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Segregation analysis in mesial temporal lobe epilepsy with hippocampal atrophy
2010; Wiley; Volume: 51; Issue: s1 Linguagem: Inglês
10.1111/j.1528-1167.2009.02445.x
ISSN1528-1167
AutoresRodrigo Secolin, Cláudia Vianna Maurer‐Morelli, Fernando Cendes, Íscia Lopes‐Cendes,
Tópico(s)Genomic variations and chromosomal abnormalities
ResumoEpilepsiaVolume 51, Issue s1 p. 47-50 Free Access Segregation analysis in mesial temporal lobe epilepsy with hippocampal atrophy Rodrigo Secolin, Rodrigo Secolin Department of Medical GeneticsSearch for more papers by this authorClaudia Maurer-Morelli, Claudia Maurer-Morelli Department of Medical GeneticsSearch for more papers by this authorFernando Cendes, Fernando Cendes Department of Neurology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, Sao Paulo, BrazilSearch for more papers by this authorIscia Lopes-Cendes, Iscia Lopes-Cendes Department of Medical GeneticsSearch for more papers by this author Rodrigo Secolin, Rodrigo Secolin Department of Medical GeneticsSearch for more papers by this authorClaudia Maurer-Morelli, Claudia Maurer-Morelli Department of Medical GeneticsSearch for more papers by this authorFernando Cendes, Fernando Cendes Department of Neurology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, Sao Paulo, BrazilSearch for more papers by this authorIscia Lopes-Cendes, Iscia Lopes-Cendes Department of Medical GeneticsSearch for more papers by this author First published: 19 January 2010 https://doi.org/10.1111/j.1528-1167.2009.02445.xCitations: 3 Address correspondence to Iscia Lopes-Cendes, MD, PhD, Department of Medical Genetics, FCM – UNICAMP, Tessália Vieira de Camargo, 126, Cidade Universitária Zeferino Vaz, 13084-971 Campinas, SP, Brazil. E-mail: icendes@unicamp.br AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat It is well known that among epilepsies with focal seizure onset, temporal lobe epilepsies (TLEs) are the most common forms (Gloor, 1991). Mesial temporal lobe epilepsy (MTLE) is one type of TLE frequently associated with mesial temporal sclerosis (MTS), a neuropathologic abnormality that can be diagnosed in vivo by high-resolution brain imaging as hippocampal atrophy (HA) and abnormal signal intensity (Berkovic et al., 1991; Cendes et al., 1993a). MTS, which is characterized by selective neuronal loss and gliosis in regions of hippocampus and hilus, has been associated with predisposing environmental factors, such as prolonged febrile seizures (FS) in childhood (Abou-Khalil et al., 1993; Cendes et al., 1993b). Familial forms of TLE have been identified, suggesting that genetic factors could be involved in the determination of different types of TLE (Berkovic et al., 1996; Ottman et al., 1995; Gambardella et al., 2000). Familial recurrence of MTLE associated with HA has also been reported (Cendes et al., 1998; Fernandez et al., 1998; Kobayashi et al., 2001). Extensive phenotypic studies in large MTLE families showed a certain degree of variability in clinical and imaging findings, but most affected individuals have a benign course of the disease. In these families HA was observed in patients who had refractory seizures, requiring surgical treatment (Kobayashi et al., 2003a), as well as in individuals who had only a single partial seizure and, unexpectedly, in 34% of asymptomatic first-degree relatives of patients (Kobayashi et al., 2002, 2003b). These initial observations suggested that genetic factors may play a role in MTLE associated with HA. In order to further investigate this issue we performed complex segregation analysis in a sample of nuclear families of probands with MTLE and HA. Methods Ascertainment of patients and data collection Ascertainment of patients and clinical data collection are systematically performed in all probands with MTLE followed at the epilepsy clinic of our university hospital. The diagnosis of MTLE was based on clinical and electroencephalography (EEG) findings as defined by the International League against Epilepsy (ILAE) criteria (1989). Information on probands was collected regardless of family history and obtained from all patients who fulfilled the clinical and EEG criteria for MTLE. Subsequently, extended family history was obtained from the probands as well as available family members. HA was detected by volumetric magnetic resonance imaging (MRI) (Kobayashi et al., 2001, 2002). For calculation purposes the sample was divided into nuclear families, including the probands and their first-degree relatives. The ascertainment probability (π) was used for ascertainment correction (Lalouel & Morton, 1981; Ginsburg et al., 2003). All individuals evaluated provided written informed consent and this study was approved by the research ethics committee of our institution. We considered as affected only individuals with MTLE associated with HA confirmed by MRI; unaffected individuals who did not present MTLE regardless of the presence of HA; and unknown individuals with MTLE but not evaluated with MRI. Segregation analysis Segregation analysis was performed under the mixed model implemented by the POINTER software (available at http://cedar.genetics.soton.ac.uk/pub/PROGRAMS/pointer, University of Southampton, U.K.) (Lalouel & Morton, 1981). The mixed model assumes a phenotype (x) with independent contribution of a major gene locus (g), a multifactorial component (c), and an environmental component (e). The overall phenotype is defined as x = g + c + e, and total variance is defined as V = G + C + E. The major locus has two alleles (A, a) and the genotype frequencies follow the Hardy-Weinberg equilibrium. Four parameters were estimated: dominance (d), or the relative position of heterozygote mean, where d = 1 indicates a dominant gene, whereas d = 0.5 indicates additive and d = 0 indicates a recessive gene; displacement (t) between the two extreme homozygote means; allele frequency (q); and heritability (H), which represents the proportion between the variance of multifactorial component and total variance (H = C/V). Transmission probabilities (τ1, τ2, and τ3) were analyzed for Mendelian pattern of transmission from parents to offspring. These parameters—τ1, τ2, and τ3–denote probabilities of transmitting allele A for genotypes AA, Aa, and aa, respectively. Under Mendelian transmission, τ1 = 1, τ2 = 0.5, τ3 = 0 and no transmission, τ1 = τ2 = τ3. Models were estimated by maximizing conditional likelihood (L) of nuclear family phenotypes. The difference between −2lnL under a general model with m parameters and −2lnL under a nested model with n parameters is χ2 asymptotically distributed, with m−n degrees of freedom, where p-values <0.05 reject the analyzed model. Because these results can be biased for multiple tests, p-values were adjusted using false discovery rate (FDR) correction (Storey & Tibshirani, 2003) by p.adjust function in R environment (R Development Core Team, 2006). In addition, we used the Akaike Information Criterion (AIC) (Akaike, 1974), which is −2lnL plus twice the number of free parameters in the model. This comparison has the advantage that one model does not have to be a subset of the other one. The model with lowest AIC indicates most parsimonious fit of the observed data. Results We evaluated a total of 698 individuals, distributed into 148 nuclear families, which were ascertained from 76 unrelated probands with MTLE (π = 0.60 for ascertainment correction). There were 95 nuclear families (64.2%) with only one affected individual and 53 (35.8%) with two or more affected individuals (Table 1). There were 123 affected, 543 unaffected, and 32 unknown individuals. Among the 543 unaffected individuals, we found 15 individuals with HA; 91 individuals without HA; and 437 individuals who did not have MRI studies performed. Among the 123 affected individuals, there were 20 (12%) who reported an antecedent of febrile seizures. Table 1. Proportion of affected individuals per family No. of individuals/nuclear family No. of nuclear families (%) 1 95 (64.2) 2 22 (14.9) 3 15 (10.1) 4 4 (2.7) 5 7 (4.7) 6 5 (3.4) Total 148 (100) As shown in Table 2, our results rejected the random model (χ24 = 133.760; p < 0.001) and the absence of a major a gene (χ23 = 133.760; p < 0.001). We could not reject the multifactorial model (χ21 = 0.002; p = 0.999), as well as recessive (χ22 = 2.084; p = 0.407), codominant (χ22 = 0.112; p = 0.999), and dominant (χ22 = 0.002; p = 0.999) inheritance. However, comparison of AIC values indicated that the autosomal dominant model (AIC = 315.096) is more parsimonious than recessive (AIC = 317.178) and codominant (AIC = 315.206) models. In addition, we did not reject a Mendelian transmission (χ23 = 3.665; p = 0.450) in comparison with non-Mendelian transmission (χ23 = 30.159; p < 0.001). Table 2. Segregation analysis performed for mesial temporal lobe epilepsy (MTLE) with hippocampal atrophy (HA). Values between square brackets were fixed for calculation purposes Model d t Q H τ1 τ2 τ3 −2lnL χ2 d.f. p* Test AIC 1. Mixed 1.000 1.736 0.286 0.064 [1] [0.5] [0] 311.094 319.094 2. Sporadic [0] [0] [0] [0] [1] [0.5] [0] 444.854 133.760 4 0.000 2 × 1 444.854 3. Absence major gene [0] [0] [0] 0.700 [1] [0.5] [0] 444.854 133.760 3 0.000 3 × 1 446.854 4. Multifactorial 1.002 1.736 0.286 [0] [1] [0.5] [0] 311.096 0.002 1 0.999 4 × 1 317.096 5. Recessive (d = 0) [0] 1.921 0.700 [0] [1] [0.5] [0] 313.178 2.084 2 0.407 5 × 1 317.178 6. Codominant (d = 0,5) [0.5] 2.841 0.287 [0] [1] [0.5] [0] 311.206 0.112 2 0.999 6 × 1 315.206 7. Dominant (d = 1) [1] 1.738 0.286 [0] [1] [0.5] [0] 311.096 0.002 2 0.999 7 × 1 315.096 8. Mendelian [1] 1.637 0.346 [0] 1.000 0.962 0.000 229.637 81.459 3 0.000 7 × 8 239.637 9. Non-Mendelian [1] 1.808 0.299 [0] [0.701] [0.701] [0.701] 444.854 215.217 3 0.000 9 × 8 448.854 d, dominance; t, displacement; q, allele frequency; H, heritability; τ1, τ2, τ3, probabilities of transmitting allele A for genotypes AA, Aa and aa, respectively; L, likelihood; χ2, chi-square; d.f., degrees of freedom; p*, corrected p-values; AIC, Akaike Information Criterion. Discussion Complex segregation analysis has been successfully used to evaluate the transmission of a trait from pedigree data in several diseases (Jarvik, 1998), showing that complex segregation analysis is a powerful and reliable tool even in the molecular genetics era. Complex segregation analysis can determine whether a Mendelian locus has an effect on a particular phenotype. In addition, it can test for the possible inheritance pattern and the magnitude of environmental and polygenic effects that could be influencing the final phenotype. All these inferred parameters can be subsequently used in linkage analysis, fine mapping, and other gene identification strategies related to the phenotype (Jarvik, 1998). Several studies have suggested different inheritance patterns in various epilepsy syndromes. Direct observation of pedigrees with generalized epilepsy with febrile seizures plus, benign familial neonatal convulsions, autosomal dominant nocturnal frontal epilepsy, and familial partial epilepsy with variable foci is consistent with autosomal dominant inheritance with incomplete penetrance; whereas, most progressive myoclonus epilepsy syndromes present an autosomal recessive mode of inheritance (Callenbach et al., 2005). Moreover, Ottman et al. (1995) suggested an autosomal dominant inheritance in a single family with partial epilepsy and auditory auras based in a preliminary segregation analysis. Although Berkovic et al. (1996) have proposed an autosomal dominant inheritance in a familial form of TLE with no MRI abnormalities, to our knowledge there is no previous segregation analysis performed in MTLE with HA. The relationship between MTLE and MTS has been recognized in classical histopathologic studies (Gloor, 1991; Blümcke et al., 1999) and more recently correlated with neuroimaging findings identified in vivo by high-resolution MRI (Cendes et al., 1993a; Kobayashi et al., 2001), making HA a surrogate marker for MTS in patients with intractable MTLE. Until recently, only environmental risk factors were associated with the development of HA and MTLE, especially the occurrence of prolonged childhood FS (Cendes et al., 1993b). However, more recently, evidence suggesting the involvement of genetic factors predisposing to HA in MTLE was found by the study of a large cohort of families segregating MTLE (Kobayashi et al., 2001, 2002, 2003a). These previous clinical observations are supported by our results, since our complex segregation analysis strongly suggests that MTLE with HA could be influenced by a major gene inherited in an autosomal dominant pattern. In addition, our results showed that a multifactorial effect could not be rejected, indicating that genes of minor effect could be acting as modifiers of the final phenotype. In fact, a certain degree of clinical variability is observed in patients with MTLE especially regarding seizures severity (Baulac et al., 2004). These genes of minor effect (or modifiers genes) could also explain the remarkable differences in disease severity observed even within families in which individuals with MTLE have good seizure control on antiepileptic medication; whereas, other affected family members have medically refractory seizures, needing surgical treatment (Kobayashi et al., 2001, 2003a). In addition, the still-complex relationship between the presence of MTS and the occurrence of seizures could be, at least in part, explained by genetic variants (i.e., sequence polymorphisms) in these genes of minor effect. In this context, it is interesting to note the presence of 15 individuals (first-degree relatives of probands with MTLE) who did not have seizures but show HA on volumetric MRI. These individuals, if found to carry the same major gene mutation as individuals with HA and MTLE, could be also carriers of genetic variants in genes of minor effect, which may protect them against seizures even in the presence of morphologic changes in the mesial temporal structures. With the recent development of tools and strategies for disease gene mapping (Vink & Boomsma, 2002; The International HapMap Consortium, 2005), the identification of major genes, as well as of genes of minor effect, may be helpful in the better understanding of the mechanisms associated with the development of MTLE and HA and could help to clarify the complex relationship between MTS and the occurrence of seizures in patients with MTLE. 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