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Single Gene Generalized Epilepsy in Africa
Ashraf Y. Mohamed, Ahmed M. Musa
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Single Gene Generalized Epilepsy in Africa Ashraf Y. Mohamed1
Ahmed M. Musa2
1 Institute of Endemic Diseases, University of Khartoum,
Khartoum, SudanQ1 2 Department of Immunology, Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan
Address for correspondence Dr. Ahmed M. Musa, Q2 Institute of Endemic Diseases, University of Khartoum, The Medical Campus, PO Box 102, Khartoum, Sudan (e-mail: [email protected]
; [email protected]
► ► ► ►
epilepsy familial single gene Africa
The study of families with epilepsy has unraveled several mysteries about the pathophysiology of the disease. However, the majority of those studies were conducted on non-African populations. Africa is strongly believed to be the origin of humans and thus the African genome must give a more comprehensive view of Mendelian diseases. In this review, we have navigated the genes predisposing to familial genetic epilepsies in Africa and compared those to the genes identiﬁed worldwide looking for a unique African ﬂavor in familial epilepsies.
Materials and Methods
Epilepsy is a group of chronic brain disorders characterized clinically by recurrent seizures and psychosocial manifestations.1 It affects approximately 50 million individuals worldwide, 20% of them live in Africa.1 The role of genetics in epilepsy has been progressively acknowledged, and this appears explicitly in the report of the International League Against Epilepsy (ILAE) commission on classiﬁcation and terminology.2 Genetic epilepsies have been adopted as one of three descriptive terms to denote the etiological classes of epilepsy.2 According to the ILAE, a speciﬁc change in DNA may cause a disease. Unlike in most complex diseases, the effects of genes in the pathology of Mendelian disorders are established. However, the knowledge derived from Mendelian conditions can be utilized in studying their non-Mendelian counterparts.3 The recent advances in the clinical use of molecular cytogenetics and high-throughput DNA sequencing technologies make a revolution in medicine eminent. Epilepsy is getting its own share in this revolution, and several genes predisposing to its familial types have been identiﬁed worldwide. Although Africa has been a home of families with epilepsy since the ancient ages, studies and data on the genetic mechanisms of epilepsy are meager.4 In this review, the genes predisposing to familial genetic epilepsies in Africa are navigated and compared with those identiﬁed worldwide.
PubMed (http://www.ncbi.nlm.nih.gov/pubmed/) was searched using three terms: familial, epilepsy, and Africa (154 results); single gene, epilepsy, and Africa (12 results); and familial and epilepsy and country (186 results). To our knowledge, one study was missed by this strategy and found using the Online Mendelian Inheritance in Man database (http://omim.org). Twelve studies on African families originating from Tunisia (seven), Morocco (two), Egypt (one), Algeria (one), and South Africa (one) were reviewed. The ClinVar database (www.ncbi.nlm.nih.gov/clinvar/) was searched looking for disease-associated variants identiﬁed worldwide similar to those identiﬁed in the African families. To classify epilepsy we have adopted the terms suggested by the report of the ILAE commission on classiﬁcation and terminology, 2005–2009.2 According to this report, the concept of genetic epilepsy is that the epilepsy is, as best as understood, the direct result of a known or presumed genetic defect(s) in which seizures are the core symptom of the disorder. On the other hand, structural/metabolic epilepsies are deﬁned as epilepsies caused by structural or metabolic conditions, even if these conditions have a genetic origin. Familial and linkage studies that have addressed the issue of single genes mutations predisposing to primary generalized familial genetic epilepsies in Africa were included.
received July 17, 2014 accepted after revision October 28, 2014
Copyright © 2015 by Georg Thieme Verlag KG, Stuttgart · New York
Issue Theme Epilepsy in Numerical Chromosomal Abnormalities; Guest Editor: Dr. Toshiyuki Yamamoto
DOI http://dx.doi.org/ 10.1055/s-0035-1555601. ISSN 2146-457X.
Single Gene Epilepsy in Africa
Febrile Seizures (FS) and Generalized Epilepsy with Febrile Seizures Plus
Febrile convulsions are age-related disorders, almost always characterized by generalized seizures that occur during an acute febrile illness. Most febrile convulsions are brief and uncomplicated, but some may be more prolonged and followed by transient or permanent neurologic sequelae.5 In 1997, Ingrid et alQ36 have described generalized epilepsy with febrile seizures plus (GEFSþ) as a single genetic syndrome whose expression comprises a spectrum of clinical epilepsy phenotypes. However, it took around another 5 years to ﬁnd that Dravet syndrome, which was ﬁrst described in 1978, is the most severe phenotype within the GEFSþ spectrum.7–9 Eleven genetic loci (named from FEB1 to FEB11) have been mapped in different studies that were performed in Australia, Japan, China, the United States, France, Italy, Morocco, and Belgium.10–23 Salzmann et al23 mapped the 11th locus at the interval 8q12.1-q13.2 in four siblings in a consanguineous Moroccan family. Three of the patients had pure FS and one patient had FS associated with temporal lobe epilepsy. The authors revealed a homozygous missense mutation (p.Ala270Val) in CPA6 (carboxypeptidase A6) gene with an autosomal recessive inheritance. A maximum two-point logarithm of the odds (LOD) score of 2.18 was achieved at the D8S553 marker.23 CPA6 is a member of the M14 metallocarboxypeptidase family. Carboxypeptidases have functions ranging from digestion of food to selective biosynthesis of neuroendocrine peptides.24 CPA6 may also process many other neuropeptides, several of which are known to affect glutamate release and epilepsy in animal models.25 Based on biochemical analysis, humans homozygous for the p.Ala270Val mutation would have approximately 40% of normal levels of CPA6 activity due to a defect in the protein, presumably a protein-folding defect that leads to reduced secretion.23 In another study, Fendri-Kriaa et al26 reported a novel mutation in a known gene associated with FS when they studied Tunisian families with the disease. They detected a c.374G > T mutation that lead to arginine to leucine substitution at position 125 (p.R125L) of the protein product of SCN1B (sodium channel, voltage-gated, type I, β subunit gene). Linkage studies showed a LOD scores of 0.712 (parametric) and 0.59 (nonparametric) at the marker D19S414 in the GEFSþ1 locus under the recessive model.26 SCN1B is crucial in the assembly, expression, and functional modulation of the heterotrimeric complex of the sodium channel. Its association with neurofascin may target the sodium channels to the nodes of Ranvier of developing axons and retain these channels at the nodes in mature myelinated axons.27 The variation of p.R125L is in a highly conserved extracellular domain of the protein. It might affect the structure and stability of the protein by loss of hydrogen bonding or changing the electrostatic and intrinsic characteristics of the protein.26 Mutations in GABRA1 (GABA [gamma-aminobutyric acid] A receptor, subunit α 1 gene), SCN9A (sodium channel, voltage-gated, type IX, α subunit gene), and SCN1B and Journal of Pediatric Epilepsy
SCN1A (sodium channel, voltage-gated, type I, α subunit gene) are known to be associated with GEFSþ.28–32 The majority of mutations causing Dravet syndrome arise de novo,9,33–35 and most commonly they are paternal in origin.36 In Africa, four studies have addressed the genetic mutations that predispose to GEFSþ and all of them were in Tunisia. In the ﬁrst, Mrabet et al37 screened two families with the disease for mutations in the SCN1B, SCN1A, and GABRG2 (GABA A receptor, subunit gamma 2 gene) genes using direct sequencing but no mutation was detected. The same result was obtained by Fendri-Kriaa et al36,38 when genome-wide scan was applied for the ﬁrst time in a Tunisian family with GEFSþ. Belhedi et al39 identiﬁed a locus on chromosome 22q13.31 to be linked to GEFSþ in three ﬁrst cousins in a consanguineous Tunisian family with a mean age at onset of 3 years. Parametric linkage using an autosomal recessive model of inheritance showed suggestive linkage to a region on chromosome 22q13.31 ﬂanked by the markers rs3203726 and rs728592. This region was further reﬁned by using homozygosity mapping to a 527-Kb region (chr22: 47243816– 47772028, GRCh37/hg19). The last nine exons and the 3′ untranslated region of TBC1D22A (TBC1 domain family, member 22A gene) which encodes the member 22A of RabGTPase activator with a TBC1 domain family is located in this region. Direct sequencing of this gene as well as KCNJ4 (potassium channel, inwardly rectifying subfamily J, member 4 gene) did not point to a causative mutation, while mutations in FEB1, FEB2, FEB3, FEB4, FEB5, FEB6, FEB11, GEFSþ1, GEFSþ2, GEFSþ3, and GEFSþ4 loci were excluded by linkage studies.39 A mutation believed to be involved in GEFSþ is a heterozygous transition (c.1811G > A) on the SCN1A gene leading to arginine to histidine substitution (p.R604H) in the SCN1A protein detected on screening a Tunisian family for the disease.40 This mutation was also reported among others including a patient from Australia with Dravet syndrome. However, the authors classiﬁed the mutation in this patient as nonpathogenic.9 SCN1A mediates the voltage-dependent sodium ion permeability of excitable membranes.41
Childhood and Juvenile Absence Epilepsy Childhood absence epilepsy (pyknolepsy) occurs in children of school age with a peak manifestations age of 6 to 7 years, with a strong genetic predisposition in otherwise normal children.5 Juvenile absence epilepsy occurs around puberty and is mostly sporadic.5 Mutations in several genes have been proposed to predispose to juvenile absence epilepsy including EFHC1 (EF-hand domain [C-terminal] containing 1 gene)42 and CLCN2 (chloride channel, voltage-sensitive 2 gene)43 among others. Childhood absence epilepsy is associated with GABRG2,44 GABRA1,45 GABRB3 (GABA A receptor, subunit β 3 gene),46 CACNA1A (calcium channel, voltage-dependent, P/Q type, α 1A subunit gene),47 and CACNA1H (calcium channel, voltage-dependent, T type, α 1H subunit gene)48 among others. In Africa, Abouda et al49 studied 14 patients from ﬁve Tunisian families. Consanguinity loops could be deﬁned in three out of the ﬁve families. After suggesting an autosomal
Single Gene Epilepsy in Africa recessive inheritance, linkage analysis and direct sequencing excluded mutations in CACNA1A, CACNA2D2 (calcium channel, voltage-dependent, α 2/delta subunit 2 gene), CACNG2 (calcium channel, voltage-dependent, gamma subunit 2 gene), and CACNB4 (calcium channel, voltage-dependent, β 4 subunit gene), which are orthologs of genes responsible for autosomal recessive absence seizure in mice; since up to the time of the study no genes were identiﬁed for causing autosomal recessive childhood absence epilepsy in human.
Juvenile Myoclonic Epilepsy Juvenile myoclonic epilepsy (JME) or Janz syndrome appears around puberty and represents one of the most common genetically determined epilepsy syndromes.50 It was discovered in Switzerland51 and France,52 adequately described in Germany53 and Uruguay,54 and has been intensively studied worldwide thereafter. To date, ﬁve Mendelian JME genes are listed in the Online Mendelian Inheritance in Man database (http://omim.org and http://www.ncbi.nlm.nih.gov/omim/). These are CACNB4,55 CASR (calcium-sensing receptor gene),56 GABRA1,57 GABRD (GABA A receptor, subunit delta gene),28 and EFHC1.58 Different patterns of inheritance have been described in JME.57,59 In Africa, a single study on a consanguineous Tunisian family addressed the genetics of JME. After proposing an autosomal recessive mode of inheritance, genome wide parametric linkage analysis showed suggestive linkage to chromosome 2q and autozygosity analysis strongly sug-
gested two candidate regions. The ﬁrst was on 2q23.3 ﬂanked by rs1519707 and rs7581918 and the second on 2q24.1 ﬂanked by rs6728625 and rs843206. Sequencing two candidate genes (CACNB4 and KCNJ3) did not point to any culprit mutation.60
Progressive Myoclonic Epilepsy Progressive myoclonic epilepsies (PMEs) are an unusual and heterogeneous group of epilepsies, with debilitating progression, resistance to conventional treatment and poor prognosis. It is estimated that these diseases are responsible for up to 1% of epileptic syndromes in children and adolescents around the world.61,62 Although it is an arbitrary classiﬁcation, we had classiﬁed PME into genetic, metabolic, and unclassiﬁed disorders to comply with the revised terminology of the ILAE2 and our main focus in this review was on the genetic class. Under metabolic PME, we located disorders that result from defects in enzymes, for instance, sialidosis63 and enzyme inhibitors, for instance, Unverricht–Lundborg disease,64 deposition diseases like Lafora disease65 and neuronal ceroid lipofuscinoses,66 and mitochondrial diseases, for example, myoclonic epilepsy with ragged red ﬁbers.67 Although dentatorubral pallidoluysian atrophy is a trinucleotide repeat expansion disease,68 we labeled it as unclassiﬁed because epilepsy is not the core feature in all its forms.69 Brief description of diagnostic modalities, patterns of inheritance, and most common mutated genes in metabolic and unclassiﬁed PMEs is provided in ►Table 1.
Table 1 Metabolic and unclassiﬁed progressive myoclonic epilepsiesQ4 Disease Unverricht–Lundborg disease90 Lafora disease
Known causative genes3
Diagnostic modalities beside genetic studies
Detection of Lafora bodies during examination of the eccrine ducts of sweat glands in a skin biopsy92
Neuronal ceroid lipofuscinosis93
Accumulation of auto ﬂuorescent ceroid lipofuscin in tissues66
Classical late infantile94
TPP1, CLN, CLN6, CLN8, MFSD8, PPT1
Finish variant late infantile95
CLN5, CLN3, ATP13A2, PPT1, TPP1 CLN6, CTSF
Autosomal recessive/ autosomal dominant
Myoclonic epilepsy with ragged red ﬁbers98
MTTK, MTTH, MTTL1, MTTS1
Detection of ragged muscle ﬁbers on muscle biopsy99
High levels of sialylated oligosaccharides on urine chromatography101
Juvenile (Batten disease)
Adult (Kufs disease)97
Journal of Pediatric Epilepsy
Single Gene Epilepsy in Africa
More than two decades ago, some studies from Japan70,71 had reported a unique form of myoclonic epilepsy that did not ﬁt to other myoclonic epilepsy phenotypes. Since that time more than 60 families with related phenotypes mainly from Asia and Europe were reported but under different names. Familial cortical myoclonic tremor and epilepsy (FCMTE) lacks the time constrains of early life myoclonic epilepsies, the morning jerks of the JME, the loss of tone of the myoclonic atonic epilepsy, and the frank progression of the PME. Although FCMTE can be differentiated from other epileptic syndromes, currently it is not listed by the ILAE as a separate entity.70,72 Linkage to chromosomes 2, 5, 8, and 3 has been reported with autosomal dominant patterns of FCMTE73–76 and one study identiﬁed a mutation in ADRA2B (adrenoceptor α 2B gene), which encodes the α 2B adrenergic receptor as causal mutation.77 In Africa, Stogman et al78 detected a frame shift mutation in CNTN2 (contactin 2 gene) with an autosomal recessive pattern of inheritance in a family from Egypt. CNTN2 encodes contactin-2, a glycosylphosphatidylinositol-anchored neuronal membrane protein. CNTN2 in conjunction with another transmembrane protein (CNTNAP2) contributes to the organization of axonal domains at nodes of Ranvier by maintaining voltage-gated potassium channels at the juxtaparanodal region.79 In this study, ﬁve siblings and their parents have been genotyped. A LOD score of 3.6 under an autosomal recessive model was obtained on chromosome 1q31.3-q3.2 between rs927510 and rs724054. Carr et al80 identiﬁed a novel form of epilepsy in 17 patients from two South African families with no reported consanguinity. It is known as familial adult myoclonic epilepsy 3 (FAME3). This phenotype is between the familial adult myoclonic epilepsy and the PME phenotypes. FAME3 was differentiated from familial adult myoclonic epilepsy because the former had an earlier age at onset, more frequent seizures, dementia, and corticospinal and cerebellar dysfunction. The absence of abnormal storage materials or any evidence of neuronal ceroid lipofuscinosis on routine histology of the axillary apocrine glands or electron microscopy; the absence of CSTB (cystatin B gene), DRPLA (dentatorubral pallidoluysian atrophy gene), FAME1 (8q22.3-q24.1), and FAME2 (2p11q12.2) loci mutations; and a normal muscle biopsy differentiated FAME3 from the known PMEs.80 No causal mutation was identiﬁed. Another form of myoclonic epilepsy was reported by Van Bogaert et al81 in three females from two consanguinity loops in a large inbred Moroccan family. The phenotype was at the milder side of the PME spectrum where some response to certain antiepileptic medications was noted. The known causes of PMEs were excluded. An autosomal recessive pattern of inheritance was assumed and a combined multipoint LOD score of 4 at the marker D7S663 at chromosome 7q11.2 was obtained. C to T transition (c.295C > T) which substitutes arginine codon by a stop codon (p.R99X) on the product of KCTD7 (potassium channel tetramerization domain containing 7 gene) was believed to be the causal mutation.81 Members of the KCTD gene family, including KCTD7, encode predicted proteins containing an N-terminal domain that is Journal of Pediatric Epilepsy
homologous to the T1 domain in voltage-gated potassium channels.81 In patch clamp experiments, KCTD7 expression hyperpolarizes the cell membrane and reduces the excitability of transfected neurons.82 This was the ﬁrst study to report the KCTD7 gene mutation as a cause of PME and was followed by two studies; the ﬁrst linked a mutation in this gene to a form of neuronal ceroid lipofuscinosis83 and the second84 linked mutations in the same gene to a phenotype of PME related to that reported by Van Bogaert et al.81 KCTD7 mutations were screened in the study of Ferlazzo et al85 in addition to mutations in EPM2A (epilepsy, progressive myoclonus type 2A gene), EPM2B, CSTB, A8344G and T8356C (associated with myoclonic epilepsy with ragged red ﬁbers), and A3243G and C3271T (associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes [MELAS]), and all were found to be negative in an Algerian family. In this family, four siblings had PME and cognitive impairment with a median age at onset of 9.25 years. An autosomal recessive pattern of inheritance was assumed and all known metabolic causes of PME were excluded. No linkage study was performed.85 Detailed description of candidate loci for causing generalized genetic familial epilepsies in Africa was provided in ►Table 2.
Discussion Few studies have addressed the issue of mutations predisposing to primary generalized familial genetic epilepsies in Africa. Only ﬁve genes were identiﬁed to predispose to the condition so far. Out of these ﬁve genes, only the CNTN2 gene is unique (up to now) to the African population, while mutations in the highly related CNTNAP2 gene were identiﬁed to predispose to epilepsy in non-African families.86 Mutations in the SCN1A gene were reported in non-African families.32 Interestingly, the c.1811G > A mutation in SCN1A gene which was believed to predispose to epilepsy in a Tunisian family40 was also found in an Australian patient.9 However, in this patient, it was labeled as nonpathogenic and a different mutation was identiﬁed to be the potential culprit.9 More than 400 single gene mutations have been shown to predispose to a variety of Mendelian conditions that involve epilepsy at some point of their spectrum of presentation.87 The increased understanding of functional effects of mutations has provided potential gene therapy approaches to prevent seizures.88 Studying conditions that involve seizure as the core symptom can further reﬁne the hunt for better understanding of the pathophysiology of the more common complex genetic epilepsies. We believe that a comparative approach in studying genetic epilepsies in different populations can be the ﬁrst step out of the premises of single genes and their pathways toward the environment, looking for differences in the pattern of genetic involvement between different populations. Africa is the origin of humans89; thus, we assume that the African population can play a pivotal role in this comparative approach. The advances in next generation sequencing and wholeexome sequencing will deﬁnitely accelerate our
5q13.3, 19q13.4, 7p14.2
D5S407D5S424, D19S210D19S902, D7S510-D7S516
1.04 0.8 0.61
c.295C > T rs267607199
c.374C > T No rs
c.809C > T rs114402678
c.1811G > A rs121918769
Amino acid change
Abbreviations: FCMTE, familial cortical myoclonic tremor and epilepsy; FSþ, febrile seizure plus; FS, febrile seizure; GEFSþ, generalized epilepsy with febrile seizure plus; JME, juvenile myoclonic epilepsy; LOD, logarithm of the odds score; N, novel mutation; PME, progressive myoclonic epilepsy; R, reported mutation. a LOD score was insigniﬁcant and the marker was identiﬁed using the transmission disequilibrium test. b The marker was identiﬁed assuming an autosomal recessive model.
Table 2 Candidate loci for causing generalized genetic familial epilepsies in Africa
Single Gene Epilepsy in Africa
Journal of Pediatric Epilepsy
Single Gene Epilepsy in Africa
understanding of epilepsy. Applying these technologies on the heterogeneous African genome could contribute enormously to the global knowledge. In conclusion, understanding the mechanisms of epilepsy has received a great attention worldwide, given the high prevalence of the disease and its impacts on patients’ lives. Unfortunately, this is not the case in Africa where only a few studies have addressed this issue. Africa is the origin of humans; this is why we expect that studying the African genome will have a great impact on our understanding of epilepsy and other diseases.
Acknowledgment The authors acknowledge the contribution of Dr. Nada Abdelmagid (Karolinska Institute, Sweden) in providing ideas and assisting in shaping this work.
1 World Health Organization, International Bureau for Epilepsy,
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