Chapter 12 - DNA testing in hereditary neuropathies

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Abstract

The inherited neuropathies are a clinically and genetically heterogeneous group of disorders in which there have been rapid advances in the last two decades. Molecular genetic testing is now an integral part of the evaluation of patients with inherited neuropathies. In this chapter we describe the genes responsible for the primary inherited neuropathies. We briefly discuss the clinical phenotype of each of the known inherited neuropathy subgroups, describe algorithms for molecular genetic testing of affected patients and discuss genetic counseling. The basic principles of careful phenotyping, documenting an accurate family history, and testing the available genes in an appropriate manner should identify the vast majority of individuals with CMT1 and many of those with CMT2. In this chapter we also describe the current methods of genetic testing. As advances are made in molecular genetic technologies and improvements are made in bioinformatics, it is likely that the current time-consuming methods of DNA sequencing will give way to quicker and more efficient high-throughput methods, which are briefly discussed here.

Introduction

The inherited neuropathies are a clinically and genetically heterogeneous group of disorders. Rapid advances have been made in understanding the genetic causes of the inherited neuropathies in the last two decades since identification of the chromosome 17 duplication in 1991 (Reilly and Shy, 2009). Molecular genetic testing is now an integral part of the evaluation of patients with inherited neuropathies. Approximately 40 genes and more than 44 loci have now been identified as causing hereditary neuropathies (Table 12.1, Table 12.2, Table 12.3) (Reilly and Shy, 2009; http://www.molgen.ua.ac.be/CMTMutations).

Inherited neuropathies can be divided into two main groups: those in which the neuropathy is the primary or predominant feature (e.g., Charcot−Marie−Tooth disease, CMT), and those in which the neuropathy is part of a more generalized neurological or multisystem disorder (Table 12.4). The latter group encompasses a large collection of disorders, some of which are discussed further in other chapters of this book. In this chapter we will focus only on DNA testing in the primary inherited neuropathies.

A detailed history and examination followed by neurophysiology (and appropriate laboratory tests where indicated) are necessary to determine firstly whether the neuropathy is likely to be acquired or genetic. If there is a family history of a similar neuropathy then a genetic cause is likely but in the absence of such a family history certain clinical features make a genetic cause more likely. These include a prolonged clinical course, slow and steady progression, symmetrical examination findings, foot deformities, uniform neurophysiology, and the lack of positive sensory symptoms in the presence of sensory signs. However, in clinical practice, exceptions to this rule occur not infrequently. Determination of the clinical phenotype is critical prior to performing any genetic analysis; as in the primary inherited neuropathies the phenotype guides testing. In this chapter we will briefly discuss the clinical phenotypes of each of the primary inherited neuropathies; however, more detailed discussion is found in other chapters in this book.

Section snippets

Phenotypic Guides to Genetic Testing

If an inherited neuropathy is suspected on the basis of clinical symptoms and signs and/or a family history, there are several questions which should be answered before proceeding to molecular genetic testing:

  • •

    Is the disease a pure neuropathy or are there other features? If other features are present or if neuropathy is not the primary feature then one needs to consider other disorders (see Table 12.4).

  • •

    What type of neuropathy is it? Is it motor and sensory (CMT), predominantly motor (distal

Autosomal dominant Charcot−Marie−Tooth disease type 1

The most common cause of CMT1 is the chromosome 17 duplication (CMT1A, causes ~ 80%; Latour et al., 2006) and this should be checked first in any patient where CMT1 is suspected even if apparently sporadic. In patients with no definite male-to-male inheritance in their families, GJB1 should be checked if the chromosome 17 duplication is negative, otherwise MPZ should be checked next followed by PMP22 sequencing. The remaining CMT1 genes should be checked next as demonstrated in Fig. 12.1;

Methods of Genetic Testing

Molecular genetics has seen rapid advances in recent years with the identification of new genes. In addition, advances in technology mean that current diagnostic methods may soon be out-dated. Here, we briefly describe the diagnostic methods which are currently most frequently used in the molecular genetic diagnosis of hereditary neuropathies. There are two main groups of methods: for the detection of major rearrangements (e.g., CMT1A duplication or HNPP deletion) either qualitative or

Advances in Genetic Testing

Major technological advances have been achieved in molecular genetic testing in the last few years, which are likely to become standard techniques in the near future.

Genetic Counseling

Genetic diseases are different from other medical conditions as they imply risks to other family members as well as to future children. In addition, at present there are no specific treatments for genetic neuropathies. Thus, it is vital that patients are adequately counseled prior to having a genetic test.

Genetic counseling is defined as a:

“communication process that deals with the occurrence, or risk of occurrence, of a (possible) genetic disorder in the family. The process involves an attempt

Conclusions and Future Developments

In this chapter, we have described the genes known to be responsible for the primary inherited neuropathies. We have briefly discussed the clinical phenotype of each of the known inherited neuropathy subgroups, described algorithms for molecular genetic testing of affected patients, and discussed genetic counseling. We have also briefly described the current methods of genetic testing and recent advances in these techniques.

Genetics is a rapidly moving field; with over 40 genes now known to

Acknowledgments

MMR is grateful to the Medical Research Council (MRC) and the Muscular Dystrophy Campaign and SMM and MMR are grateful to the NINDS/ORD (1U54NS065712-01) for their support. This work was undertaken at University College London Hospitals/University College London, which received a proportion of funding from the Department of Health's National Institute for Health Research Biomedical Research Centres funding scheme.

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