Genetic Counseling



Genetic Counseling


Frances Elmslie



Introduction

Genetic counseling has become an integral component of care of many conditions that display mendelian inheritance, and increasingly those that show complex inheritance, such as autism. However, individuals with epilepsy have not been offered genetic counseling in the past, as the genetic contribution to their seizures may not have been recognized or it was felt that little could be offered. As mendelian forms of epilepsy have been described and mutations in the causative genes identified, this situation is beginning to change, and increasing numbers of people with epilepsy are being referred to the genetics clinic. This chapter will summarize the geneticist’s approach to the individual with epilepsy and discuss the issues raised by the availability of genetic counseling and genetic testing.


The Process of Genetic Counseling

Genetic counseling may be defined as “a communication process that deals with human problems associated with the occurrence, or the risk of occurrence, of a genetic disorder in a family.”

This process is undertaken in an attempt to help individuals and families:



  • Comprehend the medical facts including the diagnosis, probable course of the disorder, and available management.


  • Appreciate the way heredity contributes to the disorder and the risk of recurrence in specified relatives.


  • Understand the alternatives for dealing with the risk of recurrence.


  • Choose a course of action that seems to them appropriate in view of their risk, their family goals, and their ethical and religious standards and act in accordance with that decision.


  • Make the best adjustment to the disorder in an affected family member and/or to the risk of recurrence of that disorder.9

Until recently, geneticists have not often been involved in the care of women with epilepsy, but as more genes are identified that are implicated in the etiology of epilepsy, the involvement of a geneticist will become more important. It is recommended that any individual who is undergoing genetic testing, particularly when the testing has implications for the family, be seen by the clinical genetics team or an individual who has received training in genetics.

Two main groups of individuals undertake genetic counseling: Clinical geneticists, who are medically trained, and genetic counselors, who come from a variety of different backgrounds, including nursing and scientific. The roles of these two groups are complementary, but different. The primary role of the clinical geneticist is to try to establish a diagnosis, which may or may not be genetic, in order to counsel accurately about offspring risks or risks to other family members. Genetic counselors counsel families in which the diagnosis is established and usually where the condition displays mendelian inheritance. They provide follow-up and support for families in which a genetic diagnosis has been made. In order to be able to counsel an individual accurately, one needs to establish an accurate diagnosis, and in the context of epilepsy, it would be essential to identify predisposing conditions in which epilepsy forms part of the phenotype. Therefore, the clinical geneticist undertakes the genetic management of patients with epilepsy, although a genetic counselor may provide long-term support.

Blandfort et al.6 established three main reasons why a person with epilepsy may seek genetic counseling:



  • An individual with epilepsy may be concerned about the risk of his or her offspring developing epilepsy.


  • The parent of a child with epilepsy may be concerned about the risk of future siblings, or an apparently unaffected sibling, developing epilepsy.


  • A woman with treated epilepsy may be concerned about the risk of malformation and developmental delay in a child exposed to anticonvulsants in utero.

Until recently, most epilepsy patients seen in the genetics department fell into the second category. The parents of a child with severe epilepsy, often in the context of developmental delay or another neurologic deficit, seek advice about the risk of having another similarly affected child. In addition, the clinical geneticist has a role in confirming or refuting a diagnosis of a fetal anticonvulsant syndrome and in advising about future pregnancies. However, it has only been recently that individuals with a significant family history of epilepsy have been referred to the genetics department, and this comes with the increasing recognition of mendelian forms of epilepsy.


A Framework for Genetic Counseling

One of the primary goals of genetic counseling is to provide information to enable a couple or an individual to make an informed reproductive choice. This is achieved by nondirective counseling, which helps to ensure that decisions are made in the context of the individual’s beliefs, values, and background. This differs from some other areas of medicine, in which, for example, a physician may make a specific recommendation about one form of treatment over another. An important component of an individual’s ability to make an informed choice is the risk that his or her future children will be affected. It is therefore imperative that the risk given by the geneticist be as accurate as possible and based on knowledge of the family, the specific epilepsy syndrome, electroencephalographic (EEG) and cranial imaging findings, and the presence or absence of a predisposing condition.


Reproductive decisions are based on the couple’s perception of the risk figure given and the burden on the parents if a child is affected. Perception of risk varies enormously from one couple to another. For example, one couple may consider a risk of 2% to be high and another may view it as low, although this will be influenced by the severity of the condition for which the risk is being given.


The Geneticist’s Approach to Epilepsy


The Family History

The first component of a genetics consultation is the compilation of the family tree. This should be as detailed as possible, and as a minimum should go back and forward two generations from the consultand. Information on first and second cousins should be included if possible. The amount of information that families share differs from family to family. The accuracy of the family information is a particular problem in epilepsy, in which the phenotype is often age dependent, and may be forgotten, or even hidden. In many families, one or more family member will have or have had epilepsy because of the high prevalence in the general population. Occasionally, the family tree will show clear evidence of mendelian inheritance, most commonly autosomal dominant inheritance. It is possible that some people in such a family do not have seizures, but their siblings and children do. These people are described a nonpenetrant; that is, they carry a mutation in a specific gene but never manifest the disease. All autosomal dominant idiopathic epilepsy genes described to date show incomplete penetrance.

If consanguinity is present, autosomal recessive inheritance should be considered but not presumed. The family history may suggest X-linked inheritance if there is no male-to-male transmission, or if males are more severely affected. Similarly exclusive female transmission may indicate a mitochondrial disorder.

Wherever possible, the diagnoses volunteered by the consultand should be confirmed directly with the treating physician, because accurate information is needed to give accurate risk figures.


Identifying Predisposing Conditions

Conditions that may present with epilepsy have been covered elsewhere. The most important conditions to identify for the purposes of genetic counseling are those that would significantly alter the recurrence risk. A thorough evaluation of the proband would include a full clinical evaluation, including the following:



  • Clinical examination including Wood light examination


  • Developmental assessment in a child


  • EEG data


  • Cranial imaging


  • Other investigations informed by the clinical presentation (e.g., tests for a suspected metabolic disorder; echocardiography and renal imaging for suspected tuberous sclerosis)

These investigations are most effectively done in partnership with the pediatrician or neurologist who cares for the patient.

An example of an important predisposing condition is that of tuberous sclerosis (TS). Individuals with TS may present with epilepsy at any time from infancy to early adulthood, but approximately 25% of children presenting with infantile spasms will have TS, and therefore all such children should be fully screened for TS. Once a diagnosis of TS is established in a child, the parents should be screened clinically, and if a mutation is identified in the child, by genetic testing. If TS has arisen de novo in the child, the recurrence risk is approximately 2% because of the possibility that one parent carries the mutation in their gonads (gonadal mosaicism), but if a parent has clinical evidence of TS or carries the familial mutation, the recurrence risk is 50%.

Chromosomal analysis would be indicated if the epilepsy occurs in the context of learning difficulties or a physical abnormality. In addition, epilepsy that is difficult to manage (such as that seen in ring chromosome 20 mosaicism) would be an indication for chromosomal analysis. Once a child has been found to have a chromosomal abnormality, it is important to exclude a familial rearrangement in an asymptomatic parent, because this may have implications for future children.

A full metabolic workup is indicated in an infant with early-onset seizures or if there is evidence of regression or precipitating factors such as intercurrent illness.

If cranial imaging reveals a neuronal migration abnormality, further investigations should be performed in an attempt to distinguish between genetic and nongenetic forms.


Identifying the Specific Epilepsy Syndrome

A specific epilepsy diagnosis is important, because family studies have demonstrated that certain epilepsy syndromes show a greater genetic predisposition than others, and this will affect the offspring or sibling risks. Some patients do not know their precise epilepsy diagnosis, and in some instances no attempt has been made to classify their epilepsy, particularly if the diagnosis was made many years ago. Therefore, unless the geneticist has specialist knowledge of epilepsy, the patient will need assessment by a neurologist as well. Factors that are particularly important to consider are the following:



  • Age of onset


  • Seizure types


  • EEG features


  • Acute precipitating factors


  • Previous history


  • Presence of neurologic dysfunction other than seizures


Genetic Risks

Individuals seeking genetic advice fall into two main groups: Those who have epilepsy themselves and want to understand the risk to their offspring, and parents of a child with epilepsy who are concerned about the risk to their future offspring.


Mendelian Epilepsies

When a diagnosis of a mendelian condition has been established, the risk to offspring or siblings is straightforward. In autosomal dominant conditions in which a parent is affected, the risk of a child inheriting the gene mutation is 50%. However, the risk of developing epilepsy will be lower because of nonpenetrance. Genetic studies have shown that penetrance in most autosomal dominant mendelian epilepsy syndromes is of the order of 70%, and therefore the offspring risk of epilepsy can be modified to 35% (0.5 × 70%). If the parents are unaffected and are concerned about a sibling risk, the family history and the results of genetic testing must be taken into account (discussed in more detail below).








Table 1 Recurrence Risks According to Type of Epilepsy and Whether Parent or Sibling Affected

















































Type of epilepsy Parent affected Sibling affected Reference
Idiopathic generalized epilepsy 2.5%–5% 2%–5% 3
Childhood absence epilepsy 8%–10% 4%–6% 3
Juvenile myoclonic epilepsy 6%–10% 6%–7% 12
Photosensitive epilepsy 6%–10% 6%–10% 6
Infantile spasms Unknown 1%–2% for infantile spasms (X linkage and tuberous sclerosis excluded) 6
Partial epilepsy 2%–3% 2%–3% 3
Benign childhood epilepsy with centrotemporal spikes 12%–15% (estimate) 12%–15% 6
Febrile convulsions 10% 10%–20% 6
Modified from Blandfort M, Tsuboi T, Vogel F. Genetic counselling in the epilepsies. Human Genet. 1987;76:303–331.

Only gold members can continue reading. Log In or Register to continue

Stay updated, free articles. Join our Telegram channel

Aug 1, 2016 | Posted by in NEUROLOGY | Comments Off on Genetic Counseling

Full access? Get Clinical Tree

Get Clinical Tree app for offline access