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1.
Artigo em Inglês | MEDLINE | ID: mdl-30194038

RESUMO

We aim to further delineate the phenotype associated with pathogenic variants in the SLC35A2 gene, and review all published literature to-date. This gene is located on the X chromosome and encodes a UDP-galactose transporter. Pathogenic variants in SLC35A2 cause a congenital disorder of glycosylation. The condition is rare, and less than twenty patients have been reported to-date. The phenotype is complex and has not been fully defined. Here, we present a series of five patients with de novo pathogenic variants in SLC35A2. The patients' phenotype includes developmental and epileptic encephalopathy with hypsarrhythmia, facial dysmorphism, severe intellectual disability, skeletal abnormalities, congenital cardiac disease and cortical visual impairment. Developmental and epileptic encephalopathy with hypsarrhythmia is present in most patients with SLC35A2 variants, and is drug-resistant in the majority of cases. Adrenocorticotropic hormone therapy may achieve partial or complete remission of seizures, but the effect is usually temporary. Isoelectric focusing of transferrins may be normal after infancy, therefore a congenital disorder of glycosylation should still be considered as a diagnosis in the presence of a suggestive phenotype. We also provide evidence that cortical visual impairment is part of the phenotypic spectrum.

2.
Am J Med Genet A ; 176(5): 1049-1054, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29681108

RESUMO

WDR45 gene-associated neurodegeneration with brain iron accumulation (NBIA), referred to as beta-propeller protein-associated neurodegeneration (BPAN), is a rare disorder that presents with a very nonspecific clinical phenotype in children constituting global developmental delay. This case report illustrates the power of a combination of trio exome sequencing, in silico splicing analysis, and mRNA analysis to provide sufficient evidence for pathogenicity of a relatively intronic variant in WDR45, and in so doing, find a genetic diagnosis for a 6-year-old patient with developmental delay and seizures, a diagnosis which may otherwise have only been found once the characteristic MRI patterns of the disease became more obvious in young adulthood.

3.
Neurology ; 90(1): e55-e66, 2018 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-29196579

RESUMO

OBJECTIVE: To characterize the phenotypic spectrum, molecular genetic findings, and functional consequences of pathogenic variants in early-onset KCNT1 epilepsy. METHODS: We identified a cohort of 31 patients with epilepsy of infancy with migrating focal seizures (EIMFS) and screened for variants in KCNT1 using direct Sanger sequencing, a multiple-gene next-generation sequencing panel, and whole-exome sequencing. Additional patients with non-EIMFS early-onset epilepsy in whom we identified KCNT1 variants on local diagnostic multiple gene panel testing were also included. When possible, we performed homology modeling to predict the putative effects of variants on protein structure and function. We undertook electrophysiologic assessment of mutant KCNT1 channels in a xenopus oocyte model system. RESULTS: We identified pathogenic variants in KCNT1 in 12 patients, 4 of which are novel. Most variants occurred de novo. Ten patients had a clinical diagnosis of EIMFS, and the other 2 presented with early-onset severe nocturnal frontal lobe seizures. Three patients had a trial of quinidine with good clinical response in 1 patient. Computational modeling analysis implicates abnormal pore function (F346L) and impaired tetramer formation (F502V) as putative disease mechanisms. All evaluated KCNT1 variants resulted in marked gain of function with significantly increased channel amplitude and variable blockade by quinidine. CONCLUSIONS: Gain-of-function KCNT1 pathogenic variants cause a spectrum of severe focal epilepsies with onset in early infancy. Currently, genotype-phenotype correlations are unclear, although clinical outcome is poor for the majority of cases. Further elucidation of disease mechanisms may facilitate the development of targeted treatments, much needed for this pharmacoresistant genetic epilepsy.

4.
Epileptic Disord ; 20(1): 35-41, 2018 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29171397

RESUMO

Accurate diagnosis of a distinct epilepsy syndrome is based on well-defined electroclinical features that differentiate separate nosological entities. In clinical practice, however, syndromes may overlap and cases may present with unusual manifestations posing a diagnostic challenge. This heterogeneity has been documented in several cases presenting with eyelid myoclonia with or without absences (EMA) diagnosed either as Jeavons syndrome (JS) variants or as genetic generalised epilepsies defined by the presence of this unique clinical entity. The hallmark of JS is the triad: (1) eyelid myoclonia with or without absences, (2) eye closure-induced paroxysms, and (3) photosensitivity. The presence of massive myoclonus, intellectual disability, or slowing of the EEG background are not typical features of the syndrome and may cause delay in making the correct diagnosis. Adding to the variability of clinical features, we describe two female paediatric patients with probable genetic epilepsy who presented with EMA but demonstrated clear atypical features, such as prominent myoclonic seizures, atonic components on video-EEG, and cognitive impairment. We also note the presence of interictal and ictal posterior discharges during eyelid myoclonia in one, supporting similar previous observations leading to consideration of EMA as an occipital cortex-initiated seizure activity. [Published with video sequences on www.epilepticdisorders.com].


Assuntos
Epilepsias Mioclônicas/diagnóstico , Epilepsia Generalizada/diagnóstico , Mioclonia/diagnóstico , Adolescente , Criança , Eletroencefalografia , Epilepsias Mioclônicas/classificação , Epilepsias Mioclônicas/fisiopatologia , Epilepsia Generalizada/classificação , Epilepsia Generalizada/fisiopatologia , Feminino , Humanos , Mioclonia/classificação , Mioclonia/fisiopatologia
5.
Pediatr Neurol ; 50(5): 515-7, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24656461

RESUMO

BACKGROUND: Narcolepsy is a chronic disease and is commonly diagnosed in adulthood. However, more than half of the patients have onset of symptoms in childhood and/or adolescence. The full spectrum of clinical manifestations, namely excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis, is usually not present at disease onset, delaying diagnosis during childhood. Mean delay in diagnosis since symptom onset is known to be several years. Initial manifestations can sometimes be as subtle as only partial drooping of eyelids leading to confusion with a myasthenic condition. PATIENTS: We present two children who presented with "cataplectic facies," an unusual facial feature only recently described in children with narcolepsy with cataplexy. RESULT: The diagnosis of narcolepsy was confirmed by multiple sleep latency test along with human leukocyte antigen typing and cerebrospinal fluid hypocretin assay. CONCLUSION: The diagnosis of narcolepsy with cataplexy at onset can be challenging in young children. With more awareness of subtle signs such as cataplectic facies, earlier diagnosis is possible. To date, only 11 children between 6 and 18 years of age presenting with typical cataplectic facies have been reported in the literature. We present two patients, one of whom is the youngest individual (4 years old) yet described with the typical cataplectic facies.


Assuntos
Facies , Narcolepsia/diagnóstico , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Antígenos HLA/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/líquido cefalorraquidiano , Masculino , Narcolepsia/fisiopatologia , Neuropeptídeos/líquido cefalorraquidiano , Orexinas , Polissonografia
6.
Brain ; 136(Pt 5): 1578-91, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23599387

RESUMO

Migrating partial seizures of infancy, also known as epilepsy of infancy with migrating focal seizures, is a rare early infantile epileptic encephalopathy with poor prognosis, presenting with focal seizures in the first year of life. A national surveillance study was undertaken in conjunction with the British Paediatric Neurology Surveillance Unit to further define the clinical, pathological and molecular genetic features of this disorder. Fourteen children with migrating partial seizures of infancy were reported during the 2 year study period (estimated prevalence 0.11 per 100,000 children). The study has revealed that migrating partial seizures of infancy is associated with an expanded spectrum of clinical features (including severe gut dysmotility and a movement disorder) and electrographic features including hypsarrhythmia (associated with infantile spasms) and burst suppression. We also report novel brain imaging findings including delayed myelination with white matter hyperintensity on brain magnetic resonance imaging in one-third of the cohort, and decreased N-acetyl aspartate on magnetic resonance spectroscopy. Putaminal atrophy (on both magnetic resonance imaging and at post-mortem) was evident in one patient. Additional neuropathological findings included bilateral hippocampal gliosis and neuronal loss in two patients who had post-mortem examinations. Within this cohort, we identified two patients with mutations in the newly discovered KCNT1 gene. Comparative genomic hybridization array, SCN1A testing and genetic testing for other currently known early infantile epileptic encephalopathy genes (including PLCB1 and SLC25A22) was non-informative for the rest of the cohort.


Assuntos
Epilepsias Parciais/diagnóstico por imagem , Epilepsias Parciais/fisiopatologia , Estudos de Coortes , Hibridização Genômica Comparativa/métodos , Eletroencefalografia/métodos , Epilepsias Parciais/genética , Feminino , Humanos , Lactente , Imagem por Ressonância Magnética/métodos , Masculino , Mutação/genética , Vigilância da População/métodos , Radiografia
7.
Dev Med Child Neurol ; 53(2): 188-90, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21244414

RESUMO

Congenital brachial plexus palsy (CBPP) usually occurs secondarily to intrapartum trauma, but this is not always the case. Cervical ribs have previously been reported to increase the risk of CBPP in association with birth trauma. We report the cases of two children (one female, one male) with congenital lower brachial plexus palsy in whom the presence of non-ossified cervical ribs was the only identified risk factor. In the female child magnetic resonance imaging (MRI) of the brain, spinal cord, and brachial plexus revealed no abnormality except for the presence of bilateral cervical ribs at the level of the seventh cervical (C7) vertebra. Chest radiography was normal, which suggested that the cervical ribs identified on the MRI were fibrous bands or cartilaginous ribs rather than ossified ribs. In the male child, MRI of the spine and brachial plexus was normal but he was noted to have bilateral cervical ribs at C7. These were not identifiable on chest radiography and, therefore, are likely to reflect fibrous bands or cartilaginous ribs.


Assuntos
Neuropatias do Plexo Braquial/congênito , Síndrome da Costela Cervical/congênito , Costela Cervical/anormalidades , Neuropatias do Plexo Braquial/diagnóstico , Neuropatias do Plexo Braquial/fisiopatologia , Costela Cervical/fisiopatologia , Síndrome da Costela Cervical/diagnóstico , Síndrome da Costela Cervical/fisiopatologia , Pré-Escolar , Eletromiografia , Feminino , Seguimentos , Antebraço/inervação , Mãos/inervação , Humanos , Processamento de Imagem Assistida por Computador , Lactente , Recém-Nascido , Imagem por Ressonância Magnética , Masculino , Nervo Mediano/fisiopatologia , Debilidade Muscular/congênito , Debilidade Muscular/diagnóstico , Debilidade Muscular/fisiopatologia , Atrofia Muscular/congênito , Atrofia Muscular/diagnóstico , Atrofia Muscular/fisiopatologia , Condução Nervosa/fisiologia , Exame Neurológico , Nervo Ulnar/fisiopatologia
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