Genetic counseling M. Hoeltzenbein

Introduction

The number of genes known to be involved in pathogenesis of peripheral neu- ropathies is increasing rapidly. At the same time more and more, mostly ex- ceedingly rare, disease entities and their genetic causes are discovered. Genet- ic conditions are different from other medical diagnoses as they might imply risks to other family members as well as to unborn children. In addition, a genetic diagnosis is permanent and currently often untreatable or incurable.

In order to meet the specific needs and demands of patients and their relatives, a close collaboration between neurologists, clinical geneticists and molecular diagnostic laboratories is necessary. This chapter on genetic counseling was written based on the experience of the author in clinical genetics at university hospitals in Germany and therefore mainly reflects the situation in Germany.

12.1 Definition of genetic counseling and consequences

The term genetic counseling was introduced in 1947 to describe the rela- tionship between clinical geneticists and those to whom they provide infor- mation about the etiology, natural history, and recurrence risks of heredi- tary disorders [14].

In 1975the American Society of Human Genetics defined genetic coun- seling as ªa communication process which deals with the human problems associated with the occurrence, or the risk of occurrence, of a genetic dis- order in a family. This process involves an attempt by one or more appro- priately trained persons to help the individual or family to

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

z Appreciate the way heredity contributes to the disorder, and the risk of recurrence in specified relatives,

z Understand the alternatives for dealing with the risk of recurrence, z Choose the course of action which seems to them appropriate in view of

their risk, their family goals, and their ethical and religious standards, and to act in accordance with that decision, and

M. Hoeltzenbein

z Make the best possible adjustment to the disorder in an affected family member and/or to the risk of recurrence of that disorder.º [1]

Especially with respect to genetic diagnosis consequent implementation of these guidelines for practical genetic counseling means

z Genetic counseling has to be voluntary for the client,

z All diagnostic tests should be preceded by individual counseling,

z Prenatal diagnostic testing does not preclude termination of pregnancy in case of a pathological result, and

z Family planning and reproductive decisions are entirely in the hands of the consulters [4, 11].

Genetic counseling is provided by clinical geneticists. Access to genetic counseling is open to everybody interested in or at risk of a genetic disor- der. Persons seeking such advice are called counselees or clients.

The main reasons for referral to a department of medical genetics are z Diagnosis or risk of a genetic disease in the consulter or in a relative, z Congenital birth defects,

z Mental retardation,

z Down syndrome or other chromosomal alterations, z Frequent miscarriages or previous stillbirth, z Advanced maternal age, and

z Request of information on possibilities of prenatal diagnostics.

12.2 Course and general principles of genetic counseling

Genetic counseling of patients with neurologic diseases is often performed when a molecular diagnosis is wanted or the results of genetic tests have to be discussed. Even if there is no possibility of genetic confirmation of a disease, counseling can be important to explain risk figures in case of a clearly inherited disorder or a high probability of a genetic disease.

Genetic counseling starts with careful listening to the family's wishes or concerns. A construction of a three-generation pedigree is followed by tak- ing medical history, additional clinical assessments or initiation of investi- gations. After reviewing medical records and gathering necessary informa- tion about the family history, further diagnostic options like molecular testing are discussed. Frequently, a diagnosis has to be searched for over a longer period of time in clinical genetics. Finally, after diagnosis and con- firmation of etiology all biological and medical facts including the rele- vance and consequences for the family can be discussed with the client.

Accurate diagnosis and knowledge about etiology is of utmost importance for further genetic counseling.

It is generally agreed upon that contact to other family members at risk

should not be made directly by the counselor, but only through the client

himself. Clients often feel guilty or stigmatized after diagnosis of a genetic disease in the family and it is important to recognize and allay this appre- hension. In addition, common misconceptions on heredity may also need to be resolved.

For about 30 years non-directiveness has remained central to the practice of genetic counseling, particularly when issues of family planning and re- productive decisions are being made in order to prevent consulters from taking over pre-determined decisions from their counselors. However, dur- ing recent years it became more and more evident that strict employment of the term non-directiveness is not always possible, on the other hand not always helpful or wanted in the counseling process [15]. In addition, sur- veys suggest that, regardless of the mode of genetic counseling, the en- counter fails to alter previously made reproductive decisions [9]. Therefore, it has been recommended to acknowledge the autonomy of the individual and interpret non-directiveness in a broader sense.

12.3 Diagnostic/molecular testing

Whereas initially molecular analysis of neurologic diseases was only per- formed in departments of medical genetics, more and more molecular labo- ratories are set up in departments of neurology for research purpose, per- forming molecular analysis of their own patients. In contrast to Huntington's disease, where clinical diagnosis can be confirmed by detection of the trinu- cleotide expansion, the situation for the hereditary neuropathies is different.

Genetic heterogeneity and mutations in different genes that can often be as- sociated with a remarkable phenotypic overlap often necessitate analysis of several genes, before the disease causing mutation can be identified.

Based on the family history and neurological findings, including nerve conduction and EMG studies, molecular genetic testing can be initiated after informed consent of the patient. This is easily possible for the fre- quent HMSN I/CMT1 with about 70% of affected patients carrying a dupli- cation of a part of chromosome 17p and also for CMTX caused by muta- tions in the small gene encoding the gap junction protein beta 1 (GJB1) [7]. Mutation or linkage analysis of other known genes involved in reces- sive and dominant CMT diseases can in most cases be offered either on a diagnostic or on a research basis now.

12.3.1 Predictive testing of late-onset disorders

Genetic analysis of a person at risk for a late-onset disease will allow a

statement about the future risk to develop a certain disease. Experiences

gained with predictive testing in Huntington's disease have been suggested

to be a model for the study of other late-onset disorders. International

guidelines have been developed and found useful by patients or at risk per- sons [8]. Detailed counseling by an experienced geneticist is required and psychosocial support is usually offered before genetic testing can be per- formed in late-onset disorders.

Pfeiffer et al. [12] asked adult patients with HMSN I/CMT1 for their rele- vant disability and found a similar psychosocial burden as patients with stroke and a similar disability. Of the interviewed patients with HMSN I/

CMT1, 36% voted against childbearing, if the prospective child would have a similar disability.

Due to the broad spectrum of clinical symptoms, general guidelines for counseling patients with hereditary peripheral neuropathies cannot be giv- en. For most autosomal-dominantly inherited neuropathies, the situation is often different from Chorea Huntington. Symptoms might already be pres- ent in young adults and nerve conduction studies would usually reveal, if a person at risk is affected or not, so that molecular analysis in this situation would no longer be a predictive test.

Parents often ask for testing of their healthy children and it is important to understand and think about their needs. Among geneticists, there is currently a consensus that children should not be tested for late-onset neurological dis- orders in the absence of treatment or prophylactic measurements and that this decision should be deferred until the individual is of sufficient intellectual and emotional maturity [2]. However, if the child has a disorder that requires a diagnosis, genetic testing might be the most appropriate investigation.

For further details on predictive testing referring to the ªStellungnahme zur postnatalen prådiktiven genetischen Diagnostikº [10] and ªRichtlinien zur prådiktiven genetischen Diagnostik der Bundesårztekammerº [3], or similar documents published by the association of medical geneticists of the respective countries is recommended.

12.3.2 Prenatal testing

Prenatal testing has been developed and is employed mainly for early onset and untreatable diseases with severe mental and/or physical disability. As a prerequisite accurate diagnosis and direct or indirect molecular or biochem- ical test options have to be available. Routinely performed is chorionic villus sampling at about 12 weeks and amniocentesis around 16 weeks of preg- nancy. Both procedures have a small risk of miscarriage. Therefore, it is very important to offer counseling already before a planned pregnancy.

Requests for prenatal testing for typically adult-onset conditions such as

autosomal-dominant or X-linked neuropathies are not common. Differences

in perspective may exist among medical professionals and within families

regarding the use of prenatal testing, particularly if the testing is being

considered for the purpose of pregnancy termination. Although most cen-

ters would consider decisions about prenatal testing to be the choice of the

parents, careful discussion of these issues is appropriate.

12.3.3 Preimplantation diagnostics

Prenatal diagnosis of CMT1A might be a difficult issue for future parents.

In order to avoid termination of pregnancy in case of an affected child, in some countries preimplantation diagnosis for CMT1A is offered and has been performed in individual cases [6]. However, preimplantation diagno- sis is not allowed in Germany at the moment, although there is an ongoing discussion about this.

12.4 Special issues of genetic counseling

A major task for clinical genetics is dealing with neuropathies as one fea- ture of a complex disease associated with further symptoms. These could be specific syndromes that are associated with further symptoms like Fabry's disease or Refsum's syndrome or new disease entities or other com- plex phenotypes not yet classified, like neuropathies with X-linked mental retardation or deafness [13].

Cytogenetic aberrations, which are not routinely detected by molecular analysis, should be excluded in the presence of mental retardation or fre- quent miscarriages in the affected patient or his family. For example, larger duplications of chromosome 17p11 might cause a more severe phenotype with mental retardation. In addition, balanced chromosomal rearrange- ments like translocations or inversions segregating with a specific neuropa- thy in a family would allow further molecular-cytogenetic work up and fi- nally identification of a the disease causing gene [5].

References

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with genetic testing in pediatrics. Pediatrics 107:1451±1455

3. Bekanntmachungen der Bundesårztekammer (2003) Richtlinien zur prådiktiven genetischen Diagnostik. Dtsch Ørztebl 6 A:277±285

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