Familial Creutzfeldt-Jakob Disease
by Scott H. McMillan

In 1920, a strange phsycodisorder was described by H.G. Creutzfeldt, The symptoms of this disease included a relapsing course with remissions, cortical symptoms referable to the motor and sensory centers, intellectual deficit with predominance of physcomotor manifestations, progressive course, a noninflamatory diffuse cell disease with cell out-fall throughout a gray substance. This disease first recorded by H.G. Creutzfeldt and one year later by A Jakob has now been given their names ( Creutzfeldt-Jakob Disease).
Creutzfeldt-Jakob disease simply stated is a rare degeneration of the brain, causing headache, progressive dementia, seizures, and death within a year of symptom onset. Most of the CJD cases are sporadic with some large sporadic bursts being evident in certain areas throughout the world. Approximately 5-15% of cases are inherited as an autosomal dominant trait with a 0.56 penetrance. CJD is one disorder in a disease category that is believed to be caused by a infectious protein particle called a prion. A debate looking at the mechanism of action of these protein particles is ongoing. However there are some common threads that tie all prion diseases together.
Infectious prion particles are made of an abnormal isoform of the prion protein encoded by a chromosomal gene. A unknown post-translational process converts cellular prion proteins into the abnormal isoform (Prusiner). Point mutations in the prion protein genes of humans have been linked to the development of the neurodegeneration. In Familial CJD a point mutation causing missense of the reading frame on chromosome 20p is suspect to the cause of the disorder. The wild type PRNP gene encodes for the protein portion of a glycoprotein that accumulates in fibers outside cells in a few disorders including CJD.
A case study of a large German family that emigrated to the United States at the turn of the last century had nine individuals die of CJD. All of these individuals where between the ages of 45-70. While the family was being studied at the National Institute of Neurological Disorders and Stroke, two members died. Their DNA was subsequently studied revealing a point mutation in the open reading frame of the PRNP gene on chromosome 20p. This mutation, GAG mutated to AAG at codon 200, caused a missense of the reading frame (Goldfarb et al.). Glu was being read as Lys. This mutation altered the protein product by elimination the recognition site for the restriction enzyme BSMA 1. Thus, if BSMA 1 is added to the DNA of a family member with a mutant PRNP allele, it will result in the production of large fragments on an electrophoresis gel. To test this hypothesis, the DNA from two deceased family members and nine close relatives were amplified via PCR. PCR primers corresponding to opposite ends of the PRNP gene coding region were used. The PCR was cycled thirty-five times resulting in a 3.44 x 1010 or (235) increase in sample. The resulting DNA fragments were separated and displayed using agarose gel electrophoresis.
The results of the gel suggested that the characteristic large fragments of the CJD patients was observed in several individuals. Individuals three and four contained two bands and were judged heterozygous for CJD. The BSMA 1 restriction enzyme did not one allele corresponding to the large fragments, but did cut the other allele corresponding to the small fragments. These patients had one good and one bad copy of the gene. Individuals five and six, who were wild type for the PRNP gene, had only small fragments. Two other individuals were homozygous wild type for the PRNP gene, meaning that they probably would not develop the disorder. However, this is not always the case. In a study of Libyan and Tunisian Jews with Familial CJD which have shown the codon 200 allele, one patient of which was homozygous for the allele had a clinical presentation similar to a typical CJD heterozygote ( Prusiner). Knowing this, it might be possible to relate these genetic traits to a with the time delay of symptom onset. Most patients were between 45-70 years of age. If CJD was only dependent of the mutation at the codon 200, then more young cases should be noted. But in fact this is not the case, and a detailed mechanism of action is not understood at this time which could explain these occurrences.
During a consultation with an 18 year old family member, the young man wanted to know his risk of developing the condition. The young mans father had succumbed to the disease and his mother was homozygous wild type. Understanding that the disease was indeed familial and has persisted infections over time, it is safe to tell the man that he had a genetic predisposition to developing the disorder. He may have ccarried the gene for the disorder but may not express the phenotype.
By running the BSMA 1 gel on his DNA, it would be possible to analyze his current situation. If he comes up as a heterozygote, than he has one normal and one mutant copy of the gene. Knowing that the penetrance of CJD is 0.56, the young man will have approximately a 50% chance in expressing the gene later in life. Also knowing that he is the progeny of an autosomal dominant father and a homozygous mother, he has a 50% chance of being homozygous. Assuming that he is homozygous, he will probably not develop the condition. However there is the case mentioned earlier that shows that he might have a slight chance of developing clinical symptoms (Prusiner).
After a detailed explanation is presented to the 18 old family member, the time delay of developing the disorder should be included. At 18 years of age, he still has a lot of time before symptoms would even begin to appear. He must be helped in coping with the idea that he might succumb to the disease that has taken many of his ancestors. The patient must be helped to make the most of the life he has, and not worry about what might be.


"Novel infectious agents and the central nervous system" Ciba Foundation Symposium 1988, 135. John Wiley and Sons Ltd., Chichester, UK.

"Clinicopathological aspects of CDJ." Elsevier / Nishimura 1985, Japan. Edited by T. Mizutani and H. Shiraki.

Lev G. Goldfarb, Eva Mitova, Paul Brown, Ban Hock Toh, D. Carleton Gajdusek. Mutation in codon 200 of scraphie amyloid protein gene in two clusters of CJD in Slovakia. Prusiner, Stanley B. Molecular Biology of Prion Diseases. Science, vol. 252, June 14 1991. Pages 1515-1520.

Fatal Familial Insomnia and Familial Creutzfeldt-Jakob Disease: Different prion proteins determined by a DNA polymorphism. Lucia Monari et al. Proc. Natl. Acad. Sci. USA, vol. 91, pp 2839-2842, March 1994.

Return Case Studies in Virtual Genetics 1996-1997