|
|
|
|
|
|
|
The History of TSE (Prion Diseases) Caring for a loved one with CJD Getting tested for the CJD Mutation
|
FAMILIAL CJD Approximately
5-10% of all cases of TSE have now been found to result from one or
another of more than two dozen different mutations in the gene that
encodes the ‘prion’ protein. The
translated portion of the gene has 253 codons, and mutations occur in many
different regions, but the majority are found between codons 175 and 220,
which in the encoded protein are composed of alpha helical domains (Figure). The preponderance of
mutations in this region is not surprising because the change from a
normal to an abnormal protein shape is associated with the conversion of
alpha helices to beta sheets, and the mutated replacement of amino acids
within the helices is thus well positioned to facilitate the conversion. All
of the mutations are inherited in an autosomal dominant pattern, that is
to say, if one parent carries the mutation, there is a 50-50 chance for
each child to inherit the mutation. If
a family consisted of 100 children, half of them would carry the mutation
and half of them would not, but in the more realistic situation of
families with smaller numbers of children, the proportion that inherits
the mutation may not reflect these statistical odds: one, two, or three of
four children may be found to be mutation-positive.
Genetic testing can be easily accomplished from a small sample of
blood, but the choice of wishing to learn the result is a very individual
matter, and should never be made without the involvement of a
knowledgeable genetic counselor, and serious thought about its
consequences. For example, it
might be supposed that knowing a negative test result would be cause for
great relief and happiness, but it may also be cause for intense guilt:
how is that I escaped and my sister did not? Depending
on the mutation, the inherited forms of disease have been classified as
CJD, Gerstmann- Sträussler-Scheinker disease (GSS), or Fatal familial
insomnia (FFI). These names
have more historical than real importance, and result from the fact that
certain mutations have been linked to more or less distinctive clinical
and pathological features (Table).
By far the most commonly occurring mutation is located on codon
200, and produces an illness that is indistinguishable from sporadic CJD
(for a detailed description, see the 'Symptoms' section in Sporadic CJD).
Unlike most other mutations, it also has the distinction of being
‘incompletely penetrant’ – that is, not all individuals who carry
the mutation will develop the disease.
GSS typically begins at an earlier age than sporadic CJD, has a
prominent cerebellar (incoordination) component and evolves over a longer
period of time (years rather than months).
Microscopic examination of the brain may show little or no spongy
change, but always shows a characteristic profusion of plaques composed of
‘prion’ protein. FFI was
so named because most patients have a severe and intractable insomnia in
addition to the usual features of CJD. Today,
we know that all three 'diseases' are merely variations on a theme, and
that they can all be considered as being fundamentally the same, and
caused by the same disease process. In
fact, there are so many clinical shadings and exceptions to the
stereotypic classifications, not only between families with identical
mutations, but even among members of the same family, that making
predictions about the features and duration of illness on the basis of
different mutations is not a recommended exercise.
The more interesting matter is to understand how a disease that is
transmissible by inoculation could also be inherited, and we do not yet
have an answer to that question. Prevention
and therapy Familial disease could in principle be eradicated in a single generation by the use of pre-natal genetic testing of the fetus and therapeutic abortion, but this extremely sensitive issue is a matter of individual choice based on ethical and religious considerations, and will certainly never be accepted by all families with inherited disease. Another therapeutic approach would probably meet with much less resistance – a genetic engineering method to neutralize the gene that encodes the ‘prion’ protein, which we know to be essential to the development of disease. The method has succeeded in mice that have had the gene ‘knocked out’ before being challenged with a TSE infection – no mice came down with the disease. However, the technical difficulties of genetic engineering have so far impeded this strategy in all inherited human disease, including TSE. When these difficulties are solved, familial disease may be the first kind of TSE to be successfully treated.
Table. Mutations
of the chromosome 20 'prion' gene associated with inherited forms of
transmissible spongiform encephalopathy.
CJD = Creutzfeldt-Jakob disease; GSS = Gerstmann-Straussler-Scheinker syndrome; FFI
= fatal familial insomnia. Figure Figure. Two-dimensional structure of the 'prion' protein, showing regions of alpha helix (orange circle) and beta sheet (green rectangle) formations, and sites at which mutations in the encoding gene have introduced alternative amino acids. |
