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Ann Neurol ; 85(6): 921-926, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30937933


SLC1A2 is a trimeric transporter essential for clearing glutamate from neuronal synapses. Recurrent de novo SLC1A2 missense variants cause a severe, early onset developmental and epileptic encephalopathy via an unclear mechanism. We demonstrate that all 3 variants implicated in this condition localize to the trimerization domain of SLC1A2, and that the Leu85Pro variant acts via a dominant negative mechanism to reduce, but not eliminate, wild-type SLC1A2 protein localization and function. Finally, we demonstrate that treatment of a 20-month-old SLC1A2-related epilepsy patient with the SLC1A2-modulating agent ceftriaxone did not result in a significant change in daily spasm count. ANN NEUROL 2019;85:921-926.

Mol Genet Metab ; 123(3): 317-325, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29279279


Asparagine Synthetase Deficiency (ASD) is a recently described inborn error of metabolism caused by bi-allelic pathogenic variants in the asparagine synthetase (ASNS) gene. ASD typically presents congenitally with microcephaly and severe, often medically refractory, epilepsy. Development is generally severely affected at birth. Tone is abnormal with axial hypotonia and progressive appendicular spasticity. Hyperekplexia has been reported. Neuroimaging typically demonstrates gyral simplification, abnormal myelination, and progressive cerebral atrophy. The present report describes two siblings from consanguineous parents with a homozygous Arg49Gln variant associated with a milder form of ASD that is characterized by later onset of symptoms. Both siblings had a period of normal development before onset of seizures, and development regression. Primary fibroblast studies of the siblings and their parents document that homozygosity for Arg49Gln blocks cell growth in the absence of extracellular asparagine. Functional studies with these cells suggest no impact of the Arg49Gln variant on basal ASNS mRNA or protein levels, nor on regulation of the gene itself. Molecular modelling of the ASNS protein structure indicates that the Arg49Gln variant lies near the substrate binding site for glutamine. Collectively, the results suggest that the Arg49Gln variant affects the enzymatic function of ASNS. The clinical, cellular, and molecular observations from these siblings expand the known phenotypic spectrum of ASD.

J Child Neurol ; 32(1): 127-131, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27770045


TUBB2A is a gene that has recently been reported in association with structural brain abnormalities. Only 3 cases have been reported to date with disparate brain morphologic abnormalities, although all patients have presented with developmental delay and infantile-onset epilepsy. We report a fourth patient with a de novo variant in TUBB2A that is predicted to be pathogenic, presenting with developmental delay, spastic diplegia, exaggerated startle, and anterior temporal pachygyria in the absence of epilepsy. This report serves to further delineate the phenotype of the TUBB2A-related disorders. Focal anterior temporal pachygyria may facilitate recognition of additional cases of this tubulinopathy.

Variação Genética , Lisencefalia/genética , Tubulina (Proteína)/genética , Encéfalo/diagnóstico por imagem , Pré-Escolar , Predisposição Genética para Doença , Humanos , Lisencefalia/diagnóstico por imagem , Masculino , Fenótipo
Ann Neurol ; 76(4): 581-93, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25044251


OBJECTIVE: Recently, Christianson syndrome (CS) has been determined to be caused by mutations in the X-linked Na(+) /H(+) exchanger 6 (NHE6). We aimed to determine the diagnostic criteria and mutational spectrum for CS. METHODS: Twelve independent pedigrees (14 boys, age = 4-19 years) with mutations in NHE6 were administered standardized research assessments, and mutations were characterized. RESULTS: The mutational spectrum was composed of 9 single nucleotide variants, 2 indels, and 1 copy number variation deletion. All mutations were protein-truncating or splicing mutations. We identified 2 recurrent mutations (c.1498 c>t, p.R500X; and c.1710 g>a, p.W570X). Otherwise, all mutations were unique. In our study, 7 of 12 mutations (58%) were de novo, in contrast to prior literature wherein mutations were largely inherited. We also report prominent neurological, medical, and behavioral symptoms. All CS participants were nonverbal and had intellectual disability, epilepsy, and ataxia. Many had prior diagnoses of autism and/or Angelman syndrome. Other neurologic symptoms included eye movement abnormalities (79%), postnatal microcephaly (92%), and magnetic resonance imaging evidence of cerebellar atrophy (33%). Regression was noted in 50%, with recurrent presentations involving loss of words and/or the ability to walk. Medical symptoms, particularly gastrointestinal symptoms, were common. Height and body mass index measures were below normal ranges in most participants. Behavioral symptoms included hyperkinetic behavior (100%), and a majority exhibited high pain threshold. INTERPRETATION: This is the largest cohort of independent CS pedigrees reported. We propose diagnostic criteria for CS. CS represents a novel neurogenetic disorder with general relevance to autism, intellectual disability, Angelman syndrome, epilepsy, and regression.

Ataxia/complicações , Ataxia/genética , Deficiências do Desenvolvimento/genética , Epilepsia/complicações , Epilepsia/genética , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/genética , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Microcefalia/complicações , Microcefalia/genética , Mutação/genética , Transtornos da Motilidade Ocular/complicações , Transtornos da Motilidade Ocular/genética , Trocadores de Sódio-Hidrogênio/genética , Adolescente , Ataxia/patologia , Transtorno Autístico/etiologia , Transtorno Autístico/genética , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/patologia , Progressão da Doença , Eletroencefalografia , Epilepsia/etiologia , Epilepsia/patologia , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Genótipo , Humanos , Deficiência Intelectual/patologia , Imagem por Ressonância Magnética , Masculino , Microcefalia/patologia , Transtornos da Motilidade Ocular/patologia , Fenótipo , Análise de Regressão , Adulto Jovem