Commission on the Search for Epilepsy Genes
Subcommission on Phenotype Characterization

Olivier Dulac (Chair), Samuel Berkovic,
W. Donald Shields, V. Elving Anderson

GENE SEARCHING IN THE EPILEPSIES:
CLINICAL REQUIREMENTS PRIOR TO MOLECULAR GENETIC STUDY

The precise contribution of genetic factors to the epilepsies is unknown. Recent research has resulted in the identification of a number of idiopathic epilepsies with simple Mendelian inheritance and has suggested that many, if not a majority, of the epilepsies have some genetic component. Understanding the genetic component to a patient's epilepsy can be an important clue to the diagnosis. Identifying the genetic factors should contribute to the development of more specific treatments and, perhaps prevention, of idiopathic epilepsies.

Genetic analysis of the epilepsies is a partnership between clinicians who are able to accurately characterize the phenotypes to the current best level of understanding, and molecular geneticists who analyze the samples from carefully characterized families.

I. Ethical considerations: They are particularly important in this setting. Only the patient (proband) can be initially contacted and investigated. With his/her consent, parents and the family physician can then be contacted to gather complementary information, including EEG recordings. In addition, the proband is requested to contact other affected relatives before any direct contact can be made with them. Complementary EEG recordings for the sake of the genetic study can only be made with the consent of each affected member.

Clinical data for genetic studies need be protected by strict confidentiality, particularly regarding data bases. The identity of each given individual should not be available from the computerized data base.

Blood samples can only be drawn following written informed consent, from each affected individual, or their parent/guardian in the case of affected minors. [SB1] Taking blood

samples from unaffected minors for research, following parental consent, is controversial Researchers should consult their local institutional review boards on this matter.

II. Constructing the pedigree: A pedigree can be constructed relatively quickly and should denote both sides of the patient's family and clearly indicate the relationship of the patient to other affected individuals (Table 1). A history of epilepsy is not sufficient. The clinician should inquire whether family members have had any type of paroxysmal attack including febrile convulsions or isolated seizures, psychomotor retardation or cognitive deterioration, since childhood epilepsy, particularly idiopathic epilepsy, may produce mild or even no seizures from the onset. The patient often may not know much about his family history but should be encouraged to talk to the others in the family, particularly the elderly matriarchs who may know of early childhood attacks in other family members, long since forgotten. Thus, it is common that the family history is "fleshed out" by the patient who provides more significant detail at subsequent visits. The contribution of a genealogist may be useful to enlarge the size of the family.

Large multiplex families are virtually never referred to the clinical researcher as a fait accompli in terms of numbers of affected individuals or clinical detail. The usual situation is that the researcher begins with a kindred of four or five affected family members. Contacts with all branches of the family over as many generations as can be ascertained are then made in search of a history of seizures in any individual. Affected branches of a family often do not know of the existence of more distantly related individuals with epilepsy. This process may involve contacting hundreds of family members and isolating those branches of the family with a history of seizures for more detailed study. A single large family with 20-30 affected individuals takes approximately one year to undergo a comprehensive assessment.

Attention to details is important in constructing a pedigree. It is worth recording the date of birth (if known) of family members, name changes (i.e. married women), and the country of origin of a person's ancestors. Often first names recur in a family tree and the date of birth is essential to prevent confusion amongst family members with the same name.

When taking the family history, it is also important to ask about the patient's mother's obstetric history. If the patient's mother had an undue number of miscarriages or stillbirths, this may point to a genetic etiology following sex-linked dominant inheritance with lethality in males. Some rare developmental malformations which may cause epilepsy and follow this inheritance pattern have recently been recognized. .

The familial nature of the patient's epilepsy may only become apparent with time as further extended family history comes to light or new members of the family develop epilepsy. The older generations may initially be reticent to discuss a family history of seizures as they feel guilty about "passing on" a disorder. With gentle education regarding genetic issues, as well as time, they may volunteer carefully guarded family secrets of major clinical and research relevance.

The pedigree should then be drawn, identifying for each affected individual the epilepsy syndrome. However, at this point, there is no need to decide the mode of inheritance of the seizure disorder.

Table 1. Checklist for routine pedigree construction

III. Defining the phenotype: Careful delineation of the phenotype in the proband and subsequently in other affected relatives is the first step in clinical genetic studies. The phenotype is defined on the basis of:

• past medical history with attention to antecedent events potentially related to epilepsy,
• age of seizure onset,
• detailed description of seizures experienced,
• whether they consist of single or several types,
• associated neurological and cognitive signs,
• EEG and neuroimaging findings,
• outcome.

Precision in the characterization of phenotypes should be as high as possible. In field work, however, it may rarely be possible to obtain video-EEG monitoring and document seizures. Many individuals will be assessed years after the epilepsy has remitted. Reliance must be placed on careful history taking from the subject and their family. Ideally, standardized seizure questionnaires should be used, in addition to a clinical interview and evaluation by an epileptologist. Every effort should be made also to get information from treating doctors or medical centers when the epilepsy was active.

Family members affected by the familial epilepsy may not necessarily have the same phenotype as the proband. Phenotypic assignment must be done in an objective way. Whenever possible, the diagnosis of each individual should be made without knowledge of the diagnoses in other family members. When concluding this analysis, it may appear that the clinical and EEG characteristics fit with one of the presently identified epilepsy syndrome. However, in some instances, previously unrecognized syndromes are identified by thorough phenotypic analysis of familial epilepsies.

The occurrence of seizures in some family members may be unrelated to the familial epilepsy, and occur as a result of damage to the brain or a genetic predisposition other than that shared by family members, thus producing a phenocopy. So the clinician must carefully assess the data on each putatively affected individual to determine if they should be designated as affected with the familial epilepsy.

On the other hand, it may be difficult to determine whether or not a non-symptomatic individual is affected by the gene. In some instances, it may be useful to record an awake or even a sleep EEG in such family members.

IV. Priority for molecular genetic studies: A data base should be set up to document all large families with five or more affected individuals. High priority should then be given to large informative families where linkage to specific chromosomal regions is likely to be achievable. When a locus or a gene has been shown to be related to a specific phenotype, new families with the same phenotype should be collected in order to identify possible genetic heterogeneity.

Some institutions may not be able to identify such large families. If so, effort should be concentrated in collecting smaller families, including sib-pairs, with similar well-characterized phenotypes. Multicentre studies may then be required and should be encouraged.

Gene Searching In The Epilepsies

Annual Report 2000 Table of Contents