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Hereditariness of Huntington’s Disease
Unique hereditary material is stored in the nucleus of every cell in the human body. This
hereditary material is also called DNA (deoxyribonucleic acid). The DNA is divided over 23
chromosome pairs, 46 chromosomes in total. Of each pair, one chromosome is inherited
from the father and one from the mother. Parts of chromosomes are also called genes [see
Figure 1].
Figure 1. Chromosomes and base pairs
Huntington’s is an autosomal dominant heritable disease. Autosomal means that the gene is
not carried on one of the sex chromosomes, as a result of which men and women run an
equal risk of developing the disease. Dominant means that if one of the parents has the
deviant gene, each child has a 50% chance of inheriting the disease, and that anyone who
has the gene will automatically develop the disease. If the children of a parent with
Huntington ’s disease does not inherit the deviant gene, they will not develop the disease.
Neither will the following generations; it does not skip a generation.
DNA
Chromosomes are made up of genes, which in turn are made up of a number of materials,
including the so-called bases. There are 4 different types of bases: Cytosine (C), Guanine
(G), Thymine (T) and Adenine (A). These bases can be seen in the figure above as the
coloured pieces that form a connection between the ‘spine’ or backbone of the DNA. The
bases form pairs: Thymine (T) always with Adenine (A), and Cytosine (C) always with
Guanine (G). The sequence and repetition of the base pairs form codes for the production of
proteins. Proteins fulfil an enormous variety of biological functions, both inside and outside
the cell.
Huntington and Huntingtin
Huntington’s disease is caused by a deviant gene on the 4th chromosome that is built up of
a number of CAG repetitions. Healthy people also have this gene, but in people with
Huntington’s disease the number of CAG repetitions is much higher. In healthy people there
is a maximum of 28 repetitions; in people with Huntington’s disease it is 40 or more. The
age at which the first symptoms become manifest depends on the number of CAG
repetitions; the higher the number of repetitions, the earlier in life the disease manifests.
The Huntington gene contains a code for the production of the Huntingtin protein. The
precise function of Huntingtin is unknown, but the protein plays a role in certain neuron
processes in a part of the brain and elsewhere in the body. In people with Huntington’s
disease, however, something goes wrong. The code on the gene that is responsible for the
production of the protein is mutated, resulting in the protein also being different than
normal. Neurons break a part of this altered protein into pieces, as a result of which the
proteins accumulate in the cells. One of the split protein parts is poisonous to the neurons
and is probably the reason for those neurons wasting away. This wasting away of neurons is
also called atrophy.
Certain parts of the brain, the basal ganglia (nucleus caudatus and putamen) and the
cerebral cortex, are particularly affected by the altered (mutated) proteins. These parts of
the brain are involved in movement coordination, and also in various thought processes.
Figure 2 shows the effects of Huntington’s disease on the basal ganglia.
Figure 2. A cross-section of the brain of a Huntington patient (above) and that of a healthy individual (below)
[source: http://kobiljak.msu.edu]
The grey area
As has been said, healthy people have a maximum of 28 CAG repetitions of the Huntington
gene, whereas people with Huntington’s disease have more than 40. A number of repetitions
between 29 and 40 is referred to as the ‘grey area’. People with 29-34 repetitions do not get
the disease, but they might pass it on to their children, and people with 35-40 might develop
the disease and might, moreover, pass it on to their children.
Spontaneous mutations
There appears to be a question of a so-called ‘spontaneous mutation’ in 1 to 2% of
Huntington patients. This is what is referred to when Huntington’s disease has not previously
appeared in the family. However, as has already been said, the disease cannot skip a
generation. Scientists have not yet discovered how spontaneous mutation occurs exactly, but
it probably has something to do with the so-called grey area, as described above. An
individual with 30 CAG repetitions has a longer Huntington gene than normal, but still this
person does not develop the disease. It is possible that small errors are made in the copying
of DNA for the formation of egg and seed cells, resulting in the number of CAG repetitions in
the cells being larger than in the body cells of the individual. In this way, although the
parent does not have the disease, the child could still develop Huntington’s. In such cases it
is more common for Huntington’s to be passed on by the father rather than the mother. This
might be because more DNA copies have to be made to form seed cells than egg cells, which
could increase the risk for errors to arise.
Heritability
Imagine that you are the son of a father who has Huntington’s disease. Your mother is
healthy. We can symbolically represent the genealogy as follows: the healthy woman, your
mother, is represented by an empty circle. She is connected to her husband, your father,
who is represented by a square, and because he is ill, we colour in the square. Together
they are connected to you, their son. Because you do not know whether you will develop the
disease just like your father, we place a question mark.
You are 20 years old and your father was healthy until a few years ago, when he began to
slowly go downhill. You know that your grandmother on your father’s side had similar
symptoms before her death. Your grandmother is represented by a coloured circle. Your
grandfather was healthy. One of your father’s brothers and one of his sisters have already
died of the disease, whereas you still have a (healthy) aunt and uncle. The disease does not
appear on your mother’s side.
What are the chances of you developing the disease?
Your father has the deviant gene that causes Huntington’s disease (shown in red) on one
chromosome 4. The disease is dominantly inheritable and therefore manifests in your father
despite there being a healthy gene on the other chromosome 4. In the fertilized ovum there
is one chromosome 4 from the mother and one chromosome 4 from the father. As far as
Huntington’s disease is concerned, there are four possible combinations with every
pregnancy.
In the first two possibilities, you inherit the Huntington gene from your father and you will
become ill later in life. In the second two possibilities, you inherit two healthy genes from
your parents and you will not develop Huntington’s disease. You therefore have a 1 in 2
chance, or a 50% chance, of inheriting the disease. The same applies for your brothers or
sisters, who also each have a 50% chance of inheriting the same disease. Only if you inherit
the deviant gene can you pass it on to your children. Every pregnancy runs the 1 in 2 risk of
the child later developing the disease.
[Source paragraph hereditariness: brochure with the video "Aan genen zijde, overerving bij
de mens", C.M.E. Katholieke Universiteit Leuven]