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1.
Am J Hum Genet ; 111(5): 841-862, 2024 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-38593811

RESUMEN

RNA sequencing (RNA-seq) has recently been used in translational research settings to facilitate diagnoses of Mendelian disorders. A significant obstacle for clinical laboratories in adopting RNA-seq is the low or absent expression of a significant number of disease-associated genes/transcripts in clinically accessible samples. As this is especially problematic in neurological diseases, we developed a clinical diagnostic approach that enhanced the detection and evaluation of tissue-specific genes/transcripts through fibroblast-to-neuron cell transdifferentiation. The approach is designed specifically to suit clinical implementation, emphasizing simplicity, cost effectiveness, turnaround time, and reproducibility. For clinical validation, we generated induced neurons (iNeurons) from 71 individuals with primary neurological phenotypes recruited to the Undiagnosed Diseases Network. The overall diagnostic yield was 25.4%. Over a quarter of the diagnostic findings benefited from transdifferentiation and could not be achieved by fibroblast RNA-seq alone. This iNeuron transcriptomic approach can be effectively integrated into diagnostic whole-transcriptome evaluation of individuals with genetic disorders.


Asunto(s)
Transdiferenciación Celular , Fibroblastos , Neuronas , Análisis de Secuencia de ARN , Humanos , Transdiferenciación Celular/genética , Fibroblastos/metabolismo , Fibroblastos/citología , Análisis de Secuencia de ARN/métodos , Neuronas/metabolismo , Neuronas/citología , Transcriptoma , Reproducibilidad de los Resultados , Enfermedades del Sistema Nervioso/genética , Enfermedades del Sistema Nervioso/diagnóstico , RNA-Seq/métodos , Femenino , Masculino
2.
Proc Natl Acad Sci U S A ; 120(4): e2209964120, 2023 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-36669111

RESUMEN

Sonic hedgehog signaling regulates processes of embryonic development across multiple tissues, yet factors regulating context-specific Shh signaling remain poorly understood. Exome sequencing of families with polymicrogyria (disordered cortical folding) revealed multiple individuals with biallelic deleterious variants in TMEM161B, which encodes a multi-pass transmembrane protein of unknown function. Tmem161b null mice demonstrated holoprosencephaly, craniofacial midline defects, eye defects, and spinal cord patterning changes consistent with impaired Shh signaling, but were without limb defects, suggesting a CNS-specific role of Tmem161b. Tmem161b depletion impaired the response to Smoothened activation in vitro and disrupted cortical histogenesis in vivo in both mouse and ferret models, including leading to abnormal gyration in the ferret model. Tmem161b localizes non-exclusively to the primary cilium, and scanning electron microscopy revealed shortened, dysmorphic, and ballooned ventricular zone cilia in the Tmem161b null mouse, suggesting that the Shh-related phenotypes may reflect ciliary dysfunction. Our data identify TMEM161B as a regulator of cerebral cortical gyration, as involved in primary ciliary structure, as a regulator of Shh signaling, and further implicate Shh signaling in human gyral development.


Asunto(s)
Hurones , Proteínas Hedgehog , Animales , Femenino , Humanos , Ratones , Embarazo , Sistema Nervioso Central/metabolismo , Cilios/genética , Cilios/metabolismo , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Ratones Noqueados , Transducción de Señal
3.
J Pediatr Hematol Oncol ; 43(2): e195-e197, 2021 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-31764519

RESUMEN

Neurocutaneous melanocytosis (NCM) is a disorder characterized by multiple or large congenital nevi and excessive proliferation of melanocytes in the leptomeninges and brain parenchyma. The majority of NCM is a result of somatic mosaicism due to a single postzygotic mutation in codon 61 of NRAS. Patients with NCM are at high risk of developing leptomeningeal melanoma. The prognosis for leptomeningeal melanoma is poor with no known effective treatment options. We describe the clinical features, treatment, and outcome of 4 children with NCM and leptomeningeal melanoma and discuss the latest molecular findings and treatment options for this rare condition.


Asunto(s)
GTP Fosfohidrolasas/genética , Melanoma/patología , Melanosis/complicaciones , Proteínas de la Membrana/genética , Neoplasias Meníngeas/patología , Síndromes Neurocutáneos/complicaciones , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Masculino , Melanoma/tratamiento farmacológico , Melanoma/etiología , Melanosis/genética , Melanosis/patología , Neoplasias Meníngeas/tratamiento farmacológico , Neoplasias Meníngeas/etiología , Mutación , Síndromes Neurocutáneos/genética , Síndromes Neurocutáneos/patología , Pronóstico , Estudios Retrospectivos , Adulto Joven
4.
Epilepsy Behav ; 86: 131-137, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-30006259

RESUMEN

OBJECTIVE: We studied our collective open-label, compassionate use experience in using cannabidiol (CBD) to treat epilepsy in patients with CDKL5 deficiency disorder and Aicardi, Doose, and Dup15q syndromes. METHODS: We included patients aged 1-30 years with severe childhood-onset epilepsy who received CBD for ≥10 weeks as part of multiple investigator-initiated expanded access or state access programs for a compassionate prospective interventional study: CDKL5 deficiency disorder (n = 20), Aicardi syndrome (n = 19), Dup15q syndrome (n = 8), and Doose syndrome (n = 8). These patients were treated at 11 institutions from January 2014 to December 2016. RESULTS: The percent change in median convulsive seizure frequency for all patients taking CBD in the efficacy group decreased from baseline [n = 46] to week 12 (51.4% [n = 35], interquartile range (IQR): 9-85%) and week 48 (59.1% [n = 27], IQR: 14-86%). There was a significant difference between the percent changes in monthly convulsive seizure frequency during baseline and week 12, χ2(2) = 22.9, p = 0.00001, with no difference in seizure percent change between weeks 12 and 48. Of the 55 patients in the safety group, 15 (27%) withdrew from extended observation by week 144: 4 due to adverse effects, 9 due to lack of efficacy, 1 withdrew consent, and 1 was lost to follow-up. SIGNIFICANCE: This open-label drug trial provides class III evidence for the long-term safety and efficacy of CBD administration in patients with treatment-resistant epilepsy (TRE) associated with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes. Adjuvant therapy with CBD showed similar safety and efficacy for these four syndromes as reported in a diverse population of TRE etiologies. This study extended analysis of the prior report from 12 weeks to 48 weeks of efficacy data and suggested that placebo-controlled randomized trials should be conducted to formally assess the safety and efficacy of CBD in these epileptic encephalopathies.


Asunto(s)
Síndrome de Aicardi/tratamiento farmacológico , Anticonvulsivantes/uso terapéutico , Cannabidiol/uso terapéutico , Cromosomas Humanos 13-15/genética , Epilepsias Mioclónicas/tratamiento farmacológico , Síndromes Epilépticos/tratamiento farmacológico , Espasmos Infantiles/tratamiento farmacológico , Adolescente , Adulto , Síndrome de Aicardi/diagnóstico , Anticonvulsivantes/química , Cannabidiol/química , Niño , Preescolar , Epilepsias Mioclónicas/diagnóstico , Síndromes Epilépticos/diagnóstico , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Proteínas Serina-Treonina Quinasas/deficiencia , Espasmos Infantiles/diagnóstico , Trisomía/genética , Adulto Joven
5.
Nat Genet ; 35(3): 270-6, 2003 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-14578885

RESUMEN

Loss-of-function mutations in RELN (encoding reelin) or PAFAH1B1 (encoding LIS1) cause lissencephaly, a human neuronal migration disorder. In the mouse, homozygous mutations in Reln result in the reeler phenotype, characterized by ataxia and disrupted cortical layers. Pafah1b1(+/-) mice have hippocampal layering defects, whereas homozygous mutants are embryonic lethal. Reln encodes an extracellular protein that regulates layer formation by interacting with VLDLR and ApoER2 (Lrp8) receptors, thereby phosphorylating the Dab1 signaling molecule. Lis1 associates with microtubules and modulates neuronal migration. We investigated interactions between the reelin signaling pathway and Lis1 in brain development. Compound mutant mice with disruptions in the Reln pathway and heterozygous Pafah1b1 mutations had a higher incidence of hydrocephalus and enhanced cortical and hippocampal layering defects. Dab1 and Lis1 bound in a reelin-induced phosphorylation-dependent manner. These data indicate genetic and biochemical interaction between the reelin signaling pathway and Lis1.


Asunto(s)
Encéfalo/embriología , Moléculas de Adhesión Celular Neuronal/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Transducción de Señal , 1-Alquil-2-acetilglicerofosfocolina Esterasa , Animales , Humanos , Ratones , Ratones Mutantes Neurológicos , Proteínas del Tejido Nervioso , Proteína Reelina , Serina Endopeptidasas
6.
Am J Med Genet A ; 155A(7): 1574-80, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21638761

RESUMEN

Rhombencephalosynapsis (RES) is a rare congenital brain malformation typically identified by magnetic resonance imaging and characterized by fusion of the cerebellar hemispheres and dentate nuclei and vermian agenesis or hypogenesis. Although RES is frequently found in conjunction with other brain malformations and/or congenital anomalies, no specific molecular etiology has been discovered to date and no animal models exist. We identified two half sisters with alobar or semi-lobar holoprosencephaly (HPE) and partial RES, suggesting that genes linked to HPE may also contribute to RES. A deletion of seven base pairs in exon one of the ZIC2 gene (c.392_98del7) was identified in each of the two half sisters with HPE and partial RES. To identify genetic causes of RES and to assess whether genes identified in HPE have a role in RES, we tested 11 additional individuals with RES by high-resolution chromosome analysis, chromosomal microarray analysis, and sequencing of four HPE genes. No mutations in ZIC2 or in other genes that cause HPE were identified, suggesting that mutation of ZIC2 is a rare cause of, or contributor to, RES associated with HPE. In addition, an individual with a complex rearrangement of chromosome 22q13.3 and RES was identified, suggesting the presence of a dosage-sensitive gene that may contribute to RES in this region.


Asunto(s)
Holoprosencefalia/genética , Mutación/genética , Proteínas Nucleares/genética , Rombencéfalo/anomalías , Rombencéfalo/patología , Factores de Transcripción/genética , Adolescente , Niño , Preescolar , Bandeo Cromosómico , Hibridación Genómica Comparativa , Femenino , Holoprosencefalia/diagnóstico , Humanos , Lactante , Masculino , Hermanos
7.
Am J Med Genet A ; 155A(9): 2071-7, 2011 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-21834044

RESUMEN

Polymicrogyria is a disorder of neuronal development resulting in structurally abnormal cerebral hemispheres characterized by over-folding and abnormal lamination of the cerebral cortex. Polymicrogyria is frequently associated with severe neurologic deficits including intellectual disability, motor problems, and epilepsy. There are acquired and genetic causes of polymicrogyria, but most patients with a presumed genetic etiology lack a specific diagnosis. Here we report using whole-exome sequencing to identify compound heterozygous mutations in the WD repeat domain 62 (WDR62) gene as the cause of recurrent polymicrogyria in a sibling pair. Sanger sequencing confirmed that the siblings both inherited 1-bp (maternal allele) and 2-bp (paternal allele) frameshift deletions, which predict premature truncation of WDR62, a protein that has a role in early cortical development. The probands are from a non-consanguineous family of Northern European descent, suggesting that autosomal recessive PMG due to compound heterozygous mutation of WDR62 might be a relatively common cause of PMG in the population. Further studies to identify mutation frequency in the population are needed.


Asunto(s)
Anomalías Múltiples/genética , Exoma , Malformaciones del Desarrollo Cortical/genética , Proteínas del Tejido Nervioso/genética , Adulto , Secuencia de Bases , Proteínas de Ciclo Celular , Niño , Anomalías Craneofaciales/genética , Femenino , Mutación del Sistema de Lectura , Pruebas Genéticas , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Imagen por Resonancia Magnética , Masculino , Mutación , Análisis de Secuencia de ADN , Eliminación de Secuencia , Hermanos
8.
Neurol Clin ; 39(3): 699-704, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34215381

RESUMEN

The adaption of online or virtual technologies to deliver care, to meet professionally, and to interview has transformed child neurology. Although these technologies were brought to bear out of necessity, it is hoped that in a postpandemic world, these useful tools will continue to benefit the field. Here we discuss the tools and their future.


Asunto(s)
COVID-19 , Enfermedades del Sistema Nervioso , Neurología , Pediatría , Telemedicina , Niño , Humanos , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/terapia , Neurología/tendencias , Pediatría/tendencias , Telemedicina/tendencias
9.
Neurol Clin ; 39(3): 719-722, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34215383

RESUMEN

The molecular understanding of the pathogenic mechanisms responsible for neurologic diseases of children has led to a remarkable period of research that addresses the root causes of diseases. The promise of this research has been realized with cures and treatments that correct underlying deficiencies. The breakneck rate at which new research is being proposed promises to usher in a transformation of child neurology from a diagnostic and supportive field into an interventional one. Training child neurology residents in clinical research and therapeutic intervention is increasingly important to assure the ongoing ability to support research discoveries and treatment.


Asunto(s)
Internado y Residencia , Enfermedades del Sistema Nervioso , Neurología , Niño , Humanos , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/terapia
10.
Neurol Clin ; 39(3): 689-697, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34215380

RESUMEN

Child neurology programs can be net margin generators for children's hospitals. The relative value unit (RVU) expectations for child neurologists are heavily influenced by proceduralists (neurophysiologists, Botox injectors, and so forth) and means in most RVU data sets are not realistic expectations for Evaluation and Management coding, outpatient neurologists. Yet each neurologist has a net revenue/expense ratio of 1.97 for a hospital neurology enterprise, so each of the neurologists generates nearly twice their salary for the hospital. Downstream revenue is even more impressive. Each neurologist generates about $2,000,000.00 in downstream revenue per year.


Asunto(s)
Hospitales Pediátricos , Neurología , Niño , Administración Financiera de Hospitales , Humanos , Neurólogos , Neurología/educación
11.
Pediatr Neurol ; 121: 20-25, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34126318

RESUMEN

BACKGROUND: Neonatal cerebral sinus venous thrombosis (CSVT) causes high morbidity and mortality. Factors associated with either favorable or unfavorable long-term outcomes have not been clearly established. This study aimed to determine the factors involved in long-term neurological outcomes in patients with neonatal CSVT. METHODS: This was a retrospective cohort study of patients with neonatal CSVT at a single institution. Clinical factors associated with long-term neurological outcomes were examined. RESULTS: A total of 67 patients met study inclusion criteria for radiologically confirmed neonatal CSVT. The mean patient follow-up duration was four years (range one week to 16 years, median six years). We observed a favorable neurological outcome defined by a pediatric stroke outcome measures (PSOM) score of 0 to 0.5 in 26 (53%) of osurviving patients at follow-up. An unfavorable neurological outcome as defined by PSOM score >0.5 was observed in 23 survivors (47%). Death was reported in 18 (27%) patients, of which 10 patients died due to direct complications of CSVT. Congential heart disease and genetic disease were associated with significantly increased odds for all-cause death. Cardiorespiratory failure and altered mental status during the initial neurological examination were significantly associated with increased odds of death due to CSVT. Among surviving patients, higher PSOM scores were associated with premature birth (i.e., gestational age < 37 weeks), traumatic birth, site of thrombosis in the straight sinus, site of thrombosis in the internal cerebral veins, and hemorrhagic infarct. In contrast, lower PSOM scores were associated with a normal neurological examination at presentation, thrombosis in only superficial sinuses, and hemorrhage without infarct. There was no statistically significant association between the type and duration of CSVT treatment. CONCLUSIONS: The major factors influencing outcome of neonates following CSVT included comorbid medical conditions, abnormal neurological examination at presentation, location of venous thrombosis, and type of cerebral injury. These results can help guide further studies in neonatal CSVT aiming to decrease morbidity and mortality with the goal of improving long-term neurological outcomes.


Asunto(s)
Enfermedades del Recién Nacido , Evaluación de Resultado en la Atención de Salud , Trombosis de los Senos Intracraneales , Accidente Cerebrovascular , Adolescente , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Enfermedades del Recién Nacido/mortalidad , Enfermedades del Recién Nacido/patología , Enfermedades del Recién Nacido/terapia , Masculino , Estudios Retrospectivos , Trombosis de los Senos Intracraneales/complicaciones , Trombosis de los Senos Intracraneales/mortalidad , Trombosis de los Senos Intracraneales/patología , Trombosis de los Senos Intracraneales/terapia , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/mortalidad , Accidente Cerebrovascular/patología , Accidente Cerebrovascular/terapia
12.
Clin Neuropsychol ; 33(5): 890-904, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30698067

RESUMEN

Objective: Complete prenatal cerebellar infarction is rare and few reports exist documenting developmental outcomes. We report outcome data on a child who sustained a stroke to the bilateral cerebellar hemispheres at 25 weeks gestation, and was subsequently seen for follow-up neuropsychological evaluations at ages 5 years, 5 months and 7 years, 9 months. Method: Retrospective chart review. Results: Findings from the initial evaluation at age 5 were consistent with a diagnosis of intellectual disability based on developmental testing and parent-reported adaptive behavior. Deficits in social communication, relatedness, and reciprocity were identified, though diagnosis of an autism-spectrum disorder (ASD) was deferred given the difficulty of interpreting these findings in the context of his physical and cognitive disabilities. Re-assessment at age 7 included comprehensive autism assessment, and a diagnosis of ASD was confirmed. Neuropsychological testing revealed minimal developmental skill progression over the assessment interval. Conclusions: These findings add to growing evidence that the cerebellum plays an important role in social development, and that early cerebellar injury may represent an acquired pathway for ASD. Complex medical histories may obscure or delay diagnosis of ASD, highlighting the importance of early evaluation using a multidisciplinary approach.


Asunto(s)
Infarto Encefálico/complicaciones , Encéfalo/patología , Pruebas Neuropsicológicas/normas , Conducta Social , Niño , Preescolar , Humanos , Masculino , Estudios Retrospectivos
13.
Am J Med Genet A ; 146A(13): 1637-54, 2008 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-18536050

RESUMEN

Polymicrogyria is a malformation of cortical development characterized by loss of the normal gyral pattern, which is replaced by many small and infolded gyri separated by shallow, partly fused sulci, and loss of middle cortical layers. The pathogenesis is unknown, yet emerging data supports the existence of several loci in the human genome. We report on the clinical and brain imaging features, and results of cytogenetic and molecular genetic studies in 29 patients with polymicrogyria associated with structural chromosome rearrangements. Our data map new polymicrogyria loci in chromosomes 1p36.3, 2p16.1-p23, 4q21.21-q22.1, 6q26-q27, and 21q21.3-q22.1, and possible loci in 1q44 and 18p as well. Most and possibly all of these loci demonstrate incomplete penetrance and variable expressivity. We anticipate that these data will serve as the basis for ongoing efforts to identify the causal genes located in these regions.


Asunto(s)
Aberraciones Cromosómicas , Malformaciones del Desarrollo Cortical/genética , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Adolescente , Adulto , Aneuploidia , Encéfalo/patología , Niño , Preescolar , Rotura Cromosómica , Deleción Cromosómica , Cromosomas Artificiales Bacterianos/genética , Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 2/genética , Cromosomas Humanos Par 21/genética , Cromosomas Humanos Par 4/genética , Cromosomas Humanos Par 6/genética , Femenino , Humanos , Hibridación Fluorescente in Situ , Lactante , Recién Nacido , Cariotipificación , Masculino , Malformaciones del Desarrollo Cortical/patología , Fenotipo , Translocación Genética
14.
Neurosci Lett ; 439(1): 100-5, 2008 Jul 04.
Artículo en Inglés | MEDLINE | ID: mdl-18514414

RESUMEN

Reelin, an extracellular protein that signals through the Dab1 adapter protein, and Lis1 regulate neuronal migration and cellular layer formation in the brain. Loss of Reelin and reduction in Lis1 activity in mice or humans results in the disorganization of cortical structures. Lis1, the product of the Pafah1b1 gene associates with Alpha1 (the product of the Pafah1b3 gene) and Alpha2 (the product of the Pafah1b2 gene) to form the Pafah1b heterotrimeric complex. This complex interacts biochemically and genetically with the Reelin pathway, however, the role of Alpha1 and Alpha2 in brain development is poorly understood. We previously demonstrated that compound mutations of Pafah1b1 with genes in Reelin pathway result in layering defects and the appearance of hydrocephalus in double mutant mice. Here, we generate triple mouse mutants to investigate the effect of individual Pafah1b Alpha subunits on cellular layer formation and hydrocephalus. We found that Pafah1b3 mutations exacerbate the layering defects, whereas Pafah1b2 mutations strongly suppress the hydrocephalus phenotype of compound mutant mice. The data indicate that the two Pafah1b Alpha subunits have profoundly different effects on brain development and interact in a significantly different manner with the Reelin signaling pathway.


Asunto(s)
1-Alquil-2-acetilglicerofosfocolina Esterasa/genética , 1-Alquil-2-acetilglicerofosfocolina Esterasa/metabolismo , Moléculas de Adhesión Celular Neuronal/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Hidrocefalia/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Mutación , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Serina Endopeptidasas/metabolismo , Animales , Animales Recién Nacidos , Regulación del Desarrollo de la Expresión Génica/genética , Regulación del Desarrollo de la Expresión Génica/fisiología , Genotipo , Hipocampo/patología , Hidrocefalia/patología , Ratones , Ratones Mutantes , Proteínas Asociadas a Microtúbulos/genética , Proteína Reelina
15.
J Pediatr Pharmacol Ther ; 22(4): 256-260, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28943819

RESUMEN

OBJECTIVE: Pediatric patients often require larger doses of antiepileptic drug (AED) than adults in order to attain therapeutic serum concentrations and/or achieve seizure control. Safety and efficacy data are often extrapolated from adult literature; hence, optimal dosage may only be determined anecdotally or based on expert opinion. With limited pediatric dosing guidelines, milligrams per day that are based on weight may exceed the maximum adult dose. The primary objective of this study is to evaluate the safety of exceeding maximum doses as specified by the US Food and Drug Administration or manufacturers of commonly used AEDs in pediatric patients. METHODS: This study is a single-center, retrospective analysis of all pediatric patients seen in the outpatient clinic between October 2010 and October 2014 who were prescribed a dose that exceeds the maximum approved dose of oxcarbazepine, zonisamide, topiramate, levetiracetam, lamotrigine, or clobazam. Baseline demographics (ie, sex, age, race/ethnicity, weight, height, diagnosis), serum drug concentrations, and appropriate laboratory tests were collected. Side effects were reviewed. RESULTS: During the 4-year study period, 41,137 prescriptions were included. A total of 2% of prescriptions exceeded the maximum dose of 1 of the included AEDs. The most common AED prescribed above the maximum dose was levetiracetam (53%), whereas lamotrigine was the least common (6%). The largest doses prescribed exceeded the maximum by 3-fold (i.e., levetiracetam dose of 9000 mg/day). CONCLUSION: It appears safe to use doses exceeding the maximum approved dose of the evaluated AEDs in pediatric patients, with appropriate counseling and monitoring for adverse effects.

17.
Enzymes ; 38: 37-42, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26612645

RESUMEN

The heterotrimeric brain platelet-activating factor acetylhydrolase (PAFAH1B1) contains two catalytic subunits and a regulatory subunit. This complex plays important, surprising roles in brain development and in spermatogenesis. The regulatory subunit, PAFAH1B1 (LIS1 protein), is critically regulated and when deficient leads to the devastating human neurological disorder Lissencephaly, or smooth brain. The role of the protein in brain development is not the catalysis of platelet-activating factor, rather the entire brain platelet-activating factor acetylhydrolase complex serves a signaling role, coordinating important pathways in brain development. The role of this complex in spermatogenesis was not foreseen, but appears to function to regulate a critical level of the PAFAH1B1 protein, such that too much of this protein or too little of this protein can lead to a disruption of spermatogenesis. Brain platelet-activating factor is thus a signaling complex, important for brain development and for spermatogenesis.

18.
Neurol Clin ; 20(4): 917-39, 2002 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-12616675

RESUMEN

The progress made in the understanding of the genetics of human brain malformations has lead to insight into the formation of brain and into mechanisms of disease affecting brain. It bears upon neurologists and geneticists to recognize the patterns of diseases of brain formation, to properly diagnose such disorders, to assess the recurrence risk of these malformations, and to guide families with appropriate expectations for outcomes. This article may serve as a guide to neurologists in their approach to these disorders. Because this area is one of rapid progress, the clinician is advised to seek more current information that may be available through on-line databases and other sources.


Asunto(s)
Encefalopatías/genética , Discapacidades del Desarrollo/genética , 1-Alquil-2-acetilglicerofosfocolina Esterasa , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Encéfalo/anomalías , Moléculas de Adhesión Celular Neuronal/genética , Niño , Proteínas Contráctiles/genética , Proteínas de la Matriz Extracelular/genética , Enfermedades Fetales/etiología , Filaminas , Proteínas de Homeodominio/genética , Humanos , Imagen por Resonancia Magnética , Proteínas de la Membrana , Proteínas de Microfilamentos/genética , Proteínas Asociadas a Microtúbulos/genética , Proteínas del Tejido Nervioso , Mutación Puntual/genética , Proteínas/genética , Proteína Reelina , Serina Endopeptidasas , Factor de Transcripción HES-1
19.
Brain Dev ; 26(6): 351-62, 2004 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-15275695

RESUMEN

Recent genetic insight into the mechanisms of human brain malformation have allowed one to consider a classification of these disorders by the genetic disruption. In this article an attempt is made to classify human cortical dysplasias by the known genetic disruptions or insults that lead to them. The discussion of malformation is within the context of the embryologic processes that have thought to have gone awry. Human disorders of segmentation, cell proliferation, telencephalic cleavage, differentiation, and neuronal migration are discussed. As this is a rapidly changing area, the reader is encouraged to check online databases for updates on the genetic insights that have been gained since the publication of this article.


Asunto(s)
Corteza Cerebral/anomalías , Regulación del Desarrollo de la Expresión Génica/genética , Malformaciones del Sistema Nervioso/clasificación , Malformaciones del Sistema Nervioso/genética , Tipificación del Cuerpo/genética , Diferenciación Celular/genética , División Celular/genética , Movimiento Celular/genética , Corteza Cerebral/patología , Corteza Cerebral/fisiopatología , Humanos , Recién Nacido , Malformaciones del Sistema Nervioso/fisiopatología
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