| José Serratosa (Chair),
Samuel Berkovic, Mark Gardiner,
Dick Lindhout, Ana-Elina Lehesjoki. Elving Anderson
GENE SEARCHING IN THE EPILEPSIES:
CLINICAL APPLICATIONS
Objective: to describe the usefulness of what we know about epilepsy
genes and to develop guidelines on how to correctly apply available
knowledge
Recent advances in mapping and isolating human epilepsy genes are
beginning to have a major impact on the diagnosis and the genetic
counseling of families with epilepsy. As the molecular basis of
the genetic epilepsies are being rapidly elucidated, clinicians
and other health specialists involved in the care of patients with
epilepsy must be prepared to answer specific questions made by patients
and their relatives in regard to genetic aspects of the epilepsies.
Epilepsy is not a single disease but a wide symptom complex due
to a wide variety of diseases and syndromes with different genetic
components. Accordingly, when confronted with a question regarding
genetic aspects, clinicians should first have a precise diagnosis
in the index patient. Further, in the case of a positive family
history of epilepsy, a precise diagnosis should be made in other
available affected family members as well. A minimum diagnostic
work-up should include a full medical history, physical examination,
an EEG or video-EEG recording and, in some cases, a magnetic resonance
imaging. In some rare forms of epilepsy, and when epilepsy as part
of a syndrome or metabolic disease is suspected, additional special
tests are needed. Nevertheless, an adequate diagnosis can be reached
in the majority of cases. The diagnosis should include a classification
of seizures, a classification of the epilepsy syndrome and the etiology.
Once a clinical diagnosis is made (definite or probable) the applications
of the recent advances in the field can be considered.
The epilepsies can be subdivided in number of different etiological
categories according to the role of genetic factors in its occurrence,
including epilepsies with autosomal dominant, autosomal recessive,
x-linked, polygenic, and multifactorial patterns of inheritance.
Each category has its specific features with respect to 1) examinations
needed for verification, 2) establishing recurrence risk, 3) availability
of genetic tests, and 4) genetic counseling procedures. Therefore,
the application of currently available molecular genetic diagnostic
tools may vary between categories, with respect to its use as a
diagnostic tool, its values and limitations in genetic counseling,
and its usefulness in development and establishment of phenotype-
and genotype-specific treatments.
1. Diagnostic applications
Recognition of new epilepsies
During the last decade, a number of epilepsy syndromes have been
localized to specific regions of the human genome, and in many of
these syndromes, the gene has been identified through detection
of disrupting mutations. The research efforts which have led to
these discoveries, also facilitated the delineation of new epilepsy
syndromes not described previously. Examples of the main genetic
epilepsies recently described include autosomal dominant nocturnal
frontal lobe epilepsy, familial temporal lobe epilepsy, familial
temporal lobe epilepsy with auditory symptoms, autosomal dominant
partial epilepsy with variable foci, autosomal dominant rolandic
epilepsy with speech dyspraxia, benign familial infantile convulsions,
and generalized epilepsy with febrile seizures plus. The recognition
of these syndromes is important for adequate classification of patients
which will lead to a higher quality of patient care. Recognizing
the recently described syndromes may be of key importance in epilepsy
units where epilepsy surgery is performed since the genetic partial
epilepsies are probably not amenable to surgical treatment and proper
antiepileptic drug therapy should render most patients seizure-free.
Genetic testing in the epilepsies for diagnostic purposes
Several genetic epilepsy syndromes for which the responsible gene
has been mapped or identified can now be diagnosed using molecular
genetic testing. For epilepsies in which the responsible gene has
been identified, genetic testing may be done through direct mutation
detection. For epilepsies in which only the chromosome localization
is known, indirect methods such as linkage analysis may be an option.
However, for linkage analysis to be informative, a critical number
of affected relatives is necessary and DNA samples from family members
must be available. The diagnostic applications of mutation detection
and linkage analysis may be further limited in the case of genetic
locus heterogeneity (i.e. different genes may induce the same epilepsy
syndrome).
Direct mutation tests can now be performed for many of the rare
severe genetic epilepsies: EPM1 (Unverricht-Lundborg disease), EPM2
(Lafora disease), infantile neuronal ceroid lipofuscinosis (CLN1),
late infantile neuronal ceroid lipofuscinosis (CLN2), juvenile neuronal
ceroid lipofuscinosis (CLN3), late infantile Finnish variant ceroid
lipofuscinosis (CLN5), myoclonus epilepsy and red-ragged fibers
(MERRF), dentatorubral-pallidoluysian atrophy (DRPLA), double cortex-lissencephaly
syndrome and sialidosis, among others. An interesting example is
that of Unverricht-Lundborg disease (including Mediterranean and
Baltic types) which has been shown to be caused by mutations in
the gene coding for cystatin B. The most common mutation is an expansion
of a dodecamer repeat in a non-coding region. Normal subjects have
2-3 repeats whereas mutated alleles present 60 or more repeats.
In some cases where verification of a clinical diagnosis is needed,
molecular testing is already being used to confirm the suspected
diagnosis. In the recent years, MERRF has been frequently diagnosed
by mutation detection in many centers throughout the world. In other
epilepsies, such as late infantile variant ceroid lipofuscinosis
or CLN6, the responsible gene is unknown and only the gene locus
has been identified; still diagnostic testing can be offered to
selected families by using closely linked DNA markers. The information
that can be given in this situation is associated to a probability
of being affected or not.
The role of genetic diagnostic testing in some more benign and
common epilepsies remains to be determined even though a gene or
locus has been identified. Examples of benign and/or common epilepsies
in which a gene has been identified include benign familial neonatal
convulsions, some forms of autosomal dominant nocturnal frontal
lobe epilepsy, and some forms of generalized epilepsy with febrile
seizures plus. Examples of benign and/or common epilepsies in which
only a locus is known (no gene has been identified so far) include
benign familial infantile convulsions, juvenile myoclonic epilepsy
(JME), and some forms of autosomal dominant nocturnal frontal lobe
epilepsy. It appears hard to justify a genetic test for benign conditions
which are easily diagnosed by using widely available diagnostic
tests or even just by history (such as JME). As complex patterns
of inheritance, incomplete penetrance, and locus or allelic heterogeneity
are usually present in the common epilepsies, the significance of
a negative genetic test may frequently be questioned.
Genetic testing directed to the identification of allelic variants
responsible for common epilepsies may be useful when specific drugs
for each variant become available. For example, if it is proven
that JME is caused by several different mutations, then each of
these mutations may respond differentially to specific compounds.
Genetic testing would then be useful to identify the type of JME
mutation(s) present in a particular patient and the specific target
drug could be prescribed.
A major disadvantage of genetic testing at present time is that
many mutation tests are not widely available and are only being
performed at selected research laboratories. The clear exception
is the test for the MERRF mutation(s) which is widely available.
Availability of testing is evolving fast as technology spreads quickly
in the field of molecular genetics.
The limitations of the currently available methods for DNA diagnosis
should also be considered, mainly: 1) A specific clinical diagnosis
is needed for focused analysis; 2) A negative result never rules
out a specific diagnosis as all loci or mutations responsible for
a genetic disease are not known and, in consequence, all cannot
be tested; 3) Diagnosis through linkage analysis is dependent on
the number of clinically informative affected relatives, availability
of DNA samples from relatives; and 4) The application of prenatal
diagnosis will usually be limited to severe conditions with a poor
prognosis and requires early assessment of the diagnosis, knowledge
of the responsible gene or locus, and, therefore, early referral
when pregnancy is planned (usually several weeks before conception).
Genetic testing in the epilepsies for genetic counseling purposes
The role of genetic counseling in the severe genetic epilepsies
is clear. However, ethical issues may make it hard to justify genetic
testing in the benign epilepsies. The standard objectives and rules
of genetic testing and genetic counseling in human disease certainly
also apply to the epilepsies. The goals of genetic counseling are
to evaluate the risk of recurrence, to communicate to the patient
and family members the possibilities of recurrence, to provide information
and counseling about the disease, and to provide information about
reproductive options. Genetic counseling should be done by appropriately
trained individuals. Genetic testing in children and adolescents
should be only performed after considering that the primary goal
is to promote the well-being of the individual, that children and
adolescents are part of a family network, and that they grow through
successive stages of cognitive and moral development. The impact
of potential benefits (psychosocial benefits, diagnostic information,
preventive measures and therapies) and harms should be considered.
Timely benefit to the child or adolescent is essential. If medical
or psychosocial benefits will not accrue until adulthood, then genetic
testing is not justified until adulthood. If medical or psychosocial
benefits are uncertain, the decision of competent adolescents and
their families should be respected. In any case, genetic testing
should not be performed when harm outweighs benefits. Education
should accompany genetic testing. Permission of parents and assent
of the child or adolescent should be obtained. Competent adolescents
have priority of request over parents. When genetic counseling is
performed during the course of biomedical research, information
should be transmitted exclusively by personnel specialized in genetic
counseling. The information should be kept confidential (it belongs
to the individual) and patients should be informed that it is not
definitive until the study has been completed and sometimes, not
even then.
2. Prognostic applications
Adequate diagnosis based on genetic information can provide patients
with key prognostic information such as remission index and response
to specific treatments. For example, in the progressive myoclonus
epilepsies the diagnosis of Unverricht-Lundborg disease implies
an almost normal life span and mild or no dementia. In contrast,
in other progressive myoclonus epilepsies (such as Lafora disease
or the neuronal ceroid lipofuscinoses) the prognosis is very poor
and patients invariably die after a few years of disease progression.
3. Therapeutic applications
Development of new design AEDs based on discovery of epilepsy
genes
As the genes and corresponding proteins responsible for the genetic
epilepsies are being identified, it is becoming feasible and reasonable
to try to design antiepileptic drugs that act on the true target:
the mutated gene product (the "rational approach" to antiepileptic
drug development). The possibility of developing new AEDs based
on the knowledge of the function of genes involved in the production
of specific epilepsy phenotypes appears to be a very promising approach
in the near future. However, at this time, most cloned epilepsies
are rare and the investment necessary for the development of a new
antiepileptic drug for these rare epilepsies is unlikely to take
place. When genes involved in common epilepsies are characterized,
the advantages of the "rational approach" will become
clear. Drug companies (already interested in cloning genes for common
epilepsies) should be encouraged to participate in an acceptable
way.
Development of new modalities of treatment for the epilepsies:
Gene therapy trials appear to be clearly justified for the severe
genetic epilepsies. However, the use of gene therapy in the more
benign and common epileptic conditions is difficult to justify.
Gene Searching In The Epilepsies
Annual Report 2000 Table of Contents
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