RESUMEN
Mutations in the SCN8A gene, encoding the voltage-gated sodium channel NaV1.6, are associated with a range of neurodevelopmental syndromes. The p.(Gly1625Arg) (G1625R) mutation was identified in a patient diagnosed with developmental epileptic encephalopathy (DEE). While most of the characterized DEE-associated SCN8A mutations were shown to cause a gain-of-channel function, we show that the G1625R variant, positioned within the S4 segment of domain IV, results in complex effects. Voltage-clamp analyses of NaV1.6G1625R demonstrated a mixture of gain- and loss-of-function properties, including reduced current amplitudes, increased time constant of fast voltage-dependent inactivation, a depolarizing shift in the voltage dependence of activation and inactivation, and increased channel availability with high-frequency repeated depolarization. Current-clamp analyses in transfected cultured neurons revealed that these biophysical properties caused a marked reduction in the number of action potentials when firing was driven by the transfected mutant NaV1.6. Accordingly, computational modeling of mature cortical neurons demonstrated a mild decrease in neuronal firing when mimicking the patients' heterozygous SCN8A expression. Structural modeling of NaV1.6G1625R suggested the formation of a cation-π interaction between R1625 and F1588 within domain IV. Double-mutant cycle analysis revealed that this interaction affects the voltage dependence of inactivation in NaV1.6G1625R. Together, our studies demonstrate that the G1625R variant leads to a complex combination of gain and loss of function biophysical changes that result in an overall mild reduction in neuronal firing, related to the perturbed interaction network within the voltage sensor domain, necessitating personalized multi-tiered analysis for SCN8A mutations for optimal treatment selection.
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Potenciales de Acción , Discapacidades del Desarrollo , Epilepsia , Canal de Sodio Activado por Voltaje NAV1.6 , Neuronas , Canal de Sodio Activado por Voltaje NAV1.6/genética , Canal de Sodio Activado por Voltaje NAV1.6/metabolismo , Humanos , Neuronas/metabolismo , Neuronas/patología , Epilepsia/genética , Epilepsia/patología , Epilepsia/metabolismo , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/patología , Animales , Masculino , Femenino , Células HEK293 , MutaciónRESUMEN
INTRODUCTION: In recent years, the increasing prevalence of autism-spectrum disorder has resulted in an increased demand for therapies including occupational therapy. In this pilot trial, we aimed to compare the efficacy of group versus individual occupational therapy among toddlers with autism as a means to improve accessibility to care. METHODS: Toddlers (2-4 years) undergoing autism evaluation in our public child developmental centre were recruited and randomised to receive 12 weekly sessions of group or individual occupational therapy based on the same mode of intervention: Developmental, Individual-Differences and Relationship-based (DIR). Primary outcomes related to intervention implementation included waiting days, nonattendance, intervention period, number of sessions attended and therapist satisfaction. Secondary outcomes were the Adaptive Behaviour Assessment System questionnaire, the Paediatric Quality of Life Inventory and the Peabody Developmental Motor Scale (PDMS-2). RESULTS: Twenty toddlers with autism were included, 10 in each occupational therapy mode of intervention. Children waited fewer days before beginning group occupational therapy compared to individual therapy (52.4 ± 28.1 vs. 108.8 ± 48.0 days p < 0.01). Mean numbers of nonattendance was similar for both interventions (3.2 ± 2.82 vs. 2 ± 1.76, p > 0.05). Worker satisfaction scores were similar at the beginning and end of the study (6.1 ± 0.4 vs. 6.07 ± 0.49, p > 0.05). There were no significant differences between the percentage changes in individual and group therapy outcomes for adaptive score (6.0 ± 16.0 vs. 4.5 ± 17.9, p > 0.05), quality of life (1.3 ± 20.9 vs. 18.8 ± 24.5, p > 0.05) and fine motor skills (13.7 ± 36.1 vs. 15.1 ± 41.5, p > 0.05). CONCLUSIONS: In this pilot study, the group DIR-based occupational therapy for toddlers with autism improved access to services and allowed earlier interventions, with no clinical inferiority to individual therapy. Further research is required to examine group clinical therapy benefit.
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Trastorno Autístico , Terapia Ocupacional , Humanos , Preescolar , Proyectos Piloto , Terapia Ocupacional/métodos , Calidad de Vida , Salud PúblicaRESUMEN
AIM: To evaluate muscle haemodynamics and oxygen metabolism in adults with cerebral palsy (CP) at rest and during exercise. METHOD: This cross-sectional study included 12 adults with spastic CP (four females, eight males; mean age [SD] 29 years 6 months [7 years 10.8 months]) and 13 typically developing individuals (seven females, six males; mean age [SD] 26 years 6 months [1 year 1.9 months]). Near-infrared spectroscopy was used to assess changes in muscle blood flow (mBF), muscle oxygen consumption (mVO2 ), and muscle oxygen saturation in the vastus lateralis and rectus femoris muscles during three conditions: rest, low load at 20% maximum voluntary contraction (MVC), and high load at 80% MVC. RESULTS: MBF was lower in participants with CP than in typically developing participants at rest (p < 0.001) and at 20% MVC (p = 0.007) in both muscles. Increased load caused a reduction in mBF in typically developing participants and an increase in CP. MVO2 in typically developing participants increased from rest to 20% MVC and was reduced at 80% MVC compared with 20% MVC. In participants with CP, there was no change with load in the rectus femoris muscle; however, there was an increase in the vastus lateralis muscle from rest to 20% MVC, and 80% MVC had a similar value. Muscle saturation was higher in participants with CP across all conditions (vastus lateralis, p < 0.001; rectus femoris, p = 0.0518). INTERPRETATION: Oxidative metabolism in CP is not limited by oxygen delivery (mBF), because high muscle saturation suggests oxygen availability. Adults with CP demonstrate muscular responses to exercise that are inconsistent with typical high-workload activation, probably because of inefficient fibre recruitment and secondary anomalies.
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Parálisis Cerebral , Músculo Esquelético , Masculino , Femenino , Humanos , Adulto , Estudios Transversales , Hemodinámica , Oxígeno , ElectromiografíaRESUMEN
BACKGROUND AND OBJECTIVES: To expand the clinical knowledge of GPAA1-related glycosylphosphatidylinositol (GPI) deficiency. METHODS: An international case series of 7 patients with biallelic GPAA1 variants were identified. Clinical, biochemical, and neuroimaging data were collected for comparison. Where possible, GPI-anchored proteins were assessed using flow cytometry. RESULTS: Ten novel variants were identified in 7 patients. Flow cytometry samples of 3 available patients confirmed deficiency of several GPI-anchored proteins on leukocytes. Extensive phenotypic information was available for each patient. The majority experienced developmental delay, seizures, and hypotonia. Neuroimaging revealed cerebellar anomalies in the majority of the patients. Alkaline phosphatase was within the normal range in 5 individuals and low in 1 individual, as has been noted in other transamidase defects. We notably describe individuals either less affected or older than the ones published previously. DISCUSSION: Clinical features of the cases reported broaden the spectrum of the known phenotype of GPAA1-related GPI deficiency, while outlining the importance of using functional studies such as flow cytometry to aid in variant classification.
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BACKGROUND: Cystic periventricular leukomalacia (cPVL) is a strong indicator of subsequent motor and developmental impairments in premature infants. There is a paucity of publications on biomarkers of cPVL. OBJECTIVES: To determine C-reactive protein (CRP) levels during the first week of life of preterm infants who later developed cPVL and to identify the association between CRP levels with perinatal factors. METHODS: We retrospectively included infants ≤ 32 weeks gestation and/or birth weights ≤ 1500 grams; 17 with a cranial ultrasound diagnosis of cPVL and 54 with normal ultrasounds. Serum CRP levels were measured during days 1-7 (CRP1-7d) of life and subdivided into two timing groups: days 1-3 (CRP1-3d) and days 4-7 (CRP4-7d). RESULTS: The cPVL group had significantly higher mean CRP4-7d levels compared to controls (12.75 ± 21.2 vs. 2.23 ± 3.1, respectively, P = 0.03), while CRP1-3d levels were similar. CRP1-7d levels were significantly correlated with maximal fraction of inspired oxygen during the first 12 hours of life (FiO2-12h, r = 0.51, P < 0.001]. Additional risk factors were not associated with CRP levels. CONCLUSIONS: Our finding of elevated CRP4-7d levels and later development of cPVL supports earlier studies on the involvement of inflammation in the pathogenesis of cPVL. Whether CRP could serve as a biomarker of cPVL and its correlation with outcomes, awaits further trials. Furthermore, the correlation between FiO2-12h and CRP1-7d levels suggest that hypoxia and/or hyperoxia may serve as a trigger in the activation of inflammation during the first days of life of preterm infants.
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Encéfalo/diagnóstico por imagen , Proteína C-Reactiva/análisis , Inflamación/sangre , Leucomalacia Periventricular , Biomarcadores/sangre , Diagnóstico Precoz , Femenino , Edad Gestacional , Humanos , Recién Nacido , Recien Nacido Prematuro , Leucomalacia Periventricular/sangre , Leucomalacia Periventricular/diagnóstico , Masculino , Consumo de Oxígeno/inmunología , Medición de Riesgo , Factores de Riesgo , Ultrasonografía/métodosRESUMEN
BACKGROUND: Small for gestational age (SGA) and large for gestational age (LGA) newborns are at increased risk for developmental, metabolic and cardiovascular morbidities. AIMS: To compare the metabolic biomarkers of SGA and LGA infants with those of appropriate for gestational age (AGA) newborns in order to shed more light on a possible pathogenesis of those morbidities. STUDY DESIGN: An observational retrospective study. SUBJECTS: 70,809 term newborns divided into AGA, SGA, LGA, and severe subcategories (<3rd percentile or ≥97th percentile). OUTCOME MEASURES: 18 metabolites were measured by dried blood tandem mass spectrometry and compared in between groups in univariate and multivariate logistic regression. RESULTS: SGA newborns had a significant likelihood for elevated methionine, proline, free carnitine, and reduced valine levels compared to AGA newborns (P < .0001). Severe SGA showed more apparent trends including elevated leucine. LGA newborns had a significant likelihood for low citrulline, glutamine, proline, tyrosine, and elevated leucine levels (P ≤ .0033). Severe LGA newborns showed the same trends, with the exception of citrulline and glutamine. CONCLUSIONS: SGA and LGA newborns demonstrate distinct metabolic biomarkers in newborn screening. Most of the altered metabolites in the SGA group were elevated while those in the LGA group were decreased in comparison to AGA newborns. These trends were more apparent in the severe SGA subgroup while they mostly remained the same in the severe LGA subgroup. Whether these metabolic changes are involved with or can predict long-term outcome awaits further trials.
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Recién Nacido Pequeño para la Edad Gestacional , Biomarcadores , Peso al Nacer , Edad Gestacional , Humanos , Lactante , Recién Nacido , Estudios RetrospectivosRESUMEN
AIMS: To report a novel mutation associated with developmental delay, epilepsy, and neonatal diabetes-DEND Syndrome, responsive to a novel management combination. METHODS: We describe the investigation, treatment, and genetic diagnosis of a newborn diagnosed with DEND syndrome. RESULTS: The patient was found to be de-novo heterozygous for pathogenic KCNJ11 missense variant: c.190G > A, p. (Val64Met), associated with DEND syndrome, responsive to a combination of super high doses of sulfonylurea (SU) and oral high-dose steroids. A single case was reported so far due to this mutation, presenting with severe DEND syndrome, treated by insulin only. His phenotypic description and management during 18 months, demonstrates this mutation is responsive to super-high doses of SU combined with high dose 6 weeks steroids protocol. CONCLUSIONS: We have identified a heterozygous missense mutation as the etiology for severe DEND syndrome in a one-day old neonate, presenting with asymptomatic hyperglycemia, responsive to a novel management combination.
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Diabetes Mellitus , Canales de Potasio de Rectificación Interna/genética , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/genética , Heterocigoto , Humanos , Hipoglucemiantes , Recién Nacido , Masculino , Mutación , Prednisolona , Compuestos de SulfonilureaRESUMEN
OBJECTIVE: Pathogenic variants in SCN3A, encoding the voltage-gated sodium channel subunit Nav1.3, cause severe childhood onset epilepsy and malformation of cortical development. Here, we define the spectrum of clinical, genetic, and neuroimaging features of SCN3A-related neurodevelopmental disorder. METHODS: Patients were ascertained via an international collaborative network. We compared sodium channels containing wild-type versus variant Nav1.3 subunits coexpressed with ß1 and ß2 subunits using whole-cell voltage clamp electrophysiological recordings in a heterologous mammalian system (HEK-293T cells). RESULTS: Of 22 patients with pathogenic SCN3A variants, most had treatment-resistant epilepsy beginning in the first year of life (16/21, 76%; median onset, 2 weeks), with severe or profound developmental delay (15/20, 75%). Many, but not all (15/19, 79%), exhibited malformations of cortical development. Pathogenic variants clustered in transmembrane segments 4 to 6 of domains II to IV. Most pathogenic missense variants tested (10/11, 91%) displayed gain of channel function, with increased persistent current and/or a leftward shift in the voltage dependence of activation, and all variants associated with malformation of cortical development exhibited gain of channel function. One variant (p.Ile1468Arg) exhibited mixed effects, with gain and partial loss of function. Two variants demonstrated loss of channel function. INTERPRETATION: Our study defines SCN3A-related neurodevelopmental disorder along a spectrum of severity, but typically including epilepsy and severe or profound developmental delay/intellectual disability. Malformations of cortical development are a characteristic feature of this unusual channelopathy syndrome, present in >75% of affected individuals. Gain of function at the channel level in developing neurons is likely an important mechanism of disease pathogenesis. ANN NEUROL 2020;88:348-362.
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Encéfalo/diagnóstico por imagen , Epilepsia/diagnóstico por imagen , Epilepsia/genética , Canal de Sodio Activado por Voltaje NAV1.3/genética , Trastornos del Neurodesarrollo/diagnóstico por imagen , Trastornos del Neurodesarrollo/genética , Canales de Sodio/genética , Adolescente , Adulto , Niño , Preescolar , Femenino , Feto/diagnóstico por imagen , Variación Genética/genética , Células HEK293 , Humanos , Lactante , MasculinoRESUMEN
AIMS: To determine the impact on families (IOF) of former preterm infants (gestational ageâ¯<â¯32â¯weeks) after posthemorrhagic hydrocephalus requiring shunt (PHH-S), and to identify risk factors of family dysfunction. STUDY DESIGN: 38 preterm infants with PHH-S were matched for gestational age, birthweight, and gender with preterm infants with normal cranial ultrasonography. IOF questionnaire was administered at 5.7⯱â¯2â¯years (higher IOF score indicates worse impact). RESULTS: Families of PHH-S children exhibited significantly worse IOF compared to controls in financial (9.2⯱â¯2.2 vs 5.9⯱â¯1.4), family-personal (26.6⯱â¯5.2 vs 20.2⯱â¯2.8), and disruptive social (21.4⯱â¯4.9 vs 16.7⯱â¯3.1) domains (Pâ¯<â¯0.001). Multivariate regression incorporating neonatal risk factors revealed an independent effect of parenchymal brain involvement (ß:0.4, P:0.002) and neonatal seizures (ß:0.3, p:0.007) on total IOF. Neurosensory morbidity was significantly higher in the PHH-S group, including cerebral palsy (81.6%), epilepsy (47.4%), problems with vision (63.2%), feeding (39.5%) and hearing (18.4%), chronic health problems (44.7%) and hospital admissions in the last 6â¯months (44.7%). Worse IOF scores of PHH-S families were associated with socioeconomic status and neurodevelopmental morbidities: cerebral palsy severity, feeding problems, number of neurosurgeries, low cognitive, personal-social, and adaptive scores (Pâ¯<â¯0.05). Multivariate analysis indicated an independent contribution from cerebral palsy severity (ß:0.5, p:0.002) and socioeconomic status (ß:-0.4, P: 0.01). CONCLUSIONS: Families of preterm children after PHH-S exhibit significantly worse IOF scores compared to families of preterm peers. Worse IOF is associated with severe hemorrhage, neurodevelopmental morbidities and socioeconomic status. A family centered intervention is warranted after PHH-S.
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Hemorragia Cerebral/epidemiología , Parálisis Cerebral/epidemiología , Relaciones Familiares , Hidrocefalia/epidemiología , Enfermedades del Prematuro/epidemiología , Recien Nacido Prematuro/crecimiento & desarrollo , Adulto , Preescolar , Femenino , Humanos , Hidrocefalia/cirugía , Recién Nacido , Recien Nacido Prematuro/psicología , Enfermedades del Prematuro/psicología , Masculino , Clase Social , Derivación VentriculoperitonealRESUMEN
AIM: To determine the health-related quality of life (HRQoL) of children born preterm (gestational age <32wks) after post-haemorrhagic hydrocephalus requiring shunt (PHH-S), and to examine the impact of perinatal and neurological morbidity on their QoL. METHOD: Forty infants (18 females, 22 males; aged 2y 2mo-8y 4.5mo) born preterm with PHH-S were matched for gestational age, birthweight, and sex with infants born preterm with normal cranial ultrasonography. Pediatric QoL Inventory parent-proxy report was administered at a mean age of 5 years 8 months. RESULTS: Children with PHH-S exhibited significantly lower mean HRQoL compared with controls in motor (36 [SD 34.9] vs 96.2 [SD 6.6]), emotional (59.8 [SD 26.7] vs 80.6 [SD 18.8]), social (55.6 [SD 29.7] vs 89.6 [SD 16.6]), and school (40.5 [SD 22.9] vs 89.7 [SD 15.2]) domains (p<0.001). Multivariate regression incorporating neonatal risk factors revealed an independent effect of parenchymal brain involvement (ß=-0.6, p<0.01) and neonatal seizures (ß=-0.2, p<0.02) on total HRQoL. Low HRQoL of children with PHH-S was associated with neurodevelopmental morbidities: cerebral palsy (CP), epilepsy, vision and feeding problems, low cognitive, personal-social, and adaptive scores (p<0.05). Multivariate analysis indicated an independent contribution from severe CP (ß=-0.4, p<0.001) and low personal-social score (ß=0.5, p<0.001). INTERPRETATION: Children born preterm after PHH-S exhibit significantly lower HRQoL scores compared with preterm born peers. HRQoL is associated with neonatal cerebral complications and neurodevelopmental morbidities. WHAT THIS PAPER ADDS: Children born preterm, after post-haemorrhagic hydrocephalus requiring shunt, have low health-related quality of life (HRQoL). A low HRQoL is associated with parenchymal brain involvement and with neurological morbidity. Severe cerebral palsy and low personal-social developmental scores have independent contributions to HRQoL.
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Hemorragia Cerebral/complicaciones , Hidrocefalia/complicaciones , Enfermedades del Prematuro/etiología , Calidad de Vida , Estudios de Casos y Controles , Hemorragia Cerebral/fisiopatología , Hemorragia Cerebral/psicología , Niño , Preescolar , Femenino , Humanos , Hidrocefalia/fisiopatología , Hidrocefalia/psicología , Lactante , Recién Nacido , Recien Nacido Prematuro , Enfermedades del Prematuro/fisiopatología , Enfermedades del Prematuro/psicología , MasculinoRESUMEN
Voltage-gated sodium channel alpha subunit 2 (SCN2A) gene mutations are associated with neonatal seizures and a wide range of epilepsy syndromes. Previous reports suggest that traditional sodium channel blockers (SCBs) such as phenytoin, carbamazepine, and lamotrigine have a beneficial effect on SCN2A-related neonatal seizures, as they counteract the gain-of-function effect of mutated Nav1.2 channels. Additionally, SCBs are beneficial against other sodium and potassium channel-related neonatal seizures. There are, however, few reports describing the effect of the new SCB lacosamide against neonatal and infantile epileptic seizures. We report herein two neonates with intractable neonatal seizures with SCN2A pathogenic missense variants. Both infants showed temporary seizure relief following IV administrations of phenytoin, but were resistant to a combination of antiepileptic drugs, while complete seizure control was achieved following lacosamide administration. We suggest that SCBs, e.g. phenytoin, should be introduced early for refractory neonatal seizures of non-lesional and presumably genetic origin. If any beneficial response to a SCB is noted, this should prompt an initiation of additional SCBs. New clinical trials will provide data on the efficacy and safety of the new SCB lacosamide for genetic neonatal seizures and perhaps neonatal seizures in general.
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Epilepsia/tratamiento farmacológico , Epilepsia/genética , Enfermedades del Recién Nacido/tratamiento farmacológico , Lacosamida/farmacología , Canal de Sodio Activado por Voltaje NAV1.2/genética , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacología , Epilepsia Refractaria/tratamiento farmacológico , Epilepsia Refractaria/genética , Electroencefalografía , Femenino , Humanos , Recién Nacido , Enfermedades del Recién Nacido/genética , Lacosamida/administración & dosificación , Masculino , Mutación Missense , Espasmos Infantiles/tratamiento farmacológico , Espasmos Infantiles/genética , Bloqueadores del Canal de Sodio Activado por Voltaje/administración & dosificaciónRESUMEN
De novo germline mutations in GNB1 have been associated with a neurodevelopmental phenotype. To date, 28 patients with variants classified as pathogenic have been reported. We add 18 patients with de novo mutations to this cohort, including a patient with mosaicism for a GNB1 mutation who presented with a milder phenotype. Consistent with previous reports, developmental delay in these patients was moderate to severe, and more than half of the patients were non-ambulatory and nonverbal. The most observed substitution affects the p.Ile80 residue encoded in exon 6, with 28% of patients carrying a variant at this residue. Dystonia and growth delay were observed more frequently in patients carrying variants in this residue, suggesting a potential genotype-phenotype correlation. In the new cohort of 18 patients, 50% of males had genitourinary anomalies and 61% of patients had gastrointestinal anomalies, suggesting a possible association of these findings with variants in GNB1. In addition, cutaneous mastocytosis, reported once before in a patient with a GNB1 variant, was observed in three additional patients, providing further evidence for an association to GNB1. We will review clinical and molecular data of these new cases and all previously reported cases to further define the phenotype and establish possible genotype-phenotype correlations.
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Subunidades beta de la Proteína de Unión al GTP/genética , Estudios de Asociación Genética , Mutación/genética , Adolescente , Niño , Preescolar , Estudios de Cohortes , Epilepsia/genética , Femenino , Subunidades beta de la Proteína de Unión al GTP/química , Humanos , Masculino , Sistema Nervioso/crecimiento & desarrollo , Fenotipo , Embarazo , Estructura Terciaria de ProteínaRESUMEN
BACKGROUND: It has been suggested that sleep disordered breathing (SDB) during pregnancy may adversely influence maternal as well as fetal well being. OBJECTIVES: To examine the effect of maternal SDB on neonatal neurological examination and perinatal complications. METHODS: Pregnant women of singleton uncomplicated pregnancies were prospectively recruited from a community and hospital low risk obstetric surveillance. All participants completed a sleep questionnaire in the second trimester and underwent ambulatory sleep evaluation (WatchPAT, Itamar Medical, Caesarea, Israel). They were categorized as SDB (apnea hypopnea index > 5) and non-SDB. Maternal and newborn records were reviewed and a neonatal neurologic examination was conducted during the first 48 hours. RESULTS: The study group included 44 women and full-term infants; 11 of the women (25%) had SDB. Mean maternal age of the SDB and non-SDB groups was 32.3 ± 2.8 and 32.5 ± 4.7 years, respectively (P = 0.86). Mean body mass index before the pregnancy in the SDB and non-SDB groups was 25.8 ± 4.7 and 22.0 ± 2.5 kg/m2, respectively (P = 0.028). No differences were found between infants born to mothers with SDB and non-SDB in birth weight (3353.8 ± 284.8 vs. 3379.1 ± 492.4 g), gestational age (39.5 ± 0.9 vs. 39.2 ± 1.5 weeks), 5 minute Apgar scores (9.8 ± 0.6 vs. 9.9 ± 0.3), and neurologic examination scores (95.2 ± 3.9 vs. 94.6 ± 4.1). P value for all was not significant. CONCLUSIONS: Our preliminary results suggest that maternal mild SDB during pregnancy has no adverse effect on neonatal neurologic examination or on perinatal complications.
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Puntaje de Apgar , Complicaciones del Embarazo/epidemiología , Resultado del Embarazo , Síndromes de la Apnea del Sueño/complicaciones , Adulto , Peso al Nacer , Índice de Masa Corporal , Femenino , Humanos , Recién Nacido , Israel , Masculino , Embarazo , Sueño/fisiología , Síndromes de la Apnea del Sueño/epidemiología , Encuestas y CuestionariosRESUMEN
PURPOSE: To study the relationship between central hypotonia and motor development, and to determine the relative contribution of nuchal, truncal, and appendicular hypotonia domains to motor development. METHODS: Appendicular, nuchal, and truncal tones of high-risk infants were assessed, as was their psychomotor developmental index (PDI). Infants with peripheral hypotonia were excluded. RESULTS: We included 164 infants (mean age 9.6 ± 4 months), 36 with normal tone in all 3 domains and 128 with central hypotonia. Twenty-six of the latter had hypotonia in 1 domain and 102 had multiple combinations of 3 domains. Hypotonia domains were distributed as follows: truncal (n = 115), appendicular (n = 93), and nuchal (n = 70). Each domain was significantly associated with PDI scores (P < .001) but not with a later diagnosis of cerebral palsy. On linear regression, nuchal hypotonia had the strongest contribution to PDI scores (ß = -0.6 [nuchal], -0.45 [appendicular], and -0.4 [truncal], P < .001). CONCLUSIONS: Central hypotonia, especially nuchal tone, is associated with lowered motor development scores.
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Discapacidades del Desarrollo/fisiopatología , Discapacidades del Desarrollo/rehabilitación , Hipotonía Muscular/fisiopatología , Hipotonía Muscular/rehabilitación , Modalidades de Fisioterapia , Desarrollo Infantil/fisiología , Discapacidades del Desarrollo/diagnóstico , Femenino , Edad Gestacional , Humanos , Lactante , MasculinoRESUMEN
BACKGROUND: Periventricular white matter (WM) hyperechoic flares that do not evolve into cystic lesion(s) are frequently encountered on cranial ultrasonography (CUS) of preterm infants. Subjective interpretation of its presence, however, is challenging and its association with maturation and neurodevelopment remains undefined. OBJECTIVES: To determine the relationship between quantitative WM echogenicity and postnatal and postmenstrual ages and the relationship between quantitative WM echogenicity and neuromotor development at term equivalent. METHODS: We measured the mean pixel brightness intensity at the frontoparietal and parieto-occipital WM, choroid plexus and calvarium bone on sequential neonatal CUS scans of preterm infants born at <34â weeks gestation. The relative echogenicity (RE) was derived by dividing the mean WM echogenicity to that of the choroid plexus (RE(CP)) or bone (RE(BN)). The Lacey Assessment of the Preterm Infant was administered before discharge. RESULTS: 58 preterm infants (the mean gestational age 30.6±2.3â weeks and the mean birth weight 1211.9±224.7â g) were included. The RE(CP) of the frontoparietal WM decreased significantly with advancing postnatal and postmenstrual ages (r=-0.4, p<0.0001). The RE(BN) values of the frontoparietal and parieto-occipital WM during intermediate and late predischarge CUS studies, respectively, were significantly associated with neuromotor status at term (p<0.05). The RE(CP) and RE(BN) measured during the first week of life were not associated with neuromotor status at term. CONCLUSIONS: Quantitative measurements of the periventricular WM echogenicity are feasible in neonatal CUSs of premature infants and may reflect microstructural developmental changes. An optimal echogenicity quantification technique and its correlation with long-term outcome remain to be determined.
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Desarrollo Infantil/fisiología , Plexo Coroideo/diagnóstico por imagen , Recien Nacido Prematuro/fisiología , Cráneo/diagnóstico por imagen , Sustancia Blanca/diagnóstico por imagen , Femenino , Edad Gestacional , Humanos , Recién Nacido , Embarazo , Estudios Prospectivos , UltrasonografíaRESUMEN
OBJECT The object of this study was to use diffusion tensor imaging (DTI) to evaluate and characterize white matter changes in hydrocephalus. METHODS The authors performed a retrospective analysis of DTI in a cohort of patients with hydrocephalus (n = 35), 19 of whom had both pre- and postsurgical imaging studies. These patient's DTI values were compared with values extracted from age-dependent trend lines computed from a healthy subject group (n = 70, age span 14 months-14 years). Several DTI parameters in different regions of interest (ROIs) were evaluated to find the most sensitive parameters for clinical decision making in hydrocephalus. RESULTS Compared with healthy controls, patients with active hydrocephalus had a statistically significant change in all DTI parameters. The most sensitive and specific DTI parameter for predicting hydrocephalus was axial diffusivity (λ1) measured at the level of the corona radiata. Diffusion tensor imaging parameters correlated with several conventional radiological parameters in the assessment of hydrocephalus but were not superior to them. There was no convincing correlation between clinical disease severity and DTI parameters. When examining the pre- and postsurgical effect, it was found that DTI may be a sensitive tool for estimating tissue improvement. CONCLUSIONS This large-cohort study with a multidisciplinary approach combining clinical, neurological, radiological, and multiple DTI parameters revealed the most sensitive DTI parameters for identifying hydrocephalus and suggested that they may serve as an important tool for the disorder's quantitative radiological assessment.
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Imagen de Difusión Tensora , Hidrocefalia/diagnóstico , Adolescente , Niño , Preescolar , Humanos , Hidrocefalia/cirugía , Lactante , Estudios RetrospectivosRESUMEN
OBJECTIVE: We evaluated seizure outcome in a large cohort of familial neonatal seizures (FNS), and examined phenotypic overlap with different molecular lesions. METHODS: Detailed clinical data were collected from 36 families comprising two or more individuals with neonatal seizures. The seizure course and occurrence of seizures later in life were analyzed. Families were screened for KCNQ2, KCNQ3, SCN2A, and PRRT2 mutations, and linkage studies were performed in mutation-negative families to exclude known loci. RESULTS: Thirty-three families fulfilled clinical criteria for benign familial neonatal epilepsy (BFNE); 27 of these families had KCNQ2 mutations, one had a KCNQ3 mutation, and two had SCN2A mutations. Seizures persisting after age 6 months were reported in 31% of individuals with KCNQ2 mutations; later seizures were associated with frequent neonatal seizures. Linkage mapping in two mutation-negative BFNE families excluded linkage to KCNQ2, KCNQ3, and SCN2A, but linkage to KCNQ2 could not be excluded in the third mutation-negative BFNE family. The three remaining families did not fulfill criteria of BFNE due to developmental delay or intellectual disability; a molecular lesion was identified in two; the other family remains unsolved. SIGNIFICANCE: Most families in our cohort of familial neonatal seizures fulfill criteria for BFNE; the molecular cause was identified in 91%. Most had KCNQ2 mutations, but two families had SCN2A mutations, which are normally associated with a mixed picture of neonatal and infantile onset seizures. Seizures later in life are more common in BFNE than previously reported and are associated with a greater number of seizures in the neonatal period. Linkage studies in two families excluded known loci, suggesting a further gene is involved in BFNE.
Asunto(s)
Epilepsia Benigna Neonatal/diagnóstico , Epilepsia Benigna Neonatal/genética , Estudios de Cohortes , Femenino , Humanos , Recién Nacido , Canal de Potasio KCNQ2 , Masculino , Linaje , Convulsiones , Resultado del TratamientoAsunto(s)
Parálisis Cerebral/epidemiología , Parálisis Cerebral/terapia , Familia , Femenino , Humanos , MasculinoRESUMEN
OBJECTIVE: We sought to examine the effect of maternal sleep-disordered breathing (SDB) on infant general movements (GMs) and neurodevelopment. STUDY DESIGN: Pregnant women with uncomplicated full-term pregnancies and their offspring were prospectively recruited from a community and hospital low-risk obstetric surveillance. All participants completed a sleep questionnaire on second trimester and underwent ambulatory sleep evaluation (WatchPAT; Itamar Medical, Caesarea, Israel). They were categorized as SDB (apnea hypopnea index>5) and controls. Infant GMs were assessed in the first 48 hours and at 8-11 and 14-16 weeks of age. At 12 months of age the Infant Developmental Inventory and the Brief Infant Sleep Questionnaire were administered. RESULTS: In all, 74 women and their full-term infants were studied. Eighteen (24%) women had SDB. Mean birthweight was 3347.1±423.9 g. Median Apgar score at 5 minutes was 10 (range, 8-10). In adjusted comparisons, no differences were found between infants born to mothers with SDB and controls in GM scores in all 3 evaluations. Low social developmental score was detected at 12 months in 64% of infants born to SDB mothers compared to 25% of infants born to controls (adjusted P=.036; odds ratio, 16.7). Infant snoring was reported by 41.7% of mothers with SDB compared to 7.5% of controls (P=.004). CONCLUSION: Our preliminary results suggest that maternal SDB during pregnancy has no adverse effect on neonatal and infant neuromotor development but may affect social development at 1 year.