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Ann Neurol ; 86(2): 181-192, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31177578


OBJECTIVE: Recent reports have described single individuals with neurodevelopmental disability (NDD) harboring heterozygous KCNQ3 de novo variants (DNVs). We sought to assess whether pathogenic variants in KCNQ3 cause NDD and to elucidate the associated phenotype and molecular mechanisms. METHODS: Patients with NDD and KCNQ3 DNVs were identified through an international collaboration. Phenotypes were characterized by clinical assessment, review of charts, electroencephalographic (EEG) recordings, and parental interview. Functional consequences of variants were analyzed in vitro by patch-clamp recording. RESULTS: Eleven patients were assessed. They had recurrent heterozygous DNVs in KCNQ3 affecting residues R230 (R230C, R230H, R230S) and R227 (R227Q). All patients exhibited global developmental delay within the first 2 years of life. Most (8/11, 73%) were nonverbal or had a few words only. All patients had autistic features, and autism spectrum disorder (ASD) was diagnosed in 5 of 11 (45%). EEGs performed before 10 years of age revealed frequent sleep-activated multifocal epileptiform discharges in 8 of 11 (73%). For 6 of 9 (67%) recorded between 1.5 and 6 years of age, spikes became near-continuous during sleep. Interestingly, most patients (9/11, 82%) did not have seizures, and no patient had seizures in the neonatal period. Voltage-clamp recordings of the mutant KCNQ3 channels revealed gain-of-function (GoF) effects. INTERPRETATION: Specific GoF variants in KCNQ3 cause NDD, ASD, and abundant sleep-activated spikes. This new phenotype contrasts both with self-limited neonatal epilepsy due to KCNQ3 partial loss of function, and with the neonatal or infantile onset epileptic encephalopathies due to KCNQ2 GoF. ANN NEUROL 2019;86:181-192.

Ann Emerg Med ; 74(4): 503-508, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30826069


Acute flaccid myelitis is a debilitating illness characterized by acute onset of limb weakness, with one or more spinal segments displaying magnetic resonance imaging-confirmed gray matter lesions. Since the first outbreak in 2014, tracking by the Centers for Disease Control and Prevention has demonstrated biennial epidemics in the United States, with a current outbreak occurring in 2018. The cases of 3 children with acute flaccid myelitis who were initially thought to have common nonneurologic diagnoses are presented. Emergency physicians need to be vigilant to recognize the subtleties of acute flaccid myelitis because the illness progression is rapid and therapy is nuanced.

J Child Neurol ; 31(9): 1156-60, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27071467


We categorized the causes of acute ataxia in the pediatric population-referred to the Division of Neurology-at a large, urban pediatric medical center. Of the 120 cases identified over the past 11 years, post-infectious cerebellar ataxia was the most commonly diagnosed (59%), followed by drug intoxication, opsoclonus-myoclonus ataxia syndrome, episodic ataxia, acute cerebellitis, cerebellar stroke, ADEM, meningitis, cerebral vein thrombosis, Leigh's disease, Miller-Fisher syndrome, and concussion. Among the patients with post-infectious cerebellar ataxia, 85% were 1-6 years old and all had a history of antecedent viral illness. CSF pleocytosis was present in 40% of patients; all had normal brain MRIs. The majority (91%) recovered within 30 days. We conclude that post-infectious cerebellar ataxia remains the most common cause of acute ataxia in childhood and that it carries a good prognosis. We also differentiate acute post-infectious cerebellar ataxia from other causes with similar presentations.

Ataxia/epidemiologia , Ataxia/etiologia , Doença Aguda , Ataxia/diagnóstico por imagem , Ataxia/terapia , Encéfalo/diagnóstico por imagem , Doenças Cerebelares/diagnóstico por imagem , Doenças Cerebelares/epidemiologia , Doenças Cerebelares/etiologia , Doenças Cerebelares/terapia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Infecção/complicações , Infecção/epidemiologia , Infecção/terapia , Imagem por Ressonância Magnética , Masculino , Estudos Retrospectivos
J Inherit Metab Dis ; 37(3): 431-7, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24271936


OBJECTIVE: To describe the natural history of Sanfilippo syndrome type A. METHODS: We performed a retrospective review of 46 children (21 boys, 25 girls) with Sanfilippo syndrome type A evaluated between January 2000 and April 2013. Assessments included neurodevelopmental evaluations, audiologic testing, and assessment of growth, adaptive behavior, cognitive behavior, motor function, and speech/language skills. Only the baseline evaluation was included for patients who received hematopoietic stem cell transplantation. RESULTS: Median age at diagnosis was 35 months, with a median delay between initial symptoms to diagnosis of 24 months. The most common initial symptoms were speech/language delay (48%), dysmorphology (22%), and hearing loss (20%). Early behavioral problems included perseverative chewing and difficulty with toilet training. All children developed sleep difficulties and behavioral changes (e.g., hyperactivity, aggression). More than 93% of the children experienced somatic symptoms such as hepatomegaly (67%), abnormal dentition (39%), enlarged tongue (37%), coarse facial features (76%), and protuberant abdomen (43%). Kaplan-Meier analysis showed a 60% probability of surviving past 17 years of age. CONCLUSIONS: Sanfilippo type A is characterized by severe hearing loss and speech delay, followed by a rapid decline in cognitive skills by 3 years of age. Significant somatic disease occurs in more than half of patients. Behavioral difficulties presented between 2 and 4 years of age during a rapid period of cognitive decline. Gross motor abilities are maintained during this period, which results in an active child with impaired cognition. Sleep difficulties are concurrent with the period of cognitive degeneration. There is currently an unacceptable delay in diagnosis, highlighting the need to increase awareness of this disease among clinicians.

Mucopolissacaridose III/diagnóstico , Adaptação Psicológica , Adolescente , Criança , Pré-Escolar , Cognição , Feminino , Perda Auditiva/diagnóstico , Humanos , Lactente , Masculino , Mucopolissacaridose III/psicologia , Estudos Retrospectivos