Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 6 de 6
Filtrar
Más filtros












Base de datos
Intervalo de año de publicación
1.
Children (Basel) ; 10(8)2023 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-37628319

RESUMEN

BACKGROUND: Currently, no local database in Israel collects neurodevelopmental outcomes of very low birth weight (VLBW) preterm infants. We investigated neurodevelopmental outcomes in one district of the largest healthcare organization in Israel. METHODS: A cross-sectional study including all VLBW (<1500 g) preterm infants born between 1 January 2006 and 31 December 2016 who were followed in any of seven child development centers in Israel's Northern District. Data were retrospectively collected from the computerized medical record database. RESULTS: Out of 436 participants, 55.1% had normal developmental outcomes. A total of 8.9% had cerebral palsy (CP), 12.2% had a global developmental delay (GDD), and 33.4% had a language delay. Out of the extremely preterm infants (n = 109), 20.2% had CP, 22.0% had GDD, and 44.9% had language delay. We found a statistically significant higher rate of abnormal neurodevelopment outcomes in non-Jews compared to Jews (57% vs. 37.8%, respectively, p < 0.0001). CONCLUSIONS: We found a relatively high overall rate of CP in our local population and a significant difference in neurodevelopmental outcomes between Jews and non-Jews. This study emphasizes the need for an expanded and detailed national database collecting post-discharge outcomes, as well as an assessment of national healthcare resource allocation and inequalities in preterm infants' post-discharge care.

2.
Brain ; 145(7): 2301-2312, 2022 07 29.
Artículo en Inglés | MEDLINE | ID: mdl-35373813

RESUMEN

Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown. We refine the phenotype and report 19 additional individuals harbouring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available. Additionally, we provide follow-up data from two previously reported cases. All affected individuals exhibited infantile-onset, treatment-resistant epilepsy. Additional clinical features included moderate to profound global developmental delay/intellectual disability (20/20), hypotonia (12/20) and delayed motor development (19/20). Brain MRI findings included cerebral atrophy (13/20), supported by post-mortem histological examination in patient-derived brain tissue, cerebellar vermis atrophy (5/20), and callosal hypoplasia (4/20). Functional studies in transfected cell lines confirmed the deleteriousness of all identified variants and indicated at least three distinct pathological mechanisms: (i) defective cell membrane expression; (ii) impaired LGI1-binding; and/or (iii) impaired interaction with the postsynaptic density protein PSD-95. We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics.


Asunto(s)
Proteínas ADAM , Encefalopatías , Epilepsia Refractaria , Proteínas del Tejido Nervioso , Proteínas ADAM/genética , Proteínas ADAM/metabolismo , Atrofia , Encefalopatías/genética , Homólogo 4 de la Proteína Discs Large , Humanos , Péptidos y Proteínas de Señalización Intracelular , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo
3.
J Med Genet ; 59(8): 759-767, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-34321325

RESUMEN

OBJECTIVE: To determine the yield of genetic diagnoses using chromosomal microarray (CMA) and trio whole exome sequencing (WES), separately and combined, among patients with cryptogenic cerebral palsy (CP). METHODS: Trio WES of patients with prior CMA analysis for cryptogenic CP, defined as disabling, non-progressive motor symptoms beginning before the age of 3 years without known cause. RESULTS: Given both CMA analysis and trio WES, clinically significant genetic findings were identified for 58% of patients (26 of 45). Diagnoses were eight large CNVs detected by CMA and 18 point mutations detected by trio WES. None had more than one severe mutation. Approximately half of events (14 of 26) were de novo. Yield was significantly higher in patients with CP with comorbidities (69%, 22 of 32) than in those with pure motor CP (31%, 4 of 13; p=0.02). Among patients with genetic diagnoses, CNVs were more frequent than point mutations among patients with congenital anomalies (OR 7.8, 95% CI 1.2 to 52.4) or major dysmorphic features (OR 10.5, 95% CI 1.4 to 73.7). Clinically significant mutations were identified in 18 different genes: 14 with known involvement in CP-related disorders and 4 responsible for other neurodevelopmental conditions. Three possible new candidate genes for CP were ARGEF10, RTF1 and TAOK3. CONCLUSIONS: Cryptogenic CP is genetically highly heterogeneous. Genomic analysis has a high yield and is warranted in all these patients. Trio WES has higher yield than CMA, except in patients with congenital anomalies or major dysmorphic features, but these methods are complementary. Patients with negative results with one approach should also be tested by the other.


Asunto(s)
Parálisis Cerebral , Parálisis Cerebral/diagnóstico , Parálisis Cerebral/genética , Preescolar , Variaciones en el Número de Copia de ADN , Humanos , Análisis por Micromatrices , Mutación/genética , Secuenciación del Exoma/métodos
4.
Brain ; 141(3): 698-712, 2018 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-29365063

RESUMEN

Polymicrogyria is a malformation of cortical development. The aetiology of polymicrogyria remains poorly understood. Using whole-exome sequencing we found de novo heterozygous missense GRIN1 mutations in 2 of 57 parent-offspring trios with polymicrogyria. We found nine further de novo missense GRIN1 mutations in additional cortical malformation patients. Shared features in the patients were extensive bilateral polymicrogyria associated with severe developmental delay, postnatal microcephaly, cortical visual impairment and intractable epilepsy. GRIN1 encodes GluN1, the essential subunit of the N-methyl-d-aspartate receptor. The polymicrogyria-associated GRIN1 mutations tended to cluster in the S2 region (part of the ligand-binding domain of GluN1) or the adjacent M3 helix. These regions are rarely mutated in the normal population or in GRIN1 patients without polymicrogyria. Using two-electrode and whole-cell voltage-clamp analysis, we showed that the polymicrogyria-associated GRIN1 mutations significantly alter the in vitro activity of the receptor. Three of the mutations increased agonist potency while one reduced proton inhibition of the receptor. These results are striking because previous GRIN1 mutations have generally caused loss of function, and because N-methyl-d-aspartate receptor agonists have been used for many years to generate animal models of polymicrogyria. Overall, our results expand the phenotypic spectrum associated with GRIN1 mutations and highlight the important role of N-methyl-d-aspartate receptor signalling in the pathogenesis of polymicrogyria.


Asunto(s)
Mutación/genética , Proteínas del Tejido Nervioso/genética , Polimicrogiria/genética , Receptores de N-Metil-D-Aspartato/genética , Animales , Niño , Preescolar , Análisis Mutacional de ADN , Agonistas de Aminoácidos Excitadores/farmacología , Salud de la Familia , Femenino , Ácido Glutámico/farmacología , Glicina/metabolismo , Glicina/farmacología , Células HEK293 , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Potenciales de la Membrana/genética , Modelos Moleculares , Mutagénesis/genética , N-Metilaspartato/farmacología , Técnicas de Placa-Clamp , Polimicrogiria/diagnóstico por imagen , Ratas , Transfección
5.
Mol Genet Metab ; 110 Suppl: S66-70, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24206931

RESUMEN

INTRODUCTION: Phenylalanine (Phe) deficiency and its clinical manifestations have been previously described mostly as sporadic case reports dating back to the 1960's and 1970's. In these reports, low plasma Phe levels were associated with listlessness, eczematous eruptions and failure to gain weight, most often in infants in their first year of life. CASE REPORT: Herein we describe a 9 month old female patient with known phenylketonuria, who presented with an unusual constellation of symptoms, including severe erythema and desquamation, alopecia, keratomalacia, corneal perforation, failure to thrive and prolonged diarrhea. The diagnostic possibilities of acrodermatitis enteropathica and vitamin deficiencies were ruled out, and further investigation into her medical history led to the conclusion that during the weeks preceding the hospitalization, the patient's diet consisted of the phenylalanine-free medical formula alone, without the addition of a standard infant formula or food as recommended. Subsequently, dietary control of the blood phenylalanine levels brought swift and marked resolution of the dermatological lesions, with renewal of hair growth. OBJECTIVE: Following this experience, and due to the relative paucity of data regarding the clinical manifestations of low serum phenylalanine levels in humans and their putative pathogenetic mechanisms, we sought to further investigate the effects of a phenylalanine-free diet in a mouse study. MATERIALS AND METHODS: For this purpose, twenty mice were randomly allocated to receive either a phenylalanine-deficient diet (n=10) or a normal diet (n=10). Weight was measured weekly, and laboratory tests were obtained including complete blood count, electrolyte studies, and phenylalanine and tyrosine levels. Finally, necropsies and histopathological examinations of different tissues were performed in selected mice, either early after diet initiation, late after diet initiation or following re-introduction of normal diets. The study was then repeated in additional two groups of mice, for a period of up to thirteen weeks, with a total of 63 mice. RESULTS: Gross lesions noted on necropsy in the Phe-deficient mice included scruffy coat, tendency toward weight loss, a reduction in thymic mass, and most notably severe gastric dilation, all of which were not seen in the controls. Histologic findings included thymic depletion, hepatocellular vacuolation, and exocrine pancreatic atrophy. No histopathological lesions were evident in the brain, nor were significant lesions in the eyes. CONCLUSIONS: Diagnosis of the iatrogenic condition of phenylalanine deficiency, which manifests in gastrointestinal, dermatological and ocular findings, requires a high index of suspicion. Mice fed a phenylalanine-deficient diet display to some extent similar organ involvement, although no eye abnormalities were evident.


Asunto(s)
Fenilalanina/sangre , Fenilalanina/deficiencia , Fenilcetonurias/complicaciones , Fenilcetonurias/dietoterapia , Fenilcetonurias/patología , Alopecia/etiología , Animales , Peso Corporal , Perforación Corneal/etiología , Diarrea Infantil/etiología , Modelos Animales de Enfermedad , Insuficiencia de Crecimiento/etiología , Femenino , Humanos , Lactante , Fórmulas Infantiles/administración & dosificación , Masculino , Ratones , Fenilcetonurias/sangre , Distribución Aleatoria , Tirosina/sangre , Deficiencia de Vitamina A/etiología
6.
Epilepsy Res Treat ; 2011: 963637, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-22937236

RESUMEN

Although the ketogenic diet (KD) has been widely accepted as a legitimate and successful therapy for epilepsy and other neurological disorders, its mechanism of action remains an enigma. The use of the KD causes major metabolic changes. The most significant of them seems to be the situation of chronic ketosis, but there are others as well, for instance, high level of polyunsaturated fatty acids (PUFAs). These "primary" influences lead to "secondary", in part adaptive, effects, for instance changes in mitochondrial density and gene expression. Clinically, the influences of the diet are considered as anticonvulsive and neuroprotective, although neuroprotection can also lead to prevention of seizures. Potential clinical implications of these mechanisms are discussed.

SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...