Rett-like phenotypes: expanding the genetic heterogeneity to the KCNA2 gene and first familial case of CDKL5-related disease.

Several genes have been implicated in Rett syndrome (RTT) in its typical and variant forms. We applied next-generation sequencing (NGS) to evaluate for mutations in known or new candidate genes in patients with variant forms of Rett or Rett-like phenotypes of unknown molecular aetiology. In the first step, we used NGS with a custom panel including MECP2, CDKL5, FOXG1, MEF2C and IQSEC2. In addition to a FOXG1 mutation in a patient with all core features of the congenital variant of RTT, we identified a missense (p.Ser240Thr) in CDKL5 in a patient who appeared to be seizure free. This missense was maternally inherited with opposite allele expression ratios in the proband and her mother. In the asymptomatic mother, the mutated copy of the CDKL5 gene was inactivated in 90% of blood cells. We also identified a premature stop codon (p.Arg926*) in IQSEC2 in a patient with a Rett-like phenotype. Finally, exome sequencing enabled us to characterize a heterozygous de novo missense (p.Val408Ala) in KCNA2 encoding the potassium channel Kv 1.2 in a girl with infantile-onset seizures variant of RTT. Our study expands the genetic heterogeneity of RTT and RTT-like phenotypes. Moreover, we report the first familial case of CDKL5-related disease.

RELN and VLDLR mutations underlie two distinguishable clinico-radiological phenotypes.

Pontocerebellar hypoplasias (PCH) are characterized by lack of development and/or early neurodegeneration of cerebellum and brainstem. We report five patients referred for PCH, showing atypical clinical and magnetic resonance imaging (MRI) features suggestive of defects in the Reelin pathway. We screened for mutations in RELN or VLDLR and compared the phenotype of these patients with that of previously reported patients. All patients had profound cerebellar hypoplasia on MRI with peculiar cerebellar morphology, associated with flattened pons and neocortical abnormalities. Patient 1 had profound motor and intellectual disability with moderate lissencephaly suggestive of RELN mutations and was shown to harbor a splicing homozygous RELN mutation. The four other patients had a milder phenotype consistent with CARMQ1 (cerebellar ataxia and mental retardation with or without quadrupedal locomotion). These patients showed mild simplification or thickening of cortical gyration and had VLDLR mutations. Reelin signaling regulates neuronal migration in the developing mammalian brain. VLDLR is a key component of the Reelin pathway. Our patients had a very small and dysplatic cerebellar vermis that should suggest the involvement of these genes. Moreover, differences in clinical severity, involvement of the cerebellar hemispheres, together with the severity of the neocortical defect, enables RELN-mutated patients to be distinguished from VLDLR-mutated patients.

Phenotypic variability in Rett syndrome associated with FOXG1 mutations in females.

BACKGROUND: The FOXG1 gene has been recently implicated in the congenital form of Rett syndrome (RTT). It encodes the fork-head box protein G1, a winged-helix transcriptional repressor with expression restricted to testis and brain, where it is critical for forebrain development. So far, only two point mutations in FOXG1 have been reported in females affected by the congenital form of RTT. Aim To assess the involvement of FOXG1 in the molecular aetiology of classical RTT and related disorders. METHODS: The entire multi-exon coding sequence of FOXG1 was screened for point mutations and large rearrangements in a cohort of 35 MECP2/CDKL5 mutation-negative female patients including 31 classical and four congenital forms of RTT. RESULTS: Two different de novo heterozygous FOXG1-truncating mutations were identified. The subject with the p.Trp308X mutation presented with a severe RTT-like neurodevelopmental disorder, whereas the p.Tyr400X allele was associated with a classical clinical RTT presentation. CONCLUSIONS: These new cases give additional support to the genetic heterogeneity in RTT and help to delineate the clinical spectrum of the FOXG1-related phenotypes. FOXG1 screening should be considered in the molecular diagnosis of RTT.

A detailed analysis of the MECP2 gene: prevalence of recurrent mutations and gross DNA rearrangements in Rett syndrome patients.

Mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2) have been found to be a cause of Rett syndrome (RTT). In order to provide further insights into the distribution and the spectrum of mutations, we investigated, in addition to the whole coding sequence, a phylogenetically conserved sequence within the 3' untranslated region (3' UTR) of the MECP2 gene for 55 sporadic RTT, including 47 typical and 8 nonclassical cases. We have developed an approach based on conformation-sensitive gel electrophoresis, sequence analysis and, for the first time, Southern blot analysis. Mutation detection, including unreported gross DNA rearrangements, was achieved in 79% of classical RTT and 25% of nonclassical RTT patients. The high prevalence of recurrent mutations allows us to propose a molecular diagnosis strategy for RTT.

New Types of Stable Aldehydes: Formylphosphane and Formylphosphane Oxide.

The reactivity of the formyl group in alpha-phosphorus-substituted aldehydes 1 can be tuned by adjusting the coordination number of the phosphorus atom. When X is a lone pair, the formylphosphanes obtained are stable compounds, whereas when X=O a relatively unstable formylphosphane oxide is produced. R=iPr(2)N, cHex(2)N.

[Total permanent auricular paralysis. Review of the literature apropos of 109 cases]. / La paralysie auriculaire permanente totale. Revue de la littérature à propos de 109 cas.

Analysis of 109 well documented cases of permanent total atrial paralysis reported in the literature illustrated the features of this arrhythmia which is a well defined entity consisting of suppression of all electrical and mechanical activity of both atria lasting for more than 6 months. Standard electrocardiogram reveals junctional bradycardia of about 40 bpm without any visible P waves and narrow supraventricular QRS complexes in 80% of cases. This diagnosis can only be confirmed by meticulous bipolar endocavitary recordings exploring all atrial walls without recording an auriculogram and by right intra-atrial and coronary sinus stimulation which proves to be ineffective. This disease has a male predominance in two-thirds of cases and a familial nature in 18% of cases. Seventy one per cent of affected subjects are under the age of 50 years. In 33% of cases, it is associated with Emery-Dreifuss muscular dystrophy, in which it constitutes a specific sign allowing this dystrophy to be differentiated from all other forms, especially facio-scapulo-humeral myopathy, and in 30% of cases, it is associated with a degenerative disease such as diabetes, amyloidosis or primary cardiomyopathy. Idiopathic dilatation of the right atrium is revealed in 15% of cases. The arrhythmia is responsible for syncope or faintness in 31% of cases, cerebral vascular accidents in 21% of cases and heart failure in 35% of cases. Cardiac activation is dependent on a junctional escape rhythm. The mechanism of the lesion responsible is atrial fibrosis which may extend to the sinoatrial node. The treatment of choice consists of implantation of a VVI or VVIR mode cardiac pacemaker in combination with anticoagulant therapy.

Vertebral-artery dissection following a judo session: a case report.

A few days after a judo session, an 11-year-old boy presented with an ischemic stroke with dizziness, aphasia and ataxia. CCT scan revealed a left thalamic infarct. Angiography showed a fibromuscular dysplasia (FMD) of the left vertebral artery probably complicated by dissection. Subsequent evolution was favorable. This observation points out the fact that the association of a cervical pain with neurological signs of vertebrobasilar stroke, especially occurring after a cervical trauma or rotatory motion, should alert to the possibility of vertebral-artery dissection. The diagnosis is mainly based on angiographic criteria. Accurate diagnosis has implications for prognosis and probably for acute medical treatment.

Transplantation of umbilical cord blood in neuroblastoma.

It has been shown that umbilical cord blood contains concentrations of hematopoietic progenitor cells equal to those of normal adult bone marrow. We successfully performed transplantation of cord blood combined with a hematopoietic growth factor (rGM-CSF) in a seven year old child suffering from neuroblastoma. Cord blood cells were collected from an HLA identical sibling at the time of delivery and stored in liquid nitrogen. The patient was conditioned with busulfan 600 mg/m2 and cyclophosphamide 200 mg/kg before receiving the thawed cells. There were no immediate side effects. Hematological reconstitution occurred promptly (granulocytes greater than 0.5 x 10(9)/L on day 13, platelets greater than 30 x 10(9)/L on day 40), although at day 10 the child experienced acute grade II cortico-sensitive GvHD. Mixed hematopoietic chimerism was observed 2 months later and complete remission lasted for 8 months.

[Counseling for the prevention of HIV infections in pediatric situations]. / Conseils de prévention de l'infection au VIH en situation pédiatrique.

Health care professionals who are not adequately informed may have irrational attitudes when caring for HIV-infected pediatric patients. Prevention of contamination rests on thorough knowledge of high-risk pediatric groups and of potentially contaminating situations. In the delivery room and in intensive care settings, a broad set of measures for preventing contamination by blood is needed, whereas in maternity wards preventive steps are needed only during cord stump care. In pediatric departments, care should be taken to avoid injuries with sharp, blood-soiled instruments and to cover all skin lesions. HIV-infected children should be allowed to participate in group activities if they are healthy enough to do so. If an injury should occur, management includes immediate disinfection, reporting, and serial serologic testing, as well as early AZT therapy.

[Chronic intestinal pseudo-obstruction syndrome in infants and associated anomalies]. / Le syndrome de pseudo-obstruction intestinale chronique du nourrisson et les anomalies associées.

The authors report 2 cases of functional intestinal pseudo-obstruction in infancy associated with intestinal and urologic anomalies. In the first case many intestinal obstructions occurred from the age of 3 weeks and the boy was operated on at 14 months of age. A short small bowel and an intestinal malrotation were found at surgery; the alimentary canal was completely aperistaltic, and an ileostomy was performed. Further operations were carried out, for obstruction due to adhesions, and lastly to perform another ileostomy. An antenatal diagnosis of megacystis had been made with ultrasonography. In the second case, the pseudo-obstruction syndrome occurred at the age of 1 month, due to a volvulus of the small bowel with malrotation. A second operation, one month later because of lack of intestinal transit showed an aperistaltic bowel and a colostomy was performed. The intestinal continuity was set up again at the age of 9 months and a fractional feeding was started. A megacystis was found during urologic investigations. Growth is correct for both children at 3 years of age. A review of the literature allowed to list the most frequent digestive or extradigestive anomalies associated with this syndrome.

[Capnocytophaga septicemia during bone marrow transplantation. Apropos of 2 cases]. / Septicémie à Capnocytophaga au cours de greffe de moelle osseuse. A propos de deux observations.

Two cases of septicemia due to Capnocytophaga in pediatric bone marrow recipients are reported. These gram negative rods, which are part of the normal buccal flora, cause periodontitis and localized or systemic infections, usually in immunocompromised hosts. Severe, prolonged neutropenia and mucitis due to chemotherapy and/or radiotherapy are risk factors for this opportunistic infection. Recovery can be achieved with most of the drug combinations including a beta-lactam used in hematology.

[Rubinstein-Taybi syndrome in 4 cases]. / Illustration du syndrome de Rubinstein-Taybi par quatre observations.

The authors report on 4 cases of Rubinstein-Taybi syndrome. The specific features of this clinical entity of unknown aetiology, are emphasized: mental retardation, characteristic faecies, broad thumbs and large toes; short stature and cryptorchidism are often associated.

[Infections and bone marrow autograft carried out for leukemias in children. Apropos of 47 cases]. / Infections et autogreffes de moelle osseuse réalisées pour leucémies chez l'enfant. A propos de 47 observations.

This study included 44 children undergoing autologous marrow transplantation for leukemia between August 1979 and June 1987. Three of them received a second transplant. In the phase of neutropenia, 38 children presented with fever. Nineteen septicemia occurred (13 Gram positive cocci, 6 Gram negative bacteria), and 2 interstitial pneumonitis were observed. All children with documented infection or a fever of unknown origin recovered after treatment, except 3, who died from infection. The latest antimicrobial therapy used was a combination of an aminoglycoside and a third generation cephalosporin. When necessary, vancomycin or amphotericin B were added. After engraftment (granulocyte count greater than 0.5 X 10(9)/l) 14 septicemia (which recovered) and 10 herpes zoster infections were observed. Only one patient died of infection (herpes zoster with encephalitis).

[Neurologic effects of acyclovir after an allogenic marrow graft]. / Effets neurologiques de l'aciclovir après greffe de moelle allogénique.

On the 4th day of acyclovir treatment for Herpes simplex pneumonia, a 28 month-old girl who had received allogenic marrow transplant for stage IV neuroblastoma presented with severe neurologic disorders including coma and choreic movements. These symptoms disappeared 9 days after acyclovir was stopped. The disturbance in acyclovir kinetics because of acute renal failure and/or a cerebral cortex atrophy might explain the poor neurologic tolerance of acyclovir. This reversible neurologic involvement on a prone patient should be known as a differential diagnosis of Herpes simplex encephalitis.