Infantile spasms, dystonia, and other X-linked phenotypes caused by mutations in Aristaless related homeobox gene, ARX

Clinical data from 50 mentally retarded (MR) males in nine X-linked MR families, syndromic and non-specific, with mutations (duplication, expansion, missense, and deletion mutations) in the Aristaless related homeobox gene, ARX, were analysed. Seizures were observed with all mutations and occurred in 29 patients, including one family with a novel myoclonic epilepsy syndrome associated with the missense mutation. Seventeen patients had infantile spasms. Other phenotypes included mild to moderate MR alone, or with combinations of dystonia, ataxia or autism. These data suggest that mutations in the ARX gene are important causes of MR, often associated with diverse neurological manifestations. (C) 2002 Elsevier Science B.V. All rights reserved.

Sodium channel alpha 1-subunit mutations in severe myoclonic epilepsy of infancy and infantile spasms

Background: Mutations in SCN1A, the gene encoding the alpha1 subunit of the sodium channel, have been found in severe myoclonic epilepsy of infancy (SMEI) and generalized epilepsy with febrile seizures plus (GEFS(+)). Mutations in SMEI include missense, nonsense, and frameshift mutations more commonly arising de novo in affected patients. This finding is difficult to reconcile with the family history of GEFS(+) in a significant proportion of patients with SMEI Infantile spasms (IS), or West syndrome, is a severe epileptic encephalopathy that is usually symptomatic. In some cases, no etiology is found and there is a family history of epilepsy. Method: The authors screened SCN1A in 24 patients with SMEI and 23 with IS. Results: Mutations were found in 8 of 24 (33%) SMEI patients, a frequency much lower than initial reports from Europe and Japan. One mutation near the carboxy terminus was identified in an IS patient. A family history of seizures was found in 17 of 24 patients with SMEI. Conclusions: The rate of SCN1A mutations in this cohort of SMEI patients suggests that other factors may be important in SMEI. Less severe mutations associated with GEFS(+) could interact with other loci to cause SMEI in cases with a family history of GEFS(+). This study extends the phenotypic heterogeneity of mutations in SCN1A to include IS.

Molecular basis of infantile reversible cytochrome c oxidase deficiency myopathy

Childhood-onset mitochondrial encephalomyopathies are usually severe, relentlessly progressive conditions that have a fatal outcome. However, a puzzling infantile disorder, long known as `benign cytochrome c oxidase deficiency myopathy` is an exception because it shows spontaneous recovery if infants survive the first months of life. Current investigations cannot distinguish those with a good prognosis from those with terminal disease, making it very difficult to decide when to continue intensive supportive care. Here we define the principal molecular basis of the disorder by identifying a maternally inherited, homoplasmic m.14674T > C mt-tRNA(Glu) mutation in 17 patients from 12 families. Our results provide functional evidence for the pathogenicity of the mutation and show that tissue-specific mechanisms downstream of tRNA(Glu) may explain the spontaneous recovery. This study provides the rationale for a simple genetic test to identify infants with mitochondrial myopathy and good prognosis.

Inflammation and Remodeling in Infantile, Juvenile, and Adult Allergic Sensitized Mice

Background: Airway structural changes occur early in childhood asthma, but it is unknown whether the development of airway alterations in children is similar to that of adults. We compared inflammation and remodeling parameters in allergic sensitized infantile, juvenile, and adult mice. Methods: Infantile mice (18D) were sensitized with three intraperitoneal injections (i.p.) of ovalbumin (OVA) at days 5 and 7 and challenged with OVA at days 14-16. The 18D1 group received an additional challenge at days 9-11. The juvenile mice (40D) received challenges at days 22-24 and 36-38. Adult mice (100D) were sensitized at days 60-62 and received three inhalations at days 77-79 and 96-98. Animals were submitted to whole body plethysmography. Airway eosinophils, CD3+ T-lymphocytes, IL-5+ cells, mucus content, collagen and reticular fibers density, and smooth muscle thickness were quantified. Results: All sensitized animals presented with airway hyperresponsiveness, without differences in eosinophil cell density The density of CD3+ T-cells was higher in the 100D and 1801 groups than in the 18D and 40D groups. Infantile sensitized groups demonstrated increased interleukin-5 expression in the airways. Infantile mice demonstrated more mucus in the bronchiolar epithelium than the 40D and 100D mice. The 18D animals demonstrated less collagen than the 18D1 group. Juvenile and adult mice had increased airway smooth muscle thickness when compared to age-matched controls, but no differences were observed in the infantile groups. Conclusion: We have shown that infantile mice develop inflammatory and structural alterations in the airways that are partially different from those developed in older animals. Pediatr Pulmonol. 2011;46:650-665. (C) 2011 Wiley-Liss, Inc.

Ultrasound findings in infantile systemic hyalinosis

To describe clinical and ultrasound findings in a patient with infantile systemic hyalinosis (ISH). A 5-month-old boy was evaluated of joint contractures. In addition to clinical and laboratory investigations, an ultrasound of his joints was done and compared to a child with similar age. On examination, a short neck, gingival hyperplasia and papular rash were noted. Joint examination showed painful passive movement, reduced range of motion, and joint contractures in knees, elbows, and small joints of the hands, without any evidence of synovial thickness. Ultrasound of the affected joints showed irregular cortical surface of MCPs and PIP, the presence of osteophytes and bone erosions, increased synovial fluid without evidence of synovial hyperplasia. This is the first report to show evidence of US findings in ISH. Ultrasound findings may help to distinguish ISH from JIA in early stages.

Immunofluorescent antibody to rotavirus and antigen excretion in infantile acute diarrhoea

A serological study was carried out to evaluate the causal relationship of acute diarrhoea and rotavirus in children under five years of age. The rotaviral infection was demonstrated in paired sera by determining the antibody titers by immunofluorescence test (IF). Bovine rotavirus-infected MA-104 cell culture was used as substratum for IF. Out of 80 paired sera it was shown that 23 (28.75%) presented seroconversion, 19 (23.75%) samples showed a twofold increase in their titers and 38 (47.5%) had no increase in rotavirus antibody. This result is discussed on the light of previously obtained results on viral antigen detection by counterimmunoelectrosmophoresis (CIEOP).

Histoplasmin and paracoccidioidin skin reactivity in infantile population of Northern Argentina

In order to estimate ages at which etiological agents of systemic mycoses initiate infection, histoplasmin and paracoccidioidin skin tests were performed in 344 children of both sexes, between 2 and 15 years old. They were selected from a statistically significant population sample Gral. San Martín city (Northeast Argentina). Tests were read 48h after injection and considered positive if a 5 mm on larger induration was present. Circulating antibodies were also evaluated by agar gel immunodiffusion. The overall infection rate for H. capsulatum was 9.2%, belonging to children from 4 to 14 years old, without significant differences among sexes. Five children from 2 to 14 years old were positive to paracoccidioidin (1.6%). None of the children had specific antibodies neither signs of active mycosis. Results show H. capsulatum infection can be found from age 4, while for P. brasiliensis the lower limit was two years old. These findings may contribute to better knowledge on infantile fungal infection in a geographical region where no previous references can be found.

Infantile Cystinosis

Infantile cystinosis is a rare disorder which leftuntreated results in end -stage renal disease early in life. Together with dehydration and electrolyte imbalance due to renal tubular Fanconi syndrome, endstage renal disease used to be the leading cause of death in children with cystinosis. Specific therapy with cysteamine (cystine -depleting agent) has changed the course of this disease. Instead of being fatal in childhood, it can nowadays be considered a multisystemic adult disorder. The authors report a case of a child diagnosed with Fanconi syndrome at 14 months of age and infantile cystinosis at 19 months of age in whom oral cysteamine treatment led to a good outcome during childhood.

GM1 Gangliosidosis, Late Infantile Onset Dystonia, and T2 Hypointensity in the Globus Pallidus and Substantia Nigra

BACKGROUND: GM1 gangliosidosis is a rare disease due to mutations in the GLB1 gene and autosomal recessive deficiency of b-galactosidase. There is considerable overlap between classical phenotypes and clinical and imaging findings, which are often difficult to interpret. PATIENT: The patient in this study had dysmorphism, dysostosis, progressive dystonia, and T2 hypointensity in the basal ganglia. Partially similar clinical and radiologic findings were described previously in two reports. CONCLUSIONS: T2 hypointensity in the globus pallidus should, in the appropriate clinical setting, lead to consideration of thediagnosis of GM1 gangliosidosis.

The Role of Propranolol in the Treatment of Infantile Hemangioma

INTRODUCTION: Infantile hemangioma (IH) is one of the most common childhood tumors. There are various medical or surgical therapeutic options, all with suboptimal results. Recently, the successful use of propranolol for involution of IH was described. We report the results of a single-center experience with this therapeutic option. OBJECTIVE: To prospectively assess the efficacy and safety of propranolol in children with infantile hemangioma. METHODS: We performed a prospective analysis of clinical data of all patients with IH referred to a pediatric cardiology center for baseline cardiovascular assessment prior to propranolol therapy. Propranolol was given at a starting dose of 1 mg/kg/day and titrated to a target dose of 2-3 mg/kg/day according to clinical response. Efficacy was assessed through a photograph-based severity scoring scale. Safety was assessed by collecting data regarding significant side effects. RESULTS: Starting in 2010, 30 patients (15 female) were referred for propranolol treatment of IH, at a median age of six months (1-63 months). The mean target propranolol dose was 2.8 mg/kg/day, with a mean duration of therapy of 12 months. All patients experienced significant reduction of IH size and volume. There were no side effects. CONCLUSIONS: In our experience propranolol appears to be a useful and safe treatment option for severe or complicated IH, achieving a rapid and significant reduction in their size. No adverse effects were observed, although until larger clinical trials are completed, potential adverse events should be borne in mind and consultation with local specialists is recommended prior to initiating treatment.

Rotavirus genotyping in gastroenteritis cases of an infantile population from Western Brazilian Amazonia

INTRODUCTION: During the period from 2000 to 2002, 79 rotavirus-positive stool samples were collected from children presenting diarrhea in the Western Brazilian Amazon. METHODS: Molecular characterization of the G and P genotypes was performed using RT-PCR and electropherotyping analysis by polyacrylamide gel electrophoresis. RESULTS: A total of 59 samples were confirmed as group A rotavirus. A long electrophoretic profile was exhibited by the G1P[8], G3P[8], and G4P[8] genotypes. The G1P[8] genotype was found in greater proportion. The short electropherotype was exhibited only by G2 genotype strains. CONCLUSIONS: The proportion of the rotavirus genotypes observed was not different from that in other areas of Brazil. This study is the first genotyping of rotavirus in the Western Brazilian Amazon.

Aprendizaje durante la ontogenia temprana: Estudio de la participación del sistema opioide en la modulación de aprendizajes mediados por el etanol. LEARNING AND EARLY ONTOGENY: ANALYSIS OF THE INVOLVEMENT OF OPIOID SYSTEM IN FETAL AND INFANTILE ETHANOL-MEDIATED EXPERIENCIES.

Este plan de trabajos es continuidad de una línea de investigación centrada en evaluar los mecanismos responsables de la adquisición, expresión y persistencia de experiencias con el etanol. A partir de ello, indagar acerca de los efectos de esta experiencia sobre comportamientos de búsqueda y autoadministración de etanol en neonatos e infantes de rata. Se pretende analizar la participación del sistema opiáceo en los mecanismos implicados en una memoria fetal y/o infantil, generada como consecuencia de la exposición etílica. En una primera etapa, nos proponemos establecer de qué manera experiencias prenatales con la droga modulan el patrón de auto-administración de alcohol y otros reforzadores, como sacarosa. En este primer bloque de experimentos realizaremos manipulaciones fetales para determinar con mayor grado de especificidad la posible acción del sistema opiáceo en los mecanismos de adquisición de una memoria etílica prenatal. Se realizarán administraciones de etanol y el antagonista opiáceo, directamente a nivel fetal, y se evaluará esta experiencia en un paradigma de condicionamiento neonatal positivo, mediado por la droga. De acuerdo a la evidencia previa, esperamos que la exposición prenatal con la droga facilite la expresión de conductas de consumo y búsqueda del etanol o hacia las claves que señalizan al psicotrópico, tanto durante la infancia como en el neonato. A su vez, cuando la droga es presentada bajo los efectos de un antagonista opiáceo esperamos que estas conductas muestren un perfil similar a las desplegadas por sujetos controles. El segundo bloque de experimentos ha sido ideado con el objeto de indagar acerca de la posible participación del sistema opiáceo en la modulación de los aspectos reforzantes de la droga, a través de un esquema de auto-administración etílica infantil. Se utilizará un paradigma de condicionamiento instrumental adaptado para ratas infantes que consta de dos instancias, una de adquisición de la conducta instrumental (DPs 14-17) en la cual los animales reciben un pulso de refuerzo, como consecuencia de la ejecución de la conducta operante. En una segunda fase se analiza el patrón de búsqueda del reforzador ya que se registra la respuesta instrumental, sin que ocurra el refuerzo por la misma. Para analizar la participación del sistema opiáceo, durante la fase de adquisición de la conducta operante (DPs 16 y 17) los animales serán re-expuestos a mínimas cantidades del reforzador, bajo los efectos de un antagonista opiáceo, momentos previos al ensayo instrumental correspondiente para cada uno de estos días (Exp. 3). Esperamos que el bloqueo del sistema opiáceo, durante esta re-exposición al etanol, sea suficiente para disminuir el patrón de respuesta instrumental hacia el refuerzo etílico. Un último experimento incorporará un tercer evento de re-exposición al etanol -bajo los efectos del antagonista- previo al ensayo de extinción de la conducta instrumental (DP 18). Este nuevo evento tiene por objeto analizar la participación de este sistema neurobiológico en los mecanismos de búsqueda de etanol. Si el sistema opiáceo participa en la modulación de patrones tanto de búsqueda como consumatorios del reforzamiento por etanol, se espera que la re-exposición a la droga bajo los efectos del antagonista, inhiba estas respuestas tanto durante la sesión de adquisición, como de extinción de la conducta operante. Este proyecto intenta profundizar en el conocimiento de los mecanismos que regulan reconocimiento, aceptación, búsqueda y consumo de etanol, como consecuencia de experiencias tempranas con la droga. A su vez, es importante identificar y estudiar los sistemas neurobiológicos involucrados en estos mecanismos. Es por ello que se intenta determinar el rol que ejerce el sistema opiáceo en la adquisición de estas experiencias etílicas a nivel fetal e infantil, que se conoce promueven la búsqueda y el consumo de la droga. Our work is directed to analyze the involvement of the opioid system in the generation of pre- and early postnatal ethanol-related memories. As a first step, maternal manipulations with ethanol will be done. Infants will be evaluated in a paradigm of infantile self-administration of different reinforcers (ethanol, sucrose or water), employing a model of operant conditioning adapted to infant rats. A second experiment will be conducted in order to analyze if a central administration of ethanol, directly to the fetus, modifies subsequent patterns of neonatal conditioned responses to an artificial nipple, mediated by ethanol reinforcing effects. Fetal presentation of ethanol will be accompanied with the injection of an opioid antagonist in order to analyze the involvement of this system in acquisition processes of a fetal ethanol-mediated memory. A second set of studies will be conducted to analyze appetitive and consummatory behaviors in an infant model of ethanol self-administration. Involvement of opioid system in the acquisition or expression of this experience will be also inquired. Infant rats (PDs14-17) have to display a target behavior (nose-poke) to gain access to 5% sucrose or 3.75% ethanol. On PD18 an extinction session will be included. At PDs16-17, 6-hr before training, pups will be re-exposed to ethanol under opioid antagonism effects (naloxone). In a follow up experiment, a re-exposure trial will be included at PD18. Prior extinction, pups will receive naloxone and will be re-exposed to ethanol. We aim to observe if opioid system is modulating etha¬nol reinforcing effects, in terms of both appetitive and consummatory behaviors.

Acute infantile encephalopathy predominantly affecting the frontal lobe (AIEF): A European case.

Acute infantile encephalopathy predominantly affecting the frontal lobes (AIEF) has been described as a new entity, based on MRI findings (acute abnormal diffusion-weighted imaging signals in the frontal lobes followed by atrophy) and exclusion of other acute encephalopathies. Patients present with acute onset of fever, status epilepticus, and coma. Different causal mechanisms have been suggested such as localized viral infection, toxic insult due to cytokines, or postictal damage. Only children of Japanese descent have been described. We report the case of a Caucasian girl whose history and MRI findings were similar to the Japanese cases. She had a massive regression with verbal apraxia, while cognitive development was less affected; she initially presented with a cluster of complex partial seizures (and not convulsive status epilepticus), making epileptic or post anoxic-ischemic sequelae highly unlikely. The place of this proposed entity among other recently described acute encephalopathies with abnormal diffusion on MRI is discussed.