Testing for pharmacogenomic predictors of ppRNFL thinning in individuals exposed to vigabatrin.

Background: The anti-seizure medication vigabatrin (VGB) is effective for controlling seizures, especially infantile spasms. However, use is limited by VGB-associated visual field loss (VAVFL). The mechanisms by which VGB causes VAVFL remains unknown. Average peripapillary retinal nerve fibre layer (ppRNFL) thickness correlates with the degree of visual field loss (measured by mean radial degrees). Duration of VGB exposure, maximum daily VGB dose, and male sex are associated with ppRNFL thinning. Here we test the hypothesis that common genetic variation is a predictor of ppRNFL thinning in VGB exposed individuals. Identifying pharmacogenomic predictors of ppRNFL thinning in VGB exposed individuals could potentially enable safe prescribing of VGB and broader use of a highly effective drug. Methods: Optical coherence topography (OCT) and GWAS data were processed from VGB-exposed individuals (n = 71) recruited through the EpiPGX Consortium. We conducted quantitative GWAS analyses for the following OCT measurements: (1) average ppRNFL, (2) inferior quadrant, (3) nasal quadrant, (4) superior quadrant, (5) temporal quadrant, (6) inferior nasal sector, (7) nasal inferior sector, (8) superior nasal sector, and (9) nasal superior sector. Using the summary statistics from the GWAS analyses we conducted gene-based testing using VEGAS2. We conducted nine different PRS analyses using the OCT measurements. To determine if VGB-exposed individuals were predisposed to having a thinner RNFL, we calculated their polygenic burden for retinal thickness. PRS alleles for retinal thickness were calculated using published summary statistics from a large-scale GWAS of inner retinal morphology using the OCT images of UK Biobank participants. Results: The GWAS analyses did not identify a significant association after correction for multiple testing. Similarly, the gene-based and PRS analyses did not reveal a significant association that survived multiple testing. Conclusion: We set out to identify common genetic predictors for VGB induced ppRNFL thinning. Results suggest that large-effect common genetic predictors are unlikely to exist for ppRNFL thinning (as a marker of VAVFL). Sample size was a limitation of this study. However, further recruitment is a challenge as VGB is rarely used today because of this adverse reaction. Rare variants may be predictors of this adverse drug reaction and were not studied here.

Symptomatology of carbamazepine- and oxcarbazepine-induced hyponatremia in people with epilepsy.

OBJECTIVE: To ascertain whether adverse effects experienced by people taking carbamazepine or oxcarbazepine could be attributed to carbamazepine- or oxcarbazepine-induced hyponatremia (COIH). METHODS: We performed an observational study, collecting data between 2017 and 2019 on serum sodium levels and adverse effects retrospectively in people with epilepsy while receiving treatment with either carbamazepine (CBZ) or oxcarbazepine (OXC). We defined hyponatremia as sodium level ≤134 mEq/L and severe hyponatremia as sodium level ≤128 mEq/L. Adverse effects experienced were compared between groups of individuals with and without hyponatremia. RESULTS: A total of 1370 people using CBZ or OXC were identified, of whom 410 had at least one episode of hyponatremia. We checked for symptoms related to the use of CBZ and OXC in 710 people (410 with and 300 without hyponatremia) and found relevant information in 688. Adverse effects occurred in 65% of people with hyponatremia compared to 21% with normal sodium levels (odds ratio [OR] 7.5, P ≤ .001) and in 83% of people with severe hyponatremia compared to 55% in those with mild hyponatremia (P ≤ .001). Significant predictors of adverse effects were the drug (OXC vs CBZ), and the number of concomitant anti-seizure medications. Dizziness (28% vs 6%), tiredness (22% vs 7%), instability (19% vs 3%), and diplopia (16% vs 4%) were reported more often in the hyponatremia group than in patients with normal levels. SIGNIFICANCE: People with COIH had a 7-fold increased risk of developing adverse effects during treatment. Clinicians should consider ascertainment of sodium levels in patients taking CBZ and OXC and act upon findings.

A genome-wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine.

OBJECTIVE: To ascertain the clinical and genetic factors contributing to carbamazepine- and oxcarbazepine-induced hyponatremia (COIH), and to carbamazepine (CBZ) metabolism, in a retrospectively collected, cross-sectional cohort of people with epilepsy. METHODS: We collected data on serum sodium levels and antiepileptic drug levels in people with epilepsy attending a tertiary epilepsy center while on treatment with CBZ or OXC. We defined hyponatremia as Na+ ≤134 mEq/L. We estimated the CBZ metabolic ratio defined as the log transformation of the ratio of metabolite CBZ-diol to unchanged drug precursor substrate as measured in serum. RESULTS: Clinical and genetic data relating to carbamazepine and oxcarbazepine trials were collected in 1141 patients. We did not observe any genome-wide significant associations with sodium level in a linear trend or hyponatremia as a dichotomous trait. Age, sex, number of comedications, phenytoin use, phenobarbital use, and sodium valproate use were significant predictors of CBZ metabolic ratio. No genome-wide significant associations with CBZ metabolic ratio were found. SIGNIFICANCE: Although we did not detect a genetic predictor of hyponatremia or CBZ metabolism in our cohort, our findings suggest that the determinants of CBZ metabolism are multifactorial.

Review on the relevance of therapeutic drug monitoring of levetiracetam.

Therapeutic Drug Monitoring (TDM) of anti-epileptic drugs (AEDs) is not routinely performed, although this can guide the dosage regimen to achieve greater efficacy and safety. Levetiracetam (LEV) has been introduced as an AED with an almost perfect pharmacokinetic (PK) profile. Nonetheless, recent research challenges this statement and therefore we aimed to explore factors that modify LEV PK. Age and enzyme-inducing drugs (EIDs) appear to be major factors influencing the PK profile of LEV. Therefore, 30-50% lower dosages should be used in the elderly (> 65 years of age) and the dosing regimen should be guided by monitoring SDC (TDM). In contrast, higher LEV dosages are necessary in children aged between 2 months and 12 years (compared to adults) due to a 30-70% increase of LEV clearance (CL). Higher dosages are also required if a patient receives EIDs, again due to a higher CL of LEV (range 24-60%). This could also be true for pregnant women. LEV TDM is currently not common in the clinical setting due to the wide therapeutic range and the low prevalence of side-effects. However, LEV dose should on the one hand be increased in certain physiological situations (pregnancy, neonates) and patients on EIDs (especially carbamazepine). On the other hand, dose reductions are necessary when the LEV CL is impaired (elderly). Nevertheless, current data to support regular LEV TDM are lacking. Prospective research is needed to explore the importance of LEV TDM in elected patient groups; i.e. neonates, elderly, patients on EIDs and pregnant women.

Carbamazepine- and oxcarbazepine-induced hyponatremia in people with epilepsy.

OBJECTIVE: To ascertain possible determinants of carbamazepine (CBZ)- and oxcarbazepine (OXC)-induced hyponatremia in a large cohort of people with epilepsy. METHODS: We collected data on serum sodium levels in people with epilepsy who were attending a tertiary epilepsy center while on treatment with CBZ or OXC. We defined hyponatremia as Na+ ≤134 mEq/L and severe hyponatremia as Na+ ≤128 mEq/L. RESULTS: We identified 1,782 people who had used CBZ (n = 1,424) or OXC (n = 358), of whom 50 were treated with both drugs. Data on sodium level measurements were available in 1,132 on CBZ and in 289 on OXC. Hyponatremia occurred in 26% of those taking CBZ and 46% of those taking OXC. This was severe in 7% in the CBZ group and 22% in the OXC group. Hyponatremia was symptomatic in 48% and led to admissions in 3%. Age over 40 years, high serum levels of CBZ and OXC, and concomitant use of other antiepileptic drugs were the main risk factors for hyponatremia in both treatment groups. Female patients on OXC were at a higher risk than male patients of hyponatremia. The risk of hyponatremia on CBZ was significantly associated with the risk of hyponatremia on OXC within a subgroup that used both drugs consecutively. SIGNIFICANCE: Hyponatremia is a common problem in people taking CBZ or OXC. Regular ascertainment of sodium levels in those taking either drug is recommended and results should be acted on.

Clinical and genetic analysis of a family with two rare reflex epilepsies.

PURPOSE: To determine clinical phenotypes, evolution and genetic background of a large family with a combination of two unusual forms of reflex epilepsies. METHOD: Phenotyping was performed in eighteen family members (10 F, 8 M) including standardized EEG recordings with intermittent photic stimulation (IPS). Genetic analyses (linkage scans, Whole Exome Sequencing (WES) and Functional studies) were performed using photoparoxysmal EEG responses (PPRs) as affection status. RESULTS: The proband suffered from speaking induced jaw-jerks and increasing limb jerks evoked by flickering sunlight since about 50 years of age. Three of her family members had the same phenotype. Generalized PPRs were found in seven members (six above 50 years of age) with myoclonus during the PPR. Evolution was typical: Sensitivity to lights with migraine-like complaints around adolescence, followed by jerks evoked by lights and spontaneously with dropping of objects, and strong increase of light sensitivity and onset of talking induced jaw jerks around 50 years. Linkage analysis showed suggestive evidence for linkage to four genomic regions. All photosensitive family members shared a heterozygous R129C mutation in the SCNM1 gene that regulates splicing of voltage gated ion channels. Mutation screening of 134 unrelated PPR patients and 95 healthy controls, did not replicate these findings. CONCLUSION: This family presents a combination of two rare reflex epilepsies. Genetic analysis favors four genomic regions and points to a shared SCNM1 mutation that was not replicated in a general cohort of photosensitive subjects. Further genetic studies in families with similar combination of features are warranted.

Sudden cardiac arrest in people with epilepsy in the community: Circumstances and risk factors.

OBJECTIVE: To ascertain whether characteristics of ventricular tachycardia/fibrillation (VT/VF) differed between people with epilepsy and those without and which individuals with epilepsy were at highest risk. METHODS: We ascertained 18 people with active epilepsy identified in a community-based registry of sudden cardiac arrest (SCA) with ECG-confirmed VT/VF (cases). We compared them with 470 individuals with VT/VF without epilepsy (VT/VF controls) and 54 individuals with epilepsy without VT/VF (epilepsy controls). Data on comorbidity, epilepsy severity, and medication use were collected and entered into (conditional) logistic regression models to identify determinants of VT/VF in epilepsy. RESULTS: In most cases, there was an obvious (10/18) or presumed cardiovascular cause (5/18) in view of preexisting heart disease. In 2 of the 3 remaining events, near-sudden unexpected death in epilepsy (SUDEP) was established after successful resuscitation. Cases had a higher prevalence of congenital/inherited heart disease (17% vs 1%, p = 0.002), and experienced VT/VF at younger age (57 vs 64 years, p = 0.023) than VT/VF controls. VT/VF in cases occurred more frequently at/near home (89% vs 58%, p = 0.009), and was less frequently witnessed (72% vs 89%, p = 0.048) than in VT/VF controls. Cases more frequently had clinically relevant heart disease (50% vs 15%, p = 0.005) and intellectual disability (28% vs 1%, p < 0.001) than epilepsy controls. CONCLUSION: Cardiovascular disease rather than epilepsy characteristics is the main determinant of VT/VF in people with epilepsy in the community. SCA and SUDEP are partially overlapping disease entities.

Seizure precipitants in a community-based epilepsy cohort.

Epileptic seizures can be provoked by several factors. Better understanding of these factors may improve a patient's sense of control and could reduce seizures. In daily practice, the recognition of seizure precipitants relies heavily on clinical or video-EEG evidence, which can be difficult to obtain. Studies of seizure provocation are largely based on selected hospital-based patient populations, which may lead to biased occurrence estimates. Self-reported seizure precipitants are rarely studied, yet are necessary to understand the experiences of patients and improve epilepsy management. We performed a cross-sectional community-based study of 248 epilepsy patients, selected by pharmacy records of anti-epileptic drug use. Self-reported seizure precipitants and potential associated characteristics were assessed using questionnaires. Almost half of all patients (47 %) reported one or more seizure precipitants, of which stress, sleep deprivation, and flickering lights were the most common. In this community-based setting, light-provoked seizures were especially frequent compared to the literature. Idiopathic generalized epilepsy (IGE), a lower age at seizure onset, and having auras or prodromes were found to be important independent prognostic factors associated with provoked seizures. IGE and a younger age at seizure onset have been linked to provoked seizures in earlier reports. The finding of auras or prodromes as a prognostic factor was unexpected, though case reports have described provoked seizures in patients having auras. Assessment of these factors may facilitate the early recognition of seizure precipitants in daily clinical practice. This is important for the optimization of epilepsy management for a large group of patients, as provoked seizures are expected to occur frequently.

Structural genomic variation in childhood epilepsies with complex phenotypes.

A genetic contribution to a broad range of epilepsies has been postulated, and particularly copy number variations (CNVs) have emerged as significant genetic risk factors. However, the role of CNVs in patients with epilepsies with complex phenotypes is not known. Therefore, we investigated the role of CNVs in patients with unclassified epilepsies and complex phenotypes. A total of 222 patients from three European countries, including patients with structural lesions on magnetic resonance imaging (MRI), dysmorphic features, and multiple congenital anomalies, were clinically evaluated and screened for CNVs. MRI findings including acquired or developmental lesions and patient characteristics were subdivided and analyzed in subgroups. MRI data were available for 88.3% of patients, of whom 41.6% had abnormal MRI findings. Eighty-eight rare CNVs were discovered in 71 out of 222 patients (31.9%). Segregation of all identified variants could be assessed in 42 patients, 11 of which were de novo. The frequency of all structural variants and de novo variants was not statistically different between patients with or without MRI abnormalities or MRI subcategories. Patients with dysmorphic features were more likely to carry a rare CNV. Genome-wide screening methods for rare CNVs may provide clues for the genetic etiology in patients with a broader range of epilepsies than previously anticipated, including in patients with various brain anomalies detectable by MRI. Performing genome-wide screens for rare CNVs can be a valuable contribution to the routine diagnostic workup in patients with a broad range of childhood epilepsies.

Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32.

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, P(meta) = 2.5 × 10(-9), OR[T] = 0.81) and 17q21.32 (rs72823592, P(meta) = 9.3 × 10(-9), OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, P(meta) = 9.1 × 10(-9), OR[T] = 0.68) and at 1q43 for JME (rs12059546, P(meta) = 4.1 × 10(-8), OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, P(meta) = 4.0 × 10(-6)) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndromes.

Patterns of peripapillary retinal nerve fiber layer thinning in vigabatrin-exposed individuals.

PURPOSE: To explore the relationship of peripapillary retinal nerve fiber layer (ppRNFL) thinning in individuals exposed to the antiepileptic drug vigabatrin with respect to 2 separate variables: cumulative vigabatrin exposure and severity of vigabatrin-associated visual field loss (VAVFL). DESIGN: Cross-sectional observational study. PARTICIPANTS: Subjects were older than 18 years, 129 with vigabatrin-treated epilepsy (vigabatrin-exposed group) and 87 individuals with epilepsy never treated with vigabatrin (nonexposed group). METHODS: All subjects underwent ppRNFL imaging using spectral-domain optical coherence tomography. Eighty-four vigabatrin-exposed individuals underwent Goldmann kinetic perimetry. The visual field examined from the right eye was categorized as normal (n = 47), mildly abnormal (n = 18), or moderately to severely abnormal (n = 19). In 91 vigabatrin-exposed individuals, the cumulative vigabatrin exposure could be ascertained: 41 subjects received 1000 g or less, 23 subjects received more than 1000 g but equal to or less than 2500 g, 16 subjects received more than 2500 g but equal to or less than 5000 g or less, and 11 subjects received more than 5000 g. MAIN OUTCOME MEASURES: Differences in ppRNFL thickness across the twelve 30° sectors: (1) among all nonexposed individuals and all vigabatrin-exposed individuals, (2) between each vigabatrin-exposed group, according to cumulative vigabatrin exposure, and the nonexposed group, (3) among different vigabatrin-exposed subjects grouped according to cumulative vigabatrin exposure, and (4) among vigabatrin-exposed subjects grouped according to severity of VAVFL. RESULTS: The ppRNFL was significantly thinner in vigabatrin-exposed compared with nonexposed individuals in most 30° sectors (P<0.004). The temporal, temporal superior, and temporal inferior 30° sectors, as well as the nasal 30° sector, were not affected. There was a trend for increasing ppRNFL thinning with increasing cumulative vigabatrin exposure. The nasal-superior 30° sector was significantly thinner in group 1 (≤1000 g) compared with nonexposed individuals (P<0.05) and in vigabatrin-exposed individuals with normal visual fields compared with nonexposed individuals (P<0.05). CONCLUSIONS: After vigabatrin exposure in individuals receiving cumulative doses of 1000 g or less or in the presence of normal visual fields, ppRNFL thinning in the nasal superior 30° sector may occur. With higher cumulative doses of vigabatrin exposure, additional ppRNFL thinning was observed. The temporal aspects of the ppRNFL are spared, even in individuals with large cumulative vigabatrin exposures and moderate or severe VAVFL.

Retinal nerve fiber layer thickness in vigabatrin-exposed patients.

OBJECTIVE: Vigabatrin-associated visual field loss (VAVFL) occurs in 25 to 50% of exposed patients and is routinely monitored using perimetry, which has inherent limitations. Using optical coherence tomography (OCT), retinal nerve fiber layer (RNFL) thinning has been described in a small number of vigabatrin-exposed patients. We explored the relationship between RNFL thickness and visual field size, to determine whether OCT is a suitable tool to use in patients exposed to vigabatrin. METHODS: Two hundred one vigabatrin-exposed subjects with epilepsy, divided into 2 groups, and 90 healthy controls participated. Visual fields were obtained using Goldmann kinetic perimetry and quantified using mean radial degrees (MRD). RNFL imaging was performed using either spectral-domain (Group 1) or time-domain (Group 2) OCT. RESULTS: Thirty-nine of 201 (19.4%) patients were unable to perform perimetry. Thirteen (6.5%) patients were unable to perform OCT. A total of 51.6% of patients showed VAVFL. Average RNFL thickness was significantly thinner in patients (77.9 µm) compared to healthy controls (93.6 µm) (p < 0.001). There was a strong correlation between MRD and average RNFL thickness for Group 1 (r = 0.768, p < 0.001) and Group 2 (r = 0.814, p < 0.001). OCT RNFL imaging showed high repeatability. INTERPRETATION: OCT provides a useful tool to assess people exposed to vigabatrin, and can provide an accurate estimate of the extent of visual field loss in the absence of a reliable direct measure of the visual field. The strong linear relationship found between RNFL thickness and visual field size provides some evidence that irreversible VAVFL may be related to loss of retinal ganglion cell axons.

Drug monitoring of lamotrigine and oxcarbazepine combination during pregnancy.

Little is known about pregnancy-induced alterations in the pharmacokinetics of the newer antiepileptic drugs, especially when used in combinations. Two women receiving combination therapy of lamotrigine (LTG) and oxcarbazepine (OXC) were followed prospectively during pregnancy and puerperium. Steady-state concentrations of LTG and the active metabolite of OXC, 10-hydroxycarbazepine (MHD), were measured at regular intervals using a dried blood spot method, and clearances were calculated. A strong effect of pregnancy on the clearance of both LTG and MHD was seen. An increase in seizure frequency occurred in both women. This stresses the importance of therapeutic drug monitoring of LTG and MHD during pregnancy. In case of breakthrough seizures or increased seizure frequency, dosage adjustment of both drugs may be required.

A comparison of midazolam nasal spray and diazepam rectal solution for the residential treatment of seizure exacerbations.

Rectal diazepam is established as a standard rescue or emergency treatment for seizure or status epilepticus; however, the rectal route of administration has not been universally accepted. To determine if an alternative route of administration of a benzodiazepine was equally effective, we compared a novel midazolam HCl concentrated nasal spray (MDZ-n) with diazepam rectal solution (DZP-r) in the treatment of prolonged seizures in a residential epilepsy center. In 21 adult patients with medically refractory epilepsy, 124 seizure-exacerbations were treated by their caregivers, alternatively with 10 mg DZP-r and 10 mg concentrated MDZ-n, two or three treatments with each medication for each patient. No difference was demonstrated in efficacy or time to effect between the two drugs. Common treatment emerging adverse effects were drowsiness for both drugs in more than 50% of the administrations, and short-lasting local irritation after 29% of MDZ-n. No severe adverse events occurred. The nasal spray was preferred to the rectal solution by 16 of 21 caregivers and patients conjointly. MDZ-n was equal to DZP-r with respect to efficacy and side effects in the suppression of seizure exacerbations. The majority of patients and caregivers preferred the nasal spray over the rectal formulation.

15q13.3 microdeletions increase risk of idiopathic generalized epilepsy.

We identified 15q13.3 microdeletions encompassing the CHRNA7 gene in 12 of 1,223 individuals with idiopathic generalized epilepsy (IGE), which were not detected in 3,699 controls (joint P = 5.32 x 10(-8)). Most deletion carriers showed common IGE syndromes without other features previously associated with 15q13.3 microdeletions, such as intellectual disability, autism or schizophrenia. Our results indicate that 15q13.3 microdeletions constitute the most prevalent risk factor for common epilepsies identified to date.

Heterogeneity at the JME 6p11-12 locus: absence of mutations in the EFHC1 gene in linked Dutch families.

PURPOSE: The EFHC1 gene, encoding a protein with a Ca(2+)-sensing EF-hand motif, is localized at 6p12 and was recently reported as mutated in six Mexican juvenile myoclonic epilepsy (JME) families linked to this region. We had previously confirmed linkage between JME and 6p11-12 in 18 Dutch families, and shown exclusionary lod scores at 6p21.3. We therefore evaluated the relevance of EFHC1 in our set of 6p11-12-linked families. METHODS: We screened all coding and regulatory regions of EFHC1 by direct sequencing, and the detected variants were tested in a case-control association study. RESULTS: We found none of the five mutations previously reported in the Mexican families, but identified nine variants, three of which are novel: 5' upstream region (c.-146_147delGC), nonsynonymous (R159W, R182H, M448T, I619L), intronic (IVS3 + 10A>G, IVS8 + 175_176delTT, IVS10 + 59C>T), and 3' UTR (c.+121C>A). These variants did not cosegregate with JME and did not account for the observed linkage at the 6p11-12 locus. Furthermore, no significant association was detected between JME and these variants in 112 unrelated patients and 180 controls. Finally, none of the mutations reported in Mexican families was found in 100 unrelated patients. CONCLUSIONS: We found no evidence that EFHC1 is a major genetic risk factor for JME susceptibility in Dutch patients. The EFHC1 variants reported in Mexican families may be mendelian variants specific for those families, suggesting that for Dutch patients and possibly many other populations, the main disease variant at the 6p11-12 is yet to be identified.

A novel splicing mutation in KCNQ2 in a multigenerational family with BFNC followed for 25 years.

PURPOSE: A large multigenerational family with benign familial neonatal convulsions (BFNC) was revisited to identify the disease-causing mutation and to assess long-term outcome. METHODS: We supplemented the original data with recent clinical and neurophysiologic data on patients and first-degree relatives, including information on seizure recurrence. We conducted linkage analysis at the EBN1 and EBN2 loci, followed by mutation analysis of KCNQ2. We evaluated the qualitative effect of the KCNQ2 mutation at the messenger RNA (mRNA) level by using reverse-transcribed total RNA isolated from leukocytes. RESULTS: Thirteen relatives had a history of neonatal convulsions, 11 of whom showed remission within 2 months. One patient showed an atypical course of neonatal convulsions, developing photosensitive myoclonic epilepsy at age 13 years. We found suggestive linkage of the BFNC phenotype to the 20q13-EBN1 locus (lod score, 2.03) and an intronic mutation IVS14-6 C>A in KCNQ2 segregating with the trait in all affected members, but absent in 100 unrelated control subjects. This mutation creates a new, preferentially used, splice site. Alternative splicing adds 4 nt containing a premature stop codon to the transcript, resulting in a truncated protein after position R588. CONCLUSIONS: We detected and characterized a novel splicing mutation in the brain-specific KCNQ2 gene by using easily accessible blood leukocytes. Aberrant splicing cosegregates with BFNC but not with photosensitivity.

Oligogenic inheritance in photosensitive juvenile myoclonic epilepsy?

The interplay of multiple genetic factors, as opposed to monogenic inheritance, is suspected to play a role in many idiopathic generalized epilepsies. This leads to a digenic or oligogenic inheritance model, which although rather simplified, may explain at least some of the clinical observations. Here we describe a family in which the clinical phenotype in the offspring can be explained by a combination of photosensitivity and epilepsy traits that segregated independently of each other. This case history demonstrates the need to evaluate family histories in more detail in order to uncover potential clinical markers for genetic factors in complex epilepsies.