Jean-Paul Misson

Identification of radial glial cells within the developing murine central nervous system:studies based upon a new immunohistochemical marker

The monoclonal antibody RC2 was generated in mouse by conventional hybridoma methodology. The antigen recognized by RC2 is robust, allowing aldehyde fixation appropriate to high resolution light and electron microscopic analyses. From the neural tube stage of fetal development the antibody delineates throughout the central nervous system a subpopulation of neuroepithelial cells which have a radial bipolar morphology. A descending process extends to the ventricular margin, and an ascending process contacts the glial limiting membrane by one or more endfeet varicosities. The persistence of these cells through the neurogenetic period allows their identification as radial glial. From as early as E9-10 the fibers appear to be organized in simple straight fascicles. Later in fetal development these fascicles show marked region-specific transformations in density and trajectory, particularly in association with cerebral corticogenesis and with cerebellar and basal ganglia development. The bipolar forms continue to stain with RC2 until they disappear in the postnatal period. Concurrently with a progressive perinatal loss of stained bipolar radial glia, RC2 identifies multipolar cell forms at various levels of the brain wall, as consistent with the transformation of radial glia into astrocytes. RC2 also recognizes monopolar cell forms in the spinal cord and the cerebellum as early as E15, and in the dentate gyrus of the hippocampal formation from the day of birth. Monopolar forms in the cerebellum are inferred to be progenitors of Bergmann glia. Although Bergmann glia are known to persist in adult life, these cells do not stain with RC2 beyond the 2nd postnatal week. The robustness of the antigen recognized by RC2 makes this probe a valuable tool to study the morphological transformations of the bipolar radial glia during their mitotic turnover. It also provides a sensitive stain for the study of the organization and the histogenetic role of the overall radial fiber system.

Early neurogenesis and teratogenesis in whole mouse embryo cultures. Histochemical, immunocytological and ultrastructural study of the premigratory neuronal-glial units in normal mouse embryo and in mouse embryos influenced by cocaine and retinoic acid.

Abstract. Yolk sacs of postimplantation mouse embryos were cultured in a mixture of human and rat sera. The central nervous system of these cultured normal embryos was studied from the stage of 5–9 somites (approximately 8.5 postcoital days) to 20–21 somites (approximately 9.5 postcoital days) and compared with in vivo embryos at the same stages. This developmental period covers most of the neural tube closure, the early premigratory differentiation of the neuroectodermal epithelium, and the glial commitment of a population of germinative cells. The neuronal and glial elements of the in vitro cultivated embryos were found to be identical to the corresponding neural tissue in in vivo embryos (light and electron microscopic comparisons); the morphological identity between the in vivo and in vitro embryos was confirmed by morphometry and by stainings revealing the differentiation of the glial elements and precursors. The study of the neuronal-glial units in this material revealed that the fascicular organization of the radial glial cells occurs before the stage of 20 somites. When submitted to a single low dose of retinoic acid at the 7-somite stage, the expression of the epitope recognized by radial cell 2(RC2), a glial marker, is delayed in the in vitro embryos 12–16 hours, but the glycogen and the other glial parameters mature in time. The in vitro embryos exposed to cocaine at the 7-somite stage displayed a prosencephalon remaining deprived of almost all glial cytological features during the entire culture period, although the other developmental parameters evolved normally. This in vitro whole embryo model seems to be a powerful tool for studying early neurogenesis and teratogenesis.

Efficacy of Sublingual Lorazepam Versus Intrarectal Diazepam for Prolonged Convulsions in Sub-Saharan Africa.

In Sub-Saharan Africa, intrarectal diazepam is the first-line anticonvulsant mostly used in children. We aimed to assess this standard care against sublingual lorazepam, a medication potentially as effective and safe, but easier to administer. A randomized controlled trial was conducted in the pediatric emergency departments of 9 hospitals. A total of 436 children aged 5 months to 10 years with convulsions persisting for more than 5 minutes were assigned to receive intrarectal diazepam (0.5 mg/kg, n = 202) or sublingual lorazepam (0.1 mg/kg, n = 234). Sublingual lorazepam stopped seizures within 10 minutes of administration in 56% of children compared with intrarectal diazepam in 79% (P < .001). The probability of treatment failure is higher in case of sublingual lorazepam use (OR = 2.95, 95% CI = 1.91-4.55). Sublingual lorazepam is less efficacious in stopping pediatric seizures than intrarectal diazepam, and intrarectal diazepam should thus be preferred as a first-line medication in this setting.

Heterogeneity of sponastrime dysplasia: Delineation of a variant form with severe mental retardation

We report a child with short stature, osteopenia with metaphyseal striations and severe mental retardation. This child shows radiological and clinical features of SPONASTRIME. dysplasia. Only three sibships with this disorder have been reported. In two families, affected patients were of normal intelligence. In the third one, as well as our case, the dysplasia was complicated by severe mental retardation of unknown origin. The severity of the retardation m our case and a previous report, and some difference in the gestalt and radiological aspects, suggest that SPONASTRIME dysplasia is a heterogeneous disorder. We provisionally propose to split SPONASTRIME dysplasia in two phenotypically distinct subgroups, and to delineate here a “new‘ variant with microcephaly and severe mental impairment.

Prenatal diagnosis of pyruvate carboxylase deficiency by direct measurement of catalytic activity on chorionic villi samples.

Pyruvate carboxylase (PC) deficiency is a rare metabolic disorder in infants and children, most frequently with fatal outcome. Its prenatal diagnosis by radiometric assay in cultured amniocytes has previously been reported. We present and discuss the prenatal diagnosis of PC deficiency by direct measurement of PC activity in chorionic villi, in two subsequent pregnancies in a family who previously lost a child affected by PC deficiency. In the next pregnancy PC was unmeasurably low in chorionic villi whereas in control samples its activity was between 0·8 and 3·3 nmol min−1 mg protein−1. Following elective termination of the pregnancy PC was shown to be totally inactive in post‐mortem fetal liver. In the most recent pregnancy of the probands mother PC was normally active in the chorionic villi. The product of this pregnancy was a normal boy. Copyright

Temple-Baraitser syndrome: a rare and possibly unrecognized condition

Temple–Baraitser syndrome, previously described in two unrelated patients, is the association of severe mental retardation and abnormal thumbs and great toes. We report two additional unrelated patients with Temple–Baraitser syndrome, review clinical and radiological features of previously reported cases and discuss mode of inheritance. Patients share a consistent pattern of anomalies: hypo or aplasia of the thumb and great toe nails and broadening and/or elongation of the thumbs and halluces, which have a tubular aspect. All patients were born to unrelated parents and occurred as a single occurrence in multiple sibships, suggesting sporadic inheritance from a de novo mutation mechanism. Comparative genomic hybridization in Patients 1, 2 and 3 did not reveal any copy number variations. We confirm that Temple–Baraitser syndrome represents a distinct syndrome, probably unrecognized, possibly caused by a de novo mutation in a not yet identified gene.

La tachycardie ventriculaire catecholergique du jeune enfant: un diagnostic souvent meconnu

Resume La tachycardie ventriculaire polymorphe catecholergique est un diagnostic important chez l’enfant qui presente des syncopes et dont le cœur est normal, en raison de son pronostic severe. Observation. – Un garcon âge de 3 ans a ete pris en charge pour la survenue de syncopes declenchees par l’effort et l’emotion. L’arythmie ventriculaire, consistant en salves de tachycardie ventriculaire bidirectionnelle, etait reproductible a l’effort. Sous traitement betabloquant, syncopes et arythmies malignes ont disparu. Conclusion. – Malgre sa faible incidence, la tachycardie ventriculaire polymorphe catecholergique est une importante cause de syncope et de mort subite induites par l’effort et l’emotion chez l’enfant.

Phenotype–Genotype Correlation in Children with Neurofibromatosis Type 1

Abstract Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder with an incidence of ˜1 in 4,000 live births. Neurofibromin, the gene product, is ubiquitously expressed at high levels in the nervous system and functions as a tumor suppressor. Haploinsufficiency of neurofibromin through mutation leads to an increased risk of developing benign and malignant tumors in affected individuals. Although NF1 has complete penetrance, it displays considerable inter‐ and intrafamilial variability in phenotypic expression which poses disease prediction and management problems. Some NF1 genotype‐phenotype correlations have been described. To evaluate the genetic component of variable expressivity in NF1, we examined the phenotypic correlations between affected relatives in 52 NF1 patients from 45 families.

Convulsions prolongées chez l’enfant en Afrique subsaharienneAspects cliniques et prise en charge

BACKGROUND There is a paucity of epidemiologic studies of prolonged seizures (persisting for more than 5 minutes) in the Democratic Republic of Congo (DRC) and in Rwanda. OBJECTIVE We sought to analyze the clinical presentation, causes, pharmacologic management, and shortterm course of these seizures. METHODS We enrolled 436 children, aged five months to ten years, who presented with prolonged seizures at the pediatric emergency departments of nine hospitals. Findings: Overall, 57.8% of the children were younger than three years; 7% had pre-existing psychomotor delay. Although 21% had had previous seizures, only 13% were receiving antiepileptic therapy. On presentation, 63.5% of the patients had fever and 26% were in status epilepticus. The seizures were focal in 21% of the cases. Malaria was the most common cause, involving 63% of the cases. The recurrence rate was 38%, and the mortality rate 4%. CONCLUSION Prolonged seizures in DRC and Rwanda are frequently associated with fever, most commonly caused by malaria. The immediate use of long-acting antiepileptic drug could improve their outcomes.

Evaluation of Adherence to a Convulsion Management Protocol for Children in Rwanda

Inappropriate seizure management may result in high morbidity and mortality. We assessed the adherence of health professionals in southern Rwanda to a national protocol for pharmacological management of seizures in children. A questionnaire featuring a 5-year-old child with generalized prolonged seizures was administered. The questions focused on the choice of initial treatment and the sequence of management following failure of the initial treatment choice. Benzodiazepine was chosen as initial therapy by 93.7% of physicians and 90.9% of nurses. Only 49.2% of physicians and 41% of nurses would repeat the initial treatment in case of failure of the first dose and 47% of doctors would wait 30 min to intervene. In case of refractory status epilepticus, 34% of physicians would give three doses of benzodiazepine, whereas 19% did not know what to do. These results suggest poor adherence to national protocol.