Marie bieniek bieniek at
Tue Aug 15 11:39:36 EST 1995

Here is the Online Mendelian Inheritance in Man (OMIM) entry for 
I was out last week, so I missed the original request. I hope this helps.




          Clinical Features 
          Biochemical Features 
          Mode Of Inheritance 
     Population Genetics 
     Animal Models 
     See Also 
     Clinical Synopsis 
     Edit History 


A number sign (#) is used with this entry because of evidence that the 
disorder is caused by mutations in the prion protein gene
(PRNP; 176640). 



Jakob et al. (1950) gave a follow-up on the first reported family, the 
Backer kindred. Three generations may have been
affected, with male-to-male transmission. Davidson and Rabiner (1940) 
described 3 affected sibs. Friede and Dejong (1964)
and later May et al. (1968) described affected father and 3 daughters. 
Onset was between 38 and 45 years. The illness lasted
only 10 months to 2 years. The disorder began with forgetfulness and 
nervousness and progressed with jerky, trembling
movements of the hands, loss of facial expression, and unsteady gait. 
Pathologic findings included severe status spongiosus,
diffuse nerve cell degeneration and some glial proliferation. 
Creutzfeldt-Jakob disease may be a mixed category. 

Gibbs et al. (1968) reported a transmissible agent that reproduced the 
disease in a chimpanzee injected with brain material
from a 59-year-old English male. The familial disease appears to be no 
different from the sporadic one. Ferber et al. (1974)
succeeded in transmitting the familial disease to the chimpanzee where 
the findings were the same as those from transmission of
the sporadic disease. Among families studied by Gajdusek (1973) was one 
with 14 affected members from one of whom the
disease was transmitted to the chimpanzee. Zlotnik et al. (1974) 
transmitted the disease to the squirrel monkey.
Person-to-person transmission through a corneal transplant was suggested 
by the experience reported by Duffy et al. (1974).
The transmission through cadaver-derived human growth hormone and through 
transplants, homografts, and surgical
instruments was referred to as 'friendly fire' in medicine by Brown et 
al. (1992). 

Rosenthal et al. (1976) reported a remarkable kindred in which the 
proband had clinically typical Creutzfeldt-Jakob disease,
but neuropathologic studies showed encephalopathy. A first cousin had 
chronic spongiform dementia without spongy changes
at autopsy. Both had PAS-positive, eosinophilic plaques throughout the 
brain. The pedigree indicated neurologic disease with
or without subacute or chronic dementia in 16 members of the kindred. A 
general, genetically determined susceptibility to
neurologic disease was postulated. 

In a Chilean family, Cartier et al. (1985) described a brother and sister 
and possibly a third sib who had the unusual ataxic form
of Creutzfeldt-Jakob disease. 


Bockman et al. (1985) found that purified fractions from the brains of 2 
patients with CJD contained protease-resistant proteins
ranging in molecular weight from 10,000 to 50,000. These proteins reacted 
with antibodies raised against the scrapie prion
protein PrP 27-30. Rod-shaped particles found in the brain tissue of the 
patients were similar to those from rodents with either
scrapie or experimental CJD. After staining with Congo red dye, the 
protein polymers from patients with CJD showed green
birefringence under polarized light. Bockman et al. (1985) suggested that 
the amyloid plaques of CJD may be paracrystalline
arrays of prions similar to those found in scrapie-infected hamsters 
(DeArmond et al., 1985). For further information on prion
function, see 176640). 




Masters et al. (1979) found that about 15% of cases are familial. From a 
study of 73 families, Masters et al. (1981) concluded
that 15% of cases of CJD have a family history consistent with autosomal 
dominant transmission. Onset of disease is
significantly earlier in familial cases. A maternal effect has not been 
found. Temporal and spatial separations between affected
relatives suggested that incubation periods range at least from 1 to 4 
decades. Affected sibs tend to die at the same age and not
at the same time (Masters et al., 1981). In 4 families, CJD occurred in 
members related by marriage. Bertoni et al. (1983)
reported 7 affected persons in 3 generations of a large kindred. They 
pointed out that 3 of 4 patients studied in detail were first
observed with supranuclear gaze paralysis, gait ataxia, and rapidly 
progressive dementia. Most of the affected persons were
farmers. Brown et al. (1984) analyzed the characteristics of those 5 to 
10% of patients who pursue a relatively long course
(more than 2 years). Patients with prolonged course showed higher 
familial representation (30%), younger age of onset
(average, 48 years), and lower frequency of myoclonus (79%) and periodic 
EEG activity (45%) than are found in series of
unselected cases. The longest course was 13 years in a case proved by 
transmissibility. Of 225 transmitted cases, 15 (7%) had
a prolonged course. The incubation period and duration of illness after 
injection into primates bore no relation to the duration of
illness in patients. Clinical differentiation from Alzheimer disease can 
be difficult in CJD patients with a long course. See
Gerstmann-Straussler-Scheinker disease (137440). 

Haltia et al. (1979) reported on 9 cases in 3 generations of a Finnish 
family. They raised the possibility of genomic integration of
a virus, although in light of subsequent discoveries of transmission via 
abnormal prion protein, this now seems unlikely (Prusiner
and Hsaio, 1994). Transmission through males and occurrence in only one 
of a pair of twins seemed to argue against
transplacental passage or transmission via mother's milk. 

In a consecutive series of 230 patients with neuropathologically verified 
CJD, Brown et al. (1986) found that men and women
were affected about equally with a mean age of onset of 61.5 years. 
Familial cases accounted for 4 to 8% of the series. Most
of the early neurologic symptoms were cerebellar or visual. 
Extrapyramidal muscular rigidity, myoclonus, and characteristic
periodic EEG complexes were observed comparatively late. The median 
duration of illness was 4 months and the mean was
7.6 months; 90% of patients died within a year of onset. Doh-ura et al. 
(1990) demonstrated that patients with
Creutzfeldt-Jakob disease with congophilic kuru plaques have the same 
pro102-to-leu missense change in their constitutional
prion protein as is found in Gerstmann-Straussler syndrome. They found 
the leu102 allele in heterozygous state in 6 of 7
patients who had CJD with congophilic kuru plaques. No patient with CJD 
without congophilic kuru plaques had this allele.
They also found the leu102 allele in some unaffected relatives of 3 
patients although there was no known familial occurrence of
a similar neurologic disorder. Goldfarb et al. (1990) were unable to find 
the codon 102 mutation described in GSS syndrome in
5 familial and 27 sporadic cases of CJD or in 3 patients with kuru. 

Brown et al. (1994) tested 15 cases of iatrogenic CJD that represented 
central infection (from dura mater or corneal
homografts and stereotactic EEG electrodes), 11 cases peripherally 
infected (from native human growth hormone or
gonadotropin), and 110 control individuals for the presence of mutations 
in the chromosome 20 amyloid gene (as that group
terms the prion gene). No patient or control had any of the known 
pathogenic point or insertional mutations found in the familial
disease, but allelic homozygosity at codon 129 was present in all but 2 
(92%) of the 26 patients, compared with 54 (50%) of
the 110 controls (p less than 0.001). Pooled data from all identified and 
tested cases of iatrogenic disease yielded a worldwide
total of 56 patients, of whom all but 4 were homozygous at codon 129 (p 
less than 0.001). 


Creutzfeldt-Jakob disease occurs in unusually high frequency in Chile 
(Masters et al., 1979). Kahana et al. (1974) described
an aggregation of cases among Libyan Jews, a finding that supports the 
viral or the genetic hypothesis or perhaps both. In a
country-wide survey of CJD in Israel, Zilber et al. (1991) diagnosed 114 
cases, among them 49 Libyan-born, with onset of
their disease during the years 1963-1987. After age adjustment, the mean 
annual incidence rate per million population was 43
among Libyan-born and 0.9 in the rest of the population. Among Jews born 
in Egypt and Tunisia, countries neighboring Libya,
the adjusted rates were higher than in the other Israelis (3.5 and 2.3 
per million, respectively). Among Libyan Jews, there was
no association between incidence rate of CJD and age at immigration, 
i.e., duration of exposure to a hypothetical infectious
factor in Libya. The percentage of familial cases among Libyan Jews (41 
to 47%) is one of the highest known. Kahana et al.
(1991) reported that the clinical presentation and evolution of the 
disease were very similar in patients born in Libya and others
without Libyan ancestry but tended to be more classical in the Libyan 
patients with higher frequency of myoclonic jerks and
periodic EEG and a progressive course of shorter duration. 


Gray tremor (gt) in the mouse is a transmissible spongiform 
encephalopathy that behaves as an autosomal recessive mutation. It
has a complex phenotype including pigmentation defects, tremor, seizures, 
hypo- and dysmyelination in central and peripheral
nervous systems, spongiform encephalopathy, and early death. The 
heterozygote is phenotypically normal but develops a mild
spongiform encephalopathy from 2 months of age onward. Sidman et al. 
(1985) produced the later-expressed vacuolating
disorder in genetically normal mice in transmission experiments. All 7 
mice of 3 strains who were allowed to survive for the
unusually long interval of 682 to 721 days after intracerebral 
inoculation of gt/gt brain homogenate in the neonatal period,
developed spongiform changes distributed as in the mutant phenotype. 


See also: Cathala et al. (1980); Galvez et al. (1983); Hadlow et al. 
(1980); Kovanen et al. (1980); Manuelidis et al. (1987);
Owen et al. (1989); Pablos-Mendez et al. (1993); Prusiner (1982); Roos et 
al. (1973); Vallat et al. (1983). 


Bertoni, J. M.; Label, L. S.; Sackelleres, J. C. and Hicks, S. P.: 
     Supranuclear gaze palsy in familial Creutzfeldt-Jakob disease. Arch. 
Neurol. 40: 618-622, 1983. 

Bockman, J. M.; Kingsbury, D. T.; McKinley, M. P.; Bendheim, P. E. and 
Prusiner, S. B.: 
     Creutzfeldt-Jakob disease prion proteins in human brains. New Eng. 
J. Med. 312: 73-78, 1985. 

Brown, P.; Cathala, F.; Castaigne, P. and Gajdusek, D. C.: 
     Creutzfeldt-Jakob disease: clinical analysis of a consecutive series 
of 230 neuropathologically verified cases. Ann.
     Neurol. 20: 597-602, 1986. 

Brown, P.; Cervenakova, L.; Goldfarb, L. G.; McCombie, W. R.; Rubenstein, 
R.; Will, R. G.; Pocchiari, M.; Martinez-Lage,
J. F.; Scalici, C.; Masullo, C.; Graupera, G.; Ligan, J. and Gajdusek, D. 
     Iatrogenic Creutzfeldt-Jakob disease: an example of the interplay 
between ancient genes and modern medicine.
     Neurology 44: 291-293, 1994. 

Brown, P.; Preece, M. A. and Will, R. G.: 
     'Friendly fire' in medicine: hormones, homografts, and 
Creutzfeldt-Jakob disease. Lancet 340: 24-27, 1992. 

Brown, P.; Rodgers-Johnson, P.; Cathala, F.; Gibbs, C. J., Jr. and 
Gajdusek, D. C.: 
     Creutzfeldt-Jakob disease of long duration: clinicopathological 
characteristics, transmissibility, and differential diagnosis.
     Ann. Neurol. 16: 295-304, 1984. 

Cartier, L.; Galvez, S. and Gajdusek, D. C.: 
     Familial clustering of the ataxic form of Creutzfeldt-Jakob disease 
with Hirano bodies. J. Neurol. Neurosurg. Psychiat.
     48: 234-238, 1985. 

Cathala, F.; Chatelain, J.; Brown, P.; Dumas, M. and Gajdusek, D. C.: 
     Familial Creutzfeldt Jakob disease: autosomal dominance in 14 
members over 3 generations. J. Neurol. Sci. 47:
     343-351, 1980. 

Davidson, C. and Rabiner, A. M.: 
     Spastic pseudosclerosis (disseminated encephalomyelopathy: 
corticopallidospinal degeneration). Arch. Neurol.
     Psychiat. 44: 578-598, 1940. 

DeArmond, S. J.; McKinley, M. P.; Barry, R. A.; Braunfeld, M. B.; 
McColloch, J. R. and Prusiner, S. B.: 
     Identification of prion amyloid filaments in scrapie-infected brain. 
Cell 41: 221-235, 1985. 

Doh-ura, K.; Tateishi, J.; Kitamoto, T.; Sasaki, H. and Sakaki, Y.: 
     Creutzfeldt-Jakob disease patients with congophilic kuru plaques 
have the missense variant prion protein common to
     Gerstmann-Straussler syndrome. Ann. Neurol. 27: 121-126, 1990. 

Duffy, P. E.; Wolf, J.; Collins, G.; DeVoe, A. G.; Streeten, B. and 
Cowen, D.: 
     Possible person-to-person transmission of Creutzfeldt-Jakob disease. 
New Eng. J. Med. 290: 692-693, 1974. (Letter)

Ferber, R. A.; Wiesenfeld, S. L.; Roos, R. P.; Bobowick, A. R.; Gibbs, C. 
J., Jr. and Gajdusek, D. C.: 
     Familial Creutzfeldt-Jakob disease: transmission of the familial 
disease to primates. In, Subirana, A.; Espadaler, J. M.
     and Burrows, E. H. (eds.): Proc. 10th Int. Cong. of Neurology, 
Barcelona, Sept. 8-15, 1973. Amsterdam: Excerpta
     Medica, 1974. Pp. 358-380. (Book Chapter)

Friede, R. L. and Dejong, R. N.: 
     Neuronal enzymatic failure in Creutzfeldt-Jakob disease: a familial 
study. Arch. Neurol. 10: 181-195, 1964. 

Gajdusek, D. C.: 
     Bethesda, Md.: personal communication, 1973. (Personal 

Galvez, S.; Cartier, L.; Monari, M. and Araya, G.: 
     Familial Creutzfeldt-Jakob disease in Chile. J. Neurol. Sci. 59: 
139-147, 1983. 

Gibbs, C. J., Jr.; Gajdusek, D. C.; Asher, D. M.; Alpers, M. P.; Beck, 
E.; Daniel, P. M. and Matthews, W. B.: 
     Creutzfeldt-Jakob disease (spongiform encephalopathy): transmission 
to the chimpanzee. Science 161: 388-389, 1968. 

Goldfarb, L. G.; Brown, P.; Goldgaber, D.; Asher, D. M.; Rubenstein, R.; 
Brown, W. T.; Piccardo, P.; Kascsak, R. J.;
Boellaard, J. W. and Gajdusek, D. C.: 
     Creutzfeldt-Jakob disease and kuru patients lack a mutation 
consistently found in the Gerstmann-Straussler-Scheinker
     syndrome. Exp. Neurol. 108: 247-250, 1990. 

Hadlow, W. J.; Prusiner, S. B.; Kennedy, R. C. and Race, R. E.: 
     Brain tissue from persons dying of Creutzfeldt-Jakob disease causes 
scrapie-like encephalopathy in goats. Ann. Neurol.
     8: 628-631, 1980. 

Haltia, M.; Kovanen, J.; van Crevel, H.; Bots, G. T. A. M. and Stefanko, 
     Familial Creutzfeldt-Jakob disease. J. Neurol. Sci. 42: 381-389, 

Jakob, H.; Pyrkosch, W. and Strube, H.: 
     Hereditary form of Creutzfeldt-Jakob disease (Backer family). Arch. 
Psychiat. 184: 653-674, 1950. 

Kahana, E.; Alter, M.; Braham, J. and Sofer, D.: 
     Creutzfeldt-Jakob disease: focus among Libyan Jews in Israel. 
Science 183: 90-91, 1974. 

Kahana, E.; Zilber, N. and Abraham, M.: 
     Do Creutzfeldt-Jakob disease patients of Jewish Libyan origin have 
unique clinical features? Neurology 41: 1390-1392,

Kovanen, J.; Tiilikainen, A. and Haltia, M.: 
     Histocompatibility antigens in familial Creutzfeldt-Jakob disease. 
J. Neurol. Sci. 45: 317-321, 1980. 

Manuelidis, L.; Sklaviadis, T. and Manuelidis, E. E.: 
     Evidence suggesting that PrP is not the infectious agent in 
Creutzfeldt-Jakob disease. EMBO J. 6: 341-347, 1987. 

Masters, C. L.; Gajdusek, D. C. and Gibbs, C. J., Jr.: 
     The familial occurrence of Creutzfeldt-Jakob disease and Alzheimer's 
disease. Brain 104: 535-558, 1981. 

Masters, C. L.; Harris, J. O.; Gajdusek, D. C.; Gibbs, C. J., Jr.; 
Bernoulli, C. and Asher, D. M.: 
     Creutzfeldt-Jakob disease: patterns of worldwide occurrence and the 
significance of familial and sporadic clustering.
     Ann. Neurol. 5: 177-188, 1979. 

May, W. W.; Itabashi, H. H. and Dejong, R. N.: 
     Creutzfeldt-Jakob disease. II. Clinical, pathologic and genetic 
study of a family. Arch. Neurol. Psychiat. 19: 137-149,

Prusiner, S. B. and Hsaio, K. K.: 
     Human prion diseases. Ann. Neurol. 35: 385-395, 1994. 

Owen, F.; Poulter, M.; Lofthouse, R.; Collinge, J.; Crow, T. J.; Risby, 
D.; Baker, H. F.; Ridley, R. M.; Hsiao, K. and
Prusiner, S. B.: 
     Insertion in prion protein gene in familial Creutzfeldt-Jakob 
disease. Lancet I: 51-52, 1989. (Letter)

Pablos-Mendez, A.; Netto, E. M. and Defendini, R.: 
     Infectious prions or cytotoxic metabolites? Lancet 341: 159-161, 

Prusiner, S. B.: 
     Novel proteinaceous infectious particles cause scrapie. Science 216: 
136-144, 1982. 

Roos, R. P.; Gajdusek, D. C. and Gibbs, C. J., Jr.: 
     The clinical characteristics of transmissible Creutzfeldt-Jakob 
disease. Brain 96: 1-20, 1973. 

Rosenthal, N. P.; Keesey, J.; Crandall, B. and Brown, W. J.: 
     Familial neurological disease associated with spongiform 
encephalopathy. Arch. Neurol. 33: 252-259, 1976. 

Sidman, R. L.; Kinney, H. C. and Sweet, H. O.: 
     Transmissible spongiform encephalopathy in the gray tremor mutant 
mouse. Proc. Nat. Acad. Sci. 82: 253-257, 1985. 

Vallat, J.-M.; Dumas, M.; Corvisier, N.; Leboutet, M.-J.; Loubet, A.; 
Dumas, P. and Cathala, F.: 
     Familial Creutzfeldt-Jakob disease with extensive degeneration of 
white matter: ultrastructure of peripheral nerve. J.
     Neurol. Sci. 61: 261-275, 1983. 

Zilber, N.; Kahana, E. and Abraham, M.: 
     The Libyan Creutzfeldt-Jakob disease focus in Israel: an 
epidemiologic evaluation. Neurology 41: 1385-1389, 1991. 

Zlotnik, I.; Grant, D. P.; Dayan, A. D. and Earl, C. J.: 
     Transmission of Creutzfeldt-Jakob disease from man to squirrel 
monkey. Lancet II: 435-438, 1974. 


          Forgetfulness and nervousness.
          Jerky, trembling hand movements.
          Unsteady gait.
          Chronic dementia.
          Supranuclear gaze paralysis.
          Gait ataxia.
          Extrapyramidal muscular rigidity. 
          Loss of facial expression. 
          Most cases sporadic. 
          Pathology includes status spongiosus, diffuse nerve cell 
degeneration and glial proliferation.
          Characteristic periodic EEG complexes.
          Mutant prion protein gene(PRIP; 176640).
          Transmissible agent in sporadic cases. 
          Autosomal dominant. 




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