Severe phenotypic spectrum of biallelic mutations in PRRT2 gene.

BACKGROUND: Heterozygous dominant mutations of PRRT2 have been associated with various types of paroxysmal neurological manifestations, including benign familial infantile convulsions and paroxysmal kinesigenic dyskinesia. The phenotype associated with biallelic mutations is not well understood as few cases have been reported. METHODS: PRRT2 screening was performed by Sanger sequencing and quantitative multiplex PCR of short fluorescent fragments. A CGH array was used to characterise the size of the deletion at the 16p11.2 locus. RESULTS: Five patients with homozygous or compound heterozygous deleterious PRRT2 gene mutations are described. These patients differ from those with a single mutation by their overall increased severity: (1) the combination of at least three different forms of paroxysmal neurological disorders within the same patient and persistence of paroxysmal attacks; (2) the occurrence of uncommon prolonged episodes of ataxia; and (3) the association of permanent neurological disorders including learning difficulties in four patients and cerebellar atrophy in 2. CONCLUSIONS: Our observations expand the phenotype related to PRRT2 insufficiency, and highlight the complexity of the phenotype associated with biallelic mutations, which represents a severe neurological disease with various paroxysmal disorders and frequent developmental disabilities.

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.

Posterior glucose hypometabolism in Lafora disease: early and late FDG-PET assessment.

Establishing an early diagnosis of Lafora disease (LD) is often challenging. We describe two cases of LD presenting as myoclonus and tonic-clonic seizures, initially suggesting idiopathic generalized epilepsy. The subsequent course of the disease was characterized by drug-resistant myoclonic epilepsy, cognitive decline, and visual symptoms, which oriented the diagnosis toward progressive myoclonic epilepsy and, more specifically, LD. Early in the evolution in the first case, and before histopathologic and genetic confirmation of LD in both cases, [18]Fluorodeoxyglucose positron emission tomography (FDG-PET) revealed posterior hypometabolism, consistent with the well-known posterior impairment in this disease. This suggests that FDG-PET could help to differentiate LD in early stages from other progressive myoclonic epilepsies, but confirmation is required by a longitudinal study of FDG-PET in progressive myoclonic epilepsy.

Novel mutations in EPM2A and NHLRC1 widen the spectrum of Lafora disease.

PURPOSE: Lafora disease (LD) is an autosomal recessive form of progressive myoclonus epilepsy with onset in childhood or adolescence and with fatal outcome caused by mutations in two genes: EPM2A and NHLRC1. The aim of this study was to characterize the mutation spectrum in a cohort of unrelated patients with presumed LD. METHODS: Sequencing of the two genes and search for large rearrangements was performed in 46 unrelated patients with suspected LD, 33 originating from France and the others from different countries. Patients were classified into two groups according to the clinical presentation. RESULTS: Mutations of various types were found in EPM2A in 10 patients and in NHLRC1 in 4 patients. Mutations were found in 14 (93%) of 15 patients with classical clinical and electroencephalography (EEG) presentation of LD and in no patients with an atypical presentation. Ten mutations were novel, including the first substitution reported in a donor splice site of EPM2A, leading to the deletion of exon 2 at the RNA level. Four large deletions, including two deletions of exon 2 with different sizes and breakpoints, were found in EPM2A, corresponding to 20% of the alleles of this gene. DISCUSSION: We described several novel mutations of EPM2A and NHLRC1 and brought additional data to the genetic epidemiology of LD. This study emphasized the high mutation rate in patients with classical LD as well as the high negativity rate of skin biopsy.

Does preterm birth affect global and configural processing differently?

AIM: We investigated whether preterm birth affects later visuocognitive function and, in particular, whether it affects global and configural perceptual processing differently. METHOD: We compared the performance of 21 healthy preterm children (8 females, 13 males; mean age 7 y 8 mo, SD 8 mo; mean gestational age 29.3 wks, SD 1.9; mean birthweight 1186.5 g, SD 377.2) with that of a matched term comparison group (8 females, 13 males; mean age 7 y 11 mo, SD 1 y 1 mo; mean gestational age >37 wks; mean birthweight >2500 g) in two perceptual tasks pinpointing differences between local and global and between local and configural processing. RESULTS: There was no difference between preterm and term children's global processing, as both groups showed a bias towards global information (preterm: t[1,20]=2.6, p=0.01; comparison group: t[1,20]=3.0, p=0.01). By contrast, no such typical pattern of performance was found for configural processing as, unlike the comparison group (t[1,20]=7.1, p<0.001), preterm children preferentially relied on local rather than on configural information (t[1,20]=-15.4, p<0.001). INTERPRETATION: These findings suggest that preterm birth may have a greater influence on the development of later perceptual skills than originally envisaged. We discuss the results according to the current and dominant view of the visual system.

Effect of desipramine on patients with breathing disorders in RETT syndrome.

Objective: Rett Syndrome (RTT) is a severe neurodevelopmental condition with breathing disorders, affecting around one in 10,000 female births. Desipramine, a noradrenaline reuptake inhibitor, reduced the number of apneas in Mecp2-deficient mice, a model of RTT. We planned a phase 2 trial to test its efficacy and its safety on breathing patterns in 36 girls with RTT. Methods: The trial was a 6-month, multicenter, randomized, double-blind, placebo-controlled study registered with ClinicalTrials.gov, number NCT00990691. Girls diagnosed according to clinical examination and confirmed by genotyping were randomly assigned in a 1:1:1 ratio to receive 2-3 mg/kg Desipramine per day (high Desipramine), 1-2 mg/kg Desipramine per day (low Desipramine), or a placebo. The primary outcome was the change of apnea hypopnea index (AHI), defined by the number of apnea and hypopnea events per hour, assessed at 6 months from baseline. Intention-to-treat analysis was applied. Results: The median change in AHI from baseline to 6 months was -31 (IQR: -37 to -11) for the high Desipramine, -17.5 (IQR: -31 to 13) for the low Desipramine, and -13 (IQR:-31 to 0) for the placebo group. We did not find any significant difference in these changes between the groups (P = 0.781). A significant inverse correlation between Desipramine plasma concentration and AHI (r = -0.44; P = 0.0002) was underlined. Interpretation: This first clinical trial of desipramine did not show clinical efficacy. Although required further studies, the significant correlation between Desipramine concentrations and improvement of AHI provided additional and relevant reasons to test the noradrenergic pathway in RTT.

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 approximately 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 approximately 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.

The incidence of Rett syndrome in France.

Since the description of Rett syndrome, only a handful of epidemiologic studies based only on clinical investigation have been reported. Mutations in the MECP2 gene are associated with Rett syndrome and French laboratories have organized a clinical and molecular network to investigate the incidence of Rett syndrome in France including the results of molecular investigations. The present study, based on a large cohort of 424 patients with Rett syndrome, found that the incidence of this disease with a MECP2 mutation varied between 0.43 to 0.71 per 10,000 females. The total population of females aged 4-15 years in November 2004 in France was estimated to be 4,337,627. The data presented here indicate a prevalence of Rett syndrome of 0.558 per 10,000 females aged 4-15 years in France. The incidence of Rett syndrome is in accordance with other European epidemiologic studies based on clinical examination. Given that this is a minimum incidence because complete inventory was not possible, this study of patients with Rett syndrome reinforces the fact that the great majority of patients with Rett syndrome have a MECP2 mutation.

Do children with Williams syndrome fail to process visual configural information?

Configural visual abilities in thirteen children with Williams syndrome (WS) compared to 13 children matched on mental age and 13 children matched on chronological age. Configural abilities were tested through four tasks (1) Silhouette (2) Fragmented (3) Mooney and (4) overlapping figures. In the first three tasks, it was necessary to take into account the global information, as the identification of the figures could not be established through a local analysis. In the fourth task, the global configuration of the display had to be ignored. Configural skills seem appropriate in the WS population. A possible dissociation between perceptual and visuo-constructive configural competences is discussed.

Global and local music perception in children with Williams syndrome.

Musical processing can be decomposed into the appreciation of global and local elements. This global/local dissociation was investigated with the processing of contour-violated and interval-violated melodies. Performance of a group of 16 children with Williams syndrome and a group of 16 control children were compared in a same-different task. Control participants were more accurate in detecting differences in the contour-violated than in the interval-violated condition while Williams syndrome individuals performed equally well in both conditions. This finding suggests that global precedence may occur at an early perceptual stage in normally developing children. In contrast, no such global precedence is observed in the Williams syndrome population. These data are discussed in the context of atypical cognitive profiles of individuals with Williams syndrome.

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.

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.

New onset refractory convulsive status epilepticus associated with serum neuropil auto-antibodies in a school aged child.

We report a case of a child that suffered from a severe new onset status epilepticus a few days after a common viral infection. Despite extensive screening, no bacterial, viral or fungal infection could be found. Using immunohistochemical analysis, we found neuronal auto-antibodies directed against the neuropil, in blood and CSF, associated with CSF oligoclonal banding. Status epilepticus was highly refractory to antiepileptic drugs, but improved few days after Intra-Venous Immunoglobulin Injection (IVIG). The patient developed ongoing temporal lobe epilepsy that was still associated with neuropil auto-antibodies. Therefore, screening for antineuronal antibodies should be helpful to characterize and maybe to handle new onset status epilepticus without any obvious aetiology. Further studies should establish the link between epilepsy and such auto-antibodies.

Transient brain magnetic resonance imaging hyperintensity in basal ganglia and brain stem of epileptic infants treated with vigabatrin.

Vigabatrin is an antiepileptic drug that produces intramyelinic edema in several animal models. This study investigates the effect of vigabatrin on the developing human brain. The authors retrospectively blindly review 34 brain magnetic resonance imaging of 22 epileptic infants (age: 9 +/- 1 months) that received vigabatrin, focusing on the presence of hyperintensity on T2- and diffusion-weighted images. Patients treated with vigabatrin displayed significant magnetic resonance imaging hyperintensity of basal ganglia and brain stem (P < .001, Wilcoxon test). This hyperintensity was transient and maximal 3 to 6 months after the beginning of vigabatrin. Hyperintensity was independent from duration and type of epilepsy, and from the presence or absence of seizures. The authors conclude that vigabatrin treatment is associated with transient hypersignal of the basal ganglia and brain stem in epileptic infants. Such transient hyperintensity is likely to be age-dependent and time-dependent because it has never been observed in adult patients.

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.

Behavioural indexes of callosal functioning in Williams syndrome.

Williams syndrome (WS) is a neurogenetic disorder that stems from a microdeletion on chromosome 7. Recent anatomical studies have found evidence for corpus callosum abnormalities in WS. However, to date, the impact of these structural differences on callosal functionality remains unclear. The aim of the present study was to investigate interhemispheric communication and hemispheric asymmetry in individuals with WS relative to mental age-matched controls. This was assessed using bilateral and unilateral presentations of visual stimuli in a picture-naming task. Results found both groups to exhibit a bilateral field advantage and a left visual advantage on unilateral presentations. However, while a significant performance increase with age was found for controls, no such correlation was found for individuals with WS. Taken together, these findings suggest that despite some evidence for an atypical developmental pathway in WS, both interhemispheric communication and hemispheric asymmetry are functionally intact in this population.

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.

Early brain lesions and face-processing development.

Studies of functional plasticity after pre- or perinatal brain damage can tell us whether the neural substrate normally involved in the development of a given ability is specific and, if so, when it becomes functionally specified and unique. Development of face processing was investigated in 5- to 17-year-old children who had a unilateral brain injury in the pre-, peri-, or postnatal period. In Studies 1 and 2, patients with a posterior injury involving the temporal regions exhibited a face-processing deficit that was independent of their age at test time. Even though differences were observed between the two hemispheres in face processing during infancy as well as in adults in cases of normal development, no clear differences between right and left injury were observed here in face-processing deficit. Poor postlesional face-processing plasticity seems to contrast with results of several studies on speech development after early unilateral injury. If the difference in the time window for postlesional plasticity between these two areas of competency is confirmed, it would suggest that the two kinds of abilities rely on neural cells which are sensitive to different plasticity factors.