We report here a familial CJD kindred of Hungarian ancestry with the E200K-129M haplotype which features five affected individuals in two successive generations. Distinctive aspects of this kindred include the type and distribution of CJD and Aβ pathological findings and the apparent incomplete penetrance. The unusual pathological finding in this family was the presence of numerous Aβ plaques in two of the three cases (II-10 and III-8) suggesting that Aβ deposition is linked with CJD pathophysiology.
Cortical Aβ plaques are observed in Alzheimer’s disease (AD) and less commonly in clinically normal older adults 18, 19
. However, in this kindred our patients were all under the age of 65. The Aβ plaques were unaccompanied by notable neurofibrillary pathology as would be characteristic of AD. The Aβ burden was not restricted to cortical areas and was also found in subcortical regions such as basal ganglia. There have been reports of Aβ plaques in other transmissible spongiform encephalopathies such as sporadic and familial Gerstmann-Sträussler syndrome (GSS) 20
, iatrogenic CJD, older sporadic CJD cases 21–33
, and in a case from a PRNP
gene insertion kindred 34
. However, to our knowledge there have been no reports of Aβ pathology among familial CJD with E200K mutation.
Neither of the two cases with Aβ plaques had a history of traumatic brain injury which has been proposed to result in increased Aβ deposition 35
genes were not screened for mutations since review of the literature did not provide conclusive evidence of these mutations coexisting with PRNP
mutations and contributing to CJD pathology 36–38
genotyping was pursued since there is a strong association of the ε4 allele and increased Aβ deposition 25, 39
. Patient III-4, who lacked Aβ pathology, had a ε2/ε3 genotype; whereas, patient III-8, who had considerable Aβ burden had ε3/ε4 genotype. APOE
genotype for patient II-10 could not be established due to limited archival clinical material.
The remarkable co-distribution of plaques and CJD-associated changes in cases II-10 and III-8 suggests that this Aβ deposition is associated with CJD pathophysiology rather than an independent process. For instance, all three cases that came to autopsy had evidence of spongiform changes and gliosis which could be present in a region in the absence of Aβ plaques; however, the converse was not the case. This suggests that spongiform change is an upstream event and is required for Aβ deposition. Several lines of evidence indicate that the PRNP
genotype and/or PrPC
have an influence on the AD phenotype and that Aβ and PrPC
metabolisms are interconnected: 1) the codon 129 methionine/valine polymorphism of the PRNP
gene is a risk factor for AD 40–43
; 2) the occurrence of mature Aβ plaques has been reported in two familial forms of prion disease (34
; present study); 3) Aβ induced synaptic dysfunction is mediated through its binding to PrPC44
; 4) the formation of Aβ is increased in scrapie-infected mice as well as in the presence of PRNP
pathogenic mutations 41
z; and 5) depletion of PrPC
or the presence of disease-associated mutant PrP in mouse N2a cells results in failed β-secretase inhibition with resultant increase in Aβ levels 42
. Taken together, these findings suggest that PrPC
plays a central role in Aβ formation and that Aβ pathology and prion disease likely influence each other. The kindred described here provides support that PrPE200K
may also result in increased Aβ deposition. The impact of E200K may be modulated by the codon 129 status on the normal allele 40, 42, 43, 45
. For instance it is known that PrP deposition patterns are different for 129MM versus 129MV 2, 46
. In the case of III-4 the codon 129 status was MV and may have resulted in differential PrP deposition and therefore the lack of downstream Aβ deposition 42
. Also, III-4 APOE
status was ε2/ε3 which may have further decreased the likelihood of Aβ deposition. Recognition of this possibility may encourage other investigators to assess potential Aβ deposition in cases with classic CJD pathology.
This kindred also demonstrates a novel genetic feature of incomplete penetrance. Patients II-2 and II-4 had no motor and cognitive impairment prior to death from acute illnesses at ages 81 and 82 and yet each had two affected siblings and had one or more affected children. Since the E200K mutation is dominantly inherited, these two individuals likely were mutation carriers without CJD features because of incomplete penetrance. Ninety-six percent of E200K mutation carriers develop the clinical CJD phenotype if they live past the age of 80 5
except for those with Slovakian heritage (such as this kindred), where penetrance may only be 59% 11, 47
Another distinctive feature of this kindred is the clinicopathological presentation. Presenting clinical features of E200K-129M typically include cognitive abnormalities in up to 83% of patients and cerebellar signs in up to 55% 2
. These initial features are followed by development of dementia in all patients, cerebellar signs in 79%, and myoclonus in 73% during the course of the disease 2
. The clinical presentation in this family also features ataxia followed by dementia. Classically the ataxia seen in E200K-129M is attributed to severe spongiform degeneration, gliosis, and neuronal loss in the cerebellum. However, in this kindred the cerebellum was spared with only moderate involvement in one case (III-4), a finding consistent with its E200K-129M haplotype 2
. Alternately, the gait disturbance observed in this family could be attributable to involvement of the spinal cord instead of the cerebellum. Cases of an amyotrophic form of CJD have been reported; however, in those instances motor signs consistent with motor neuron disease were observed 48–51
. Spinal cords were not available for analysis in this family. In typical E200K-129M, the mean age of onset is 58 years with the mean duration of 6 months 2, 52
. While the age of onset in this family ranged from 52 to 62, the duration of illness was longer as it ranged from 7 to 17 months 11
. Other typical CJD features absent in this family were positive sharp waves on EEG and prominent brain atrophy 2, 52
This is the first description of Aβ plaque pathology in familial CJD with E200K mutation. The co-distribution of Aβ deposition and spongiform degeneration in this family lends credence to the idea that these two synaptic proteins, APP and PrP, may interact to result in disease.