Josette Mancini

Mecp2 Deficiency Disrupts Norepinephrine and Respiratory Systems in Mice

Rett syndrome is a severe X-linked neurological disorder in which most patients have mutations in the methyl-CpG binding protein 2 (MECP2) gene and suffer from bioaminergic deficiencies and life-threatening breathing disturbances. We used in vivo plethysmography, in vitro electrophysiology, neuropharmacology, immunohistochemistry, and biochemistry to characterize the consequences of the MECP2 mutation on breathing in wild-type (wt) and Mecp2-deficient (Mecp2-/y) mice. At birth, Mecp2-/y mice showed normal breathing and a normal number of medullary neurons that express tyrosine hydroxylase (TH neurons). At ∼1 month of age, most Mecp2-/y mice showed respiratory cycles of variable duration; meanwhile, their medulla contained a significantly reduced number of TH neurons and norepinephrine (NE) content, even in Mecp2-/y mice that showed a normal breathing pattern. Between 1 and 2 months of age, all unanesthetized Mecp2-/y mice showed breathing disturbances that worsened until fatal respiratory arrest at ∼2 months of age. During their last week of life, Mecp2-/y mice had a slow and erratic breathing pattern with a highly variable cycle period and frequent apneas. In addition, their medulla had a drastically reduced number of TH neurons, NE content, and serotonin (5-HT) content. In vitro experiments using transverse brainstem slices of mice between 2 and 3 weeks of age revealed that the rhythm produced by the isolated respiratory network was irregular in Mecp2-/y mice but could be stabilized with exogenous NE. We hypothesize that breathing disturbances in Mecp2-/y mice, and probably Rett patients, originate in part from a deficiency in noradrenergic and serotonergic modulation of the medullary respiratory network.

Treatment with desipramine improves breathing and survival in a mouse model for Rett syndrome.

Rett syndrome (RS) is a severe X‐linked neurological disorder in which most patients have mutations in the methyl‐CpG binding protein2 (MECP2) gene. No effective treatment exists. We previously showed that the Mecp2‐deficient mice, a mouse model of RS, have highly variable respiratory rhythm and frequent apneas due to reduced norepinephrine (NE) content, and a drastic decrease of tyrosine hydroxylase (TH)‐expressing neurons in the medulla. We showed here that treating these mice with desipramine (DMI), which specifically inhibits NE reuptake, significantly improved their respiratory rhythm during several weeks. In addition, the treatment significantly extended their lifespan. At the cellular level, we showed that the reduced number of TH‐expressing neurons before treatment in the mutant animals was not due to apoptosis. Conversely, we found that DMI treatment increased the number of TH‐expressing neurons in the mutant brainstem to reach wild‐type levels. We showed that this increase was not due to cellular proliferation. We propose that the Mecp2‐deficient TH‐expressing neurons lose their ability to synthesize TH at some point during their postnatal development. Our results suggest that a pharmacological stimulation of the noradrenergic system could be a promising approach for the treatment of the respiratory dysfunction which causes a significant proportion of death in RS patients.

Topiramate: efficacy and tolerability in children according to epilepsy syndromes

To evaluate the efficacy and tolerability of topiramate (TPM) as add-on therapy in children less than 12 years of age with refractory epilepsy, according to epilepsy syndromes, we conducted an open, prospective, pragmatic and multicenter study in France. Efficacy was assessed, especially according to epilepsy syndromes, as well as tolerability. We included 207 children (41 of whom were less than 4 years of age). TPM was effective (responders with >50% decrease in seizure frequency) in 50% of 128 patients with partial epilepsy, and in 44% of 79 patients with generalized epilepsy. In case of generalized epilepsy, responders more frequently had generalized symptomatic epilepsy, severe myoclonic epilepsy and myoclono-astatic epilepsy, whereas response rate was mild in both infantile spasms and Lennox-Gastaut syndrome (LGS). Improvement was well maintained in all patients during the treatment period (median 5.6 months). Seizure frequency/severity increased (worsening) in 13% of patients with partial epilepsy and 17% with generalized epilepsy (particularly in those with infantile spasms), and resulted in withdrawal of TPM for 8%. The most frequently reported adverse events were moderate neurobehavioral and gastrointestinal disorders. Adverse events led to withdrawal of TPM from 13.5% of patients. Children less than 4 years of age had particularly good tolerability. Results confirm that TPM is effective and well tolerated in children under 12 years of age in a broad range of epilepsy syndromes, including refractory partial epilepsy, and symptomatic and myoclonic generalized epilepsy. Use of TPM should be considered in children under 4 years of age, and slow and progressive titration is important.

Age-dependent Mendelian predisposition to herpes simplex virus type 1 encephalitis in childhood.

OBJECTIVE To test the hypothesis that predisposition to childhood herpes simplex virus (HSV) type 1 encephalitis (HSE) may be determined in part by human genetic factors. STUDY DESIGN A genetic epidemiologic survey of childhood HSE (onset at age 3 months to 15 years) over a 20-year period (1985-2004) was conducted throughout France (comprising 29 university hospital neuropediatric centers). A total of 85 children fulfilled the diagnostic criteria for inclusion. Family and personal histories were obtained by face-to-face interview for 51 patients. RESULTS No familial cases of HSE were identified in our survey; however, a high proportion (20%) of the children interviewed had a relevant family history: parental consanguinity (12% of patients), early-onset herpetic keratitis in a first-degree relative (6%), or both (2%). The narrow window of high susceptibility to HSE before age 3 years (62% of patients) further indicates that predisposition to HSE is tightly age-dependent. CONCLUSIONS This survey suggests that childhood HSE, although sporadic, may result from Mendelian predisposition (from autosomal recessive susceptibility in particular), at least in some children. There likely is incomplete penetrance, however, which may reflect, at least in part, the impact of age at the time of HSV-1 infection.

Angelman syndrome resulting from UBE3A mutations in 14 patients from eight families: clinical manifestations and genetic counselling

Angelman syndrome (AS) is a neurological disorder with a heterogeneous genetic aetiology. It most frequently results from a de novo interstitial deletion in the 15q11-q13 region, but in a few cases it is caused by paternal uniparental disomy (UPD) or an imprinting mutation. The remaining 20 to 30% of AS patients exhibit biparental inheritance and a normal pattern of allelic methylation in the 15q11-q13 region. In this latter group, mutations in the UBE3A gene have recently been shown to be a cause of AS. Here we describe the phenotypic expression in 14 AS cases involving eight UBE3A mutations. These comprise 11 familial cases from five families and three sporadic cases. Subtle differences from the typical phenotype of AS were found. Consistent manifestations were psychomotor delay, a happy disposition, a hyperexcitable personality, EEG abnormalities, and mental retardation with severe speech impairment. The other main manifestations of AS, ataxia, epilepsy, and microcephaly, were either milder or absent in various combinations among the patients. In addition, myoclonus of cortical origin was frequently observed with severe fits inducing myoclonic seizures. The majority of the patients were overweight. This study showed that ataxia, myoclonus, EEG abnormalities, speech impairment, characteristic behavioural phenotype, and abnormal head circumference are attributable to a deficiency in the maternally inherited UBE3A allele. Furthermore, analysis of mutation transmission showed an unexpectedly high rate of somatic mosaicism in normal carriers. These data have important consequences for genetic counselling.

Surgical strategies and seizure control in pediatric patients with dysembryoplastic neuroepithelial tumors: a single-institution experience.

OBJECTIVES Dysembryoplastic neuroepithelial tumors (DNTs) are commonly associated with medically resistant epilepsy that usually starts in childhood. Presurgical workup and surgical strategies remain controversial. The authors present a study of long-term seizure outcome after noninvasive presurgical investigations and different surgical strategies were used in a series of pediatric patients. METHODS Twenty-four children who underwent operations at a single center between 1986 and 2006 were eligible for this retrospective study. The authors reviewed medical records including sex, age at seizure onset, age at surgery, seizure type and pharmacoresistance, lesion location, extent and complications of resection, histopathological findings, prescription of seizure and antiepileptic drugs, outcome, and tumor recurrence. RESULTS At the last follow-up examination (range 1-16 years after initial treatment, mean 6.7 years) 20 children (83.3%) were seizure free. The authors did not find the rundown phenomenon in any of the patients. Complete antiepileptic drug withdrawal was achieved in 12 children (50%). In 4 of 15 children with temporal DNTs, the lesionectomy alone failed to control seizures. These results could be explained by the wider epileptogenic zone. The only significant predictor for favorable seizure outcome was an absence of preoperative generalized seizures. CONCLUSIONS In children with extratemporal DNTs the results suggest that complete lesionectomy alone without invasive presurgical investigations are effective for long-term seizure control. For children with temporal DNTs not invading the amygdalohippocampal complex, extensive presurgical evaluations seem indicated. The absence of preoperative generalized seizures was associated with a better seizure outcome.

ISCHEMIC CEREBROVASCULAR DISEASE IN CHILDREN: RETROSPECTIVE STUDY OF 35 PATIENTS

A 10-year review of a neuropediatric department experience with childhood ischemic cerebrovascular disease identified 35 patients with arterial ischemic stroke. The ability to diagnose stroke in children has improved with the development of imaging techniques in the past few years. Children have a wide array of risk factors for ischemic strokes, since some are acquired and others are congenital. Twenty-eight associated conditions (80%) were found in our patients and we identified 17 specific causes (48.5%) among them. The cause of stroke in children is important to recognize because stroke is likely to recur depending on the etiology. (J Child Neurol 1997;12:193-199).

MRI and localized proton MRS in early infantile form of neuronal ceroid-lipofuscinosis

A patient with early infantile neuronal ceroid-lipofuscinosis was examined by magnetic resonance imaging (MRI) and image-guided localized proton MR spectroscopy of brain using short-stimulated echo times. T2-weighted MRI revealed generalized cerebral atrophy and a reduction in signal intensity in thalamus and striatum associated with the presence of hyperintense white matter. The proton MR spectrum is characterized by an unusual increase of the inositol and taurine signals and by a reduction in the level of N-acetyl-aspartate contrasting with the presence of signals from glutamate-glutamine. The presence of a resonance from N-acetyl-methyl protons of N-acetyl-glucosamine (2.04 ppm) borne by dolichol is discussed.

Neurologic Onset of Behçet's Disease: A Diagnostic Enigma in Childhood

Neuro-Behçets disease, which is uncommonly reported in childhood, encompasses a wide variety of clinical features since any part of the neuraxis may be involved. It carries a serious prognosis and represents a leading cause of death or severe disability. Neuro-Behçets disease may occur in 5%.to 50% of adults with Behçets disease and is usually subsequent to other systemic manifestations. In this report, we express the possibility of a primary neurologic presentation of Behçets disease in childhood with pseudotumor cerebri and meningoencephalitis as exclusive initial features. We focus on diagnostic problems when major features of Behçets disease are missing at the outset. We emphasize the high sensitivity of magnetic resonance imaging to make the diagnosis of cerebral vasculitis or thrombosis with a good reliability to clinical features. (J Child Neurol 1997;12:237—241).

Polymorphisms in the C-terminal domain of MECP2 in mentally handicapped boys: implications for genetic counselling

Numerous recent reports have proposed that mutations in the C-terminal domain of the MECP2 gene could be a frequent cause of mental retardation in males. We have identified two mutations in this particular domain (S359P and E397K) in two boys who were screened for MECP2 mutations in a series of 23 mentally handicapped boys fitting the clinical description of the previously reported cases. A detailed familial study based on three generations shows that the first mutation (S359P) was also inherited by a healthy cousin thus ruling out its involvement in the etiology of the phenotype of this patient. The second mutation (E397K) was also found in normal individuals. These findings clearly call for a careful consideration of the pathogenicity of the MECP2 mutations identified in sporadic male cases before genetic counselling or prenatal diagnosis is proposed to the corresponding families.