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Am J Hum Genet ; 104(1): 139-156, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30595372


Type 2A protein phosphatases (PP2As) are highly expressed in the brain and regulate neuronal signaling by catalyzing phospho-Ser/Thr dephosphorylations in diverse substrates. PP2A holoenzymes comprise catalytic C-, scaffolding A-, and regulatory B-type subunits, which determine substrate specificity and physiological function. Interestingly, de novo mutations in genes encoding A- and B-type subunits have recently been implicated in intellectual disability (ID) and developmental delay (DD). We now report 16 individuals with mild to profound ID and DD and a de novo mutation in PPP2CA, encoding the catalytic Cα subunit. Other frequently observed features were severe language delay (71%), hypotonia (69%), epilepsy (63%), and brain abnormalities such as ventriculomegaly and a small corpus callosum (67%). Behavioral problems, including autism spectrum disorders, were reported in 47% of individuals, and three individuals had a congenital heart defect. PPP2CA de novo mutations included a partial gene deletion, a frameshift, three nonsense mutations, a single amino acid duplication, a recurrent mutation, and eight non-recurrent missense mutations. Functional studies showed complete PP2A dysfunction in four individuals with seemingly milder ID, hinting at haploinsufficiency. Ten other individuals showed mutation-specific biochemical distortions, including poor expression, altered binding to the A subunit and specific B-type subunits, and impaired phosphatase activity and C-terminal methylation. Four were suspected to have a dominant-negative mechanism, which correlated with severe ID. Two missense variants affecting the same residue largely behaved as wild-type in our functional assays. Overall, we found that pathogenic PPP2CA variants impair PP2A-B56(δ) functionality, suggesting that PP2A-related neurodevelopmental disorders constitute functionally converging ID syndromes.

Deficiência Intelectual/genética , Mutação , Proteína Fosfatase 2/genética , Adolescente , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Células HEK293 , Haploinsuficiência/genética , Humanos , Masculino , Ligação Proteica/genética , Subunidades Proteicas/química , Subunidades Proteicas/metabolismo , Síndrome
Eur J Hum Genet ; 24(1): 129-34, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25966631


De novo GNAO1 variants have been found in four patients including three patients with Ohtahara syndrome and one patient with childhood epilepsy. In addition, two patients showed involuntary movements, suggesting that GNAO1 variants can cause various neurological phenotypes. Here we report an additional four patients with de novo missense GNAO1 variants, one of which was identical to that of the previously reported. All the three novel variants were predicted to impair Gαo function by structural evaluation. Two patients showed early-onset epileptic encephalopathy, presenting with migrating or multifocal partial seizures in their clinical course, but the remaining two patients showed no or a few seizures. All the four patients showed severe intellectual disability, motor developmental delay, and involuntary movements. Progressive cerebral atrophy and thin corpus callosum were common features in brain images. Our study demonstrated that GNAO1 variants can cause involuntary movements and severe developmental delay with/without seizures, including various types of early-onset epileptic encephalopathy.

Deficiências do Desenvolvimento/genética , Discinesias/genética , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Mutação de Sentido Incorreto , Espasmos Infantis/genética , Adolescente , Idade de Início , Sequência de Aminoácidos , Animais , Corpo Caloso/metabolismo , Corpo Caloso/patologia , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/patologia , Discinesias/diagnóstico , Discinesias/patologia , Eletroencefalografia , Feminino , Expressão Gênica , Genótipo , Humanos , Lactente , Dados de Sequência Molecular , Fenótipo , Alinhamento de Sequência , Espasmos Infantis/diagnóstico , Espasmos Infantis/patologia
J Child Neurol ; 22(1): 99-105, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17608316


A case of a young woman who suffers from refractory epilepsy in the form of Rasmussen encephalitis and acute intermittent porphyria is presented. The patient developed refractory partial seizures with progressive hemispheric atrophy in the first decade. Both her serum and cerebrospinal fluid contained significantly elevated levels of anti-GluR3B antibodies. Her serum also contained anti-NR2A antibodies (directed against the N-methyl-D-aspartate receptor). Seven years later, acute intermittent porphyria was diagnosed as she developed an acute episode of abdominal pain, dark urine, and hyponatremia. For several years, all attempts to discontinue porphyrinogenic antiepileptic drugs such as phenobarbital and valproate resulted in seizure worsening. During a major acute intermittent porphyria crisis, brain edema and coma developed, allowing the discontinuation of phenobarbital. On recovery, atrophy of the right hemisphere ensued. Several etiologic hypotheses are presented. Double insults, porphyria, and an autoimmune process are suggested for the development of Rasmussen encephalitis in this patient. The authors recommend testing for porphyria in cases of Rasmussen encephalitis and other intractable seizures.

Encefalite/complicações , Porfiria Aguda Intermitente/complicações , Adolescente , Autoanticorpos/metabolismo , Citocinas/metabolismo , Encefalite/imunologia , Encefalite/metabolismo , Encefalite/patologia , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Porfiria Aguda Intermitente/imunologia , Porfiria Aguda Intermitente/metabolismo , Porfiria Aguda Intermitente/patologia , Tomografia Computadorizada por Raios X/métodos
Epilepsia ; 46(5): 716-9, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15857438


PURPOSE: To report on the usefulness of adding video recording to routine EEG studies of infants and children with frequent paroxysmal events. METHODS: We analyzed the efficacy of this diagnostic means during a 4-year period. The decision whether to add video recording was made by the pediatric EEG interpreter at the time of the study. Studies were planned to last between 20 and 30 min, and, if needed, were extended by the EEG interpreter. For most studies, video recording was added from the beginning of EEG recording. In a minority of cases, the addition of video was implemented during the first part of the EEG test, as clinical events became obvious. In these cases, a new study (file) was begun. The success rate was analyzed according to the indications for the EEG study: paroxysmal eye movements, tremor, suspected seizures, myoclonus, staring episodes, suspected stereotypias and tics, absence epilepsy follow-up, cyanotic episodes, and suspected psychogenic nonepileptic events. RESULTS: Video recording was added to 137 of 666 routine studies. Mean patient age was 4.8 years. The nature of the event was determined in 61 (45%) of the EEG studies. Twenty-eight percent were hospitalized patients. The average study duration was 26 min. This diagnostic means was particularly useful for paroxysmal eye movements, staring spells, myoclonic jerks, stereotypias, and psychogenic nonepileptic events. About 46% of 116 patients for whom cognitive data were available were mentally retarded. EEG with added video recording was successfully performed in all 116 cases and provided useful information in 29 (55%) of these 53 patients. CONCLUSIONS: Adding video recording to routine EEG was helpful in 45% of cases referred for frequent paroxysmal events. This technique proved useful for hospitalized children as well as for outpatients. Moreover, it was successfully applied in cognitively impaired patients. Infants and children with paroxysmal eye movements, staring spells, myoclonic jerks, stereotypias, and pseudoseizures especially benefited from this diagnostic means. Because of its low cost and the little discomfort imposed on the patient and his or her family, this technique should be considered as a first diagnostic step in children with frequent paroxysmal events.

Eletroencefalografia/métodos , Transtornos dos Movimentos/diagnóstico , Convulsões/diagnóstico , Gravação de Videoteipe/métodos , Fatores Etários , Assistência Ambulatorial , Criança , Pré-Escolar , Eletroencefalografia/estatística & dados numéricos , Epilepsia/diagnóstico , Estudos de Avaliação como Assunto , Feminino , Hospitalização , Humanos , Lactente , Recém-Nascido , Masculino , Monitorização Fisiológica/métodos , Transtornos da Motilidade Ocular/diagnóstico , Estudos Retrospectivos , Processamento de Sinais Assistido por Computador , Gravação de Videoteipe/estatística & dados numéricos