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1.  Genetic enhancement of cognition in a kindred with cone–rod dystrophy due to RIMS1 mutation 
Journal of Medical Genetics  2007;44(6):373-380.
The genetic basis of variation in human cognitive abilities is poorly understood. RIMS1 encodes a synapse active‐zone protein with important roles in the maintenance of normal synaptic function: mice lacking this protein have greatly reduced learning ability and memory function.
An established paradigm examining the structural and functional effects of mutations in genes expressed in the eye and the brain was used to study a kindred with an inherited retinal dystrophy due to RIMS1 mutation.
Materials and methods
Neuropsychological tests and high‐resolution MRI brain scanning were undertaken in the kindred. In a population cohort, neuropsychological scores were associated with common variation in RIMS1. Additionally, RIMS1 was sequenced in top‐scoring individuals. Evolution of RIMS1 was assessed, and its expression in developing human brain was studied.
Affected individuals showed significantly enhanced cognitive abilities across a range of domains. Analysis suggests that factors other than RIMS1 mutation were unlikely to explain enhanced cognition. No association with common variation and verbal IQ was found in the population cohort, and no other mutations in RIMS1 were detected in the highest scoring individuals from this cohort. RIMS1 protein is expressed in developing human brain, but RIMS1 does not seem to have been subjected to accelerated evolution in man.
A possible role for RIMS1 in the enhancement of cognitive function at least in this kindred is suggested. Although further work is clearly required to explore these findings before a role for RIMS1 in human cognition can be formally accepted, the findings suggest that genetic mutation may enhance human cognition in some cases.
PMCID: PMC2740882  PMID: 17237123
2.  Significant hypotension following buccal midazolam administration 
BMJ Case Reports  2010;2010:bcr0920103371.
Buccal midazolam is a rescue medication to reduce the duration of or stop an epileptic seizure, and is used to prevent status epilepticus. It is available in various forms, including a buccal preparation with a strength of 10 mg/1 ml. Midazolam is a licensed medication, but the buccal formulation is currently used off-licence. The prescriber takes ultimate responsibility for its use in this way. Administered by a trained person, it is receiving widespread acceptance as an alternative and effective treatment to rectally-administered diazepam in the community. The commonest side effects of midazolam are drowsiness and somnolence, although respiratory depression and paradoxical reactions, for example, agitation, restlessness and disorientation, may also occur. Hypotension is said to be a rare side effect, but with no reported cases in people administered buccal midazolam. The authors report a case of significant hypotension associated with administration of buccal midazolam for seizure management.
PMCID: PMC3029668  PMID: 22802329
3.  Characterisation and Validation of Insertions and Deletions in 173 Patient Exomes 
PLoS ONE  2012;7(12):e51292.
Recent advances in genomics technologies have spurred unprecedented efforts in genome and exome re-sequencing aiming to unravel the genetic component of rare and complex disorders. While in rare disorders this allowed the identification of novel causal genes, the missing heritability paradox in complex diseases remains so far elusive. Despite rapid advances of next-generation sequencing, both the technology and the analysis of the data it produces are in its infancy. At present there is abundant knowledge pertaining to the role of rare single nucleotide variants (SNVs) in rare disorders and of common SNVs in common disorders. Although the 1,000 genome project has clearly highlighted the prevalence of rare variants and more complex variants (e.g. insertions, deletions), their role in disease is as yet far from elucidated.
We set out to analyse the properties of sequence variants identified in a comprehensive collection of exome re-sequencing studies performed on samples from patients affected by a broad range of complex and rare diseases (N = 173). Given the known potential for Loss of Function (LoF) variants to be false positive, we performed an extensive validation of the common, rare and private LoF variants identified, which indicated that most of the private and rare variants identified were indeed true, while common novel variants had a significantly higher false positive rate. Our results indicated a strong enrichment of very low-frequency insertion/deletion variants, so far under-investigated, which might be difficult to capture with low coverage and imputation approaches and for which most of study designs would be under-powered. These insertions and deletions might play a significant role in disease genetics, contributing specifically to the underlining rare and private variation predicted to be discovered through next generation sequencing.
PMCID: PMC3522676  PMID: 23251486
4.  Variability of sclerosis along the longitudinal hippocampal axis in epilepsy: A post mortem study 
Epilepsy Research  2012;102(1-2):45-59.
Detailed neuropathological studies of the extent of hippocampal sclerosis (HS) in epilepsy along the longitudinal axis of the hippocampus are lacking. Neuroimaging studies of patients with temporal lobe epilepsy support that sclerosis is not always localised. The extent of HS is of relevance to surgical planning and poor outcomes may relate to residual HS in the posterior remnant. In 10 post mortems from patients with long histories of drug refractory epilepsy and 3 controls we systematically sampled the left and right hippocampus at seven coronal anatomical levels along the body to the tail. We quantified neuronal densities in CA1 and CA4 subfields at each level using Cresyl Violet (CV), calretinin (CR), calbindin (CB) and Neuropeptide Y (NPY) immunohistochemistry. In the dentate gyrus we graded the extent of granule cell dispersion, patterns of CB expression, and synaptic reorganisation with CR and NPY at each level. We identified four patterns of HS based on patterns of pyramidal and interneuronal loss and dentate gyrus reorganisation between sides and levels as follows: (1) symmetrical HS with anterior–posterior (AP) gradient, (2) symmetrical HS without AP gradient, (3) asymmetrical HS with AP gradient and (4) asymmetrical cases without AP gradient. We confirmed in this series that HS can extend into the tail. The patterns of sclerosis (classical versus atypical or none) were consistent between all levels in less than a third of cases. In conclusion, this series highlights the variability of HS along the longitudinal axis. Further studies are required to identify factors that lead to focal versus diffuse HS.
PMCID: PMC3500681  PMID: 22608064
Hippocampal sclerosis; Quantitation; Calbindin; Neuropeptide Y; Calretinin
5.  Atypical face shape and genomic structural variants in epilepsy 
Brain  2012;135(10):3101-3114.
Many pathogenic structural variants of the human genome are known to cause facial dysmorphism. During the past decade, pathogenic structural variants have also been found to be an important class of genetic risk factor for epilepsy. In other fields, face shape has been assessed objectively using 3D stereophotogrammetry and dense surface models. We hypothesized that computer-based analysis of 3D face images would detect subtle facial abnormality in people with epilepsy who carry pathogenic structural variants as determined by chromosome microarray. In 118 children and adults attending three European epilepsy clinics, we used an objective measure called Face Shape Difference to show that those with pathogenic structural variants have a significantly more atypical face shape than those without such variants. This is true when analysing the whole face, or the periorbital region or the perinasal region alone. We then tested the predictive accuracy of our measure in a second group of 63 patients. Using a minimum threshold to detect face shape abnormalities with pathogenic structural variants, we found high sensitivity (4/5, 80% for whole face; 3/5, 60% for periorbital and perinasal regions) and specificity (45/58, 78% for whole face and perinasal regions; 40/58, 69% for periorbital region). We show that the results do not seem to be affected by facial injury, facial expression, intellectual disability, drug history or demographic differences. Finally, we use bioinformatics tools to explore relationships between facial shape and gene expression within the developing forebrain. Stereophotogrammetry and dense surface models are powerful, objective, non-contact methods of detecting relevant face shape abnormalities. We demonstrate that they are useful in identifying atypical face shape in adults or children with structural variants, and they may give insights into the molecular genetics of facial development.
PMCID: PMC3470710  PMID: 22975390
epilepsy; dysmorphism; structural variants; genomics; dense surface models
7.  Genome-wide mapping for clinically relevant predictors of lamotrigine- and phenytoin-induced hypersensitivity reactions 
Pharmacogenomics  2012;13(4):399-405.
An association between carbamazepine-induced hypersensitivity and HLA-A*3101 has been reported in populations of both European and Asian descent. We aimed to investigate HLA-A*3101 and other common variants across the genome as markers for cutaneous adverse drug reactions (cADRs) attributed to lamotrigine and phenytoin.
Materials & methods
We recruited patients with lamotrigine-induced cADRs (n = 46) and patients with phenytoin-cADRs (n = 44) and the 1958 British birth cohort was used as a control (n = 1296). HLA-A*3101 was imputed from genome-wide association study data. We applied genome-wide association to study lamotrigine- and phenytoin-induced cADR, and total cADR cases combined.
Neither HLA-A*3101 nor any other genetic marker significantly predicted lamotrigine- or phenytoin-induced cADRs.
HLA-A*3101 does not appear to be a predictor for lamotrigine- and phenytoin-induced cADRs in Europeans. Our genome-wide association study results do not support the existence of a clinically relevant common variant for the development of lamotrigine- or phenytoin-induced cADRs. As a predictive marker, HLA-A*3101 appears to be specific for carbamazepine-induced cADRs.
PMCID: PMC3428903  PMID: 22379998
epilepsy; GWAS; HLA-A*3101; hypersensitivity; lamotrigine; phenytoin
8.  Array comparative genomic hybridization: Results from an adult population with drug-resistant epilepsy and co-morbidities 
European Journal of Medical Genetics  2012;55(5-3):342-348.
The emergence of array comparative genomic hybridization (array CGH) as a diagnostic tool in molecular genetics has facilitated recognition of microdeletions and microduplications as risk factors for both generalised and focal epilepsies. Furthermore, there is evidence that some microdeletions/duplications, such as the 15q13.3 deletion predispose to a range of neuropsychiatric disorders, including intellectual disability (ID), autism, schizophrenia and epilepsy.
We hypothesised that array CGH would reveal relevant findings in an adult patient group with epilepsy and complex phenotypes.
82 patients (54 from the National Hospital for Neurology and Neurosurgery and 28 from King’s College Hospital) with drug-resistant epilepsy and co-morbidities had array CGH. Separate clinicians ordered array CGH and separate platforms were used at the two sites.
In the two independent groups we identified copy number variants judged to be of pathogenic significance in 13.5% (7/52) and 20% (5/25) respectively, noting that slightly different selection criteria were used, giving an overall yield of 15.6%. Sixty-nine variants of unknown significance were also identified in the group from the National Hospital for Neurology and Neurosurgery and 5 from the King’s College Hospital patient group.
We conclude that array CGH be considered an important investigation in adults with complicated epilepsy and, at least at present for selected patients, should join the diagnostic repertoire of clinical history and examination, neuroimaging, electroencephalography and other indicated investigations in generating a more complete formulation of an individual’s epilepsy.
► Copy number variants may predispose to a range of neuropsychiatric disorders. ► Array CGH may reveal relevant findings in adults with complex phenotypes. ► Likely pathogenic copy number changes were identified with a yield of 15.6%. ► Array CGH should join the diagnostic repertoire for adults with complex phenotypes.
PMCID: PMC3526772  PMID: 22342432
Array comparative genomic hybridization; Copy number variation; DNA; Epilepsy; Co-morbidity
9.  Neuropathology of 16p13.11 Deletion in Epilepsy 
PLoS ONE  2012;7(4):e34813.
16p13.11 genomic copy number variants are implicated in several neuropsychiatric disorders, such as schizophrenia, autism, mental retardation, ADHD and epilepsy. The mechanisms leading to the diverse clinical manifestations of deletions and duplications at this locus are unknown. Most studies favour NDE1 as the leading disease-causing candidate gene at 16p13.11. In epilepsy at least, the deletion does not appear to unmask recessive-acting mutations in NDE1, with haploinsufficiency and genetic modifiers being prime candidate disease mechanisms. NDE1 encodes a protein critical to cell positioning during cortical development. As a first step, it is important to determine whether 16p13.11 copy number change translates to detectable brain structural alteration. We undertook detailed neuropathology on surgically resected brain tissue of two patients with intractable mesial temporal lobe epilepsy (MTLE), who had the same heterozygous NDE1-containing 800 kb 16p13.11 deletion, using routine histological stains and immunohistochemical markers against a range of layer-specific, white matter, neural precursor and migratory cell proteins, and NDE1 itself. Surgical temporal lobectomy samples from a MTLE case known not to have a deletion in NDE1 and three non-epilepsy cases were included as disease controls. We found that apart from a 3 mm hamartia in the temporal cortex of one MTLE case with NDE1 deletion and known hippocampal sclerosis in the other case, cortical lamination and cytoarchitecture were normal, with no differences between cases with deletion and disease controls. How 16p13.11 copy changes lead to a variety of brain diseases remains unclear, but at least in epilepsy, it would not seem to be through structural abnormality or dyslamination as judged by microscopy or immunohistochemistry. The need to integrate additional data with genetic findings to determine their significance will become more pressing as genetic technologies generate increasingly rich datasets. Detailed examination of brain tissue, where available, will be an important part of this process in neurogenetic disease specifically.
PMCID: PMC3327721  PMID: 22523559
10.  Extended extraocular phenotype of PROM1 mutation in kindreds with known autosomal dominant macular dystrophy 
Mutations in prominin 1 (PROM1) have been shown to result in retinitis pigmentosa, macular degeneration and cone-rod dystrophy. Because of the putative role of PROM1 in hippocampal neurogenesis, we examined two kindreds with the same R373C PROM1 missense mutation using our established paradigm to study brain structure and function. As the protein encoded by PROM1, known as CD133, is used to identify stem/progenitor cells that can be found in peripheral blood and reflect endothelial reparatory mechanisms, other parameters were subsequently examined that included measures of vascular function, endothelial function and angiogenic capacity. We found that aspects of endothelial function assayed ex vivo were abnormal in patients with the R373C PROM1 mutation, with impaired adhesion capacity and higher levels of cellular damage. We also noted renal infections, haematuria and recurrent miscarriages possibly reflecting consequences of abnormal tubular modelling. Further studies are needed to confirm these findings.
PMCID: PMC3025782  PMID: 20859302
PROM1; CD133; endothelial; tubule; sella turcica
11.  Neurofibrillary tangle pathology and Braak staging in chronic epilepsy in relation to traumatic brain injury and hippocampal sclerosis: a post-mortem study 
Brain  2011;134(10):2969-2981.
The long-term pathological effects of chronic epilepsy on normal brain ageing are unknown. Previous clinical and epidemiological studies show progressive cognitive decline in subsets of patients and an increased prevalence of Alzheimer's disease in epilepsy. In a post-mortem series of 138 patients with long-term, mainly drug-resistant epilepsy, we carried out Braak staging for Alzheimer's disease neurofibrillary pathology using tau protein immunohistochemistry. The stages were compared with clinicopathological factors, including seizure history and presence of old traumatic brain injury. Overall, 31% of cases were Braak Stage 0, 36% Stage I/II, 31% Stage III/IV and 2% Stage V/VI. The mean age at death was 56.5 years and correlated with Braak stage (P < 0.001). Analysis of Braak stages within age groups showed a significant increase in mid-Braak stages (III/IV), in middle age (40–65 years) compared with data from an ageing non-epilepsy series (P < 0.01). There was no clear relationship between seizure type (generalized or complex partial), seizure frequency, age of onset and duration of epilepsy with Braak stage although higher Braak stages were noted with focal more than with generalized epilepsy syndromes (P < 0.01). In 30% of patients, there was pathological evidence of traumatic brain injury that was significantly associated with higher Braak stages (P < 0.001). Cerebrovascular disease present in 40.3% and cortical malformations in 11.3% were not significantly associated with Braak stage. Astrocytic-tau protein correlated with the presence of both traumatic brain injury (P < 0.01) and high Braak stage (P < 0.001). Hippocampal sclerosis, identified in 40% (bilateral in 48%), was not associated with higher Braak stages, but asymmetrical patterns of tau protein accumulation within the sclerotic hippocampus were noted. In over half of patients with cognitive decline, the Braak stage was low indicating causes other than Alzheimer's disease pathology. In summary, there is evidence of accelerated brain ageing in severe chronic epilepsy although progression to high Braak stages was infrequent. Traumatic brain injury, but not seizures, was associated with tau protein accumulation in this series. It is likely that Alzheimer's disease pathology is not the sole explanation for cognitive decline associated with epilepsy.
PMCID: PMC3187539  PMID: 21903728
Braak stage; epilepsy; head trauma; hippocampal sclerosis
12.  The application of cortical layer markers in the evaluation of cortical dysplasias in epilepsy 
Acta Neuropathologica  2010;120(4):517-528.
The diagnostic criteria for focal cortical dysplasia type I (FCD I) remain to be well and consistently defined. Cortical layer-specific markers (CLM) provide a potential tool for the objective assessment of any dyslamination. We studied expression patterns of recognised CLM using immunohistochemistry for N200, ER81, Otx1, Map1b (subsets of V/VI projection neurones), Pax6, Tbr1, Tbr2 (differentially expressed in cortical neurones from intermediate progenitor cells), Cux 1 (outer cortical layers) and MASH1 (ventricular zone progenitors). Dysplasia subtypes included FCD I and II, dysplasias adjacent to hippocampal sclerosis (HS) or dysembryoplastic neuroepithelial tumours (DNTs); all were compared to neonatal and adult controls. Laminar expression patterns in normal cortex were observed with Tbr1, Map1b, N200 and Otx1. FCDI cases in younger patients were characterised by abnormal expression in layer II for Tbr1 and Otx1. FCDII showed distinct labelling of balloon cells (Pax6, ER81 and Otx1) and dysmorphic neurones (Tbr 1, N200 and Map1b) supporting origins from radial glia and intermediate progenitor cells, respectively. In temporal lobe sclerosis cases with dysplasia adjacent to HS, Tbr1 and Map1b highlighted abnormal orientation of neurones in layer II. Dyslamination was not confirmed in the perilesional cortex of DNT with CLM. Finally, immature cell types (Otx1, Pax6 and Tbr2) were noted in varied pathologies. One possibility is activation of progenitor cell populations which could contribute to the pathophysiology of these lesions.
PMCID: PMC2923329  PMID: 20411268
Cortical layer markers; Dysplasia; Epilepsy
13.  Temporal Lobe Sclerosis Associated with Hippocampal Sclerosis in Temporal Lobe Epilepsy: Neuropathological Features 
Widespread changes involving neocortical as well as mesial temporal lobe structures can be present in patients with temporal lobe epilepsy (TLE) and hippocampal sclerosis (HS). The incidence, pathology and clinical significance of neocortical temporal lobe sclerosis (TLS) are not well characterized. We identified TLS in 30 out of 272 surgically treated cases of HS. TLS was defined by variable reduction of neurons from cortical layers II/III and laminar gliosis; it was typically accompanied by additional architectural abnormalities of layer II, i.e. abnormal neuronal orientation and aggregation. Quantitative analysis including tessellation methods for the distribution of layer II neurons supported these observations. In 40% of cases there was a gradient of TLS with more severe involvement towards the temporal pole, possibly signifying involvement of hippocampal projection pathways. There was a history of a febrile seizure as an initial precipitating injury in 73% of patients with TLS compared to 36% without TLS; no other clinical differences TLS and non-TLS cases were identified. TLS was not evident pre-operatively by neuroimaging. No obvious effect of TLS on seizure outcome was noted after temporal lobe resection; 73% became seizure-free at 2 year follow up. In conclusion, approximately 11% of surgically treated HS is accompanied by TLS. TLS is likely an acquired process with accompanying re-organizational dysplasia and an extension of mesial temporal sclerosis rather than a separate pathological entity.
PMCID: PMC2723771  PMID: 19606061
Hippocampal sclerosis; Temporal lobe sclerosis
14.  PROPELLER MRI visualizezs detailed pathology of hippocampal sclerosis 
Epilepsia  2008;49(1):33-39.
Hippocampal sclerosis (HS) is the most common cause of refractory temporal lobe epilepsy. Histopathologically, HS is characterized by neuron loss and gliosis. HS can be identified on MRI by signal increase on T2-weighted images and volume loss on T1-weighted volume images. The Periodically Rotated Overlapping Parallel Lines with Enhanced Reconstruction (“PROPELLER”) sequence has excellent contrast between grey and white matter and compensates for subjects moving during the scan. The aim of the current report was to explore PROPELLER image quality of the hippocampus compared to routine sequences.
Routine sequences (T1 volume, T2-weighted, PD and FLAIR images) and PROPELLER images were acquired in four presurgical patients with HS using a GE 3T Excite HD scanner (General Electric). Resected tissue was stained with LFB, and for GFAP, NeuN and dynorphin immunohistochemistry. Hippocampal sections were compared with PROPELLER images.
PROPELLER images were T2-weighted and had superior tissue contrast compared to routine sequences. PROPELLER images showed the internal hippocampal structures and tissue changes associated with HS. This corresponded to changes seen on histopathological sections confirming that the sequence could distinguish between different strata and subfields of the hippocampus.
The PROPELLER sequence shows promise for detailed in vivo imaging of the hippocampus in patients who did not move overtly, negating the inevitable subtle movements during scans. More detailed in vivo studies of the hippocampal formation, investigating subtle abnormalities such as end folium sclerosis, and the neocortex are now possible and may increase the diagnostic yield of MRI.
PMCID: PMC2253717  PMID: 17877734
Epilepsy; Magnetic Resonance Imaging; PROPELLER; Hippocampal sclerosis; Histopathology
15.  Cortical neuronal loss and hippocampal sclerosis are not detected by voxel-based morphometry in individual epilepsy surgery patients 
Human Brain Mapping  2009;30(10):3351-3360.
Voxel-based morphometry (VBM) has detected differences between brains of groups of patients with epilepsy and controls, but the sensitivity for detecting subtle pathological changes in single subjects has not been established. The aim of the study was to test the sensitivity of VBM using statistical parametric mapping (SPM5) to detect hippocampal sclerosis (HS) and cortical neuronal loss in individual patients. T1-weighted volumetric 1.5 T MR images from 13 patients with HS and laminar cortical neuronal loss were segmented, normalised and smoothed using SPM5. Both modulated and non-modulated analyses were performed. Comparisons of one control subject against the rest (n = 23) were first performed to ascertain the smoothing level with the lowest number of SPM changes in controls. Each patient was then compared against the whole control group. The lowest number of SPM changes in control subjects was found at a smoothing level of 10 mm full width half maximum for modulated and non-modulated data. In the patient group, no SPM abnormalities were found in the affected temporal lobe or hippocampus at this smoothing level. At lower smoothing levels there were numerous SPM findings in controls and patients. VBM did not detect any abnormalities associated with either laminar cortical neuronal loss or HS. This may be due to normalisation and smoothing of images and low statistical power in areas with larger inter-individual differences. This suggests that the methodology may currently not be suitable to detect particular occult abnormalities possibly associated with seizure onset zone in individual epilepsy patients with unremarkable standard structural MRI. Hum Brain Mapp, 2009. © 2009 Wiley-Liss, Inc.
PMCID: PMC2771105  PMID: 19347875
voxel-based morphometry; hippocampal sclerosis; neuronal loss; gliosis; epilepsy; SPM
16.  Genomic microdeletions associated with epilepsy: Not a contraindication to resective surgery 
Epilepsia  2011;52(8):1388-1392.
Several recent reports of genomic microdeletions in epilepsy will generate further research; discovery of more microdeletions and other important classes of variants may follow. Detection of such genetic abnormalities in patients being evaluated for surgical treatment might raise concern that a genetic defect, possibly widely expressed in the brain, will affect surgical outcome.
A reevaluation was undertaken of clinical presurgical data, histopathology of surgical specimen, and postsurgical outcome in patients with mesial temporal lobe epilepsy (MTLE) who have had surgical treatment for their drug-resistant seizures, and who have been found to have particular genomic microdeletions.
Key Findings
Three thousand eight hundred twelve patients with epilepsy were genotyped and had a genome-wide screen to identify copy number variation. Ten patients with MTLE, who had resective epilepsy surgery, were found to have 16p13.11 microdeletions or other microdeletions >1 Mb. On histopathology, eight had classical hippocampal sclerosis (HS), one had nonspecific findings, and one had a hamartoma. Median postsurgical follow-up time was 48 months (range 10–156 months). All patients with HS were seizure-free after surgery, International League Against Epilepsy (ILAE) outcome class 1, at last follow-up; the patient with nonspecific pathology had recurrence of infrequent seizures after 7 years of seizure freedom. The patient with a hamartoma never became seizure-free.
Large microdeletions can be found in patients with “typical” MTLE. In this small series, patients with MTLE who meet criteria for resective surgery and harbor large microdeletions, at least those we have detected, can have a good postsurgical outcome. Our findings add to the spectrum of causal heterogeneity of MTLE + HS.
PMCID: PMC3399084  PMID: 21635232
Epilepsy surgery; Hippocampal sclerosis; Temporal lobectomy; Deletions
17.  HLA-A★3101 and Carbamazepine-Induced Hypersensitivity Reactions in Europeans 
The New England journal of medicine  2011;364(12):1134-1143.
Carbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. The HLA-B★1502 allele has been shown to be strongly correlated with carbamazepine-induced Stevens–Johnson syndrome and toxic epidermal necrolysis (SJS–TEN) in the Han Chinese and other Asian populations but not in European populations.
We performed a genomewide association study of samples obtained from 22 subjects with carbamazepine-induced hypersensitivity syndrome, 43 subjects with carbamazepine-induced maculopapular exanthema, and 3987 control subjects, all of European descent. We tested for an association between disease and HLA alleles through proxy single-nucleotide polymorphisms and imputation, confirming associations by high-resolution sequence-based HLA typing. We replicated the associations in samples from 145 subjects with carbamazepine-induced hypersensitivity reactions.
The HLA-A★3101 allele, which has a prevalence of 2 to 5% in Northern European populations, was significantly associated with the hypersensitivity syndrome (P = 3.5×10−8). An independent genomewide association study of samples from subjects with maculopapular exanthema also showed an association with the HLA-A★3101 allele (P = 1.1×10−6). Follow-up genotyping confirmed the variant as a risk factor for the hypersensitivity syndrome (odds ratio, 12.41; 95% confidence interval [CI], 1.27 to 121.03), maculopapular exanthema (odds ratio, 8.33; 95% CI, 3.59 to 19.36), and SJS–TEN (odds ratio, 25.93; 95% CI, 4.93 to 116.18).
The presence of the HLA-A★3101 allele was associated with carbamazepine-induced hypersensitivity reactions among subjects of Northern European ancestry. The presence of the allele increased the risk from 5.0% to 26.0%, whereas its absence reduced the risk from 5.0% to 3.8%. (Funded by the U.K. Department of Health and others.)
PMCID: PMC3113609  PMID: 21428769
18.  Uncovering Genomic Causes of Co-Morbidity in Epilepsy: Gene-Driven Phenotypic Characterization of Rare Microdeletions 
PLoS ONE  2011;6(8):e23182.
Patients with epilepsy often suffer from other important conditions. The existence of such co-morbidities is frequently not recognized and their relationship with epilepsy usually remains unexplained.
Methodology/Principal Findings
We describe three patients with common, sporadic, non-syndromic epilepsies in whom large genomic microdeletions were found during a study of genetic susceptibility to epilepsy. We performed detailed gene-driven clinical investigations in each patient. Disruption of the function of genes in the deleted regions can explain co-morbidities in these patients.
Co-morbidities in patients with epilepsy can be part of a genomic abnormality even in the absence of (known) congenital malformations or intellectual disabilities. Gene-driven phenotype examination can also reveal clinically significant unsuspected condition.
PMCID: PMC3157359  PMID: 21858020
19.  Dravet syndrome as epileptic encephalopathy: evidence from long-term course and neuropathology 
Brain  2011;134(10):2982-3010.
Dravet syndrome is an epilepsy syndrome of infantile onset, frequently caused by SCN1A mutations or deletions. Its prevalence, long-term evolution in adults and neuropathology are not well known. We identified a series of 22 adult patients, including three adult post-mortem cases with Dravet syndrome. For all patients, we reviewed the clinical history, seizure types and frequency, antiepileptic drugs, cognitive, social and functional outcome and results of investigations. A systematic neuropathology study was performed, with post-mortem material from three adult cases with Dravet syndrome, in comparison with controls and a range of relevant paediatric tissue. Twenty-two adults with Dravet syndrome, 10 female, were included, median age 39 years (range 20–66). SCN1A structural variation was found in 60% of the adult Dravet patients tested, including one post-mortem case with DNA extracted from brain tissue. Novel mutations were described for 11 adult patients; one patient had three SCN1A mutations. Features of Dravet syndrome in adulthood include multiple seizure types despite polytherapy, and age-dependent evolution in seizure semiology and electroencephalographic pattern. Fever sensitivity persisted through adulthood in 11 cases. Neurological decline occurred in adulthood with cognitive and motor deterioration. Dysphagia may develop in or after the fourth decade of life, leading to significant morbidity, or death. The correct diagnosis at an older age made an impact at several levels. Treatment changes improved seizure control even after years of drug resistance in all three cases with sufficient follow-up after drug changes were instituted; better control led to significant improvement in cognitive performance and quality of life in adulthood in two cases. There was no histopathological hallmark feature of Dravet syndrome in this series. Strikingly, there was remarkable preservation of neurons and interneurons in the neocortex and hippocampi of Dravet adult post-mortem cases. Our study provides evidence that Dravet syndrome is at least in part an epileptic encephalopathy.
PMCID: PMC3187538  PMID: 21719429
SCN1A; Na+ channel; epilepsy; neuropathology; encephalopathy
20.  Alternative ion channel splicing in mesial temporal lobe epilepsy and Alzheimer's disease 
Genome Biology  2007;8(3):R32.
A novel microarray technology that permits the screening of alternative splice variants identifies disease-associated alternative splicing patterns in ion channel genes of patients with mesial temporal lobe epilepsy and Alzheimers disease.
Alternative gene transcript splicing permits a single gene to produce multiple proteins with varied functions. Bioinformatic investigations have identified numerous splice variants, but whether these transcripts are translated to functional proteins and the physiological significance of these alternative proteins are largely unknown. Through direct identification of splice variants associated with disease states, we can begin to address these questions and to elucidate their roles in disease predisposition and pathophysiology. This work specifically sought to identify disease-associated alternative splicing patterns in ion channel genes by comprehensively screening affected brain tissue collected from patients with mesial temporal lobe epilepsy and Alzheimer's disease. New technology permitting the screening of alternative splice variants in microarray format was employed. Real time quantitative PCR was used to verify observed splice variant patterns.
This work shows for the first time that two common neurological conditions are associated with extensive changes in gene splicing, with 25% and 12% of the genes considered having significant changes in splicing patterns associated with mesial temporal lobe epilepsy and Alzheimer's disease, respectively. Furthermore, these changes were found to exhibit unique and consistent patterns within the disease groups.
This work has identified a set of disease-associated, alternatively spliced gene products that represent high priorities for detailed functional investigations into how these changes impact the pathophysiology of mesial temporal lobe epilepsy and Alzheimer's disease.
PMCID: PMC1868939  PMID: 17343748

Results 1-20 (20)