Basic research

Genetics and epilepsy

Ortrud K. Steinlein, MD, PhD

E pilepsy is one of the most common and het-

erogeneous neurological conditions, and the molecular
pathomechanisms underlying the different seizure dis-
orders have now been studied intensively for more than
two decades.1 There exists a large group of epilepsies
that are often labeled as symptomatic, in order to dis-
tinguish them from the idiopathic epilepsies that are
believed to be mainly of genetic origin. However, with
the progress in genetic analysis, it has become more and
more obvious that no clear division exists between the
two groups of epilepsies. Findings such as SCN1A muta-
The term “epilepsy” describes a heterogeneous group of tions underlying severe myoclonic epilepsy of infancy
disorders, most of them caused by interactions between (SMEI), an epilepsy syndrome that was formerly
several or even many genes and environmental factors. labeled as symptomatic, as well as the failure to find
Much rarer are the genetic epilepsies that are due to sin- major genes for common idiopathic epilepsies such as
gle-gene mutations or defined structural chromosomal juvenile myoclonic epilepsy, raise questions about the
aberrations, such as microdeletions. The discovery of sev- usefulness of a strict classification that distinguishes
eral of the genes underlying these rare genetic epilep- between symptomatic and idiopathic cases. In the etiol-
sies has already considerably contributed to our under- ogy of most epilepsies, a combination of acquired and
standing of the basic mechanisms in epileptogenesis. The genetic factors is involved, while predominantly genetic
progress made in the last 15 years in the genetics of epi- epilepsies constitute only a minority of all seizure dis-
lepsy is providing new possibilities for diagnosis and orders (Figure 1).2 The latter nevertheless serve as an
therapy. Here, different genetic epilepsies are reviewed important source for our increasing knowledge about
as examples, to demonstrate the various pathways that the genes and gene families that can be involved in
can lead from genes to seizures. epileptogenesis, and help us gain insight into the path-
© 2008, LLS SAS Dialogues Clin Neurosci. 2008;10:29-38.
omechanisms underlying the more common forms of
epilepsy. In the following paragraphs, examples of
seizure syndromes are described that are representative
Keywords: idiopathic epilepsy; symptomatic epilepsy; channelopathy; autoso- of the different genetic mechanisms in epileptogenesis
mal dominant nocturnal frontal lobe epilepsy; benign familial neonatal convul-
sion; progressive myoclonus epilepsy; double cortex syndrome
known today. These include ion-channel disorders,
examples of the different mechanisms underlying pro-
Author affiliations: Ludwig-Maximilians-University of Munich School of gressive myoclonus epilepsies, a group of neurogenetic
Medicine, Institute of Human Genetics, Munich, Germany
disorders that can be due to either developmental
Address for correspondence: Ortrud K. Steinlein, MD, PhD, Head of Department, abnormality, and defects in energy metabolism or meta-
Ludwig-Maximilians-University of Munich School of Medicine, Institute of Human
Genetics, Goethestr. 29, 80336 Munich, Germany
bolic disturbances, as well as neuronal migration disor-
(e-mail: [Link]@[Link]) ders.

Copyright © 2008 LLS SAS. All rights reserved

29 [Link]
Basic research
Selected abbreviations and acronyms Familial nocturnal frontal lobe epilepsy
ADNFLE autosomal dominant nocturnal frontal lobe
epilepsy The gene for autosomal dominant nocturnal frontal lobe
BFIC benign familial infantile convulsions epilepsy (ADNFLE) was the first one described for an
BFNC benign familial neonatal convulsions inherited form of idiopathic epilepsy. The mean age of
CLN neuronal ceroid lipofuscinoses onset in ADNFLE is during adolescence or young adult-
EPM1 epilepsy progressive myoclonus (Unverricht- hood, with considerable intra- and interfamilial variance.
Lundborg disease) Most mutations (with the exception of low penetrance
GEFS+ generalized epilepsy with febrile seizures plus mutation I312M) demonstrate a penetrance of 70% to
MERRF myoclonic epilepsy and ragged-red fiber disease 80%. The clusters of brief motor seizures that are typical
nAChR nicotinic acetylcholine receptor of ADNFLE occur mostly out of nonREM (rapid eye
SMEI severe myoclonic epilepsy of infancy movement) sleep. Patients often have recurrent parox-
TM transmembrane regions
Common
Ion-channel mutations in epilepsy

Dysfunctions of mutated voltage- or ligand-gated ion Polygenic Oligogenic

channels have been shown to be a major cause of idio-
pathic epilepsies, at least in the rare genetic forms (Table
I). The detailed genetic and electrophysiological analy- Epilepsies
ses of different ion channels have provided significant
knowledge on the pathophysiological pathways leading
Mendelian inheritance Nonmendelian inheritance
from mutation to seizures.3 Ion-channel mutations are a
known cause of rare monogenic idiopathic epilepsies, but Autosomal dominant Mitochondrial inheritance
Autosomal recessive Chromosomal aberrations
are also suspected to play a major role in more common X-chromosomal dominant
X-chromosomal recessive
epilepsies such as juvenile myoclonic epilepsy or child-
hood and juvenile absence epilepsies. In the following
paragraphs, some monogenic epilepsies have been Rare
selected as examples, to illustrate the importance of ion Figure 1. Schematic representation of genetic and nongenetic etiologies
channels in epileptogenesis. in epilepsy.

Abbreviation Syndrome Gene(s) Chromosome Mode of inheritance

ADNFLE Autosomal dominant nocturnal frontal lobe epilepsy CHRNA4 20q13.3 AD
CHRNB2 1q21
BFNC Benign familial neonatal convulsions KCNQ2 20q13.3 AD
KCNQ3 8q24
BFNIS Benign familial neonatal-infantile seizures SCN2A 2q24 AD
GEFS+ Generalized epilepsy with febrile seizures plus SCN1A 2q24 AD, OG
SCN2A 2q24
SCN2B 11q23
GABRG2 5q31.1-q33.1
SMEI Severe myoclonic epilepsy of infancy SCN1A 2q24 AD, OG
JME Autosomal dominant juvenile myoclonic epilepsy GABRA1 5q34-q35 OG, (AD)
CACNB4 2q22-q23
CLCN2 3q26
EJM1 Juvenile myoclonic epilepsy type 1 EFHC1 6p12-p11 AD
ADPEAF Autosomal dominant epilepsy with auditory features LGI1 10q24 AD

Table I. Genes in idiopathic epilepsy. AD, autosomal dominant; OG, oligogen; (AD), rare families with monogenic inheritance have been described

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Genetics and epilepsy - Steinlein Dialogues in Clinical Neuroscience - Vol 10 . No. 1 . 2008

ysmal awakenings associated with stereotyped move- family carrying the CHRNA4-776ins3 mutation.10,11 More
ments. Most seizure episodes are of 2 to 20 s duration, but than half of the 11 mutation carriers are affected by either
some of them might last considerably longer. In sleep- schizophrenia, negative symptoms of schizophrenia, or
walking periods, patients might move around, speak severe apathy. Another ADNFLE mutation, CHRNA4-
unintelligibly, or scream for 3 min or more. Patients S252L, is associated with mental retardation and/or behav-
report aura phenomena including epigastric, sensory, or ioral problems in two families of different geographic ori-
psychic symptoms that often precede the seizures. A typ- gin. In the latter families the differences in geographic
ical seizure starts with gasps, grunts, or vocalizations fol- origin strongly suggest that the cognitive deficits are
lowed by thrashing hyperkinetic activity or tonic stiffen- caused by the mutation rather than by unrelated factors.8
ing of the limbs, and superimposed clonic jerking. Many Most of the known ADNFLE mutations have already
patients are, at least initially, not aware of their seizures, been studied in different expression systems. They typi-
or they underestimate their number of seizures per night. cally display an increased sensitivity for the natural ago-
Typical complaints are tiredness during daytime and poor nist acetylcholine, demonstrated by a shift of the agonist
sleep quality. Treatment with antiepileptic drugs such as response curve to the left. Thus, the pathomechanism
carbamazepine is effective with respect to seizure con- caused by these mutations seems to be based on a gain-
trol or reduction in many, but not all, patients.4 of-function effect that is likely to increase ion flow
In 1995 a first mutation was identified in the CHRNA4 through the channel pore. Furthermore, comparison
gene as the underlying cause in a large Australian between the mutations showed that they are character-
ADNFLE family that previously helped to map the dis- ized by different biopharmacological profiles. For exam-
order to chromosome 20q13.3.5 Since then, additional ple, reduced calcium permeability was observed for the
CHRNA4 mutations, as well as mutations in two addi- mutants CHRNA4-S248F and CHRNA4-776ins3 but not
tional genes (CHRNB2, CHRNA2), have been found in for the CHRNA4-S252L mutation. It is tempting to spec-
sleep-related frontal lobe epilepsy.6-8 CHRNA4, CHRNA2, ulate that the particular functional signatures of each
and CHRNB2 encode the α4- and β2-subunits of the neu- mutant contribute to the abovementioned observations
ronal nicotinic acetylcholine receptor (nAChR), respec- of associated neurological features or cognitive defects
[Link] nAChRs are members of the large family of lig- in ADNFLE, while the gain-of-function effect might be
and-gated ion channels. They are characterized by five responsible for the epilepsy phenotype itself.12
(identical or different) homologous subunits that assem- It has been hypothized that in presynaptically located
ble around a central axis and form a cation-selective ion nAChRs the gain-of-function effect might activate
channel. With the exception of CHRNB2-I312M the inhibitory γ-aminobutyric acid (GABA)ergic interneu-
known ADNFLE mutations in either CHRNA4 or rons. Such interneurons have an important role in con-
CHRNB2 are located within the second transmembrane trolling the activity of neuronal networks in brain struc-
domain. The second transmembrane (and in parts the tures such as neocortex and hippocampus by
third) domain mainly builds the walls of the ion channel; synchronizing the firing of the participating neurons. An
thus, it seems that ADNFLE mutations specifically target enhanced GABA release would first inhibit a larger
the channel’s gating structure. Until now, four CHRNA4 number of pyramidal cells than usual. After recovery
and three CHRNB2 mutations have been described in from inhibition, the sudden enhancement in network syn-
ADNFLE families from different parts of the world. Most chrony could eventually cause the pathological hyper-
interesting are those mutations that have occurred inde- synchronization that might give rise to a seizure.
pendently in different families, because they offer the
opportunity to study the effects genetic backgrounds Benign familial neonatal convulsions
might have on the clinical expression of the disorder.9
Not surprisingly in view of the important role of the Benign familial neonatal convulsions (BFNC) is an auto-
cholinergic system in higher brain functions, there has somal dominantly inherited seizure disorder of the new-
been evidence presented that at least some ADNFLE born. BFNC is characterized by an age of onset between
mutations not only cause epilepsy but are also associated the first day and, at latest, the fourth month of life. The
with other neurological disorders or cognitive deficits. A seizures are mostly unprovoked, generalized, or multi-
good example is presented by the Norwegian ADNFLE focal, and of the tonic and/or clonic type. They are often

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Basic research
accompanied by dyspnea, ocular symptoms, or other it is not surprising that BFNC mutations were shown to
autonomic signs. The course of the disorder is usually cause only modest reductions (20% to 30%) in potas-
benign and self-limiting, and, with or without pharma- sium currents in reconstitution experiments. Even such
cotherapy, in the majority of patients the seizures remit slight alterations of M-channel activity are obviously suf-
spontaneously within a few days or weeks. Most patients ficient to increase seizure susceptibility in affected new-
are seizure-free by the age of 6 months.13 Later in life borns.20 Only a few KCNQ2 mutations have been identi-
seizures can reoccur in about 10% to 15% of the patients, fied that, at least in reconstitution experiments, had a
starting mostly at school age or in young adulthood. dominant negative effect on channel function, ie, reduced
These late-onset seizures are often provoked, for exam- the current by more than 50%. One of these mutations
ple, by lack of sleep. Recently, it has become a point of is the R207W amino acid exchange in KCNQ2 that
discussion as to whether the term “benign” should be causes both BFNC and myokymia, a spontaneous and
used to describe the course of the disorder, since several repetitive involuntary contraction of muscle fiber groups.
BFNC families have come to attention in which some or In the BFNC/myokymia syndrome the occurrence of
all of the patients had a less than benign outcome. These both central and peripheral neurological symptoms
patients often show a higher frequency of seizures and might be explained by the unusual electrophysiological
are often not seizure-free after the age of 4 months. Two profile of the underlying mutation. The magnitude in loss
BFNC families have been described in which a mutation of current observed for R207W depends strongly on the
carrier developed drug-resistant seizures and/or epilep- pattern and time course of depolarization. It is therefore
tic encephalopathy shortly after birth, resulting in severe possible that the unusual dominant negative effect of
psychomotor retardation.14,15 Follow-up studies showed R207W establishes itself only in the peripheral nervous
that even patients that have formerly been believed to system, causing symptoms like myokymia.21
have a benign course of the disorder later often showed
moderate delays of psychomotor development. Infantile convulsion syndromes
Mutations in the voltage gated potassium channel genes
KCNQ2 (chromosome 20q13.3) and (more rarely) Benign familial infantile convulsions (BFIC) is an autoso-
KCNQ3 (chromosome 8q24) have been described in dif- mal dominantly inherited partial epilepsy syndrome of
ferent BFNC families.16-18 Both genes encode channel early childhood.22 Seizures usually start between months 4
subunits with identical structures including six trans- and 6, with remission before the age of 3 [Link] partial
membrane regions (TM), a voltage sensor in TM4, a loop seizures occur in clusters and usually respond well to
between TM5 and TM6 that builds the ion channel pore, antiepileptic drug treatment. BFIC is genetically hetero-
and a long C-terminal region that contains sequence geneous, and has been linked to loci on chromosomes
motifs for subunit assembling. So far more than 40 muta- 1q23, 2q24, 19q, and 16p12-q12 in various families.
tions have been reported for KCNQ2 and three for Interestingly, three other disorders with overlapping neu-
KCNQ3. The BFNC mutations are either missense muta- rological features map to the candidate region on chro-
tions located in one of the TMs, truncating mutations mosome 16p12-q12, including the infantile convulsions and
(nonsense, insertion/deletions or splice site mutations), choreoathetosis syndrome (ICCA; OMIM 602066), parox-
or large deletions. The majority of mutations are private, ysmal kinesigenic choreoathetosis (PKC; OMIM 128200),
ie, they have not been found in other BFNC families. and a syndrome comprising rolandic epilepsy, paroxysmal
The ion channel encoded by KCNQ2 and KCNQ3 pro- exercise-induced dystonia, and writer's cramp (EPRPDC;
vides one of the major physical equivalents of the so- OMIM 608105).Another rare seizure disorder with an age
called M-current, a potassium current which is known to of onset intermediate between BFNC and BFIC is benign
be a powerful controller of neuronal firing. M-currents familial neonatal/infantile convulsions (BFNIC). In
regulate the frequency with which action potentials are BFNIC both neonatal and early infantile onsets of the
built by opposing sustained membrane depolarization. seizures can be present in the same family. BFNIC has
They have a pivotal role in the stabilization of membrane been shown to be caused by mutations in the voltage-
potentials, and are therefore in a powerful position to gated sodium channel subunit gene SCN2A, a gene that is
control excess neuronal excitability and prevent also discussed as a minor gene for generalized epilepsy
seizures.19 Given this important role in brain excitability, with febrile seizures plus (GEFS+).23

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Genetics and epilepsy - Steinlein Dialogues in Clinical Neuroscience - Vol 10 . No. 1 . 2008

Febrile seizures, generalized epilepsy with febrile ious afebrile seizure types including absence, myoclonic,
seizures plus, and Dravet syndrome and partial seizures. Pharmacoresistant seizures and devel-
opmental delay become manifest during the second year
Febrile seizures are the most common seizure type in of life. Nearly all reported SMEI mutations are de novo,
humans; they affect 5% to 10% of children under the age and they are often truncating and/or located in function-
of 6 years. In most patients an oligo- or polygenic back- ally critical parts of the gene, while GEFS+ mutations are
ground rather than a monogenic cause of the seizures is mostly found in less highly conserved parts of SCN1A. It
assumed. Rare families with an apparent autosomal dom- is therefore likely that SMEI and GEFS+ mutations differ
inant mode of inheritance have been identified, and sev- with respect to their predicted impact on ion channel func-
eral putative gene loci described. These tentative gene tion, explaining the differences in clinical severity between
locations include FEB1 on chromosome 8q13-q21, FEB2 both syndromes.
on 19p, FEB3 on 2q23-q24, FEB4 on 5q14-q15, FEB5 on Expression experiments with different SMEI and GEFS+
6q22-q24, and FEB6 on 18p11.2. mutations have shown, probably due to different exper-
In some families febrile seizures may persist beyond the imental setups, a variety of biophysical aberrations,
age of 6 years and/or may be associated with variable including complete loss-of-function, altered gating prop-
afebrile seizures (febrile seizures plus). This probably not erties, or even gain-of-function effects. Thus, the exact
so rare syndrome has been named generalized epilepsy functional effects of SMEI and GEFS+ mutations and
with febrile seizures plus (GEFS+). Afebrile seizure their correlations to clinical phenotypes are still unclear.28
types in GEFS+ individuals include generalized tonic-
clonic seizures, myoclonic, absence, and atonic seizures, Non-ion channel genes in idiopathic epilepsy
and in some patients also partial seizures.24 The mode of
inheritance underlying GEFS+ is still a matter of debate. Most of the epilepsy genes mentioned so far code for var-
Although in some families the trait is likely to be auto- ious ion channels, or for proteins that modulate ion-chan-
somal dominant, in others it is probably better described nel function (eg, accessory channel subunits). This has led
as oligogenic or as a major gene effect. A genetic concept to the assumption that idiopathic epilepsies are a group
involving more than one gene would also better fit to the of channelopathies. However, in 2001 it was dem-
observed clinical variability in GEFS+. Several different onstrated that non-ion channel genes play at least a
ion channel genes have been implicated in GEFS+— minor role in the etiology of idiopathic epilepsies.
SCN1B, SCN1A, SCN2A, GABRG2—but in most fam- Mutations in the LGI1 gene (leucine-rich glioma inacti-
ilies the underlying mutation(s) remain elusive. The first vated gene 1) have been shown to be a cause of autoso-
GEFS+ mutation was identified in the SCN1B gene on mal dominant partial epilepsy with auditory features
chromosome 19q13.1, a gene that encodes an accessory (AD-PEAF), also called autosomal dominant lateral
subunit of the voltage gated sodium channel.25 temporal lobe epilepsy.29 This rare syndrome is charac-
Nevertheless, most of the mutations identified since then terized by simple partial seizures with mainly acoustic
were found in the SCN1A gene, one of the genes coding and sometimes also visual hallucinations.30 Some families
for the major, pore-forming α-subunit of the voltage have been described in which the seizures tend to start
gated sodium channel.2 These α-subunits are composed with a brief sensory aphasia without reduced conscious-
of four domains each containing six TM (TM1-TM6), and ness.31 The mutational spectrum known for the LGI1
the SCN1A mutations are distributed over the whole gene on chromosome 10q24 includes both missense
length of this large gene.26 mutations and truncating mutations. So far, not much is
Mutations in the SCN1A gene have also been identified in known about the function of the LGI1 gene, which codes
patients with SMEI (also known as Dravet syndrome) and for a protein characterized by a leucine-rich repeat motif
in the phenotypically overlapping syndromes of border- (LRR) in its N-terminal end and seven so-called
line SMEI (SMEB) or intractable childhood epilepsy with epilepsy-associated repeats (EARs) in the C-terminal
generalized tonic-clonic seizures (ICEGTC).27 The clinical half. The LRR motif is found mostly in proteins that par-
phenotype of SMEI is characterized by an initially normal ticipate in some kind of protein-protein interaction or
psychomotor development, onset of febrile seizures within receptor function.32,33 Two recently published articles have
the first year of life, and subsequent manifestation of var- shed some light on the possible function of LGI1 protein

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in human brain. They were able to show that two differ- ferent functions, such as metabolic disturbances, mito-
ent isoforms of LGI1 protein are expressed in brain, with chondrial dysfunction, or aberrant neuronal (precursor)
a long isoform that is secreted and a short isoform that is cell migration. The heterogeneous group of progressive
retained in the intracellular compartment. In the exper- myoclonus epilepsies that includes Unverricht-Lundborg
imental setup the secreted isoform of LGI1 binds to dif- disease (Baltic myoclonus), myoclonic epilepsy and
ferentiated PC12 cells, suggesting that a LGI1-specific ragged-red fiber disease (MERRF), neuronal ceroid lipo-
receptor complex is present on these cells. A putative fuscinosis (CLN), dentatorubropallidoluysian atrophy,
receptor for LGI1 has been identified in ADAM22, a Gaucher disease, Lafora disease, and sialidosis, is repre-
trans-membrane protein anchored to the postsynaptic sentative of the various mechanisms that might underlie
density-95 (PSD-95)-associated protein complex by different neurogenetic syndromes characterized pre-
stargazin.34 Both ADAM22 and stargazin are genetically dominantly by seizures and cognitive decline. Some of
linked to epilepsy, at least in knockout animal models. these syndromes are therefore discussed in more detail
The PSD-95 protein complex has a scaffolding function in the following sections.
at excitatory synapses and is involved in both synapto-
genesis and synaptic plasticity. It controls synaptic AMPA Unverricht-Lundborg disease
receptor surface expression, and the number of expressed
receptors could be significantly increased by LGI1 Unverricht-Lundborg disease (EPM1, also known as
expression in cultured hippocampal neurons. Thus, Baltic or Mediterranean myoclonus epilepsy) is a typical
ADPEAF mutations might cause epilepsy by interfering example of a progressive myoclonus epilepsy character-
with the protein-protein interaction between LGI1 and ized by generalized epileptic seizures, myoclonus (brief
ADAM22, causing a dysregulation of synaptic transmis- contraction of a muscle or a group of muscles), and pro-
sion.34 Additional non-ion channel genes have been gressive neurological deterioration including ataxia and
described in epilepsy families since LGI1 was first dementia. EPM1, the most common form of progressive
reported several years ago. Examples are the EFHC1 myoclonus epilepsy, is an autosomal recessive neurode-
gene and the MASS1/VLGR1 gene, but so far the respec- generative disorder with an age of onset between 6 and 18
tive initial reports have not been confirmed in indepen- years. Severe stimulus-sensitive myoclonus and general-
dent studies.35 ized tonic-clonic seizures are the main features; addition-
ally, mental deterioration, intention tremor, dysarthria, and
Progressive myoclonus epilepsies mild ataxia may develop in later stages of the disorder. So
far a few point mutations in the CSTB gene (cystatin B,
Numerous neurogenetic syndromes are known in which also stefin B) on chromosome 21q22.3 have been identi-
seizures are a predominant feature but are usually fied in different EPM1 patients (Table II). However, in the
accompanied by other neurological or non-neurological majority of patients the disorder is caused by an unstable
symptoms. The genetic causes (and therefore the path- expansion of a dodecamer repeat located in the 5' flank-
ways leading to epilepsy) found in these disorders are ing region of the CSTB gene.36 Expansion of the repeat
more diverse than those described above for idiopathic causes absence of, or greatly reduced, CSTB expression;
epilepsies. Mutated genes might be involved in many dif- thus, a loss-of-function effect is a key event in EPM1

Mutation Predicted effects

Dodecamer repeat expansion Disruption of promotor function, resulting in reduction of mRNA expression
426G>C Amino acid exchange at codon 4, affects contact of cystatin B with papain
149G>A* Amino acid exchange at codon 50
168+1_18del* Intronic deletion affecting splicing
1925G>C Abnormal splicing of pre-mRNA
2353A>G Abnormal splicing of pre-mRNA
2388T>C Stop codon mutation at codon 75, causing RNA decay or protein truncation
del2400TC Frame shift leading to premature stop codon at codon 75, causing RNA decay or protein truncation

Table II. Cystatin B mutations in Unverricht-Lundborg disease. *different nucleotide numbering

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Genetics and epilepsy - Steinlein Dialogues in Clinical Neuroscience - Vol 10 . No. 1 . 2008

pathogenesis. CSTB encodes the cystatin B protein, a dria from his or her mother (there is no paternal inheri-
widely expressed reversible inhibitor of cysteine protease tance of mitochondria since sperm mitochondria that
that is thought to have lysosome-associated physiological enter the oocyte are “digested”). The most commonly
functions. Cysteine protease inhibitors play an important found MERRF mutation is mt8344A>G that affects the
role in controlling endogenous and exogenous protease tRNALysine gene within the mtDNA.42 Due to the het-
activities, protecting organisms from protein degradation. eroplasmatic nature of the disorder the molecular diag-
Cystatin B is thought to be involved in the maintenance of nosis from blood not always reliably detects the under-
normal neuronal structure, and loss of its expression in lying mutation. Skeletal muscle frequently has the
mouse models caused increased expression of genes highest percentage of mutated mtDNA molecules in
involved in proteolysis, apoptosis, and glial [Link] MERRF patients, and this percentage correlates best
neuronal loss by apoptosis and gliosis seems to be an with the clinical severity of the disorder.43 Muscle biopsy
important mechanism in the pathogenesis of EPM1.37,38 is therefore the first choice to obtain material for diag-
There is also mounting evidence that Cystatin B might nostic mutation analysis. Close to 150 pathogenic muta-
have an additional function in the cerebellum unrelated to tions in 21 of the 22 mitochondrial tRNA genes have
its role in protease inhibition. Coprecipitation experiments been described up to now, and 50% of these mutations
showed that cystatin B interacts with different cerebellum- are located in either one of three tRNA genes,
expressed proteins that are not functioning as proteases. tRNALeu(UUR), tRNALYS, or tRNAIle. Mutations in tRNA
What this additional role of cystatin B might be remains genes might have different pathological effects, including
unknown so far.39 structural perturbances of the three-dimensional tRNA
structure, reduced or abolished binding capacity to trans-
Myoclonic epilepsy and lation factors such as the elongation factor EF-Tu, or
ragged-red fiber disease impairment of tRNA maturation. All of these mutations
affect the essential role tRNA genes have in the synthe-
Mitochondria are small intracellular organelles that pos- sis of proteins involved in energy metabolism, causing
sess their own circular DNA molecules (mtDNA). various neuromuscular and neurodegenerative disorders.
Mutations in mtDNA that interfere with or even abolish
the ability of mitochondria to perform their role in aer- Neuronal ceroid lipofuscinoses
obic respiration are known to cause a wide spectrum of
different disorders. They all have in common a pattern of The different subtypes of neuronal ceroid lipofuscinoses
symptoms that predominantly affect tissues with a high (CLN, or NCL) are (with one exception) autosomal
dependence on oxidative metabolism, such as brain, mus- recessively inherited neurodegenerative disorders
cle, and heart. The clinical manifestations of mitochon- belonging to the group of lysosomal storage diseases.44
drial disorders are extremely heterogeneous; they range The childhood forms of CLN are characterized by men-
from lesions of single tissues to severe impairments tal and motor deterioration, as well as progressive loss of
including myopathies, encephalomyopathies, cardiomy- vision, myoclonic, tonic-clonic, and atypical absence
opathies, or complex multisystem syndromes.40,41 A typi- seizures, and premature death, while dementia presents
cal example of such a mitochondrial disorder is MERRF, as the main feature in the rare adult forms of CLN. The
another member of the group of progressive myoclonus human CLNs are presently classified into eight main
epilepsies. MERRF is characterized by myoclonus, gen- genetic forms (CLN1–8). The infantile subtype of CLN,
eralized epileptic seizures, myopathy, and slowly pro- Santavuori-Haltia-Hagberg disease (CLN1), occurs pri-
gressive dementia. Additional symptoms can be hearing marily in the Finish population. The classical late-infan-
loss, ataxia, and lipomatosis. Histopathological analysis tile form of CLN, Jansky-Bielschowsky disease (CLN2),
of muscle bioptic material typically shows ragged-red starts at age 2 to 4 years with myoclonus and seizures.
fibers and abnormal mitochondria with concentric There are at least three additional subtypes that are clas-
cristae. Age of onset and clinical severity differ widely sified as variants of late infantile CLN. These include the
from patient to patient, even between siblings. This is Finnish variant (CLN5), the CLN6 variant of late infan-
mainly explained by heteroplasmy, ie, each patient inher- tile CLN, and the Turkish variant of CLN (CLN8). The
its a different mixture of normal and mutated mitochon- CLN8 gene also causes Northern epilepsy or progressive

35
Basic research
epilepsy with mental retardation, an autosomal recessive Neuronal migration disorders
epilepsy of childhood onset that is only found in parts of
northern Finland. Juvenile-onset CLN (Batten disease, The migration and maturation of neurons, synapses, and
Vogt-Spielmeyer disease) is the most common neurode- cortical neuronal networks during embryonal and fetal
generative disorder of childhood, with an age of onset at development is a sequential process composed of differ-
5 to 10 years. Kufs disease or adult CLN (CLN4) is dis- ent steps that are regulated by genetic and environmen-
tinguished clinically from the infantile and juvenile sub- tal factors.52 The cortical neurons are formed in the neu-
types by onset of progressive myoclonus epilepsy in roepithelium of the ventricular zone, and then migrate
adulthood and by the absence of ocular involvement. considerable distances to reach their final position in the
Additionally, a few rare forms exist that have not been cortex. In humans, neuronal migration in the cortex starts
genetically assigned yet, including congenital NCL and at approximately 7 weeks of gestation from the prolifer-
dominantly inherited adult onset NCL (Parry disease, ative ventricular zone. The radially migrating neurons as
Table III).45-48 well as the nonradially (tangential) migrating future
Characteristic features of CLN are an accumulation of aut- interneurons are guided by glial fibers through an inter-
ofluorescent, periodic acid-Schiff- and Sudan black B-pos- action of adhesion molecules, trophic factors, and guid-
itive granules in the cytoplasm of most nerve cells, astro- ance molecules. Any disturbances (genetic or environ-
cytic proliferation and hypertrophy, and progressive and mental) of these complicated migration and matu-rating
remarkably selective neuronal degeneration and loss.49 The processes have the potential to cause severe neurologi-
storage cytosomes characteristic for CLN mainly contain cal disorders with various symptoms, including mental
of two hydrophobic proteins, the sphingolipid activator retardation and epilepsy. Genetic neuronal migration dis-
proteins A and D (infantile form of CLN) or the subunit orders include different lissencephaly syndromes and
c of mitochondrial ATP synthase (late infantile and juve- subcortial band heterotopia, cobblestone dysplasia (a
nile CLN).50 The CLN1 and CLN2 genes code for the sol- term describing the bumpy surface of the brain that is
uble lysosomal enzymes PPT1 and tripeptidyl peptidase 1 caused by ectopic neurons and gliovascular prolifera-
(TPP1), whereas CLN3, CLN6, CLN8 and, possibly, CLN5 tion), and different gray matter heterotopia disorders
are transmembrane proteins of largely unknown functions. (see also the article by Leventer et al in this issue, p 47).
It is still unclear how a group of genes as heterogeneous
as the CLN genes can cause such a remarkably uniform Conclusion
morphological phenotype characterized by intraneuronal
accumulation of hydrophobic proteins. Different mecha- Although the number of already known epilepsy genes
nisms including both apoptotic and excitotoxic processes is impressive, they probably represent only the tip of the
are discussed, but the exact nature of the pathophysiolog- proverbial iceberg. A roughly estimated 50% of all genes
ical pathways underlying the different CLN subtypes are, at least during fetal development, expressed in brain
remain to be elucidated.51 and might therefore be regarded as candidates for

CLN subtype Eponym Gene Chromosome Inheritance

CLN1 Haltia–Santavuori disease, INCL CLN1 1p32 AR
CLN2 Jansk˘-Bielschowsky disease, LINCL CLN2 11p15 AR
CLN3 Spielmeyer-Sjögren disease CLN3 16p12 AR
CLN4a Kufs disease, ANCL NK NK AR
CLN5 vLINCL Finnish CLN5 13q22 AR
CLN6 Lake-Cavanagh disease, vLINCL CLN6 15q21–23 AR
CLN7 vLINCL Turkish NK NK AR
CLN8 Northern epilepsy, progressive epilepsy with mental retardation CLN8 8p32 AR
CLN10 Congenital CLN CTSD 11p15.5 AR
CLN4b Parry disease NK NK AD

Table III. Ceroid lipofuscinosis subtypes in humans. AR, autosomal recessive; AD autosomal dominant; INCL, infantile CLN; LINCL, late infantile CLN;
ANCL, adult NCL; vLINCL, variant late infantile CLN; NK, not known

36
Genetics and epilepsy - Steinlein Dialogues in Clinical Neuroscience - Vol 10 . No. 1 . 2008

seizure disorders. Furthermore, recent research has (aCGH) or genome-wide single nucleotide polymor-
shown that alterations of genomic DNA copy number phism (SNP) analysis will become important tools for the
and gene regulatory elements are likely to be as impor- identification of genetic alterations with potential appli-
tant for human disorders as mutations that directly affect cation to common forms of human epilepsy. ❏
genes.53 In the future, whole-genome screening methods This work was supported by a grant from the Deutsche
such as array-based comparative genomic hybridization Forschungsgemeinschaft (DFG-STE1651/1-1)

Genética y epilepsia Génétique et épilepsie

El término “epilepsia” describe un grupo hetero- Le terme « épilepsie » décrit un groupe hétérogène
géneo de trastornos, la mayoría de los cuales son de troubles dont la plupart sont dus à des interac-
causados por interacciones entre algunos o incluso tions entre quelques, ou même de nombreux gènes
muchos genes, y factores ambientales. Son bas- et des facteurs environnementaux. Plus rares sont
tante más raras las epilepsias genéticas que se les épilepsies génétiques qui sont dues à des muta-
deben a mutaciones de un gen único o aberracio- tions d’un seul gène ou à des aberrations chromo-
nes cromosómicas estructurales definidas, como las somiques de structure définies comme les microdé-
microdeleciones. El descubrimiento de algunos de létions. Notre compréhension des mécanismes de
los genes que están a la base de estas raras epilep- base de l’épileptogenèse a déjà été considérable-
sias genéticas ya ha contribuido considerablemente ment améliorée par la découverte de plusieurs de
a la comprensión de los mecanismos básicos en la ces gènes impliqués dans ces épilepsies génétiques
epileptogénesis. El progreso que se ha llevado a peu répandues. Les progrès effectués ces 15 der-
cabo en los últimos 15 años en la genética de la epi- nières années dans la génétique de l’épilepsie
lepsia está aportando nuevas posibilidades diag- ouvrent de nouvelles perspectives de diagnostic et
nósticas y terapéuticas. En este artículo se revisan, de traitement. Dans cet article, nous passons en
a modo de ejemplo, diferentes epilepsias genéticas revue différentes épilepsies génétiques comme
para demostrar las diversas vías que pueden llevar exemples illustrant les différentes voies qui mènent
desde los genes a las convulsiones. des gènes à l’apparition d’une crise comitiale.

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