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. 

MutationDisease Phenotype
Octa-repeat insertion of 24, 48, 96, 120, 144, 168, 192, or 216 base pairs between codons 51 and 91CJD, GSS, or atypical dementias
P102L (Pro Leu)GSS: classical ataxic form
P105L (Pro Leu)GSS: spastic paraparetic variant
A117V (Ala Val)GSS: pseudobulbar variant
G131V (Gly Val)GSS: classical ataxic form
Y145* (Tyr Stop)Alzheimer-like dementia
D178N (Asp Asn)CJD (129V on mutant allele)
D178N (Asp Asn)FFI (129M on mutant allele)
V180I (Val Ile)CJD
T183A (Thr Ala)Alzheimer-like dementia
H187R (His Arg)GSS: classical ataxic form
F198S (Phe Ser)GSS with neurofibrillary tangles
E200K (Glu Lys)CJD
D202N (Asp Asn)GSS with neurofibrillary tangles
V203I (Val Ile)CJD
R208H (Arg His)CJD
V210I (Val Ile)CJD
E211Q (Glu Gln)CJD
Q212P (Gln Pro)GSS with Lewy bodies
E217R (Glu Arg)GSS with neurofibrillary tangles
M232R (Met Arg)CJD

CJD = Creutzfeldt-Jakob disease; 

GSS = Gerstmann-Straussler-Scheinker syndrome;

FFI = fatal familial insomnia.

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.

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