InvestIgatIons

Genetic testing in neurologynicholas Wood

Abstractsuch is the impact of genetics in neurological disease that a knowledge

of the outline principles and where to look for the more detailed infor-

mation is necessary for all training and practising physicians. thankfully

the principles (based around Mendel’s laws) are straightforward and,

although the depth and complexity of information can be bewildering,

the internet and publicly funded websites have made the search for reli-

able information achievable. this contribution summarizes some of the

principles needed, whilst pointing the way to the more useful websites

for further information.

Keywords diagnostic and presymptomatic testing; mitochondrial;

modes of inheritance; neurogenetics; X-linked

Improving scientific knowledge from the human genome map-ping project and rapidly improving technologies means the deliv-ery of genetic discoveries into potentially useful clinical tests has gathered tremendous pace. Twenty years ago, barring the testing for relatively rare syndromes based on cytogenetic analyses, there were virtually no diagnostic tests for any neurological disease. Over the past 10–15 years, the field has mostly concerned itself with mapping disease traits, i.e. identifying the chromosomal location of a gene underlying a certain phenotype. This was suc-cessful and led to the identification of a number of genes such that now there is no area of neurology which has not seen an impact from genetic discovery. Many of the mutations explain rare syn-dromes or rare subgroups of common diseases, but in the future genetic testing will be used in the mainstream of neurology.

The majority of our approximately 25,000 genes are expressed in the nervous system, so it is perhaps no surprise to find that, of all the fields of medicine, molecular genetics has had the biggest impact on clinical neurology.

In this contribution we provide a brief summary of genetic dis-coveries relating to neurology and provide references to further information.

Genetic testing

It is important to differentiate diagnostic testing from pre- symptomatic testing.

Nicholas Wood PhD FRCP FMedSci is Professor of Clinical Neuroscience and

Neurogenetics at the UCL Institute of Neurology, National Hospital for

Neurology and Neurosurgery, Queen Square, London, UK. Competing

interests: none declared.

MeDICIne 36:10 56

Diagnostic testing is part of the normal neurological diag-nostic procedure. When faced with a patient and their family and the possibility of a neurogenetic condition, it is the duty of the neurologist to try to make as rapid and accurate a diagnosis as possible. Neurogenetic testing is now the cornerstone of this process. It is also the duty of the clinician to be able to inform the patient and family members, where appropriate, about the importance of genetic testing. In particular, not only should the neurologist know something about the disease that they are test-ing but they should also be able to describe, in accessible terms, the core clinical features of a given diagnosis and be able to dis-cuss the mode of inheritance and provide a rough estimate of the penetrance. Consent is an important component of diagnostic testing and part of this process involves the transmission of this important information.

Pre-symptomatic testing is undertaken by specialist genetic centres and involves the strict counselling protocol for individu-als who are at risk of inheriting mutations and/or developing neurological disease (see Figure 1).

Mitochondrial inheritanceOur cells contain two genomes: • the nuclear genome, which encodes the vast majority of our

proteins • the mitochondrial genome, which is a small circular molecule

of 16.5 kb that encodes proteins used in the generation of ATP.

Abnormalities in the mitochondrial genome tend to cause a variety of complicated neurological phenotypes ranging from myopathy to multisystemic dysfunction with seizures, cognitive impairment and a range of movement abnormalities (e.g. ataxia and myoclonus). They can also produce abnormalities outside the nervous system, including diabetes and short stature. All mitochondria come from our mothers so the mode of inheritance is matrilineal.

The phenotype is in part determined by the type of mutation and also the burden of mutation in any given tissue. This concept is known as heteroplasmy.

Chromosomal abnormalities

There are many developmental syndromes associated with chromosomal or subchromosomal rearrangements. The most well known is trisomy 21 giving rise to Down’s syndrome. Such patients not only have a learning disability but many go on to develop premature Alzheimer’s disease. It was this clue that helped in the identification of the first gene responsible for Alzheimer’s disease: the amyloid precursor protein gene on chro-mosome 21. However, with improving cytogenetic technologies it is becoming increasingly possible to identify smaller rearrange-ments (deletions and multiplications), which may produce a range of abnormalities. In general, the clue to a possible chro-mosomal rearrangement is an early-life syndrome (usually con-genital) with complicated features that often include dysmorphic abnormalities and multiorgan involvement. However, it is now becoming clear that submicroscopic rearrangements also play a role in disease causation. There are a number of databases that can be used to help sift through this rather large catalogue of diseases. If structural chromosomal abnormality is considered, it

6 © 2008 Published by elsevier Ltd.

InvestIgatIons

is worthwhile requesting a karyotype through the local cytoge-netics servcies.

Single gene disorders and neurology

A clear family history is essential for helping to identify the mode of inheritance. It is worth noting the difference between the lack of family history (because the parents died young, the patient was adopted or just poor knowledge about the ancestral history) and the situation where one can take a very detailed history and clearly identify or exclude other family members. One also has to consider variable expression and reduced penetrance. It is, therefore, worth asking about any neurological history in ances-tors and spreading the net wide across a range of clinical features as previous generations may have been labelled with incorrect diagnoses.

Identifying the mode of inheritanceAutosomal dominant inheritance in suggested by male–male

transmission.Autosomal recessive inheritance is suggested by multiple

affected siblings, particularly in the presence of a consanguine-ous relationship.

X-linked inheritance is suggested by a disease trait in males and no male–male transmission. It is worth remembering that X-linked dominant traits, although rarer than recessive, may affect females. In neurology, adrenomyeloneuropathy and CMT-X (due to connexin 32 mutations) are notable X-linked dominant dis-eases which may affect females.

Genetic conditions (e.g. Friedreich’s ataxia) tend to present after birth and are progressive disorders.

Congenital conditions usually present at birth or very early life with little or no progression. However, it is now clear that some congenital syndromes are genetic in origin and may be due to a defect in development caused by a gene mutation.

The age of onset provides a rough guide to the possible mode of inheritance. As a rule, recessive diseases start earlier than dominant. In general, recessive diseases are due to loss of func-tion in that the affected patient has inherited two mutations (one on each allele), which result in either decreased amounts of, or dysfunctional, protein. As both alleles are dysfunctional, there

is no ‘safety net’ and the disease starts earlier in life. Dominant disease is slightly more complicated as there is only one mutant allele. There are three broad ways in which dominant disease produces a phenotype: • loss of function or haploinsufficiency, where the 50% activity

of the normal allele is insufficient during the length of human life to maintain entirely normal function

• dominant negative, where the mutant allele exerts a negative impact at DNA, RNA or protein level

• toxic gain of function, where the mutant allele actually acquires a new injurious property that causes cellular dys-function. Huntington’s disease is an archetypal example.

Further reading

Genetics has a major impact, from the cortex down to the muscle fibre and every anatomical link in between. Mutations in genes encoding proteins in all these cell subtypes have been described. To get up-to-date knowledge on genetic syndromes it is worth looking at the online Mendelian inheritance in man (OMIM) website.1 This is frequently updated and describes a huge array of genetic conditions. Just because a gene has been identified by researchers, it does not always mean there is a test available. There is an extremely useful web page from the University of Washington in Seattle called ‘Gene clinics’, which not only pro-vides clinical information but also keeps up-to-date information on which tests are available.2 The Clinical and Molecular Genet-ics Society also has a web page that contains useful information about clinical and diagnostic services within the UK.3 For more useful websites, see Table 1.

Conclusion

Neurogenetics is now a vast subject. There are a huge number of conditions with a wide range of phenotypes for which accurate molecular genetic diagnosis is now available.

The improving technology undoubtedly means that genetic testing will become more widely available, cheaper, useful and informative. However, care must be taken with both the interpre-tation and the guidance to families. It is therefore necessary to train every neurologist to have some knowledge and background

Algorithm for genetic testing

Consent for genetic testingThis should include:

discussion on the clinical effects

of the disease; the risks to other family members, variable

expression and penetrance

Refer to local genetic counselling services

Discuss diagnosis and likely prognosis

with patient

Does the patient want to consider genetic testing?

Establish likely mode of inheritance

A detailed family history and

identification of the likely mode of inheritance

Characterize clinical phenotype

Establish likely diagnosis and the relationship of this

individual to the proband

Diagnostictesting

Presymptomatictesting

Figure 1

MeDICIne 36:10 567 © 2008 Published by elsevier Ltd.

InvestIgatIons

in this area. In particular it is important to know the modes of inheritance, the concept of variable expressivity and penetrance and, perhaps most importantly in this fast moving field, where to look for up-to-date information. ◆

Web pages related to genetic counselling and testing

Hereditary disease foundation (testing information) – http://

www.hdfoundation.org/./resources/testing.php

national Human genome Research Unit (FaQs on genetic

testing) – http://www.genome.gov/19516567

eurogentest (eU-funded network of excellence) – http://www.

eurogentest.org

the genetic Interest group – http://www.gig.org.uk/index.html

genDIa (genetic diagnostics) – http://www.gendia.net/index.html

orphanet (Portal for rare diseases and orphan drugs) – http://

www.orpha.net/consor/cgi-bin/home.php?Lng = gB

all accessed 19 June 2008.

table 1

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ReFeRenCeS

1 McKusick va, John Hopkins University. online Mendelian Inheritance

in Man (oMIM). available at: http://www.ncbi.nlm.nih.gov/sites/

entrez?db = omim (accessed 19 June 2008).

2 gene tests. available at: http://www.geneclinics.org/ (accessed 19

June 2008).

3 UK genetic testing network. available at: http://www.ukgtn.nhs.

uk/gtn/ (accessed 19 June 2008).

FuRtheR ReAdInG

Duncan Re, gillam L, savulescu J, et al. Holding your breath: interviews

with young people who have undergone predictive genetic testing

for Huntington disease. Am J Med Genet A 2007; 143: 1984–89.

Rantanen e, Hietala M, Kristoffersson U, et al. What is ideal genetic

counselling? a survey of current international guidelines. Eur J Hum

Genet 2008; 16: 445–52.

Rosenberg R, Pruisner sB, DiMauro s, Barchi RL, nestler eJ. the

Molecular and genetic basis of neurological and psychiatric disease,

3rd edn. Philadelphia: Butterworth Heinemann.

Wood nW (ed) neurogenetics for clinicians. Cambridge University press

(in press).

© 2008 Published by elsevier Ltd.