The gene disrupted in Marinesco-Sjögren syndrome encodes SIL1, an HSPA5 cochaperone.

We identified the gene underlying Marinesco-Sjögren syndrome, which is characterized by cerebellar ataxia, progressive myopathy and cataracts. We identified four disease-associated, predicted loss-of-function mutations in SIL1, which encodes a nucleotide exchange factor for the heat-shock protein 70 (HSP70) chaperone HSPA5. These data, together with the similar spatial and temporal patterns of tissue expression of Sil1 and Hspa5, suggest that disturbed SIL1-HSPA5 interaction and protein folding is the primary pathology in Marinesco-Sjögren syndrome.

Rare copy number variants are an important cause of epileptic encephalopathies.

OBJECTIVE: Rare copy number variants (CNVs)--deletions and duplications--have recently been established as important risk factors for both generalized and focal epilepsies. A systematic assessment of the role of CNVs in epileptic encephalopathies, the most devastating and often etiologically obscure group of epilepsies, has not been performed. METHODS: We evaluated 315 patients with epileptic encephalopathies characterized by epilepsy and progressive cognitive impairment for rare CNVs using a high-density, exon-focused, whole-genome oligonucleotide array. RESULTS: We found that 25 of 315 (7.9%) of our patients carried rare CNVs that may contribute to their phenotype, with at least one-half being clearly or likely pathogenic. We identified 2 patients with overlapping deletions at 7q21 and 2 patients with identical duplications of 16p11.2. In our cohort, large deletions were enriched in affected individuals compared to controls, and 4 patients harbored 2 rare CNVs. We screened 2 novel candidate genes found within the rare CNVs in our cohort but found no mutations in our patients with epileptic encephalopathies. We highlight several additional novel candidate genes located in CNV regions. INTERPRETATION: Our data highlight the significance of rare CNVs in the epileptic encephalopathies, and we suggest that CNV analysis should be considered in the genetic evaluation of these patients. Our findings also highlight novel candidate genes for further study.

Decrease in propagation of interictal epileptiform activity after introduction of levetiracetam visualized with electric source imaging.

Different neuroimaging techniques (fMRI, spectroscopy, PET) are being used to evaluate candidate drugs in pharmacological development. In patients with epilepsy fast propagation of the epileptiform activity between different brain areas occurs. Electric Source Imaging (ESI), in contrast to the aforementioned techniques, has a millisecond time resolution, allowing visualization of this fast propagation. The purpose of the current project was to use ESI to investigate whether introduction of an antiepileptic drug (levetiracetam, LEV) would change the propagation patterns of the interictal epileptiform activity. Thirty patients with epilepsy were subject to an EEG recording before (pre-LEV) and after (in-LEV) introduction of LEV. Interictal spikes with similar topographic distribution were averaged within each subject, and a distributed source model was used to localize the EEG sources of the epileptiform activity. The temporal development of the activity within 20 regions of interest (ROIs) was determined, and source propagation between different regions was compared between the pre-LEV and in-LEV recordings. Patients with epileptic seizures showed propagation in 22/24 identified spike types in the pre-LEV recordings. In the in-LEV recordings only 7/15 spike types showed propagation, and six of these seven propagating spikes were recorded in patients with poor effect of treatment. Also in patients without seizures LEV tended to suppress propagation. We conclude that the observed suppression of source propagation can be considered as an indicator of effective antiepileptic treatment. ESI might thus become a useful tool in the early clinical evaluation of new candidate drugs in pharmacological development.

Do sleep-deprived EEG recordings reflect spike index as found in full-night EEG recordings?

The sleep EEGs of many children with neurodevelopmental disorders reveal epileptiform activity. The aim of this study was to compare spike index (SI) in full-night recordings with SI in sleep-deprived EEGs in the morning; EEGs were obtained over 24 hours using ambulatory equipment. Sixteen children between the ages of 7 and 12 years were included in the study. They had to wake up at 3:00 AM and go to sleep again at 7:30 AM. Epileptiform activity was quantified, and SIs of full-night and morning recordings were compared. Two patients did not fall asleep. In one recording there was a technical problem that made calculations impossible. SIs calculated from EEGs obtained during a short nap in the morning were comparable to those calculated from full-night recordings. There seems to be a higher failure rate during morning recordings because of patients not falling asleep.

Duchenne muscular dystrophy and idiopathic hyperCKemia in the same family.

Familial hyperCKemia is a rare condition, and a combination with Duchenne muscular dystrophy (DMD) is extremely rare. A boy showed muscle weakness from the age of 10 months and presented typical signs of DMD at the age of 18 months. The diagnosis was supported by markedly elevated serum creatine kinase (CK) value as well as by neurophysiological and muscle biopsy findings at the age of 23 months. The diagnosis was confirmed by identification of a stop codon in exon 43 (p.2095Arg>X) of the dystrophin gene. Interestingly, the father and his near relatives had increased serum CK values without any clinical symptoms or signs, nor a defect in caveolin-3 gene. We suggest that the occurrence of familial hyperCKemia may have triggered the early onset of symptoms in our patient.

Linkage and association analysis of CACNG3 in childhood absence epilepsy.

Childhood absence epilepsy (CAE) is an idiopathic generalised epilepsy characterised by absence seizures manifested by transitory loss of awareness with 2.5-4 Hz spike-wave complexes on ictal EEG. A genetic component to aetiology is established but the mechanism of inheritance and the genes involved are not fully defined. Available evidence suggests that genes encoding brain expressed voltage-gated calcium channels, including CACNG3 on chromosome 16p12-p13.1, may represent susceptibility loci for CAE. The aim of this work was to further evaluate CACNG3 as a susceptibility locus by linkage and association analysis. Assuming locus heterogeneity, a significant HLOD score (HLOD = 3.54, alpha = 0.62) was obtained for markers encompassing CACNG3 in 65 nuclear families with a proband with CAE. The maximum non-parametric linkage score was 2.87 (P < 0.002). Re-sequencing of the coding exons in 59 patients did not identify any putative causal variants. A linkage disequilibrium (LD) map of CACNG3 was constructed using 23 single nucleotide polymorphisms (SNPs). Transmission disequilibrium was sought using individual SNPs and SNP-based haplotypes with the pedigree disequilibrium test in 217 CAE trios and the 65 nuclear pedigrees. Evidence for transmission disequilibrium (P < or = 0.01) was found for SNPs within a approximately 35 kb region of high LD encompassing the 5'UTR, exon 1 and part of intron 1 of CACNG3. Re-sequencing of this interval was undertaken in 24 affected individuals. Seventy-two variants were identified: 45 upstream; two 5'UTR; and 25 intronic SNPs. No coding sequence variants were identified, although four variants are predicted to affect exonic splicing. This evidence supports CACNG3 as a susceptibility locus in a subset of CAE patients.

Linkage and mutational analysis of CLCN2 in childhood absence epilepsy.

In order to assess the chloride channel gene CLCN2 as a candidate susceptibility gene for childhood absence epilepsy, parametric and non-parametric linkage analysis was performed in 65 nuclear pedigrees. This provided suggestive evidence for linkage with heterogeneity: NPL score=2.3, p<0.009; HLOD=1.5, alpha=0.44. Mutational analysis of the entire genomic sequence of CLCN2 was performed in 24 unrelated patients from pedigrees consistent with linkage, identifying 45 sequence variants including the known non-synonymous polymorphism rs2228292 (G2154C, Glu718Asp) and a novel variant IVS4+12G>A. Intra-familial association analysis using the pedigrees and a further 308 parent-child trios showed suggestive evidence for transmission disequilibrium of the G2154C minor allele: AVE-PDT chi(1)2 = 5.17, p<0.03. Case-control analysis provided evidence for a protective effect of the IVS4+12G>A minor allele: chi(1)2 = 7.27, p<0.008. The 65 nuclear pedigrees were screened for three previously identified mutations shown to segregate with a variety of idiopathic generalised epilepsy phenotypes (597insG, IVS2-14del11 and G2144A) but none were found. We conclude that CLCN2 may be a susceptibility locus in a subset of cases of childhood absence epilepsy.

Evaluation of CACNA1H in European patients with childhood absence epilepsy.

CACNA1H was evaluated in a resource of Caucasian European patients with childhood absence epilepsy by linkage analysis and typing of sequence variants previously identified in Chinese patients. Linkage analysis of 44 pedigrees provided no evidence for a locus in the CACNA1H region and none of the Chinese variants were found in 220 unrelated patients.

A population based study of epilepsy in children from a Swedish county.

BACKGROUND: Epidemiological studies of childhood epilepsy are of importance to compare incidence and prevalence rates, age distribution, inheritance, seizure types, epilepsy syndromes and treatment strategies. AIM: To perform an epidemiological study on children with epilepsy in a Swedish county using current ILAE classifications and a recent proposal. METHODS: A population-based study was performed using the hospital data register to select children aged 1 month to 16 years with the diagnosis 'convulsions' or 'epilepsy' recognized between January 1996 and December 2000. Only patients with active epilepsy were included. RESULTS: Two hundred and five children met the study criteria on the prevalence day 31st December, 2000. The total prevalence rate was 3.4/1,000 with a peak prevalence in the age group 8-11 years. The incidence year 2000 was 40/100,000. Additional neuroimpairments were registered in 47.3%. A majority of the patients, 54.0%, had focal or focal plus secondarily generalized seizures. A named syndrome could be diagnosed in 49.4%. The most common syndrome was rolandic epilepsy occurring in 17.0%. Childhood absence epilepsy occurred in 5.9%. Different disorders associated with epilepsy were found in 31.7%. The most common associated phenomenon was malformation of cortical development. Antiepileptic drug treatment was used in 81.0%, the most common first choice being valproate. CONCLUSIONS: The prevalence and incidence rates in this strictly delineated study are lower than those found in other epidemiological studies. Together with many divergences between reported studies concerning frequencies of different items, the results apparently depend on design, e.g. differences in age groups included, inclusion criteria used, and general methodology.

Headache in schoolchildren: association with other pain, family history and psychosocial factors.

Limited information exist about associations between different headache types and other pains, family history of pain, and psychosocial factors among children from the general population suffering from less severe headache. We interviewed 130 schoolchildren together with a parent to find out whether such factors differ between children with mainly infrequent and moderate migraine or tension-type headache as compared to those without primary headache. Children with headache, especially those with migraine reported other pains and physical symptoms more frequently than children without primary headache. Coherently, parents of children suffering from migraine reported their children to have significantly more somatic symptoms than parents of children without primary headache. In addition, first-degree relatives of children with headache suffered from more migraine, other pains, and physical symptoms compared with first-degree relatives of children without primary headache. Children with migraine visited the school nurse, used medication and were absent from school because of headache more often than those with tension-type headache. Few other differences in psychosocial factors were found between the three groups. Migraine among first-degree relatives and the total sum of physical symptoms in children were the strongest predictors of headache in logistic regression analysis. It is concluded that in schoolchildren with mainly infrequent and moderate headache, pain and physical symptoms cluster within individuals as well as their families, however, psychological and social problems are uncommon.

Oxidative proteome alterations during skeletal muscle ageing.

Sarcopenia corresponds to the degenerative loss of skeletal muscle mass, quality, and strength associated with ageing and leads to a progressive impairment of mobility and quality of life. However, the cellular and molecular mechanisms involved in this process are not completely understood. A hallmark of cellular and tissular ageing is the accumulation of oxidatively modified (carbonylated) proteins, leading to a decreased quality of the cellular proteome that could directly impact on normal cellular functions. Although increased oxidative stress has been reported during skeletal muscle ageing, the oxidized protein targets, also referred as to the 'oxi-proteome' or 'carbonylome', have not been characterized yet. To better understand the mechanisms by which these damaged proteins build up and potentially affect muscle function, proteins targeted by these modifications have been identified in human rectus abdominis muscle obtained from young and old healthy donors using a bi-dimensional gel electrophoresis-based proteomic approach coupled with immunodetection of carbonylated proteins. Among evidenced protein spots, 17 were found as increased carbonylated in biopsies from old donors comparing to young counterparts. These proteins are involved in key cellular functions such as cellular morphology and transport, muscle contraction and energy metabolism. Importantly, impairment of these pathways has been described in skeletal muscle during ageing. Functional decline of these proteins due to irreversible oxidation may therefore impact directly on the above-mentioned pathways, hence contributing to the generation of the sarcopenic phenotype.

Rolandic epilepsy: a challenge in terminology and classification.

History and present definition of rolandic epilepsy (RE) is briefly presented. In the literature there has often been misconceptions in the description of the syndrome, and the affinity to related conditions and structural abnormalities with rolandic discharges is often unclear. This has resulted in confusion regarding the definition and delineation of RE. A spectrum of RE based on a maturational continuum is possible. Until more is known about the genetic background of RE, a simple classification is proposed: 1) RE "pure" according to the original definition; 2) RE "plus"; 3) RE-related disorders; 4) Structural brain lesions with signs and symptoms as in RE. A summary of results from neuroimaging, neuropsychological and oromotor studies in RE "pure" is presented. Accurate clinical assessment and EEG analysis is essential for a proper classification of RE.

Hypothalamic hamartoma with gelastic seizures in Swedish children and adolescents.

BACKGROUND: Hypothalamic hamartoma with gelastic seizures (HHGS) is an uncommon, often unrecognized, epileptic syndrome with onset of symptoms during childhood. AIM: In order to study the occurrence, clinical symptoms and different investigations of HHGS in Swedish children and adolescents, a nationwide survey was undertaken. Methods. Twelve patients, three females, aged 5 to 19 years were identified and their hospital records reviewed. MRI examinations were reinvestigated. RESULTS: Gelastic seizures were noted before the age of six months in seven patients in at least three as early as the neonatal period. During the course of disease one or more other seizure types developed in 11 patients. Behaviour disorder became subsequently obvious in ten patients, and mental retardation was diagnosed in seven. Precocious puberty was diagnosed in five patients. A total of 46 MRI examinations were performed in 11 patients, revealing hypothalamic tumors, eight of which were drooping with a broad base. Interictal and ictal EEG examinations were pathological in 10 patients with nonspecific results. Nonspecific results were also found on SPECT and PET performed in six and two patients, respectively. Available antiepileptic drugs had little or no effect on gelastic seizures, but some effect on other seizure types. Precocious puberty was treated with a GnRH-agonist. Neurosurgical treatment of the hypothalamic hamartoma, performed in three patients, had a rather good outcome concerning gelastic seizures and behaviour. Vagal nerve stimulation in five patients had no effect. CONCLUSIONS: Review of the literature and experience from this group's own cases confirms that early diagnosis of HHGS is important. Hypothalamic hamartoma should be considered in any child with laughing attacks. MRI investigation is compulsory, and neurosurgery the most important treatment.

Virological and immunological aspects of seizure disorders.

The brain is a symptom-producing organ, and one of the symptoms due to a basic brain dysfunction is epilepsy. The pathophysiologic background is in most epilepsies multifactorial, as different pre-, peri-, and postnatal triggers or environmental conditions influence one or several genetic factors, where also gender is of importance. One of the genetic factors is immunodysfunction, and the trigger mechanism may be a virus infection. Viruses are the most common agents to which the human being is exposed throughout life. The herpes virus group is of special interest with respect to complications of the central nervous system. Herpes viruses, especially herpes simplex virus type 1 (HSV-1), human herpes virus type 6 (HHV-6), cytomegalovirus (CMV) and Epstein-Barr virus (EBV), are capable of establishing latent infection and reactivating under a variety of stimuli. In this review especially HHV-6 will be emphasized, as well as CMV in relation to Rasmussen's syndrome. The immunological aspects will focus on immunoglobulins, antibodies, especially the glutamate receptors, human leukocyte antigens, T- and B-lymphocytes, and their respective interaction with the antigen presenting cell. This course of events concerns the 'immunological synapse'. Finally, reports on herpes virus genomes in the human brain are discussed. A study on herpes viral DNA in brain tissue from patients operated for focal epilepsy is briefly mentioned.

Psychological and social outcome of epilepsy in well-functioning children and adolescents. A 10-year follow-up study.

BACKGROUND: From a population based study of epilepsy in Swedish children a subgroup designated well-functioning with an epilepsy diagnosis in 1997 was worked up from a medical point of view 10 years later. AIM: To describe the psychological and social outcome in this subgroup. METHODS: Thirty-one patients aged 11-22 years and their parents/partners responded to a questionnaire according to Achenbach System of Empirically Based Assessment (ASEBA) to evaluate behavioural and emotional problems, and social competence. RESULTS: Active epilepsy, diagnosed in 32%, was related to attention problems, somatic complaints, and school problems. Polytherapy, used in 16%, was related to attention problems and aggressive behaviour. School problems were found in six of seven children younger than 18 years. Internalizing, externalizing, and 'other' syndromes were found in 29% of the individuals, but a grouping of these syndromes in the clinical range only in two (6.5%), a girl with generalized tonic-clonic seizures alone, and a boy with structural focal epilepsy. Both had active epilepsy and were treated with polytherapy. All ten individuals with Rolandic epilepsy were classified as normal. The answers to the ASEBA questionnaire of individuals and parents/partners were inconsistent, and parents generally stated more problems than the individuals. SUMMARY: This 10-year follow-up study of psychological and social outcome in well-functioning children and adolescents with childhood onset epilepsy shows some emotional, behavioural, and social problems. Thus, early information to increase knowledge about epilepsy and associated psychological co-morbidities in order to decrease risk of low self-esteem, social anxiety, and depression later in life is of importance.

Alpha frequency estimation in patients with epilepsy.

We report comparison and assessment of the clinical utility of different automated methods for the estimation of the alpha frequency in electroencephalograph (EEG) and compare them with visual evaluation. A total of 56 consecutive patients, aged 17 to 78 years, who had a routine EEG recording, were included, and they were grouped as patients with epilepsy (Ep) and without epilepsy (nEp). Five different methods were used for alpha frequency estimation: visually guided manual counting and visually guided Fourier transform, and 3 methods were fully automated: time domain estimation of alpha (automatic assessment of alpha waves in time domain [ATD]) and 2 fast Fourier transform (FFT)-based methods, a segmented (automatic assessment of EEG segments by FFT) and one full FFT (automatic assessment of whole EEG by one FFT of the full recording [AWF]). The AWF discriminated significantly between Ep and nEp. Visually guided manual counting showed an almost significant difference independently in the 2 occipital electrodes. The ATD underestimated high frequencies and returned a too low mean frequency. This study shows that AWF is the best suited method for automatic assessment of the alpha frequency.

10-year outcome of childhood epilepsy in well-functioning children and adolescents.

BACKGROUND: A population based study of epilepsy in children from a Swedish county including all children aged 1 month to 16 years was reported in 2006. AIM: To describe the medical outcome, seizure types, epilepsy syndromes, treatment, individual and family history in children from this study who were well-functioning in January 1997 and the outcome after 10 years. METHODS: Forty-five individuals, 11-21 years, 19 females, and their parents responded to a questionnaire and the hospital records were reviewed. RESULTS: At the end of the 10-year period 75.6% of the patients were in remission. Focal seizures and focal seizures with secondary generalization were found in 57.8%. Rolandic epilepsy had been diagnosed in 33.3%, other idiopathic focal epilepsies in 11.0%, cryptogenic and symptomatic focal epilepsies in 22.2%, childhood absence epilepsy in 8.9%, juvenile absence epilepsy and Jeavons syndrome in each 2.2%, West syndrome in 4.4%, and other "generalized" epilepsies in 15.5%. The patients had a history of simple febrile seizures in 15.6% and of primary headache in 24.4%. Monotherapy with antiepileptic drugs was used by 64.4%, and valproate was the most common first drug of choice. A family history of epilepsy was found in 44.4%, febrile seizures in 17.7%, and primary headache in 57.8%. A coincidence of focal and generalized epilepsy phenotypes was found in some families. CONCLUSIONS: Longitudinal studies are of importance in epilepsy epidemiology. Our results reflect the selection of only well-functioning individuals with epilepsy from the population based original study.

Levetiracetam reduces the frequency of interictal epileptiform discharges during NREM sleep in children with ADHD.

BACKGROUND: Symptoms of attention deficit hyperactivity disorder (ADHD) are more common in children with epilepsy than in the general paediatric population. Epileptiform discharges in EEG may be seen in children with ADHD also in those without seizure disorders. Sleep enhances these discharges which may be suppressed by levetiracetam. AIM: To assess the effect of levetiracetam on focal epileptiform discharges during sleep in children with ADHD. METHOD: In this retrospective study a new semi-automatic quantitative method based on the calculation of spike index in 24-h ambulatory EEG recordings was applied. Thirty-five ADHD children, 17 with focal epilepsy, one with generalised epilepsy, and 17 with no seizure disorder were evaluated. Follow-up 24-h EEG recordings were performed after a median time of four months. RESULTS: Mean spike index was 50 prior to levetiracetam treatment and 21 during treatment. Seventeen children had no focal interictal epileptiform discharges in EEG at follow-up. Five children had a more than 50% reduction in spike index. Thus, a more than 50% reduction in spike index was found in 22/35 children (63%). Out of these an improved behaviour was noticed in 13 children (59%). CONCLUSION: This study shows that treatment with levetiracetam reduces interictal epileptiform discharges in children with ADHD. There is a complex relationship between epilepsy, ADHD and epileptiform activity, why it is a need for prospective studies in larger sample sizes, also to ascertain clinical benefits.