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Biomedical subjects

Sanjay M Sisodiya

Publications and source records attributed to Sanjay M Sisodiya.

At least 19 recordsLinked to original sources
PubMed2026

Multiomic approaches identify a rare CCG repeat expansion in BCLAF3 in neurodevelopmental disorders.

BACKGROUND: Tandem repeat expansions have been implicated in various neurological conditions. Here, we present a novel hypermethylated CCG repeat expansion on Xp22 in the 5'UTR of BCLAF3 in males with neurodevelopmental disorders. METHODS: We used patient-derived fibroblasts and neuronal models from a family with BCLAF3 repeat expansions to generate multiomic data and investigate downstream molecular consequences of the repeat expansion. To identify additional affected individuals with BCLAF3 repeat expansions, we screened methylation arrays (n = 12,375) and short-read genomes (n = 15,963) from probands with neurodevelopmental presentations. We also characterized BCLAF3 repeat expansions in the general population using long-read sequencing data (n = 793) and population-level short-read sequencing data (n = 410,076). RESULTS: Long-read sequencing validated hypermethylation of expanded repeats. Patient-derived cells showed repressed BCLAF3 RNA and protein expression. We show that the BCLAF3 CCG repeat expansion constitutes a previously uncharacterized fragile site (FRAXG) that shifts the surrounding chromatin compartment from open euchromatin to closed heterochromatin. Using our multiomic screening approaches, we identified three additional unrelated males and one related male cousin with long-read sequencing validated (n = 2) or short-read sequencing predicted (n = 2) repeat expansions. In one family, the BCLAF3 repeats segregate with more severe phenotypes than expected for the primary diagnoses. Long-read sequencing in three carrier mothers showed skewed X-inactivation against the repeat expansion, highlighting the potential deleterious effect of an allele with an expansion. Expansions were absent in long-read sequencing data from control populations. Assessment of the BCLAF3 repeat expansion in the UK Biobank indicates that it may be ~ 20X rarer than FMR1 repeat expansions. CONCLUSIONS: CCG repeat expansions in the 5'UTR of BCLAF3 likely constitute a novel genetic etiology associated with X-linked neurodevelopmental phenotypes in males. Future work will be essential to delineate the phenotypic spectrum and determine a disease pathomechanism.

BCLAF3↗
PubMed2025

TMS-EEG in postictal psychosis of epilepsy.

BACKGROUND: Postictal psychosis (PIP) is a poorly understood complication affecting 2 % of individuals with epilepsy. Genomic and neuroimaging studies suggest parallels with schizophrenia. OBJECTIVES: To determine whether Transcranial Magnetic Stimulation coupled with Electroencephalography (TMS-EEG), can reveal schizophrenia-like changes in PIP, especially in Natural Frequency (NF), gamma band Event-Related Spectral Perturbation (ERSP), the N100 peak, and global mean field power (GMFP). METHODS: We applied TMS-EEG targeting the non-dominant hemisphere premotor area in people with focal epilepsy (PWE) with a history of PIP (n = 7) and PWE without any history of psychosis (n = 14). Two-tailed t-tests were applied to TMS-EEG metrics previously studied in schizophrenia to look for differences between the groups, with subgroup analyses excluding participants using benzodiazepines. RESULTS: Demographic and clinical characteristics were similar across the two groups. No significant differences were seen in NF (p = 0.98). We observed a delayed N100 peak latency in the PIP group when excluding those with regular benzodiazepine use (p = 0.05) and increased global mean field power during the 400-600 ms phase of the TEP (p = 0.02). Mean ERSP within the gamma band was lower in the PIP group, though this did not reach statistical significance (p = 0.08). CONCLUSION: This is the first study to apply TMS-EEG in individuals with PIP, demonstrating feasibility and providing methodological insights for future studies. Preliminary findings, including increased GMFP and delayed N100 latency in PIP, suggest possible disruptions in cortical excitability similar to schizophrenia, warranting further investigation.

Humans↗
PubMed2006

Examining the role of common genetic variation in the gamma2 subunit of the GABA(A) receptor in epilepsy using tagging SNPs.

INTRODUCTION: Mutations in the gamma2 subunit gene of the GABA(A) receptor, GABRG2, have been shown to cause generalised epilepsy syndromes in rare familial cases. Here we set out to examine whether common variation in GABRG2 predisposes to the development of common, complex forms of epilepsy in two large independent cohorts. METHODS: We have applied a tagging single nucleotide polymorphism (tSNP) technique allowing us to satisfactorily represent common variation in the gene. However, to ensure maximal representation of functional variation and in particular in cases of low minor allele frequency (MAF), we have identified and forced known functional variation as tagging SNPs. We examined the association between tagging SNPs and subtypes of epilepsy in two independent cohorts; the first consisted of 677 cases and 384 healthy controls, the second of 684 cases and 277 healthy controls. RESULTS: We failed to detect any variation that conferred an increased risk of disease development in both cohorts. DISCUSSION: Our results suggest that common variants of strong effect in GABRG2 do not appear to play a role in the development of common, complex forms of epilepsy. This report illustrates a number of important features of study design in genetic association studies, including the simultaneous use of map and sequence-based techniques and the necessity of replication before robust conclusions can be drawn from results.

Alleles↗
PubMed2006

A pharmacogenetic exploration of vigabatrin-induced visual field constriction.

INTRODUCTION: Use of the antiepileptic drug (AED) vigabatrin is severely limited by irreversible visual field constriction, an adverse reaction to the drug reported in approximately 40% of patients. Given the evidence suggesting an idiosyncratic drug response, we set out to detect genetic variation of strong, clinically relevant effect that might guide clinicians in the safe, controlled prescribing of this otherwise usefuldrug. METHODS: Patients with a history of at least 1-year exposure to vigabatrin were enrolled at two independent referral centers. Using Goldmann perimetry, visual fields and the extent of constriction were calculated for each patient. We examined the correlation between the extent of vigabatrin induced visual field constriction and genetic variation across six candidate genes (SLC6A1, SLC6A13, SCL6A11, ABAT, GABRR1 and GABRR2). We availed of HapMap data and used a tagging SNP technique in an effort to efficiently capture all common variation within these genes. We attempted to replicate any positive associations before drawing conclusions from our results. RESULTS: The degree of visual field constriction correlated with three SNPs and one haplotype in a cohort of 73 patients. However we were unable to replicate these findings in a second independent cohort consisting of 58 patients, suggesting the initial results were possibly false positives, or variants of weak effect. CONCLUSION: Common variants of strong, clinically relevant effect do not appear to reside in the candidate genes studied here. This does not rule out the presence of genetic variants of weak effect in these genes, nor of variants of strong effect in other genes.

4-Aminobutyrate Transaminase↗
PubMed2006

Adult epilepsy.

The epilepsies are one of the most common serious brain disorders, can occur at all ages, and have many possible presentations and causes. Although incidence in childhood has fallen over the past three decades in developed countries, this reduction is matched by an increase in elderly people. Monogenic Mendelian epilepsies are rare. A clinical syndrome often has multiple possible genetic causes, and conversely, different mutations in one gene can lead to various epileptic syndromes. Most common epilepsies, however, are probably complex traits with environmental effects acting on inherited susceptibility, mediated by common variation in particular genes. Diagnosis of epilepsy remains clinical, and neurophysiological investigations assist with diagnosis of the syndrome. Brain imaging is making great progress in identifying the structural and functional causes and consequences of the epilepsies. Current antiepileptic drugs suppress seizures without influencing the underlying tendency to generate seizures, and are effective in 60-70% of individuals. Pharmacogenetic studies hold the promise of being able to better individualise treatment for each patient, with maximum possibility of benefit and minimum risk of adverse effects. For people with refractory focal epilepsy, neurosurgical resection offers the possibility of a life-changing cure. Potential new treatments include precise prediction of seizures and focal therapy with drug delivery, neural stimulation, and biological grafts.

Adult↗
PubMed2006

A novel homeobox mutation in the PITX2 gene in a family with Axenfeld-Rieger syndrome associated with brain, ocular, and dental phenotypes.

Axenfeld-Rieger Syndrome (ARS) is a genetically heterogeneous birth defect characterized by malformation of the anterior segment of the eye associated with glaucoma. Mutation of the PITX2 homeobox gene has been identified as a cause of ARS. We report a novel Arg5Trp missense mutation in the PITX2 homeodomain, which is associated with brain abnormalities. One patient had a small sella turcica likely to reflect hypoplasia of the pituitary gland and consistent with the critical role identified for Pitx2 in pituitary development in mice. Two patients had an enlarged cisterna magna, one with a malformed cerebellum, and two had executive skills deficits one in isolation and one in association with a below average intellectual capacity. The mutation caused a typical ARS ocular phenotype. All affected had iris hypoplasia, anterior iris to corneal adhesions, and corectopia. The ocular phenotype varied significantly in severity and showed some asymmetry. All affected also had redundant peri-umbilical skin, a hypoplastic maxilla, microdontia, and hypodontia missing between 20 and 27 teeth with an unusual pattern of tooth loss. Dental phenotypes were documented as they are often poorly characterized in ARS patients. All affected individuals showed an absence of first permanent molars with variable absence of other rarely absent teeth: the permanent upper central incisors, maxillary and mandibular first and second molars, and the mandibular canines. Based on the distinctive dental anomalies, we suggest that the dental phenotype can assist in predicting the presence of a PITX2 mutation and the possibility of brain abnormalities.

Abnormalities, Multiple↗
PubMed2006

A common polymorphism in the SCN1A gene associates with phenytoin serum levels at maintenance dose.

OBJECTIVES: A broad range of phenytoin doses is used in clinical practice, with the final 'maintenance' dose normally determined by trial and error. A common functional polymorphism in the SCN1A gene (one of the genes encoding the drug target) has been previously associated with maximum dose of phenytoin used clinically, and also maximum dose of carbamazepine, another antiepileptic drug with the same drug target. METHODS: We have related variation at the SCN1A IVS5-91 G>A polymorphism to maximum dose and to maintenance dose of phenytoin in 168 patients with epilepsy treated with phenytoin. We also related genotype to phenytoin serum levels at maximum dose and at maintenance dose of phenytoin. We genotyped the polymorphism using an Applied Biosystems Taqman assay. RESULTS: The polymorphism is associated with phenytoin serum concentration at maintenance dose (P=0.03). In a reduced cohort of 71 patients receiving phenytoin monotherapy this association is also significant (P=0.03). Neither association remains significant after Bonferroni correction for multiple testing. CONCLUSIONS: These results are not a replication of the original study. They do, however, support the hypothesis that this polymorphism influences the clinical use of phenytoin. They also demonstrate the utility of using multiple phenotypes in pharmacogenetics studies, particularly when attempting to separate pharmacokinetic and pharmacodynamic effects. As the SCN1A polymorphism affects phenytoin pharmacodynamics, it is particularly useful to obtain data on serum levels in addition to dose because association of a pharmacodynamic variant may be stronger with serum levels than dose as the serum level may eliminate or reduce pharmacokinetic variability.

Anticonvulsants↗
PubMed2006

Deregulation of cdk5 in Hippocampal sclerosis.

Hippocampal sclerosis (HS) is the most common cause of chronic medically refractory epilepsy in adults. Histologically, HS is characterized by segmental neuronal loss and gliosis. Although neuronal loss is important to the pathophysiology of HS, the molecular mechanisms underlying the neuronal loss remain uncertain. Recently, it has been appreciated that proteins important in neurodevelopment may also have a role in neurodegeneration. Cyclin-dependent kinase 5 (cdk5), known to be crucial in development of the normal cerebral cortex, has now been shown as pivotal in several cell death paradigms, including apoptosis and necrosis. Deregulation of cdk5 by p25 causes hyperphosphorylation of tau and may contribute to pathology in several neurodegenerative conditions. Furthermore, it has been shown that after transient forebrain ischemia, cdk5 causes specific death of CA1 neurons in the rat hippocampus by direct phosphorylation of the NR2A subunit of the NMDA receptor and subsequent excitotoxicity. Because apoptosis, necrosis, and excitotoxicity are all thought to contribute to neuronal loss in HS, we hypothesized that abnormalities of the cdk5 pathway would accompany this disorder. Surgically resected cases of HS with adjacent histologically normal lateral temporal cortex were examined for cdk5 and its activator p35/p25. We consistently found increased immunoreactivity for p35/p25 in surviving neurons within areas of neuronal loss compared with areas where neurons were preserved. Western blots showed the ratio of p25 to p35 to be greater in diseased hippocampi than in the adjacent histologically normal temporal lobe. Histone-based kinase assays demonstrated increased activity of the p25-cdk5 complex in HS compared with the temporal lobe despite neuronal loss in the hippocampal samples. Our results suggest that p25 is pathologically increased in HS and that deregulation of cdk5 by p25 might contribute to neuronal death in this condition.

Adult↗
PubMed2006

Role of SOX2 mutations in human hippocampal malformations and epilepsy.

PURPOSE: Seizures are noted in a significant proportion of cases of de novo, heterozygous, loss-of-function mutations in SOX2, ascertained because of severe bilateral eye malformations. We wished to determine the underlying cerebral phenotype in SOX2 mutation and to test the candidacy of SOX2 as a gene contributing to human epilepsies. METHODS: We examined high-resolution MRI scans in four patients with SOX2 mutations, two of whom had seizures. We determined the Sox2 expression pattern in developing murine brain. We searched for SOX2 mutation in 24 patients with typical hippocampal sclerosis and for common variations in SOX2 in 655 patients without eye disease but with epilepsy, including 91 patients with febrile seizures, 93 with hippocampal sclerosis, and 258 with temporal lobe epilepsy. RESULTS: Striking hippocampal and parahippocampal malformations were seen in all cases, with a history of febrile seizures or epilepsy in two of four cases. The Sox2 expression pattern in developing mouse brain supports the pattern of malformations observed. Mutation screening in patients with epilepsy did not reveal any abnormalities in SOX2. No associations were found between any clinical epilepsy phenotype and common variation in SOX2. CONCLUSIONS: SOX2 haploinsufficiency causes mesial temporal malformation in humans, making SOX2 dysfunction a candidate mechanism for mesial temporal abnormalities associated with chronic epilepsy. However, although mutation of SOX2 in humans causes hippocampal malformation, SOX2 mutation or variation is unlikely to contribute commonly to mesial temporal lobe epilepsy or its structural (hippocampal sclerosis) or historic (febrile seizures) associations in humans.

Adolescent↗
PubMed2005

SOX2 anophthalmia syndrome.

Heterozygous, de novo, loss-of-function mutations in SOX2 have been shown to cause bilateral anophthalmia. Here we provide a detailed description of the clinical features associated with SOX2 mutations in the five individuals with reported mutations and four newly identified cases (including the first reported SOX2 missense mutation). The SOX2-associated ocular malformations are variable in type, but most often bilateral and severe. Of the nine patients, six had bilateral anophthalmia and two had anophthalmia with contralateral microphthalmia with sclerocornea. The remaining case had anophthalmia with contralateral microphthalmia, posterior cortical cataract and a dysplastic optic disc, and was the only patient to have measurable visual acuity. The relatively consistent extraocular phenotype observed includes: learning disability, seizures, brain malformation, specific motor abnormalities, male genital tract malformations, mild facial dysmorphism, and postnatal growth failure. Identifying SOX2 mutations from large cohorts of patients with structural eye defects has delineated a new, clinically-recognizable, multisystem disorder and has provided important insight into the developmental pathways critical for morphogenesis of the eye, brain, and male genital tract.

Adolescent↗
PubMed2005

Failure to replicate previously reported genetic associations with sporadic temporal lobe epilepsy: where to from here?

Temporal lobe epilepsy (TLE), traditionally thought to develop largely due to environmental factors, has recently become the focus of association studies in an effort to determine genetic risk factors. Here we examine all previous claims of association of genetic polymorphisms with TLE by attempting replication in a cohort of 339 TLE patients of European origin. We also examine if these variants contribute to other types of epilepsy by examination in a larger cohort of 752 patients representing a range of different epilepsies. We fail to clearly replicate any of the previously reported associations and also fail to show a role for these variants in the development of other forms of epilepsy. Although our results cannot definitively rule out a role for these genes, they do suggest that most and perhaps all of the previous associations are false positives. As has been the experience with other diseases, these results highlight the importance of larger sample sizes and replication. In TLE, it appears that collaboration before publication is the best option to increase sample size sufficiently in the short term. These general principles are applicable to other studies undertaken for common complex diseases.

Amyloid↗
PubMed2005

Heterozygous mutations of OTX2 cause severe ocular malformations.

Major malformations of the human eye, including microphthalmia and anophthalmia, are examples of phenotypes that recur in families yet often show no clear Mendelian inheritance pattern. Defining loci by mapping is therefore rarely feasible. Using a candidate-gene approach, we have identified heterozygous coding-region changes in the homeobox gene OTX2 in eight families with ocular malformations. The expression pattern of OTX2 in human embryos is consistent with the eye phenotypes observed in the patients, which range from bilateral anophthalmia to retinal defects resembling Leber congenital amaurosis and pigmentary retinopathy. Magnetic resonance imaging scans revealed defects of the optic nerve, optic chiasm, and, in some cases, brain. In two families, the mutations appear to have occurred de novo in severely affected offspring, and, in two other families, the mutations have been inherited from a gonosomal mosaic parent. Data from these four families support a simple model in which OTX2 heterozygous loss-of-function mutations cause ocular malformations. Four additional families display complex inheritance patterns, suggesting that OTX2 mutations alone may not lead to consistent phenotypes. The high incidence of mosaicism and the reduced penetrance have implications for genetic counseling.

Amino Acid Motifs↗
PubMed2005

Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin.

Phenytoin and carbamazepine are effective and inexpensive anti-epileptic drugs (AEDs). As with many AEDs, a broad range of doses is used, with the final "maintenance" dose normally determined by trial and error. Although many genes could influence response to these medicines, there are obvious candidates. Both drugs target the alpha-subunit of the sodium channel, encoded by the SCN family of genes. Phenytoin is principally metabolized by CYP2C9, and both are probable substrates of the drug transporter P-glycoprotein. We therefore assessed whether variation in these genes associates with the clinical use of carbamazepine and phenytoin in cohorts of 425 and 281 patients, respectively. We report that a known functional polymorphism in CYP2C9 is highly associated with the maximum dose of phenytoin (P = 0.0066). We also show that an intronic polymorphism in the SCN1A gene shows significant association with maximum doses in regular usage of both carbamazepine and phenytoin (P = 0.0051 and P = 0.014, respectively). This polymorphism disrupts the consensus sequence of the 5' splice donor site of a highly conserved alternative exon (5N), and it significantly affects the proportions of the alternative transcripts in individuals with a history of epilepsy. These results provide evidence of a drug target polymorphism associated with the clinical use of AEDs and set the stage for a prospective evaluation of how pharmacogenetic diagnostics can be used to improve dosing decisions in the use of phenytoin and carbamazepine. Although the case made here is compelling, our results cannot be considered definitive or ready for clinical application until they are confirmed by independent replication.

Adolescent↗
PubMed2005

Genetics of drug resistance in epilepsy.

Drug resistance is a major clinical problem in epilepsy, affecting one in three patients. It is likely to have a complex multifactorial basis, with environmental and genetic contributions. Knowledge of robust genetic factors underlying drug resistance might both improve prediction and permit the development of novel rational treatments for resistance. A number of genetic association studies have been undertaken examining the effect of a range of candidate genes for resistance. Although some of these candidates have good biologic motivation for mediating resistance, currently there are no common genetic variants proven to generate the common clinical phenomenon of resistance. Much work remains to be done, but the scene is set for exciting developments that will hold therapeutic potential for patients with drug-resistant epilepsy.

Anticonvulsants↗
PubMed2005

Cell proliferation and granule cell dispersion in human hippocampal sclerosis.

Granule cell dispersion (GCD) is observed in approximately 40% of cases of hippocampal sclerosis (HS) in patients with epilepsy. Studies in animal models suggest that GCD may be a consequence of enhanced proliferation of granule cell precursors as a result of seizures. We quantified the number of cells in cycle in subfields of the hippocampus with immunohistochemistry for Mcm2 in 14 HS cases with or without severe GCD compared to 6 epilepsy patients without classical HS or GCD as well as 5 postmortem controls. Higher numbers of Mcm2-positive cells were seen in the region of the granule cell layer in patients with severe GCD, and immunolabeling with Geminin and Ki-67 confirmed a proportion were progressing through cycle. Double labeling with Mcm2 and GFAP confirmed the majority of these cycling cells were GFAP-negative and occasional cells stained colocalized with stem cell marker nestin. These findings support the view that GCD may be a phenomenon related to increased progenitor cell proliferation in patients with hippocampal damage and chronic epilepsy.

Adult↗
PubMed2005

Reliable registration of preoperative MRI with histopathology after temporal lobe resections.

PURPOSE: Conventional and novel magnetic resonance imaging (MRI) techniques can detect cerebral abnormalities in patients with refractory focal epilepsies. Correlation of preoperative MRI and histopathology is important to validate MRI findings, but in practice is far from straightforward. Peroperative neuronavigation and placement of markers on tissue is of limited use in temporal lobe resections. MRI scanning of the resected specimen for registration with in vivo MRI is complicated by anisotropic tissue deformation. We have developed a method to facilitate registration of preoperative MRI with the resected specimen and to enable correlation of MRI findings with histopathology. METHODS: Sixteen en bloc temporal lobe resections undertaken for refractory temporal lobe epilepsy were studied. The specimens were fixed in formalin and then cut coronally by using a cradle with parallel blades at 5-mm intervals to ensure evenly thick tissue slices in the same orientation. Volumetric T1-weighted preoperative MRIs were reformatted, and consecutive slices (0.94 mm) cut in the same orientation as the resected lobe were visually compared with photographs of tissue slices by two independent observers. RESULTS: In 15 (94%) of 16 cases, a <2-mm difference was found between the two observers' matches of MRI slices with tissue slices. In the last case, a 4-mm difference was noted. In all cases, a consensus was reached by the two observers. The suggested MRI-histology matches were within the resections seen on postoperative scans. CONCLUSIONS: Careful labelling and postoperative handling and slicing ensured histopathologic tissue slices of uniform thickness and slicing angle. This technique can be applied to a range of MRI datasets, enabling exploration of the pathologic basis of abnormalities on conventional and novel MRI acquisitions.

Anterior Temporal Lobectomy↗
PubMed2005

Genetics of drug resistance.

Drug resistance in epilepsy affects about a third of patients and is an important clinical problem, associated with increased morbidity and mortality. It is important to consider carefully the definition of drug resistance. Recent interest in the field has focused on the potential molecular mechanisms underlying drug resistance. Environmental and seizure-related acquired causes are likely to contribute to the multifaceted basis of resistance in most cases. Genetic causes have attracted particular attention, partly because they may allow prediction of drug resistance and, potentially, rational treatment strategies. Gene mutations, however, are unlikely to cause many cases of drug resistance. However, common variation in genes probably will turn out to generate an important contribution to drug resistance phenomena. Associations between common variations in a number of genes and clinical drug resistance have now been published. However, to date, none of these associations has been unequivocally replicated by others to the extent that the original association has been accepted. Some of these associations are considered. Despite this apparently uninspiring record, the genetics of drug resistance are likely to prove productive in the near future, but their pursuit will require painstaking studies and multicenter collaboration.

ATP Binding Cassette Transporter, Subfamily B↗