Genetics in Epilepsy

Home , Febrile seizure, Frontal lobe epilepsy

Experimental Neurobiology Vol. 12, pages 71～80, December 2003

Chang-Ho Yun1,* and Beom S. Jeon2

1Department of Neurology, College of Medicine, Inha University, Incheon 400-711, Korea, 2Department of Neurology, Seoul National University College of Medicine, Seoul 110-744, Korea

ABSTRACT

The importance of genetic contributions to the epilepsies is now well established. Mutations in over 70 genes now define biological pathways leading to the epilepsy. These mutations disrupt a very large spectrum of biologic function. Some of the inherited errors alter the intrinisic ion channel properties directly responsible for neuronal hyperexcitability and others have impact on the brain development or cellular regulation. This paper reviews the pathogenic implications of the established genetic mutations and briefly mentioned the susceptible genes in hereditary or familial epilepsy syndrome.

Key words: Genetic, epilepsy

INTRODUCTION causing epilepsies. Once the abnormalities such as genes and their products are identified, it will lead Epilepsy affects more than 0.5% of the general to an understanding of how the alterations in indi- population and has a significant hereditary compo- vidual neuronal or neural network properties cause nent. Twin studies that report concordance rates epilepsy (Delgado-Escueta et al., 1994). Probably consistently higher in monozygotic (MZ) than in di- less than 1% of patients with epilepsy are found to zygotic (DZ) twins provides strong support for a ge- have a seizure disorder caused by a single gene netic role in epilepsy (Berkovic et al., 1998). Con- mutation. The vast majority of epilepsy cases are cordance rates ranged from 10.8% in MZ pairs with considered complex traits, a combination of environ- acquired brain injuries to 70% in those without these mental factors and multiple genetic influences. Dis- defects. In DZ twins, concordance ranged from 3 to ease causing mutations have been discovered in 10%, regardless of a brain injury in the affected several rare forms of seizure disorder and the cases (Treiman and Treiman, 2001). The difference majority of genes are involved with ion homeostasis in concordance between MZ and DZ twins is so ev- leading to the notion that many seizure disorders ident, and recent genetic studies revealed some re- are caused by “ion channelopathies” (Table 1). sponsible genes in certain idiopathic epilepsy syn- Other forms of familial epilepsy are caused by mu- dromes. The focus of genetic investigation in the tations in non-ion channel genes (Table 2). This epilepsies is the identification of genetic defects article reviews recent progress made in molecular genetics of epilepsy and perspectives of molecular 󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏 *To whom correspondence should be addressed. study of epilepsy. TEL: 032-890-3418, FAX: 032-890-3864 e-mail: [email protected] 72 C-H. Yun & B.S. Jeon

Table 1. Ion channel-related genetic defects in human epilepsy Syndrome Chromosomal region Gene Gene function

ADNFLE type 1 20q13.2-q13.3 CHRNA4 α4 subunit of nicotinic Ach receptor (Steinlein et al., 1995 and 1997; Hirose et al., 1999) ADNFLE type 2 15q24 ? Nicotinic Ach receptor subunit7

ADNFLE type 3 1 (pericentromeric region) CHRNB2 β2 subunit of nicotinic Ach receptor (Fusco et al., 2000; Phillips et al., 2001) BNFC 20q13 KCNQ2 Potassium channel subunit (Singh et al., 1998) 8q KCNQ3 Potassium channel subunit (Charlier et al., 1998) 6q14 KCNQ5 Potassium channel subunit (Kananura et al., 2000) FS FEB1 8q13-q21 ? ? (Wallace et al., 1996) FEB2 19q13 ? ? (Johnson et al., 1997) FEB3 2q23-q24 ? ? (Peiffer et al., 1999) FEB4 5q14-q15 ? ? (Matsushima et al., 2002)

GEFS FEB1+ 19q13.1 SCN1B Sodium channel β1 subunit (Wallace et al., 1998)

FEB2+ 2q21-q33 SCN1A Sodium channel α1 subunit (Wallace et al., 2001)

FEB3+ 5q34 GABRG2 γ2 subunit of GABA receptor (Baulac et al., 2001) FEB4+ 2q24-q33 SCN2A Sodium channel 2 subunit (Sugawara et al., 2001a)

FS+CAE 5q34 GABRG2 γ2 subunit of GABA receptor (Wallace et al., 2001)

SMEI SMEI 2q24 SCN1A Sodium channel α1 subunit (Claes et al., 2001)

FS+ including SMEI 5q34 GARG2 γ2 subunit of GABA receptor (Harkin et al., 2002) JME 6p11-p12 LMPBI Lysosomal membrane protein (Suzuki et al., 2001)

15q CHRNA7? α7 nicotinic acetylcholine receptor (Elmslie et al., 1997)

5q32-q35 GABRA1 α1 subunit of GABA receptor (Cossette et al., 2002)

ADNFLE, autosomal dominant nocturnal frontal lobe epilepsy; BNFC, benign neonatal familial convulsion; FS, febrile seizure; GEFS, generalized epilepsy with febrile seizure; CAE, childhood absence epilepsy; SMEI, severe myoclonic epilepsy of infancy; JME, juvenile myoclonic epilepsy.

Table 2. Some non-ion channel-related genes cloned in human epilepsy Syndrome Chromosomal region Gene Gene function

PME Unverricht-Lundborg type 21q23 EPM1 Cystatin B (Virtaneva et al., 1997) Lafora's disease 6q24 EPM2 Laforin, protein tyrosine phosphatase (Minassian et al., 1998) ADPE with auditory feature 1q LGI1 Leucine-rich, glioma-inactivated 1 protein (tumor suppressor?) (Fertig et al., 2003)

Autosomal dominant nocturnal frontal lobe disorder inherited as an autosomal dominant trait epilepsy with high penetrance. Using genetic linkage analy- Autosomal dominant nocturnal frontal lobe ep- ses, the responsible gene has been mapped to ilepsy (ADNFLE) was first reported as a new clin- chromosome 20q13.2 (Phillips et al., 1995). Subse- ical entity of epilepsy in 1994. ADNFLE is charac- quent linkage studies in families with ADNFLE terized by clusters of a brief seizure with frontal showed that the candidate genes in some families lobe semiology during non-rapid eye movement with ADNFLE reside on chromosomes 15q24 and 1 (NREM) sleep, and is often misdiagnosed as night- (Steinlein et al., 1997; Phillips et al., 1998 and 2001; mare or parasomnia (Scheffer et al., 1995). Onset Hirose et al., 1999; Fusco et al., 2000). ADNFLE usually occurs in mid-childhood. Responsiveness to with genetic locus on chromosomes 20q13.2, 15q24 antiepileptic drugs such as carbamazepine is excel- and 1 are referred to as ADNFLE type 1, 2, and 3, lent except some patients. ADNFLE is a monogenic respectively. Mutations in the neuronal acetylcholine Genetics in Epilepsy 73 receptor α4 subunit (CHRNA4) gene CHRNA4, and of CHRNB2, representing apparent opposite chan- β2 subunit (CHRNB2) gene CHRNB2, have been nel function, could also be considered as another found in ADNFLE type 1 and 3, respectively. pathophysiological mechanism of ADNFLE. Thus, CHRNA4 is a subunit of neuronal nicotinic acetyl- further studies are necessary to determine the mo- choline receptor (nAChR) in the brain. CHRNA4 is lecular pathogenesis of epilepsy of ADNFLE due to assembled into a hetero-pentamer that functions as abnormalities of nAChR (Forman et al., 1996). a nAChR. Since CHRNA4 is expressed widely in the brain and forms nAChR mainly with CHRNB2, Benign familial neonatal convulsion (α4)2(β2)3 is considered as the dominant subtype Benign familial neonatal convulsions (BFNC) is of nAChR in the brain. As a structure of the α- an autosomal dominant disorder with neonatal on- subunit of AChR, CHRNA4 is typically equipped set and high penetrance, and is characterized by with a binding site for acetylcholine at the C termi- clusters of generalized and partial seizures, and nus and spans the plasma membrane four times. remits spontaneously within 8 mo. However, the For ADNFLE type 1, a missense mutation (c.839C . incidence of subsequent epilepsy later in life is T; S280F), an insertional mutation of CHRNA4 about 11% (Plouin, 1997). BFNC has been linked (c.873874insGCT; L301302) and a point mutation of to mutations in three K-channel genes, KCNQ2 on CHRNA4 (c.851C . T; S284L) in CHRNA4 has been chromosome 20 (BFNC1), KCNQ3 (BFNC2) on reported (Steinlein et al., 1997; Phillips et al., 1998; chromosome 8, and KCNQ5 (BFNC3) on chromo- Hirose et al., 1999). Electrophysiological studies of some 6 (Charlier, et al., 1998; Singh et al., 1998; AChR reveal that both mutations seem to lead to Kananura et al., 2000). Abnormalities of both KCNQ2 loss-of-function of nAChR resulting reduced calcium and KCNQ3 lead to dysfunction of the M-current, a permeability of the mutant nAChR (Steinlein, 1998; slowly activating and deactivating potassium con- Matsushima et al., 2002). Dominant inheritance in ductance critical to determining the subthreshold ADNFLE resulting from these loss-of-function muta- electrical excitability of neurons (Wang et al., 1998). tions seems to be explained as a dominant neg- KCNQ2 and KCNQ3 synergistically contribute to ative effect. For ADNFLE type 3, two missense mu- formation of the native M current. Deficient KCNQ2 tations (c.859G . C; V287L, c.859G . A; V287M) of or KCNQ3 does not necessarily abolish M-current CHRNB2, which is mapped to chromosome 1p21, but reduces it by 30%. Nominal reduction of M- have been identified (Fusco et al., 2000; Phillips et current, therefore, can undermine the inhibitory sys- al., 2001). Interestingly, the missense mutations tem of the CNS in the newborn. identified in CHRNB2 are also located at the M2 Schwake et al. (2002) reported that the increased region of CHRNB2 corresponding to mutations of currents of heterometric KCNQ2 and KCNQ3 chan- CHRNA4 described above. In contrast to the elect- nels were due to an increased expression of active rophysiological characteristics of CHRNA4 muta- channels on the plasma membrane. The C-terminus tions, however, V287L leads to slow deactivation of KCNQ2 was found to play an important role in while V287M mutation confers higher affinity to ACh such efficient surface expression. Most mutations of on the receptor. These mutations are thus consid- KCNQ2 so far found in BFNC1 are located in the ered to lead to ‘gain-of-function’ although the phe- C-terminus, some of which have been demon- notype of ADNFLE resulting from these mutations, strated to hamper the surface expression of hetero- type 3, is indistinguishable from ADNFLE type 1, metric channels with KCNQ3 and thereby reduce resulting from CHRNA4 mutations. Since nAChR is K-current. The C-terminal of KCNQ molecules bear- considered to function as an excitatory element in ing conserved amino acid sequence may serve as central nervous system and mutations of CHRNA4 a key element in assembly with homologous pore seem to cause the aforementioned ‘loss-of-function’, forming subunits, which may be essential to traffic neuronal excitation, i.e. convulsions, of ADNFLE is K-channels to the plasma membrane. Alternatively, thought to be due to secondary dysfunction of they per se may convey export signals from endo- GABAergic inhibitory system resulting from such plasmic reticulum to Golgi apparatus to control sur- loss-of-function of nAChR. However, the mutations face K-channel numbers, such as demonstrated in 74 C-H. Yun & B.S. Jeon inward rectifying K-channels, another K-channel fa- two auxiliary β subunits, β1 and β2. The α subunit mily (Ma et al., 2001). is comprised of four repeated domains each of Some mutations located in transmembrane do- which has six transmembrane segments. The fourth mains including the pore region do not interfere trans-membrane segment of each domain serves with the surface expression of channels but reduce as a voltage sensor. The α subunit is a large pore K-current (Schwake et al., 2002). Reduced K-cur- forming molecule and sufficient to function by itself rent resulting from mutations in either KCNQ2 or as a Na-channel. There are about ten subtypes of KCNQ3 can lead to relative hyperexcitability of neu- α subunit expressed differently in various tissues. rons. Thus, dysfunction of either KCNQ2 or KCNQ3 Both β1 and β2 subunits bear one transmembrane results in indistinguishable convulsions in BFNC1 domain and modulate channel function providing and 2. In fact, heterozygous knockout mice of inactivation kinetics to Na-channel. The β1 subunit KCNQ2 show neuronal hyperexcitability (Watanabe, binds to the α subunit by a non-covalent linkage, et al., 2000). while β2 subunit binds to the α subunit by a Okada et al. (2002) demonstrated that KCNQ K- disulfide bond covalent linkage. Wallace et al. channels serve as a predominant inhibitory system identified the locus for a pedigree with GEFS+ on in the CNS of neonates and GABAergic transmis- chromosome 19q13.1 and a heterozygous missense sion serves as the inhibitory system afterwards, mutation (c.363C＞G; C121W) of SCN1B, a Na- indicating that deficient KCNQ K-channels cause channel β1 subunit gene (Wallace et al., 1998). convulsions during the neonatal period. These find- C121W results in disruption of the disulfide bond in ings explains the age-dependent features of time of the molecule and interferes with the ability of the onset, early spontaneous remission, and propensity subunit to modulate the channel-gating kinetics. for future epilepsies in BFNC. Consequently, the lack of β1 subunit confers Na- channels a slower inactivation phase than that of Generalized epilepsy with febrile seizure plus wild type channels without any effect on recovery Febrile seizures (FS) are the most common pro- from inactivation. Thus, c.363C＜G; C121W is a voked seizures afflicting infants and young children. loss-of-function mutant and may allow persistent Although no specific gene responsible for simple inward Na current in neurons, i.e. neuronal hyper- FS has yet been identified, four loci have been excitability. reported for FS; FEB1 at chromosome 8q13q21; A second locus for GEFS+ was mapped to FEB2, 19p; FEB3, 2q2324; FEB4, 5q14q15 (Wallace 2q21-q33, where FEB3 resides and genes encoding et al., 1996 and 1998; Johnson et al., 1997; Peiffer several Na-channel α-subunits including Nav1.1, et al., 1998). A small proportion of patients with FS Nav1.2 and Nav1.3 (SCN1A, SCN2A, and SCN3A, develop afebrile seizures later in life. This clinical respectively) are localized (Wallace et al., 2001). subset of FS includes a generalized epilepsy with Escayg et al. (2000) later identified two mutations febrile seizures plus (GEFS+) or autosomal domi- of SCN1A in individuals with the GEFS+ pheno- nant epilepsy with febrile seizure plus; affected in- type. Two missense mutations of SCN1A first iden- dividuals not only have FS beyond 6 yr of age (FS+) tified as the cause of GEFS+ both reside in volt- but also various types of afebrile seizures including age sensor segments. Several novel missense generalized or partial epilepsy (Singh et al., 1999; mutations of SCN1A were recently identified in fam- Escayg et al., 2000). ilies with GEFS+ (Wallace et al., 1998 and 2001; Mutations of FS-related epilepsy syndromes in- Singh et al., 1999; Escayg et al., 2000). All muta- cluding GEFS+ are found in genes encoding Na- tions were heterozygous. Although the electrophys- channels (Wallace et al., 1998 and 2001; Sugawara iological characteristics of SCN1A mutations have et al., 2001a). Recently the pathogenic role of γ2 not yet been reported, it is speculated that Na in- subunit of GABAA receptor is also reported (Baulac flux is augmented in neurons. Consequently, similar et al., 2001). Neuronal voltage-gated Na-channels, to the mutation of SCN1B, increased neuronal hy- the main generator of action potentials in neurons, perexcitability of the deficient channel is expected. are composed of three subunits; one α subunit and As described, SCN2A and SCN3A have been the Genetics in Epilepsy 75 most intriguing candidate genes to investigate, been subdivided into three groups: GEFS+1, since both are mapped in the second locus for the GEFS+2 and GEFS+3, which result from muta- GEFS+ phenotype along with SCN1A. Electro- tions of SCN1B, SCN1A and GABRG2, respec- physiological characteristics of Nav1.2 bearing the tively. The high diversity of epilepsy phenotypes in mutations revealed that among them, only c.562C＜ families with GEFS+1, for which a monogenic mu- T, R188W lead to fast desensitization (Sugawara et tation of SCN1B has been confirmed as the re- al., 2001b). Since other electrophysiological proper- sponsible defect, suggests two hypotheses. One is ties of the mutant channel such as conductance that monogenic epilepsy may display a wide variety and recovery, are comparable with wild type, R188W of seizure phenotypes. In turn, some epilepsy syn- should augment Na-influx. Thus, Nav1.2 harboring dromes that are currently classified as different epi- R188W should result in hyperexcitability of neurons, lepsy syndromes could be due to the same genetic which in turn induces seizure activity. This is the defect or considered as allelic variants. Further- first evidence that genetic abnormality of SCN2A is more, since the epilepsy phenotypes of GEFS+1 associated with a disease in humans and mam- encompasses several common idiopathic epilepsy mals. phenotypes, e.g. absence and tonic-clonic seizure, Recently genetic abnormalities that cause epilep- the common idiopathic epilepsy phenotypes could sies associated with FS have been identified in the result from monogenic abnormality although they gene encoding γ2 subunit of GABAA receptor, are at present considered as polygenic or multi-

GABRG2. GABAA receptor, a ligand gated Cl-chan- factorial disorders. Alternatively, the second hypoth- nel, functions as tetramer consisting of α, β, γ, δ, esis argues that defects of Na-channels may be and π subunits. Each subunit has several subtypes only responsible for frequent febrile convulsions, such as α1 and α2. The main GABAA receptor in which may induce subsequent epilepsies. Occur- the CNS is composed of α1, β2 and γ2 subunits. rence and semiology of such subsequent epilepsies

GABAA receptor serves as the main inhibitory sys- may depend on genetic predisposition, which may tem in mature CNS but is rather excitatory in have been lineally inherited independent of the de- developing CNS (Ganguly et al., 2001: Okada et fect of SCN1B. This may hence challenge the iden- al., 2002). One mutation identified in GABRG2, a tity of the disease entity, GEFS+. Thus, it seems missense mutation c.983A＜T; K328M, located in that various Na-channels subunits, GABAA subunits the linkage between transmembrane domains 3 and and their modulators can be involved in the patho- 4 was found in a French family in which the pheno- genesis of the GEFS+ phenotype. Defects of Na- type of affected individuals was GEFS+ (Baulac et channels are known to cause temperature-sensitive al., 2001). GABAA receptor harboring K328M showed disorders such as paramyotonia congenita, which is reduced Cl-current in response to a physiological well known as myotonia aggravated by coldness. In ligand, GABA. Since GABAA receptor exerts an in- this regard, not only low temperature but also high hibitory function, dysfunction of GABAA receptor can temperature can induce paramyotonia in some indi- lead to seizure activities. Another mutation of viduals with paramyotonia congenital (Sugiura et GABRG2 was a missense mutation (c.245G＜A; al., 2000). Thus, Na-channels may be involved in R82Q) identified in a family where the phenotype of FS, the most common temperature-sensitive disor- affected individuals was FS+ followed by absences der. (Wallace et al., 2001). The R82Q mutation resides The mechanism of spontaneous secession of sim- within the first of two high-affinity benzodiazepine- ple FS has not yet been elucidated. Previous stud- binding domains of GABAA receptor. Interestingly, ies have demonstrated that electrophysiological pro- R82Q did not alter Cl-current in response to GABA perties of neuronal Na-channels are modulated by but abolished Cl-current augmented by diazepine. phosphorylation of the channels (Cantrell et al.,

GABAA receptor may respond to endozepines, puta- 1997). Furthermore, receptor protein tyrosine phos- tive endogenous benzodiazepine-like substances, and phatase β (RPTPβ) that controls the phosphoryla- prevent both febrile seizures and absences. tion indeed changes developmentally (Ratcliffe et Consequently, GEFS+ (MIM 604233), has so far al., 2000). RPTPβ is associated with both extra- 76 C-H. Yun & B.S. Jeon and intra-cellular parts of the Na-channel β1 mole- Both autosomal dominant epilepsy with febrile cule, SCN1B, in the fetus and very early age seizure plus (GEFS+) and SMEI are now asso- whereby RPTPβ has an access to the phos- ciated with mutations of genes encoding both Na phorylation site of the a subunit of Na-channels, channel subunit and the γ2-subunit of the GABA-A while RPTPβ becomes catalytically inactive secreted receptor. These mutations may contribute to low- isoform, phosphacan, losing the transmembrane do- ering the epileptogenic threshold in a nonspecific main as it matures. Phosphacan no longer interacts manner. However, as Na channel blockers and with the intracellular part of SCN1B. Consequently, GABAergic neurotransmission enhancers are the neuronal Na-channels are less phosphorylated in two major categories of AEDs used clinically, the early age and more excitable compared to the rest nature of the mutant channel may modulate the of life since phosphorylated Na-channels are known response to a given treatment. to have reduced Na-influx. GABAA receptor, which is involved in FS-related epilepsies such as GEFS Juvenile myoclonic epilepsy +3, is closely related to simple FS as well (Fukuda Among IGE, juvenile myoclonic epilepsy (JME) is et al., 1997). The response of GABAA receptor to a commonly occurring form of IGE, and is charac- benzodiazepine is temperature-sensitive (Munakata terized by awakening myoclonus, absence seizures et al., 1998). Thus, Na-channels as well as GABAA associated with fast spike-wave discharges on the receptor, including their modifications such as phos- EEG, and generalized tonic-clonic seizures. JME is phorylation, may be considered as an interesting widely accepted to be genetically determined, al- target for identifying the responsible genes for sim- though its mode of inheritance remains controver- ple FS. sial. Studies so far reported have provided evidence both for and against the existence of locus Severe myoclonic epilepsy of infancy on chromosome 6p (EJM1) or 15q (EJM2) (Elmslie Severe myoclonic epilepsy of infancy (SMEI) is a et al., 1997; Suzuki et al., 2001). Le-Hellard et al. rare disorder that occurs in isolated patients. The (1999) found no evidence that susceptibility to JME disease is characterized by generalized tonic, clo- was associated with HLA-DR13 (6p) in a French nic, and tonic-clonic seizures that are initially in- population, but Morita et al. (2000) reduced the duced by fever and begin during the first year of EJM1 region to 3.7 cM flanked by D6S436 and life. Later, patients also manifest other seizure D6S1662. However the responsible gene for JME is types, including absence, myoclonic, and simple not uncovered yet to date. However, as a candidate and complex partial seizures. Around the 2nd yr of gene for EJM1, C6orf33 (Chromosome 6 Open life, psychomotor development also becomes de- Reading Frame 33: LMPB1), an integral membrane layed. Claes et al. (2001) screened seven un- protein that targets to lysosomal structures has related patients with SMEI for mutations in SCN1A been reported (Suzuki et al., 2001). The expression and identified a mutation in each patient: four had of C6orf33 in postnatal but not in prenatal is frame shift mutations, one had a nonsense muta- inconsistent with juvenile onset of JME. The genes tion, one had a splice-donor mutation, and one had that encode lysosomal proteins have been reported a missense mutation. All mutations were de novo to be responsible for Batten disease (CLN3 gene), mutations that were not observed in control chro- classical late-infantile neuronal ceroid lipofuscinosis mosomes. For these findings, they speculated that (CLN2 gene), and sialidosis type 1 (lysosomal neu- in the majority of patients with SMEI, the mutation raminidase gene) (Mitchison et al., 1997; Sleat et results in early termination of translation, thereby al., 1997; Pshezhetsky et al., 1997). The defective producing a truncated SCN1A protein from one of gene product of Unverricht-Lundborg type epilepsy, the SCN1A alleles. Rapid degradation of these cystatin B is also thought to act as a protector truncated transcripts or proteins could lead to a against the proteinases leaking from lysosomes loss of function comparable with haploinsufficiency. (Virtaneva et al., 1997). However, all these pheno- Alternatively, some of the transcripts could lead to types are progressive myoclonus epilepsies, and abnormal proteins with a toxic increase in function. they sharply differ from symptoms of JME. It is, Genetics in Epilepsy 77 thus unclear how defects in a lysosomal membrane thought to protect against apoptosis, but the mech- protein such as LMPB1 could underlie the etiology anisms leading to Unverricht-Lundborg disease re- of JME, one of the idiopathic epilepsies. Further main to be elucidated. analysis of EJM1 is underway, and other candidate Lafora body disease: Lafora body disease is a gene(s) will also be reported shortly. polyglucosan storage disorder, and is inherited through an autosomal recessive trait. Linkage of Progressive myoclonic epilepsy Lafora body disease to the chromosome 21 locus The progressive myoclonic epilepsies (PMEs) are (EPM1) associated with PME was excluded by a collection of rare disorders presenting with the Lehesjoki et al. (1991). Serratosa et al. (1995) triad of myoclonic seizures, tonic-clonic seizures, reported linkage to a 17-cM interval of chromosome and progressive neurologic dysfunction that often 6p23-25 in nine families with a maximum multi- manifests as dementia and ataxia. PMEs generally point lod score of 10.58 and no evidence of hetero- begin in late childhood to adolescence. There is geneity. The gene (EPM2A) encoding a novel pro- ethnic and geographic variation in the frequency of tein tyrosine phosphatase (a tyrosine kinase inhib- these disease syndromes, and most of PMEs are itor) called laforin has been reported to be mutated autosomal recessive in inheritance (Kaneko and in the Lafora type PME (EPM2) (Serratosa et al., Wada, 1998). Significant progress has recently been 1999). Subsequently, a number of presumably loss- made in the mapping and isolation of genes for of-function mutations in EPM2A have been iden- symptomatic Mendelian epilepsies such as Unver- tified in families with Lafora body disease (Gomez- richt-Lundborg disease, the neuronal ceroid lipofus- Parre et al., 2000). Laforin may play regulatory cinoses, Lafora body disease, sialidosis, dentator- roles in glycogen metabolism (Ganesh et al., 2000 ubropallidoluysian atrophy and myoclonic epilepsy and 2001). A recent study suggests that laforin is with ragged red fibers. involved in translational regulationand that protein Unverricht-Lundborg disease: Unverricht-Lund- misfolding may be one of the molecular bases of borg disease (EPM1) is sometimes known as Baltic the Lafora disease phenotype caused by missense myoclonic epilepsy because of its high prevalence mutations in EPM2A (Ganesh et al., 2000). Laforin in that region. With onset between 6 and 15 yr of is functionally conserved in mammals and is in- age, the EPM1 is manifested by stimulus- sensitive volved in growth and maturation of neural networks myoclonus, tonic-clonic seizures, progressive slow (Ganesh et al., 2001). The identification of other intellectual decline, emotional lability, and eventually proteins/substrate(s) that interact with laforin, in ataxia, intentional tremor, and dysarthria. The particular the enzymes involved in glycogen syn- disorder has an autosomal recessive transmission thesis are now essential. (Norio et al., 1979), and has been mapped to 21.q22.3 in 12 Finnish families (Lehesjoki et al., CONCLUSIONS 1991). A previously described but unmapped protein, cystatin B, encoded by an intracellular pro- The discovery of dysfunction of ion channels in tease inhibitor gene, is found in this region. Cystatin idiopathic epilepsies has led to the concept of B DNA mutations have been found in affected pa- channelopathies. At the same time, the genetic tients but not in unaffected individuals (Pennacchio heterogeneity of epilepsies has also become appar- et al., 1996). The most common EPM1 mutation ent. Different genes and different mutations may results from an unstable expansion of a normally cause the same epilepsy phenotype. Intrafamilial polymorphic dodecamer repeat unit in the non- phenotypic heterogeneity is also clear. The expres- coding region upstream from the transcription start sion of the mutated genes may differ among family site of the cystatin B gene (Virtaneva et al., 1997). members, causing clinical heterogeneity, or the This expansion represents the first case of insta- gene may intervene in epileptogenesis at a very bility of a repeat unit other than trinucleotides asso- general level, affecting the epileptogenic threshold, ciated with human diseases (Lafreniere et al., 1997). and other genetic or environmental factors may Cystatin B is a cystein-protease inhibitor that is influence the electroclinical profile of the epilepsy in 78 C-H. Yun & B.S. Jeon each affected subject (Gourfinkel-An et al., 2001). GEFS+2. Nat Genet 24:343-345. 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