GNAO1: un nuevo gen a considerar en la distonía temprana de la infancia / GNAO1: a new gene to consider on early-onset childhood dystonia

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Anatomical and physiological basis of continuous spike-wave of sleep syndrome after early thalamic lesions.

OBJECTIVE: Early neonatal thalamic lesions account for about 14% of continuous spike-wave of sleep (CSWS) syndrome, representing the most common etiology in this epileptic encephalopathy in children, and promise useful insights into the pathophysiology of the disease. METHODS: We describe nine patients with unilateral neonatal thalamic lesions which progressed to CSWS. Longitudinal whole-night and high-density electroencephalograms (EEGs) were performed, as well as detailed imaging and clinical evaluation. Visual evoked potentials were used to probe cortical excitability. RESULTS: Thalamic volume loss ranged from 19% to 94%, predominantly on medial and dorsal nuclei and sparing the ventral thalamus. Lesions produced white matter loss and ventricle enlargement on the same hemisphere, which in four patients was associated with selective loss of thalamic-cortical fibers. Cortical thickness quantification failed to reveal hemispheric asymmetries. Impact on EEG rhythms was mild, with a volume-loss-related decrease in alpha power and preservation of sleep spindles. The sleep continuous spiking was lateralized to the hemisphere with the lesion. Visual cortex stimulation in five patients with posterior cortex spiking revealed an abnormal frequency-dependent excitability at 10-20Hz on the side of the lesion. SIGNIFICANCE: Unilateral selective thalamic-cortical disconnection is a common feature in our patients and is associated with both a focal pattern of CSWS and a pathological type of frequency-dependent excitability (peak: 10-20Hz). We propose that this excitability represents an abnormal synaptic plasticity previously described as the augmenting response. This synaptic plasticity has been described as absent in the corticocortical interactions in healthy experimental animals, emerging after ablation of the thalamus and producing a frequency-dependent potentiation with a peak at 10-20Hz. Because this response is potentiated by sleep states of reduced brainstem activation and by appropriate stimulating rhythms, such as sleep spindles, the simultaneous occurrence of these two factors in nonrapid-eye-movement sleep is proposed as an explanation for CSWS in our patients.

Identification of novel genetic causes of Rett syndrome-like phenotypes.

BACKGROUND: The aim of this work was to identify new genetic causes of Rett-like phenotypes using array comparative genomic hybridisation and a whole exome sequencing approach. METHODS AND RESULTS: We studied a cohort of 19 Portuguese patients (16 girls, 3 boys) with a clinical presentation significantly overlapping Rett syndrome (RTT). Genetic analysis included filtering of the single nucleotide variants and indels with preference for de novo, homozygous/compound heterozygous, or maternally inherited X linked variants. Examination by MRI and muscle biopsies was also performed. Pathogenic genomic imbalances were found in two patients (10.5%): an 18q21.2 deletion encompassing four exons of the TCF4 gene and a mosaic UPD of chromosome 3. Variants in genes previously implicated in neurodevelopmental disorders (NDD) were identified in six patients (32%): de novo variants in EEF1A2, STXBP1 and ZNF238 were found in three patients, maternally inherited X linked variants in SLC35A2, ZFX and SHROOM4 were detected in two male patients and one homozygous variant in EIF2B2 was detected in one patient. Variants were also detected in five novel NDD candidate genes (26%): we identified de novo variants in the RHOBTB2, SMARCA1 and GABBR2 genes; a homozygous variant in EIF4G1; compound heterozygous variant in HTT. CONCLUSIONS: Network analysis reveals that these genes interact by means of protein interactions with each other and with the known RTT genes. These findings expand the phenotypical spectrum of previously known NDD genes to encompass RTT-like clinical presentations and identify new candidate genes for RTT-like phenotypes.

Who needs surgery for pediatric myelomeningocele? A retrospective study and literature review.

INTRODUCTION: Children with myelomeningocele (MMC) are usually subjected to multiple surgeries. However, the number and type of surgeries are not the same in every patient with MMC over time. This report summarizes the surgical interventions in a cohort of several ages. MATERIALS AND METHODS: Data on all of the patients with MMC, aged from 1 year and 10 months to 21 years and 11 months, were retrospectively reviewed at the Dona Estefânia Hospital in Lisbon, Portugal. Data were collected by chart review and individual interviews. The factors analyzed were demographics, ambulatory status, neurological level of involvement, shunt status, Arnold-Chiari malformation type II, surgical history, and occurrence of fracture. The surgical interventions were categorized as neurosurgical, orthopedic, urinary, ulcer repair and others. RESULTS: A total of 84 alive were eligible and enrolled. The average age was 14 years and six months. A total of 59 patients received shunts (all but one ventriculoperitoneal). In the study group, the 84 patients required 663 surgeries. Neurosurgical interventions were the most frequent surgical procedure and predominated during the first 2 years of life. Surgical interventions related to shunts were the most common neurosurgical interventions. Orthopedic surgeries were more frequent in the age group 6-12 years. Urological surgeries were done mainly after 6 years of age. Surgical repair of pressure ulcers was more common after 12 years of age. CONCLUSIONS: Our study brings to light the complexity of this condition, with multiple surgeries among patients with MMC.

Atypical phenotype in two patients with LAMA2 mutations.

Congenital muscular dystrophy type 1A is caused by mutations in the LAMA2 gene, which encodes the α2-chain of laminin. We report two patients with partial laminin-α2 deficiency and atypical phenotypes, one with almost exclusive central nervous system involvement (cognitive impairment and refractory epilepsy) and the second with marked cardiac dysfunction, rigid spine syndrome and limb-girdle weakness. Patients underwent clinical, histopathological, imaging and genetic studies. Both cases have two heterozygous LAMA2 variants sharing a potentially pathogenic missense mutation c.2461A>C (p.Thr821Pro) located in exon 18. Brain MRI was instrumental for the diagnosis, since muscular examination and motor achievements were normal in the first patient and there was a severe cardiac involvement in the second. The clinical phenotype of the patients is markedly different which could in part be explained by the different combination of mutations types (two missense versus a missense and a truncating mutation).

Osteoporosis in paediatric patients with spina bifida.

UNLABELLED: The prevalence and morbidity associated with osteoporosis and fractures in patients with spina bifida (SB) highlight the importance of osteoporosis prevention and treatment in early childhood; however, the issue has received little attention. The method for the selection of appropriate patients for drug treatment has not been clarified. OBJECTIVE: To review the literature concerning fracture risks and low bone density in paediatric patients with SB. We looked for studies describing state-of-the-art treatments and for prevention of secondary osteoporosis. METHODS: Articles were identified through a search in the electronic database (PUBMED) supplemented with reviews of the reference lists of selected papers. The main outcome measures were incidence of fractures and risk factors for fracture, an association between bone mineral density (BMD) and occurrence of fracture, risk factors of low BMD, and effects of pharmacological and non-pharmacological treatments on BMD and on the incidence of fractures. We considered as a secondary outcome the occurrence of fractures in relation to the mechanism of injury. RESULTS: Results indicated that patients with SB are at increased risk for fractures and low BMD. Risk factors that may predispose patients to fractures include higher levels of neurological involvement, non-ambulatory status, physical inactivity, hypercalciuria, higher body fat levels, contractures, and a previous spontaneous fracture. Limitations were observed in the number and quality of studies concerning osteoporosis prevention and treatment in paediatric patients with SB. The safety and efficiency of drugs to treat osteoporosis in adults have not been evaluated satisfactorily in children with SB.

Epilepsy and cerebral palsy: characteristics and trends in children born in 1976-1998.

BACKGROUND: Although epilepsy is common in children with cerebral palsy (CP), no data exists on prevalence rates of CP and epilepsy. AIMS: To describe epilepsy in children with CP, and to examine the association between epilepsy and neonatal characteristics, associated impairments and CP subtypes. METHODS: Data on 9654 children with CP born between 1976 and 1998 and registered in 17 European registers belonging to the SCPE network (Surveillance of Cerebral Palsy in Europe) were analyzed. RESULTS: A total of 3424 (35%) children had a history of epilepsy. Among them, seventy-two percent were on medication at time of registration. Epilepsy was more frequent in children with a dyskinetic or bilateral spastic type and with other associated impairments. The prevalence of CP with epilepsy was 0.69 (99% CI, 0.66-0.72) per 1000 live births and followed a quadratic trend with an increase from 1976 to 1983 and a decrease afterwards. Neonatal characteristics independently associated with epilepsy were the presence of a brain malformation or a syndrome, a term or moderately preterm birth compared with a very premature birth, and signs of perinatal distress including neonatal seizures, neonatal ventilation and admission to a neonatal care unit. CONCLUSIONS: The prevalence of CP with epilepsy followed a quadratic trend in 1976-1998 and mirrored that of the prevalence of CP during this period. The observed relationship between epilepsy and associated impairments was expected; however it requires longitudinal studies to be better understood.

Disección carotídea en un niño con neumonía y empiema / Carotid dissection in a child with pneumonia and empyema

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Rett syndrome with and without detected MECP2 mutations: an attempt to redefine phenotypes.

BACKGROUND: The diagnosis of Rett syndrome (RTT) is based on a set of clinical criteria, irrespective of mutation status. The aims of this study were (1) to define the clinical differences existing between patients with Rett syndrome with (Group I) and without a MECP2 mutation (Group II), and (2) to characterize the phenotypes associated with the more common MECP2 mutations. PATIENTS AND METHODS: We analyzed 87 patients fulfilling the clinical criteria for RTT. All were observed and videotaped by the same paediatric neurologist. Seven common mutations were considered separately, and associated clinical features analysed. RESULTS: Comparing Group I and II, we found differences concerning psychomotor development prior to onset, acquisition of propositive manipulation and language, and evolving autistic traits. Based on age at observation, we found differences in eye pointing, microcephaly, growth, number of stereotypies, rigidity, ataxia and ataxic-rigid gait, and severity score. Patients with truncating differed from those with missense mutations regarding acquisition of propositive words and independent gait, before the beginning of the disease, and microcephaly, growth, foot length, dystonia, rigidity and severity score, at the time of observation. Patients with the R168X mutation had a more severe phenotype, whereas those with R133C showed a less severe one. Patients with R294X had a hyperactive behaviour, and those with T158M seemed to be particularly ataxic and rigid. CONCLUSION: A clear regressive period (with loss of prehension and language, deceleration of growth) and the presence of more than three different stereotypies, rigidity and ataxic-rigid gait seemed to be very helpful in differentiating Group I from Group II.

N170 asymmetry as an index of inferior occipital dysfunction in patients with symptomatic occipital lobe epilepsy.

OBJECTIVE: Localizing epileptic foci in posterior brain epilepsy remains a difficult exercise in surgery for epilepsy evaluation. Neither clinical manifestations, neurological, EEG nor neuropsychological evaluations provide strong information about the area of onset, and fast spread of paroxysms often produces mixed features of occipital, temporal and parietal symptoms. We investigated the usefulness of the N170 event-related potential to map epileptic activity in these patients. METHODS: A group of seven patients with symptomatic posterior cortex epilepsy were submitted to a high-resolution EEG (78 electrodes), with recordings of interictal spikes and face-evoked N170. Generators of spikes and N170 were localized by source analysis. Range of normal N170 asymmetry was determined in 30 healthy volunteers. RESULTS: In 3 out of 7 patients the N170 inter-hemispheric asymmetry was outside control values. Those were the patients whose spike sources were nearest (within 3cm) to the fusiform gyrus, while foci further away did not affect the N170 ratio. CONCLUSIONS: N170 event-related potential provides useful information about focal cortical dysfunction produced by epileptic foci located in the close neighborhood of the fusiform gyrus, but are unaffected by foci further away. SIGNIFICANCE: The N170 evoked by faces can improve the epileptic foci localization in posterior brain epilepsy.

Síndrome de Guillain-Barré tras varicela / Guillain-Barré syndrome following varicella

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Fractures in children and adolescents with spina bifida: the experience of a Portuguese tertiary-care hospital.

AIM: The morbidity associated with osteoporosis and fractures in children and adolescents with spina bifida highlights the importance of osteoporosis prevention and treatment in these patients. The aim of this study was to examine the occurrence and pattern of bone fractures in paediatric patients with spina bifida. METHOD: We reviewed the data of all paediatric patients with spina bifida who were treated in our centre between 1999 and 2008. RESULTS: One hundred and thirteen patients were included in the study (63 females, 50 males; mean age 10y 8mo, SD 4y 10mo, range 6mo-18y). The motor levels were thoracic in six, upper lumbar in 22, lower lumbar in 42, and sacral in 43 patients. Of the 113 patients, 58 (51.3%) had shunted hydrocephalus. Thirty-six (31.8%) were non-ambulatory (wheelchair-dependent [unable to self-propel wheelchair] n=3, wheelchair-independent [able to self-propel wheelchair] n=33), 13 were partial ambulators, 61 were full ambulators, and three were below the age of walking. Forty-five fractures were reported in 25 patients. The distal femur was the most common fracture site. Statistical analyses showed that patients with higher levels of involvement and in wheelchairs had a significantly increased risk of having a [corrected] fracture (p<0.001). Spontaneous fractures were the principal mechanism of injury, and an association was identified between fracture mechanism, type of ambulation, and lesion level: the fractures of patients with higher levels of motor functioning and those in wheelchairs were mainly pathological (p=0.01). We identified an association between risk of a second fracture, higher motor level lesion, and non-ambulation. There was an increased risk of having a second fracture after a previous spontaneous fracture (p=0.004). INTERPRETATION: Data in this study indicate a high prevalence of fractures in patients with spina bifida.

Mutations in the MECP2 gene are not a major cause of Rett syndrome-like or related neurodevelopmental phenotype in male patients.

Rett syndrome is a genetic neurodevelopmental disorder that affects mainly girls, but mutations in the causative MECP2 gene have also been identified in boys with classic Rett syndrome and Rett syndrome-like phenotypes. We have studied a group of 28 boys with a neurodevelopmental disorder, 13 of which with a Rett syndrome-like phenotype; the patients had diverse clinical presentations that included perturbations of the autistic spectrum, microcephaly, mental retardation, manual stereotypies, and epilepsy. We analyzed the complete coding region of the MECP2 gene, including the detection of large rearrangements, and we did not detect any pathogenic mutations in the MECP2 gene in these patients, in whom the genetic basis of disease remained unidentified. Thus, additional genes should be screened in this group of patients.

Origin of frontal lobe spikes in the early onset benign occipital lobe epilepsy (Panayiotopoulos syndrome).

OBJECTIVE: Early onset benign occipital lobe epilepsy (Panayiotopoulos syndrome [PS]) is a common and easily recognizable epilepsy. Interictal EEG spike activity is often multifocal but most frequently localized in the occipital lobes. The origin and clinical significance of the extra-occipital spikes remain poorly understood. METHODS: Three patients with the PS and interictal EEG spikes with frontal lobe topography were studied using high-resolution EEG. Independent component analysis (ICA) was used to decompose the spikes in components with distinct temporal dynamics. The components were mapped in the scalp with a spline-laplacian algorithm. RESULTS: The change in scalp potential topography from spike onset to peak, suggests the contribution of several intracranial generators, with different kinetics of activation and significant overlap. ICA was able to separate the major contributors to frontal spikes and consistently revealed an early activating group of components over the occipital areas in all the patients. The local origin of these early potentials was established by the spline-laplacian montage. CONCLUSIONS: Frontal spikes in PS are consistently associated with early and unilateral occipital lobe activation, suggesting a postero-anterior spike propagation. SIGNIFICANCE: Frontal spikes in the PS represent a secondary activation triggered by occipital interictal discharges and do not represent an independent focus.

Movement disorders in Rett syndrome: an analysis of 60 patients with detected MECP2 mutation and correlation with mutation type.

Rett syndrome (RS) is one of the best human models to study movement disorders. Patients evolve from a hyperkinetic to a hypokinetic state, and a large series of abnormal movements may be observed along their lives such as stereotypies, tremor, chorea, myoclonus, ataxia, dystonia, and rigidity. The aim of this work was to analyze movement disorders in RS patients with a detected MECP2 mutation, as well as their correlation with genotype, in a clinically and genetically well-characterized sample of patients, and thus contribute to redefine the clinical profile of this disease. In this study, we included 60 patients with detected MECP2 mutations. These were categorized and grouped for analysis, according to (1) type of change (missense or truncating, including nonsense and frameshift but also large deletions) and (2) location of the mutation. Differences were found concerning the frequency of independent gait, dystonia, type of tremor, and global score severity when comparing the group of patients with missense and truncating mutations. We also found differences in the presence, distribution, severity, or type of movement disorders in the two groups of patients according to the median duration of the disease (less than 60 months; 60 months or more). We conclude that movement disorders seem to reflect the severity and rate of progression of Rett disorder, patients with truncating mutations presenting a higher rate and more severe dystonia and rigid-akinetic syndrome, when comparing groups with similar time of disease evolution.

Analysis of the dynamics and origin of epileptic activity in patients with tuberous sclerosis evaluated for surgery of epilepsy.

OBJECTIVE: The epilepsies associated with the tuberous sclerosis complex (TSC) are very often refractory to medical therapy. Surgery for epilepsy is an effective alternative when the critical link between the localization of seizure onset in the scalp and a particular cortical tuber can be established. In this study we perform analysis of ictal and interictal EEG to improve such link. METHODS: The ictal and interictal recordings of four patients with TSC undergoing surgery for epilepsy were submitted to independent component analysis (ICA), followed by source analysis, using the sLORETA algorithm. The localizations obtained for the ictal EEG and for the average interictal spikes were compared. RESULTS: The ICA of ictal EEG produced consistent results in different events, and there was good agreement with the tubers that were successfully removed in three of the four patients (one patient refused surgery). In some patients there was a large discrepancy between the localization of ictal and interictal sources. The interictal activity produced more widespread source localizations. CONCLUSIONS: The use of ICA of ictal EEG followed by the use of source analysis methods in four cases of epilepsy and TSC was able to localize the epileptic generators very near the lesions successfully removed in surgery for epilepsy. SIGNIFICANCE: The ICA of ictal EEG events may be a useful add-on to the tools used to establish the connection between epileptic scalp activity and the cortical tubers originating it, in patients with TSC considered for surgery of epilepsy.

Idiopathic epilepsies with seizures precipitated by fever and SCN1A abnormalities.

PURPOSE: SCN1A is the most clinically relevant epilepsy gene, most mutations lead to severe myoclonic epilepsy of infancy (SMEI) and generalized epilepsy with febrile seizures plus (GEFS+). We studied 132 patients with epilepsy syndromes with seizures precipitated by fever, and performed phenotype-genotype correlations with SCN1A alterations. METHODS: We included patients with SMEI including borderline SMEI (SMEB), GEFS+, febrile seizures (FS), or other seizure types precipitated by fever. We performed a clinical and genetic study focusing on SCN1A, using dHPLC, gene sequencing, and MLPA to detect genomic deletions/duplications on SMEI/SMEB patients. RESULTS: We classified patients as: SMEI/SMEB = 55; GEFS+= 26; and other phenotypes = 51. SCN1A analysis by dHPLC/sequencing revealed 40 mutations in 37 SMEI/SMEB (67%) and 3 GEFS+ (11.5%) probands. MLPA showed genomic deletions in 2 of 18 SMEI/SMEB. Most mutations were de novo (82%). SMEB patients carrying mutations (8) were more likely to have missense mutations (62.5%), conversely SMEI patients (31) had more truncating, splice site or genomic alterations (64.5%). SMEI/SMEB with truncating, splice site or genomic alterations had a significantly earlier age of onset of FS compared to those with missense mutations and without mutations (p = 0.00007, ANOVA test). None of the remaining patients with seizures precipitated by fever carried SCN1A mutations. CONCLUSION: We obtained a frequency of 71%SCN1A abnormalities in SMEI/SMEB and of 11.5% in GEFS+ probands. MLPA complements DNA sequencing of SCN1A increasing the mutation detection rate. SMEI/SMEB with truncating, splice site or genomic alterations had a significantly earlier age of onset of FS. This study confirms the high sensitivity of SCN1A for SMEI/SMEB phenotypes.

Analysis of the generators of epileptic activity in early-onset childhood benign occipital lobe epilepsy.

OBJECTIVE: The Panayiotopoulos type of idiopathic occipital epilepsy has peculiar and easily recognizable ictal symptoms, which are associated with complex and variable spike activity over the posterior scalp areas. These characteristics of spikes have prevented localization of the particular brain regions originating clinical manifestations. We studied spike activity in this epilepsy to determine their brain generators. METHODS: The EEG of 5 patients (ages 7-9) was recorded, spikes were submitted to blind decomposition in independent components (ICs) and those to source analysis (sLORETA), revealing the spike generators. Coherence analysis evaluated the dynamics of the components. RESULTS: Several ICs were recovered for posterior spikes in contrast to central spikes which originated a single one. Coherence analysis supports a model with epileptic activity originating near lateral occipital area and spreading to cortical temporal or parietal areas. CONCLUSIONS: Posterior spikes demonstrate rapid spread of epileptic activity to nearby lobes, starting in the lateral occipital area. In contrast, central spikes remain localized in the rolandic fissure. SIGNIFICANCE: Rapid spread of posterior epileptic activity in the Panayitopoulos type of occipital lobe epilepsy is responsible for the variable and poorly localized spike EEG. The lateral occipital cortex is the primary generator of the epileptic activity.