oxford textbook of epilepsy and epileptic seizures 16 spasms ( 88 , 89 ). The transition from EIEE to West syndrome occurs in 75 % of individuals with EIEE ( 86 , 87 ). STXBP1 protein plays an essential role in synaptic vesicle release and secretion of neurotransmitters ( 90 ). The Ohtahara syndrome \200\223infantile spasms s pectrum can also be caused by polyalanine expansions of the ARX gene ( 71 , 77 ). Available information suggests a mutation rate of about 6 % for ARX in boys with isolated or X-linke d infantile spasms and no brain lesions ( 71 ) and up to 37 % for STXBP1 in infants with Oh tahara syndrome ( 90 ). However, larger series are needed to fully elucidate the phenotypic spectrum and better understand the causative role of this gene in epilepsy. manifestations of heterozygous females and hemizygous males ( 68 ). This model suggests tha t if an individual has two populations of protocadherin cells (mutated and non-mutated) the n a pathologi- cal phenotype occurs. A normal female or a transmitting male have only one p rotocadherin population of cells, protocadherin- wildtype or protocadherin-mutant cells, re spectively, then they do not present a pathological phenotype. The development of geneti- c ally modi \201 ed animal models will allow this puzzling disease mechanism to be better ex plored. ARX (aristaless-related homeobox) The ARX gene, on chromosome Xp22, is a transcription fact or that belongs to a family of paired class homeobox genes, and plays an important role in embryogenesis, especially in the development of the central nervous system ( 69 ). To date, ARX mutations have been identi \201 ed in about 10 different clinical conditions, with or without brain malformations ( 70 \200\223 72 ). Malformation phenotypes, including X-link ed lissencephaly with abnormal genitalia (XLAG), XLAG with severe hydrocephalus, and Proud syndrome (agenesis of the corpus callosum with abnormal genitalia), are associated with pro tein trun- cation mutations and missense mutations in the homeobox ( 70 , 73 ). Non-malform ation phenotypes are associated with missense muta- tions outside of the homeobox or expans ion of the second polyA tract and include X-linked infantile spasms (ISS)/West syndrome, Pa rtington syndrome (mental retardation with mild distal dystonia), and non-speci \201 c X-l inked mental retardation (XLMR) ( 70 , 73 ). Expansions in the \201 rst polyA tract cause X-linked infantile spasms (ISSX)/West syndrome (tonic spasms with clustering, severe psy- chomotor delay and hypsarrhythmia on the EEG) ( 74 , 75 ), a severe epileptic-dyskinetic en cephalopathy ( 71 ), tonic seizures and dysto- nia without infantile spasms ( 76 ), and Oht ahara syndrome ( 77 ). Progressive myoclonus epilepsies These genetically heterogeneous disorders (Table 2. 2 ) sh are clini- cal features that include action myoclonus, myoclonic jerks that are segmental a nd arrhythmic, appearing both at rest and as stimu- lus sensitive manifestations, epileptic seizures, predominantly gen- eralized tonic \200\223clonic. Progressive mental deteriorati on, cerebellar and extrapyramidal signs are also present in a variable proportion of patien ts ( 91 , 92 ). Progressive myoclonus epilepsies (PMEs) rep- resent less than 1 % of all ep ilepsy cases and have a variable geo- graphic and ethnic distribution. Many gene defects un derlying PMEs have been identi \201 ed (Table 2. 3 ) but in a considerable pro- portion of patients the cause remains unknown. Most PMEs result from the intracellular accumulation o f abnormal deposit material ( 93 ). The age onset, the rapid progression of the symptoms, a nd the prognosis are different and depend on the speci \201 c etiology and on the type of causative mutations. The diagnostic approach varies in relation to the suspected form (Tabl e 2. 4 ). While the Unverricht \200\223Lundborg disease, although disabling, can reach a de gree of stabilization, all other forms progress relentlessly, leading to severe disability or death in matter of years. CDKL5 (cyclin-dependent, kinase-like 5) Mutations in the X-linked gene CDKL5 cause early on set intracta- ble seizures, severe developmental delay and, often, subsequent appearance of Rett syndrome (RTT) \200\223like features ( 78 ). The phe- notypic spectrum associated wit h CDKL5 mutations also includes X-linked infantile spasms syndrome (ISSX) ( 79 ), a form of myo- clonic encephalopathy ( 80 ), and severe encephalopathy with refractory seizures ( 81 ). Mutations in CDKL5 are mainly found in females, suggesting gestational lethality in mal es ( 82 ). Parental germline mosaicism has been reported ( 83 ). In affected females, a see mingly normal early development, followed by onset of intrac- table seizures between the \201 rst days and 4th month of life are early key diagnostic criteria. Severe developmental delay with regression become apparent after seizures onset. Seizures are usually mani- fes ted as infantile spasms, or prolonged tonic seizures followed by spasms and myoclonus, with a peculiar electroclinical pattern ( 84 ) variably associated with, migrating focal seizur es during the course. Overall, 16.3 % of girls with early-onset intractable epilepsy, with or without infantile spasms, exhibit either mutations or genomic deletions involving CDKL5 ( 85 ). Idiopathic generalized epilepsies with complex inheritance Mode of inheritance The idiopath ic generalized epilepsies (IGEs) represent 20 \200\22330 % of all epilepsies and include a group of syndromes characterized by Table 2.2 Clinical classi \201 cation of progressive myoclonic epilepsies PMEs type Age of onset Unverricht \200\223Lundborg disease (ULD) 7 \200\22316 years Lafora disease (LD) 6 \200\22319 years Neuronal ceroid-lipofuscinoses (NCLs): \227\206 Infantile (Haltia \200\223Santavuori) \227\206 Late infantile (Jansky \200\223Bielschowsky) \227\206 Intermediate (Lake or Cavan agh) \227\206 Juvenile (Spielmeyer \200\223Vogt) \227\206 Adult (Kufs) 6 months \200\2232 years 1 \200\2234 years 5 \200\2238 years 4 \200\22314 years 15 \200\223 50 years STXBP1 (syntaxin binding protein 1) Mutations in the STXBP1 gene have been associated with Ohtahara syndrome or early infantile epileptic encephalopathy (EIEE), char- acterized by ea rly onset of tonic spasms, seizure intractability, a characteristic suppression-burst patte rn on the EEG and poor outcome with severe psychomotor retardation ( 86 , 87 ). STXBP1 muta tions have also been found in some children with infantile Myoclonic epilepsy with ragged-red \201 bres (MERRF) 3 \200\22365 years 8 \200\22315 years Sialidosis: \227\206 Type 1 \227\206 Galactosialidosis (type 2) Dentato-rubro-pallido-luysian atrophy (DRPLA) Childhood Gaucher disease (type III) Variable CHAPTER 2 neurogenetics of epilepsy 17 Table 2.3 Molecular genetics of progressive myoclonic epilepsies PMEs type Pattern of inheritance Locus Gene Unverricht \200\223Lundborg disease (ULD) AR 21q22.3 CSTB Lafora disease (LD) AR 6q 24.3 6p22.3 EPM2A NHLRC1 Neuronal ceroid-lipofuscinoses (NCLs): Infantile Late infantile Finnish variant Gipsy varia nt Turkish variant Juvenile Juvenile variant Juvenile variant Adult Congenital AR AR AR AR AR AR AR AR AR AD AR 1p34.2 11p15.4 13q22.3 15q23 4q28.2 16p12.1 8p23.3 \200\223 15q23 20q13.33 11p15.5 PPT1 TPP1 CLN5 CLN6 MFSD8 CLN3 CLN8 CLN9 CLN4 DNAJC5 CTSD tRNA Lys Myoclonic epilepsy with ragged-red \201 bres (MERRF) Mitochondrial Mt DNA Sialidosis: Type I Galactosialidosis AR AR 6p21.33 20q13.12 NEU1 CTSA Gaucher disease, type III AR 1q22 GBA Dentato-rubro-pallido-luysian atrophy (DRPLA) AD 12p13.31 ATN1 AD, autosomal dominant; AR, autosomal recessive; Mt, mitochondrial. Table 2.4 Diagnostic tools for progressive myoclonic epilepsies absence seizures, myoclonus, and generalized tonic \200\223clonic sei- zures. There is a pa rtial overlap in age of onset, type, and frequency of seizures, prognosis, and response to treatment. Among these disorders there are several subsyndromes, including childhood absenc e epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and e pilepsy with generalized tonic \200\223 clonic seizures alone. Generalized spike-wave activ ity and normal background are observed in the EEG. Among epilepsies with com- plex inherita nce, IGEs seem very suitable for genetic studies because they are common, have a relatively well-de \201 ned phenotype and occur in familial clusters. Close relatives of IGE proband s have 4 \200\22310 % risk of developing epilepsy ( 94 ). Higher risk is seen in sib- lings and offspring, and is lower in second-degree relatives. In con- trast to monogenic inherit ance, polygenic inheritance leads to a more rapid decrease of the risk in relatives as the distance from the affected individuals increases ( 95 ). Twin studies have shown higher con cordance for IGE in monozygotic than in dizygotic twins (0.76 versus 0.33), which is consis tent with polygenic inheritance ( 96 ). IGEs have a genetic etiology with complex inheritan ce. It has been suggested that they might result from the interaction of two or more genes ( 97 ). However a high degree of complexity is operating as large-scale exome sequencing of ion channels reveals that rare missense variation in known Mendelian disease genes are equ ally prevalent in healthy individuals and in those with idiopathic gen- eralized epilepsy, revealing that even deleterious ion channel muta- tions confer an uncertain risk to an indi vidual depending on the other variants with which they are combined ( 98 ). PMEs type Methods Marker Unverricht \200\223Lundborg disease (ULD) Molecular biology CSTB Lafora disease (LD) Axillar biopsy Molecular biology Lafora bodies EPM2A and NHLRC1 Neuronal ceroid- lipofuscinoses (NCLs) Biopsy Storage lipopigment in lysosomes PPT1 , TPP1 , CLN3 , CLN4 , CLN5 , CLN6 , CLN8 , CLN9 , MF SD8 , DNAJC5 , CTSD Molecular biology Myoclonic epilepsy with ragged-red \201 bres (MERRF) Muscle biopsy Molecular biology Ragged-red \201 bres A8344G substitution (90 % ) (mitochondrial DNA) \206\221 Urinary ol igosaccharides -N-acetyl neuroaminidase de \201 cit NEU1 -galactosidase de \201 cit Sialidosis Urine Lymphocytes, \201 broblasts Molecular biology Galactosialidosis Urine, leukocytes, and \201 broblasts Molecular biology CTSA -glucocerebrosidase de \201 cit GBA Gaucher disease, type III Lymphocytes, \201 broblasts Molecular biology Dentato-rubro-pallido- luysian atrophy (DRPLA) Molecular biology ATN1 oxford textbook of epilepsy and epileptic seizures 18 Molecular basis Although several chromosomal loci for different forms of IGEs have been ide nti \201 ed, they have not often been replicated. Linkage studies on a large number of fam ilies with IGE led to the identi \201 ca- tion of several susceptibility loci (18q, 2q, 3q , and 14q) ( 99 , 100 ). In rare families pathogenic mutations in single genes have been re ported. Mutations in the GABRG2 gene were identi \201 ed in fami- lies with febrile seizur es and childhood absence epilepsy ( 22 , 23 ), a mutation in the GABRA1 gene was identi \201 ed in a family with dom- inantly inherited juvenile myoclonic epilepsy ( 101 ). Mutati ons in CLCN2 have been identi \201 ed in families with heterogeneous IGE phenotypes, inclu ding CAE ( 102 ). Rare variants in CACNA1H have been identi \201 ed in CAE and other gener alized epilepsy pheno- types ( 103 , 104 ). Finally, the study of variants has provided som e evidence that GABRD ( 105 ), ME2 ( 106 ), BRD2 ( 107 ), and NEDD4L ( 108 ) are susceptibi lity genes for IGE. bands of gray matter are interposed in the white matter between the cortex and the lateral ventricles ( 110 ). Classical LIS is rare, with a prevalence of about 12 per million births. Patients with seve re LIS have early developmental delay, early diffuse hypotonia, later spastic quadriplegia, and eventual severe or profound mental retardation. Seizures occur in over 90 % of LIS chi ldren ( 112 ), with onset before 6 months in about 75 % of cases. About 80 % of children ha ve infantile spasms, although EEG does not show typical hypsarrhythmia. Most LIS children s ubse- quently have multiple seizure types. Epilepsy is present in almost all patients with SBH and is intractable in about 65 % of them. About 50 % of patients with epilepsy have foc al seizures, and the remaining 50 % have generalized epilepsy, often within the spec- trum of Lennox \200\223Gastaut syndrome ( 109 ). Two major genes have been associated with classical LIS and SBH. The LIS1 gene is responsib le for the autosomal form of LIS ( 113 ), while the doublecortin gene ( DCX ) is X-linked ( 114 , 115 ). Although either gene can result in either LIS or SBH, most cases of classical LIS are due to deletions or mutations of LIS1 ( 116 ), whereas most cases of SBH are due t o mutations of DCX ( 117 ). LIS1 -related LIS is more severe in the posterior brain regions (p > a gradient) (Fig. 2. 3 A), whereas DCX -related LIS is more severe in the anterior br ain (a > p gradient) (Fig. 2. 3 B). About 60 % of patients with p > a isolated lissencephal y (ILS) carry genomic alterations or mutations involving LIS1 ( 116 ). Most mutations (84 % ) are trun- cating ( 118 ). Small genomic deletions and duplications of LIS1 occur in almo st 50 % of patients ( 116 ). A simpli \201 ed gyral pattern in the posterior brain, with u nderlying SBH, has been associated with mosaic mutations of LIS1 ( 119 ). Miller \200\223Di eker syndrome (MDS) is caused by deletion of LIS1 and contiguous genes and features severe p > a LIS (Fig. 2. 3 C), accompanied by distinct dysmorphic facial features and additional malformations. Most DCX mutations cause a > p SBH/pachygyria. Mutations of DCX have been fo und in all reported pedigrees and in 80 % of sporadic females and 25 % of sporadic males wi th SBH ( 117 ). Genomic deletions of DCX are a rare cause of SBH or X-linked lissencephaly in patients who are mutation negative after Sanger sequencing of DCX (Fig. 2. 3 D) ( 120 ). Maternal germline or mosaic DCX mutations may occur in about 10 % of cases of either SBH o r X-linked LIS ( 121 ). Symptomatic epilepsy Epilepsies are de \201 ned symptomatic when an external cause can be identi \201 ed. Often, these epilepsies persist over time and are resistant to drug treatm ent. Advances in diagnostics, especially the use of brain MRI, has brought to attention how often structural brain anomalies, even discrete, are the cause of epilepsy. Developmental abnormalities of the cerebral cortex are a frequent cause of epi- lepsy. They occur as isol ated manifestations or may be one expres- sion of neurocutaneous diseases, vascular malform ations, structural abnormalities associated with chromosomal disorders (Down syndrome, Ange lman and Prader \200\223Willi syndromes, Ring 20 syndrome, Wolff \200\223Hirschhorn syndrom e and many pathogenic copy number variations), mitochondrial encephalomyopathies, the organ ic acidurias, and the peroxisomal diseases. All these disorders have usually an early onset . However, even a relatively late onset of seizures (2nd to 3rd decade of life) may occur w hen a discrete developmental abnormality of the brain is the cause of seizures. Malformations of the cerebral cortex It has been estimated that at least 40 % of children w ith drug- resistant epilepsy have a malformation of the cerebral cortex ( 109 ). These malf ormations consist of an abnormal distribution, organi- zation, or sometimes differentiation of the neuronal components ( 110 ). Several cortical malformations associated with epileps y are caused by alterations that occur during embryonic development, especially during the migration of neurons to form the cerebral cortex in its de \201 nitive shape. In recent ye ars, several genes have been identi \201 ed that, when mutated, cause abnormalities of cor tical development. In the following sections, the most frequent cortical malformations asso ciated with epilepsy (lissencephaly, periventricu- lar heterotopia, and polymicrogyria) and those whose disease genes have been identi \201 ed will be presented (Table 2. 5 ). Three rarer forms of LIS-pachygyria have been identi \201 ed in recent years. One form, X- linked LIS with absent corpus callosum and ambiguous genitalia (XLAG), results from mutatio ns of the ARX gene. XLAG is a severe condition that is only observed in boys. Female carrie rs have normal brain MRI scan or partial to complete agenesis of the corpus callosum, with normal cognition to mild retardation ( 73 ) (Fig. 2. 3 , E and F). A second form, due to mu tations of the TUBA1A gene, exhibits characteristics that par- tially overlap with the LIS- SBH spectrum but is often accompanied by cerebellar hypoplasia (Fig. 2. 3 G) ( 122 ). A thi rd, recessive form, results from homozygous mutations of the RELN gene and is char- acteriz ed by moderate lissencephaly, severe cerebellar hypoplasia, dysmorphic facial features, dev elopmental delay and epilepsy ( 123 ). Lissencephaly and subcortical band heterotopia Lissencephaly (LIS) and subcortical band het erotopia (SBH) are malformations resulting from anomalies in cortical neuronal migration. L IS is characterized by absent (agyria) or decreased (pachygyria) convolutions, producing co rtical thickening and a smooth cerebral surface ( 111 ). SBH is a related disorder in which Periventricular nodular heterotopia Periventricular nodular heterotopia (PNH) consists of n odules of gray matter located along the lateral ventricles with a total failure of migratio n of a subset of neurons ( 110 ); it ranges from isolated, single, to con \202 uent bilate ral nodules (Fig. 2. 3 H). Many patients CHAPTER 2 neurogenetics of epilepsy 19 Table 2.5 Genes and chromosomal loci associated with cortical malformations Cortical malformations Pattern of inheritance Gene Locus OMIM Malformations from abnormal proliferation Tuberous sclerosis AD TSC1 TSC2 9q34.13 605284 Tuberous sclerosis Malformations from abnormal migration AD 16p13.3 191092 Lissencephaly (LIS) Miller \200\223Dieker syndrome (MDS) LIS1 + YWHAE LIS1 DCX TUBA1A ARX RELN VLDLR AD 17p13.3 601545 Isolated lissencephaly sequence (ILS) or subcortical band heterotopia (SBH) AD 17p13.3 601545 ILS or SBH X-linked Xq22.3 \200\223q23 300121 ILS or SBH AD 12q12 \200\223q14 602529 X-linked lissencephaly with abnormal genitalia (XLAG) X-linked Xp22.13 300382 LIS with cerebellar hypoplasia (LCH) AR 7q22 600514 LCH group B AR 9p24.2 Periventricular nodular heterotopia (PNH) Classical bilateral PNH X-linked FLNA FLNA FLNA FMR1 Xq28 300017 Ehlers \200\223Danlos syndrome and PNH X-linked Xq28 300017 Facial dysmorphisms, severe constipation and PNH X-linked Xq28 300017 Fragile-X syndrome and PNH X-linked Xq27.3 309550 PNH with limb abnormalities (limb reduction abnormality or syndactyly) X-linked Xq28 Williams syndrome and PNH AD 7q11.23 PH AD 5p15.1 PH AD 5p15.33 Agenesis of the corpus callosum, polymicrogyria and PNH AD 6q26 \200\223qter PH AD 4p15 PH AD 5q14.3 \200\223q15 Agenesis of the corpus callosum and PNH AD ARFGEF2 LRP2 1p36.22 \200\223pter Microcephaly and PNH AR 20q13.13 605371 Donnai \200\223Barrow syndrome and PNH AR 2q24 \200\223q31 600073 Cobblestone cortical malformations Fukuyama congenital muscular dystrophy or Walker \200 \223Warburg syndrome (WWS) AR FKTN FKRP LARGE POMGnT1 POMT1 POMT2 SNAP29 9q31.2 607440 Muscle \200\223eye \200\223brain disease (MEB) or WWS AR 19q13.32 606596 MEB AR 22q12.3 603590 MEB AR 1p34.1 606822 MEB or WWS AR 9q34.13 607423 MEB or WWS AR 14q24.3 607439 CEDNIK syndrome Malformations from abnormal cortical organization AR 22q11.2 604202 Polymicrogyria (PMG) Bilateral frontoparietal PMG AR GPR56 TUBB2B SRPX2 TBR2 PAX6 16q13 604110 Asymmetric PMG AD 6p25.2 612850 PMG and rolandic seizures, oromotor dyspraxia X-linked Xq21.33 \200\223q23 300642 PMG and Agenesis of the corpus callosum (ACC), microcephaly AD 3p21.3 \200\223p21.2 604615 PMG and aniridia AD 11p13 607108 PMG AD 1p36.3 \200\223pter PMG and microcephaly AD 1q44 \200\223qter PMG and facial dysmorphisms AD 2p16.1 \200\223p23 PMG and microcephaly, hydrocephalus AD 4q21 \200\223q22 PMG AD 21q2 PMG and DiGeorge syndrome AD 22q11.2 PMG and Warburg Micro syndrome AR RAB3GAP1 2q21.3 602536 PMG and Goldberg \200\223Shprintzen syndrome AR KIAA1279 10q21.3 609367 AD, autosomal dominant; AR, autosomal recessive. oxford textbook of epilepsy and epileptic seizures 20 Fig. 2.3 Brain MRI of patients with different malformations of the cerebral cortex. A) Axia l section. Classical lissencephaly in a boy with LIS1 mutation. B) Axial section. Lissencep haly in a girl with DCX mutation. C) Axial section. Lissencephaly in a patient with Miller \200\223Dieker syndrome. D) Axial section. Severe diffuse lissencephaly with relatively sma ll frontal lobes in a boy with DCX mutation. E) and F) Coronal section and sagittal section of a boy with X-linked lissencephaly, complete corpus callosum agenesis, and ambiguous gen italia due to an ARX mutation. G) Axial section. Thickened cortex with simpli \201 ed gyra l pattern in a girl with a TUBA1A gene mutation. H) Axial section. Classical bilateral peri ventricular nodular heterotopia in a woman with a FLNA mutation. I) and J) belong to the sa me patient. I) Axial section. Bilateral perisylvian polymicrogyria. The sylvian \201 ssur es are open and the perisylvian cortex is thickened and irregular (black arrows). J) Sagitt al section. Note the abnormally vertical orientation of the sylvian \201 ssure, which app ears to be fused with the rolandic \201 ssure. K) Axial section. Bilateral frontoparietal polymicrogyria in a girl with a GPR56 mutation and Lennox \200\223Gastaut syndrome. L) Axi al section. Polymicrogyria in a patient with TUBB2B mutation. The cortical mantle is diffus ely polymicrogyric, with prominent infoldings in the posterior aspect of the abnormally ori ented sylvian \201 ssures, more on the left. have epilepsy, with normal or borderline cognitive level. However, a wide spectrum of clini cal presentations and associated features is possible, with a loose correlation between siz e of PNH, structural abnormality of the cortex, and clinical severity ( 124 ). PNH occurs m ost frequently in women as an X-linked trait ( 125 ) de \201 ned as \200\230classical bil ateral PNH \200\231, associated with high rates of prenatal lethality in male fetuses, and 50 % recurrence risk in the female off- spring. Almost 100 % of families and 26 % of sporad ic patients, har- bour mutations of the FLNA gene ( 124 ), which also cause coagulopathy an d cardiovascular abnormalities in some patients. Only a few living male patients with PNH owing to FLNA muta- tions have been reported ( 126 , 127 ). Mild missense mutations or mosaic mutations account for survival of affected male s, who can, in turn, pass their genetic defect to their daughters. A rare recessive form of PNH owing to mutations of the ARFGEF2 gene was described in two consanguineous pedigrees i n which affected chil- dren had microcephaly, severe delay, and early-onset seizures ( 128 ). PNH has been described in association with known genetic syndromes and a number of copy number variants (CNVs) in patients with variably impaired cognitive skills ( 129 ) (Table 2 . 5 ). CHAPTER 2 neurogenetics of epilepsy 21 Polymicrogyria The term \200\230polymicrogyria \200\231 (PMG) de \201 nes an excessive nu mber of abnormally small gyri that produce an irregular cortical surface with lumpy aspect ( 110 ). PMG can be localized to a single gyrus, involve a portion of one hemisphere, be bi lateral and asymmetri- cal, bilateral and symmetrical, or diffuse. The imaging appearance o f PMG varies with the patient \200\231s age. In newborns and young infants, the malformed c ortex is very thin with multiple, very small undulations. After myelination, PMG appears as thickened cortex with irregular cortex \200\223white matter junction ( 130 ). Polymicrogyr ia is associated with a wide number of patterns and syndromes and with mutations in several genes (Table 2. 5 ). Various PMG syn- dromes have been described, which have been designat ed accord- ing to their lobar topography ( 130 ). Bilateral perisylvian polymicrogyria (BPP ) (Fig. 2. 3 I, J) is the most frequent form. It is associated with mild to moderate mental retardation, epilepsy, and impaired oromotor skills. Most cases are sporadic but genetic h et- erogeneity is apparent ( 130 , 131 ). A missense mutation in the Xq22 gene SRPX2 was fo und in an affected male ( 131 ). However, SRPX2 does not account for X-linked pedigrees. BP P, frequently asym- metric and with a striking predisposition for the right hemisphere, has also been reported in association with 22q11.2 deletion ( 132 ). Bilateral frontoparietal polymicrogyria (BFPP) (Fig. 2. 3 K) has been reported in families with recessive pedigrees and has been associ- ated with mutations of the GPR56 gene ( 133 ). The imaging charac- ter istics of BFPP resemble those of the cobblestone malformative spectrum (muscle-eye-brain di sease and Fukuyama congenital mus- cular dystrophy) ( 130 ). Mutations of the TUBB2B gene h ave been associated with asymmetric polymicrogyria ( 134 ) but genotype \200\223 phenotype correlations need to be clari \201 ed (Fig. 2.3 L). Different types of PMG as part of comp lex syndromes have been associated with several different pathogenic CNVs (Table 2. 5 ) ( 1 35 ). ataxia, cognitive impairment, and, in some children, microcephaly ( 141 ). Generalized spik e-and-wave discharges and a combination of absence, myoclonic, and tonic \200\223clonic sei zures have been reported ( 142 ). A syndrome of paroxysmal exercise-induced dyskinesia and epilepsy ( 143 ) and recently an IGE phenotype ( 144 ) and more spe- ci \201 cally early-o nset absence epilepsy ( 145 ) and myoclonic-astatic epilepsy have been associated to SLC2A1 mutations ( 146 ). Chromosomal abnormalities Chromosomal abnormalities are relatively common genetically deter mined conditions that increase the risk of epilepsy. Epilepsy has been associated with over 400 different chromosomal imbal- ances ( 147 , 148 ). Among patients with epilepsy and int ellectual disability, about 6 % have chromosomal abnormalities, but this \201 gure climbs to 50 % if multiple congenital abnormalities are also present ( 147 ). The use of such cur rent techniques as high-resolution chromosome banding, \202 uorescent in situ hybridizati on (FISH), comparative genomic hybridization (array CGH), and multiplex ligand-dependent pr obe ampli \201 cation (MLPA) would certainly increase these detection rates. However, the likelihood of develop- ing seizures varies greatly among the different chromosomal disor- d ers. Chromosomal abnormalities almost constantly result from rearrangements or deletions/du plications that affect the function of more than one gene. As a consequence, even when the chromo- somal imbalance can only be detected using techniques with the highest resolution, such as array CGH, affected patients have a combination of clinical features and only excep tionally have iso- lated epilepsy. Most often cognitive impairment and dysmorphic features, even subtle, co-occur with epilepsy. The ring chromo- some 20 syndrome represents the most striking example in which a highly speci \201 c epilepsy phenotype can be, at least in so me patients, the only expression of the chromosomal disorder. Most pathogenic CNVs detected by array-CGH are rare or unique, making it dif \201 cult to collect a suf \201 cient number of patients to identify characteristic features of epileps y for each chromosomal syndrome. However, at the research level on the causes of epilepsy, the association between cryptic deletions/duplications and epilepsy is improving our abilit y to clone new critical genes, translating in turn in improved diagnosis. For example, hete rozygous missense mutations in STXBP1 in patients with infantile epileptic encepha- lopathy with suppression bursts (Ohtahara syndrome) were found after a de novo 2.0-Mb microdeletio n at 9q33.3 \200\223q34.11 in an affected girl prompted analysis of candidate genes mapping to the deleted region in patients with similar phenotypes ( 90 ). Metabolic disorders Epilepsy is part of the clinical spectrum of a large number of inher- i ted metabolic disorders ( 136 , 137 ), often within the context of a complex neurological s yndrome. Sometimes epilepsy is a promi- nent, or presenting, symptom, and, in a minority of patients can be cured by an appropriate dietary supplementation or regimen. Pyridoxine-dep endent seizures, a recessive disorder due to muta- tions of the antiquitin ( ALDH7A1 ) gene , respond dramatically to the intravenous injection of pyridoxine and recur within a few da ys if maintenance therapy is discontinued. The disorder is caused by a defect of alpha-amin o adipic semialdehyde ( -AASA) dehydroge- nase (antiquitin) in the cerebral lysine degra dation pathway ( 138 ). The possibility of dosing speci \201 c metabolites such as -AAS A ( 139 ) and of mutation analysis has meant that pyridoxine withdrawal is no longer needed to establish the diagnosis. Epilepsy related to glu- cose transporter type 1 de \201 cien cy syndrome (GLUT1-DS) provides a paradigmatic example of how once the core phenotypic spec trum of a genetically determined inherited neurometabolic disorder has been de \201 ned, a vailability of biological and molecular markers allows progressive delineation of the syndr ome spectrum. The cause of GLUT1-DS is heterozygous mutations of the SLC2A1 gene encoding G LUT1, the molecule that transports glucose across the blood \200\223brain barrier ( 140 ). Hypoglycorrachia is a key diagnostic laboratory feature. Clinical features classically comp rise a combi- nation of infantile-onset seizures, complex movement disorders, Array CGH has greatly improved the diagnostic yield of chromo- somal imbalances, allowing t he identi \201 cation of new syndromes caused by imbalances as small as a few dozen kiloba ses ( 149 ). However, little information is available on genome-wide cytogenetic array scre ening in patients speci \201 cally selected for epilepsy. Engels et al. ( 150 ) analyzed 6 0 patients with mental retardation combined with congenital anomalies, 25 % of whom also ha d epilepsy. Novel imbalances were found in six patients (10 % ), two of whom had epi- lepsy . Kim et al. ( 151 ) reported various CNVs in patients with idio- pathic generalized or par tial epilepsies and FS. A study investigating the impact of these \201 ve microdeletions on the genetic risk for common IGE syndromes, using high-density single nucleotide pol- ymo rphism arrays, in a large cohort, found signi \201 cant associations with microdeletions a t 15q11.2 and 16p13.11 ( 152 ). oxford textbook of epilepsy and epileptic seizures 22 Genetic counseling Genetic testing can be offered for single-gene or Mendelian epi- lepsy s yndromes, or epilepsy-associated disorders, if the gene has been identi \201 ed. If not, e mpirical counseling can be offered, based on the type of epilepsy, mode of inheritance, and penetrance. Although we can now carry out preclinical and prenatal diagnosis in many cases , the severity and prognosis of the epilepsy in speci \201 c individuals, particularly in those with idiopathic epilepsies, is dif- \201 cult to predict. However, in symptomatic m onogenic epilepsies, such as the progressive myoclonus epilepsies, phakomatoses, and malfor mations of cortical development, carrier detection, prenatal diagnosis, and presymptomatic testing may lead to prevention. Unfortunately, no curative treatment has emerged from any g enetic \201 nding in epilepsy to date (with the possible exception of the ketogenic diet in GLUT1 de \201 ciency syndrome), nor have the many pharmacogenomic studies in epilepsy y ielded any widely applica- ble treatment advances. This is a disappointing lack of progress , re \202 ecting as it does on the complex nature of epilepsy and its treat- ment. Counsel ing needs to consider these issues. 6 . Guerrini R , Dravet CH . Severe epileptic encephalopathies of infancy . In: Engel J, Pe dley TA (eds) Epilepsy , pp. 2285 \200\223 302 . Philadelphia, PA: Lippincott-Raven , 1997 . 7 . Guerrini R , Striano P , Catarino C , Sisodiya SM . Neuroimaging and neuropathology of Dravet syndrome . Epilepsia 2011 ; 52 : 30 \200\223 4 . 8 . Catarino CB , Liu JY , Liagkouras I , Gibbons VS , Labrum RW , Ellis R , et al . Dravet syndrome as epileptic encephalopathy: evidence from long-term course and neuropathology . Brain 2011 ; 134 : 2982 \200\223 3010 . 9 . Suls A , Claeys KG , Goossens D , Harding B , Van Luijk R , Scheers S , et al . Microdeletions involving the SCN1A gene may be common in SCN1A-mutation-negative SMEI patients . Hum Mutat 2006 ; 27 : 914 \200\223 20 . 10 . Marini C , Scheffer IE , Nabbout R , Mei D , Cox K , Dibbens LM , et al . SCN1A duplic ations and deletions detected in Dravet syndrome: implications for molecular diagnosis . Ep ilepsia 2009 ; 50 : 1670 \200\223 8 . 11 . Macdonald RL , Kang JQ . Molecular pathology of genetic epilepsies associated with GABAA receptor subunit mutations . Epilepsy Curr 2009 ; 9 : 18 \200\223 23 . 12 . Depienne C , Arzimanoglou A , Trouillard O , Fedirko E , Baulac S , Saint-Martin C , e t al . Parental mosaicism can cause recurrent transmission of SCN1A mutations associated wi th severe myoclonic epilepsy of infancy . Hum Mutat 2006 ; 27 : 389 . 13 . Marini C , Mei D , Helen CJ , Guerrini R . Mosaic SCN1A mutation Future perspectives The next steps include identifying additional genes both in mono- genic epilepsies and epilepsies with complex inheritance, geno- type \200\223phenotype correlati ons, and functional studies of the abnormal proteins. These studies may have practical appl ications for diagnosis, genetic counseling, and possible treatment. Most of the epilepsy sy ndromes listed in this chapter are characterized by marked clinical and genetic heterogenei ty. This may be explained by pleiotropic expression of a single-gene mutation, modifying ge nes, or by several genes producing a similar phenotype, at times because they affect the sa me developmental or metabolic pathway. It is hoped that a constantly updated database will be established for all the known gene mutations and polymorphisms and their clinical correl ates, so that genotype \200\223phenotype correlations can be determined. This is the object ive of the Human Variome project ( 153 ). For example, over 600 mutations in SCN1A associat ed with Dravet syndrome have now been identi \201 ed and the severity of the related pheno type can be predicted early, with reasonable accuracy for those recurrent mutations in whic h suf \201 cient numbers of clini- cal observations are available. in familial severe myoclonic epilepsy of infancy . Epilepsia 2006 ; 47 : 1737 \200\223 40 . 14 . Guerrini R , Oguni H . Borderline Dravet syndrome: a useful diagnostic category? Epilepsia 2011 ; 52 : 10 \200\2231 2 . 15 . Fujiwara T , Sugawara T , Mazaki-Miyazaki E , Takahashi Y , Fukushima K , Watanabe M , et al . Mutations of sodium channel alpha subunit type 1 (SCN1A) in intractable childhood epilepsies with frequent generalized tonic-clonic seizures . Brain 2006 ; 126 : 531 \200 \223 46 . 16 . Wallace RH , Scheffer IE , Barnett S , Richards M , Dibbens L , Desai RR , et al . Neuronal sodium-channel alpha1-subunit mutations in generalized epilepsy with febri le seizures plus . Am J Hum Genet 2001 ; 68 : 859 \200\223 65 . 17 . Harkin LA , McMahon JM , Iona X , Dibbens L , Pelekanos JT , Zuberi SM , et al . The s pectrum of SCN1A-related infantile epileptic encephalopathies . Brain 2007 ; 130 : 843 \200\223 52 . 18 . Scheffer IE , Berkovic SF . Generalized epilepsy with febrile seizures plus: a genetic disorder with heterogeneous clinical phenotypes . Brain 1997 ; 120 : 479 \200\223 90 . 19 . Wallace RH , Wang DW , Singh R , Scheffer IE , George AL Jr, Phillips HA , et al . Febrile seizures and generalized epilepsy associated with a mutation in the Na + channel beta1 subunit gene SCN1B . Nat Genet 1998 ; 19 : 366 \200\223 70 . 20 . Escayg A , MacDonald BT , Meisler MH , Baulac S , Huberfeld G , An-Gour \201 nkel I , et al . Mutations of SCN1A, encoding a neuronal sodium channel, in t wo families with GEFS + 2 . Nat Genet 2000 ; 24 : 343 \200\223 5 . References 1 . Greenberg DA , Delgado-Escueta AV , Widelitz H , Sparkes RS , 21 . Marini C , Mei D , Temudo T , Ferrari AR , Buti D , Dravet C , et al . Treiman L , Maldonado HM , et al . Juvenile myoclonic epilepsy (JME) may be linked to the B F and HLA loci on human chromosome 6 . Am J Med Genet 1988 ; 31 : 185 \200\223 92 . Idiopathic epilepsies with seizures precipitated by fever and SCN1A abnormalities . Epileps ia 2007 ; 48 : 1678 \200\223 85 . 22 . Wallace RH , Marini C , Petrou S , Harkin LA , Bowser DN , Panchal RG , et al . Mutant GABA(A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizures . Nat G enet 2001 ; 28 : 49 \200\223 52 . 23 . Baulac S , Huberfeld G , Gour \201 nkel-An I , Mit ropoulou G , Beranger A , Prud \200\231homme JF , et al . First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma2-subunit gene . Nat Genet 2001 ; 28 : 46 \200\223 8 . 2 . Steinlein OK , Mulley JC , Propping P , Wallace RH , Phillips HA , Sutherland GR , et al . A missense mutation in the neuronal nicotinic acetylcholine recepto r alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy . N at Genet 1995 ; 11:201 \200\223 3 . 3 . Heron SE , Scheffer IE , Berkovic SF , Dibbens LM , Mulley JC . Channelopathies in idiopathic epilepsy . Neurotherapeutics 2007 ; 4 : 295 \200\223 304 . 24 . Mantegazza M , Rusconi R , Scalmani P , Avanzini G , Franceschetti S . 4 . Martin MS , Tang B , Papale LA , Yu FH , Catterall WA , Escayg A . The voltage-gated so dium channel Scn8a is a genetic modi \201 er of severe myoclonic epilepsy of infancy . Hum Mol Genet 2007 ; 16 : 2892 \200\223 9 . Epileptogenic ion channel mutations: from bedside to bench and, hopefully, back again . Epi lepsy Res 2010 ; 92 : 1 \200\223 29 . 25 . Lerche H , Weber YG , Jurkat-Rott K , Lehmann-Horn F . Ion channel defects in idiopath ic epilepsies . Curr Pharm 2005 ; 11 : 2737 \200\223 52 . 5 . Gour \201 nkel-An I , Baulac S , Nabbout R , Ruberg M , Baulac M , Brice A , et al . Monogenic idiopathic epilepsies . Lancet Neurol 2004 ; 3 : 209 \200\223 18 . CHAPTER 2 neurogenetics of epilepsy 23 46 . Scheffer IE , Bhatia KP , Lopes-Cendes I , Fish DR , Marsden CD , 26 . Yu FH , Mantegazza M , Westenbroek RE , Robbins CA , Kalume F , Andermann E , et al . Autosomal dominant nocturnal frontal lobe epilepsy: a distinctive cli nical disorder . Brain 1995 ; 118 : 61 \200\223 73 . 47 . Picard F , Baulac S , Kahane P , Hirsch E , Sebastianelli R , Thomas P , Burton KA , et al . Reduced sodium current in GABAergic interneurons in a mouse model of se vere myoclonic epilepsy in infancy . Nat Neurosci 2006 ; 9 : 1142 \200\223 9 . et al . Dominant partial epilepsies. A clinical, electrophysiological and genetic study of 19 European families . Brain 2000 ; 123 : 1247 \200\223 62 . 48 . Ryvlin P , Minotti L , D emarquay G , Hirsch E , Arzimanoglou A , 27 . Ogiwara I , Miyamoto H , Morita N , Atapour N , Mazaki E , Inoue I ,