a high burden of disease and few experienced providers to manage the condition. Children with epilepsy are susceptible to higher rates of developmental impairments and refractory disease due to delays or absence of appropriate management as a result. We demonstrated that a structured education intervention on pediatric epilepsy can improve knowledge, confidence, and impact clinical practice of first level providers in Zambia. Methods. Three first-level facilities across Zambia were included. After initial pilot versions and revisions, the final course was implemented at each site. Pre- and post-intervention knowledge and confidence assessments were performed. Additionally, chart reviews were conducted prior to intervention and 4 months after completion of training at each site to assess change on management. Results. Twenty-three of the original 24 participants from all 3 sites completed the training; 48% clinical officers, 43% nurses, 9% other expertise. Of the 15 concepts tested by knowledge assessment, 12 showed trends in improvement, 7 of which were significant (P < .05). Chart reviews demonstrated significant improvement in documentation of seizure description (P = .008), seizure frequency (P = .00), and possible causes of seizures/epilepsy (P = .034). Discussion. Key elements of success to this program included hands on clinical skills building and case-based teaching, development of a program with direct and ongoing input from the target audience, and inclusion of assessments to monitor impact on clinical practice. Future studies looking at health outcomes are necessary to determine sustained impact.

3.
Pediatr Neurol ; 58: 37-40, 2016 05.
Artículo en Inglés | MEDLINE | ID: mdl-26968976

RESUMEN

BACKGROUND: Migraine is common in children and adolescents and can be disabling. Being able to predict which patients will respond to triptans based on their clinical phenotype would be helpful. Adult data suggest cranial autonomic symptoms and aura predict triptan response. This study examined clinical predictors of triptan response in pediatric migraineurs. METHODS: This chart review study included all patients less than 18 years old with migraine who were seen at the University of California, San Francisco Headache Center in 2014. Univariate χ(2) analyses were performed, followed by multivariate logistic regression modeling. RESULTS: Of 127 pediatric migraineurs, 70 (55%) had chronic migraine and 24 (19%) had aura. The majority (55%) had at least one cranial autonomic symptom. Of 65 with triptan outcome data, 47 (73%) benefitted from a triptan. In univariate analyses, triptan benefit was seen in 65% with chronic migraine versus 88% with episodic migraine (P = 0.048), 67% with aura versus 74% without (P = 0.66), and 70% with cranial autonomic symptom versus 74% without (P = 0.76). In a multivariate logistic regression model, chronic migraine, aura, and cranial autonomic symptom were not statistically significant predictors of triptan benefit: chronic migraine: 0.25 (0.06-1.04); aura: 0.65 (0.09-4.45); cranial autonomic symptom: 0.75 (0.22-2.52). CONCLUSIONS: In univariate analysis, individuals with chronic migraine were less likely to benefit from triptans. In contrast to what has been documented in adults, cranial autonomic symptoms and aura did not predict triptan response, although our small sample size limited the study's power. Larger pediatric studies are needed, and future pediatric triptan trials should provide response rates stratified by clinical variables such as aura.


Asunto(s)
Trastornos Migrañosos/diagnóstico , Trastornos Migrañosos/tratamiento farmacológico , Serotoninérgicos/uso terapéutico , Triptaminas/uso terapéutico , Adolescente , Femenino , Humanos , Modelos Logísticos , Masculino , Análisis Multivariante , Pronóstico , Resultado del Tratamiento
4.
Nat Neurosci ; 14(4): 505-12, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21378970

RESUMEN

Polyamines are endogenous molecules involved in cell damage following neurological insults, although it is unclear whether polyamines reduce or exacerbate this damage. We used a developmental seizure model in which we exposed Xenopus laevis tadpoles to pentylenetetrazole (PTZ), a known convulsant. We found that, after an initial PTZ exposure, seizure onset times were delayed in response to a second PTZ exposure 4 h later. This protective effect was a result of activity-dependent increases in synthesis of putrescine, the simplest polyamine. Unlike more complex polyamines that directly modulate ion channels, putrescine exerted its effect by altering the balance of excitation to inhibition. Tectal neuron recordings, 4 h after the initial seizure, revealed an elevated frequency of GABAergic spontaneous inhibitory postsynaptic currents. Our data suggest that this effect is mediated by an atypical pathway that converts putrescine into GABA, which then activates presynaptic GABA(B) receptors. Our data suggest that polyamines have a previously unknown neuroprotective role in the developing brain.


Asunto(s)
Citoprotección/fisiología , Modelos Animales de Enfermedad , Epilepsia/metabolismo , Larva/fisiología , Poliaminas/farmacología , Xenopus laevis , Animales , Convulsivantes/farmacología , Epilepsia/inducido químicamente , Epilepsia/patología , Larva/anatomía & histología , Larva/crecimiento & desarrollo , Técnicas de Cultivo de Órganos , Pentilenotetrazol/farmacología , Factores de Tiempo
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