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Huntingtons disease

Fig 1.

No. of CAG repeats Outcome40 Individual will develop HD

There is a strong inverse relationship between the number of repeats (called stutters) and the age of onset. This mutation causes theresulting Huntingtin protein to become disordered and it damages and kills neurones in the brain. At death, the basal ganglia is ravagedand overall brain weight is reduced by a third.

Huntington's disease

Short arm of chromosome 4

HD gene

DNA

HD gene

Transcription (in the nucleus)DNA strand

Codon (triplet of3 nucleotides which codefor a specific amino acid)

CAG codes forthe amino acidglutamine

Repeating CAG codons.The normal gene has less than 36 repeats.Mutated gene has more than 36 repeats

Abnormal huntingtin (mHtt) with morethan 36 glutamine residuesNormal cytoplasmic protein,

huntingtin (Htt) with less than 36glutamine residues

Glutamine chain

This Factsheet uses the example of Huntington's disease to develop your understanding of inheritance and the ethics of genetic testing.

ProgressionHuntingtons disease (HD) is an inherited disorder of the nervous system. The onset of the disease usually occurs between the ages of40 - 50. Initially it results in involuntary muscle movements, mild personality changes and a slow deterioration of mental ability. Laterstages bring speech disturbance, difficulties with swallowing and physical disturbance ranging from exaggerated gestures and fidgetingmovements of the hands to a continuous flow of disabling, violent movements. In the final stages of HD patients suffer severe dementiaand become completely dependent on others. There is no cure and death occurs 15 -17 years after onset.

CauseThe gene and mutation that causes HD was identified in 1993 on the short arm of chromosome 4. The Huntington gene contains a regionin which three nucleotides, cytosine, adenine and guanine (CAG), are repeated over and over again. Most people have between elevenand thirty four of these repeats. Huntingtons disease mutations increase the number of repeats up to 250 (Fig.1).

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www.curriculum-press.co.uk229 Huntingtons disease

HD is unusualHuntingtons disease has several unusual features: It is caused by a dominant gene - anyone who inherits a single

defective gene will eventually develop the disease. Although it is caused by an autosomal gene (i.e. one on a non-

sex chromosome) its inheritance is not straightforwardlyMendelian and inheritance from the mother and father differ.

The size of the base triplet (CAG) repeat or stutter increaseswith each generation, thus the symptoms become more severefrom one generation to the next as the Huntingtin proteinbecomes ever more damaged.

It occurs with unusually high frequency. It afflicts about 1 in10,000 Europeans whereas most dominant mutations that killhave frequencies of about one in a million

Typical Exam QuestionGordon has Huntingtons disease. He has three children, two boysand a girl, as shown below.

Gordon Sue

Mark Jo

Ann

Ronald JaneGillGeorge

JimMaria

Why is the frequency of HD so high?In 1941 the British geneticist J.B.S. Haldane pointed out that,unlike most genetic disorders, the onset of Huntingtons diseaseis usually when people are in middle age and have already hadchildren. Thus, the mutation hardly affects the reproductivesuccess of those who have it, but all of their children have a 50%chance of inheriting the defective gene.

Genetic TestingA blood test can determine, in almost all cases, whether a personhas the HD gene.There are three categories of testing:1. Prenatal testing is used to determine whether a foetus is at risk

of HD. This involves amniocentesis or chorionic villus sampling(CVS).

2. Presymptomatic testing, for people at risk of HD3. Confirmatory testing determines whether people showing

possible symptoms actually have HD.

To test or not to test?Deciding whether or not to take the HD test may prove extremelydifficult. Often, different members of a family will be unable to agreewhether a test should be taken. An individual who tests positivemay be able to make decisions such as not to have children. Theirsiblings may then feel pressurised to take the test too. If they provenegative, they may experience guilt about being healthy. If positive,they, like their sibling, may be at risk of discrimination from insurers/employers etc. If a sibling tests positive, then so too must one ofthe parents, yielding information that the parent may not havewanted.

What is the probability that Mark will develop the disease? Explainyour answer (2).

Markscheme

Gordon has two copies of the gene and Mark will have inherited one of

them. Thus he has a 1 in 2 chance (50%) of inheriting the faulty version

and developing HD.

At-risk individuals who decide to take the HD test are offeredcounselling sessions to ensure that they understand the implicationsof taking the test. The sessions are spread out over a period ofweeks and the individual can change their mind at any time. Aneurological examination is conducted to detect any early symptomsof HD. If any symptoms are detected the individual is given theopportunity to discontinue the test.

Typical Exam Question

Gene therapyInternationally, dozens of trials using mice are being conducted toassess the use of gene therapy to cure Huntingtons disease. Thusfar, most human trials of gene therapy have shown limited successand in a few cases have resulted in death.

Markscheme

(a)If Maria has the HD gene she must have inherited it from her mother;

therefore Gill will know she has the gene

If Maria does not have the gene, Gill is no wiser whether she has it

or not;

(b)Better to test Ronald because of risk associated with testing foetus;

If Ronald negative then fetus is OK;

(a) Marias mother Gill has refused to be tested for theHuntingtons gene. She does not want to know whether shewill develop the disease. However, Maria has decided thatshe does want to be tested for HD. Explain how Marias testresults may conflict with Gills interests (2).

(b) When Gordon is diagnosed with Huntingtons disease Janeis six weeks pregnant. If Ronald and Jane want to avoid havinga child with Huntingtons disease they would be advised tohave genetic tests. Would it be better to test Ronald or thedeveloping fetus first? Explain your answer (2).

Gordon Sue

Mark Jo

Ann

Ronald JaneGillGeorge

JimMaria

Typical Exam QuestionDescribe the steps that researchers planning human trials of genetherapies for HD should take to ensure that they are ethicallyresponsible (4).

Markscheme

Extensive prior trials on other animals to test safety;

Ensure that there is no risk from viral carrier of gene;

Offer right to withdraw;

Approval by ethical committee;

Ensure participants fully understand the risks;

Ensure participants have full information on uncertainty of benefit;

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www.curriculum-press.co.uk229 Huntingtons disease

Investigating HD using miceSome mice naturally show the symptoms of Huntingtons disease (HD mice). In an investigation four-week-old normal and HD mice werereared in two environments:

Environment 1: standard cagesEnvironment 2: environmentally enriched cages that contained paper, cardboard and plastic objects which were changed every two days

From eight weeks of age, the coordination ability of each mouse was tested at intervals by seeing whether they were able to turn roundwhen placed on a horizontal rod. Fig.2 shows the results.

Fig 2. Percentage of normal and HD mice failing the test

The key points are: no normal mice failed the test the failure of HD mice was dramatically reduced in environmentally enriched cages increasing numbers of HD mice failed the test as time went on

The significance of this research is that it suggests that providing mental and physical stimulation e.g. through physiotherapy may helpto delay the onset or development of the disease in humans.

0 5 10 15 200

20

40

60

80

100

% micefailing test

age of mice/weeks

normal mice inboth types of cage

HD mice in environmentallyenriched cages

HD mice in standard cages

Acknowledgements:This Factsheet was researched and written by Kevin Byrne.Curriculum Press, Bank House, 105 King Street, Wellington, Shropshire, TF1 1NU.Bio Factsheets may be copied free of charge by teaching staff or students, provided that their school is a registered subscriber. No part of these Factsheetsmay be reproduced, stored in a retrieval system, or transmitted, in any other form or by any other means, without the prior permission of the publisher.ISSN 1351-5136