Somatic mosaicism in a case of apparently sporadic Creutzfeldt-Jakob disease carrying a de novo D178N mutation in the PRNP gene.

Transmissible spongiform encephalopathies (TSEs) are a group of rare fatal neurodegenerative disorders. Creutzfeldt-Jakob disease (CJD) represents the most common form of TSE and can be classified into sporadic, genetic, iatrogenic and variant forms. Genetic cases are related to prion protein gene mutations but they only account for 10-20% of cases. Here we report an apparently sporadic CJD case with negative family history carrying a mutation at codon 178 of prion protein gene. This mutation is a de novo mutation as the parents of the case do not show it. Furthermore the presence of three different alleles (wild type 129M-178D and 129V-178D and mutated 129V-178N), confirmed by different methods, indicates that this de novo mutation is a post-zygotic mutation that produces somatic mosaicism. The proportion of mutated cells in peripheral blood cells and in brain tissue was similar and was estimated at approximately 97%, suggesting that the mutation occurred at an early stage of embryogenesis. Neuropathological examination disclosed spongiform change mainly involving the caudate and putamen, and the cerebral cortex, together with proteinase K-resistant PrP globular deposits in the cerebrum and cerebellum. PrP typing was characterized by a lower band of 21 kDa. This is the first case of mosaicism described in prion diseases and illustrates a potential etiology for apparently sporadic neurodegenerative diseases. In light of this case, genetic counseling for inherited and sporadic forms of transmissible encephalopathies should take into account this possibility for genetic screening procedures.

Phenotypic variability in familial prion diseases due to the D178N mutation.

BACKGROUND: Between January 1993 and December 2003, 19 patients with familial prion diseases due to the D178N mutation were referred to the regional epidemiological registry for spongiform encephalopathies in the Basque Country in Spain, a small community of some 2,100,000 inhabitants. METHODS: Ten further patients belonging to the same pedigrees were retrospectively ascertained through neurological or neuropathological records. In four of the patients, the diagnosis was confirmed by analysing DNA obtained from paraffin blocks. In this article, we report on the clinical, genetic, and pathological features of the 23 patients carrying the D178N mutation confirmed by genetic molecular analysis. Haplotyping studies suggest a founder effect among Basque born families, explaining in part this unusually high incidence of the D178N mutation in a small community. Only two patients (8%) lack familial antecedents. RESULTS: We have observed a phenotypic variability even among homozygous 129MM patients. Our findings challenge the currently accepted belief that MM homozygosity in codon 129 is always related to a fatal familial insomnia (FFI) phenotype. Indeed, seven out of 17 patients with a 129MM genotype in this series presented with a Creutzfeldt-Jakob disease (CJD) clinicopathological picture. CONCLUSIONS: The considerable clinical and pathological overlapping observed among homozygous 129MM patients favours the view that FFI and CJD178 are the extremes of a spectrum rather than two discrete and separate entities. Other genetic or environmental factors apart from the polymorphism in codon 129 may play a role in determining the phenotypic expression of the D178N mutation in the PRNP gene.

A novel mutation (K317M) in the MAPT gene causes FTDP and motor neuron disease.

BACKGROUND: Frontotemporal dementia with parkinsonism is often linked to chromosome 17 and is related to mutations in the MAPT gene. In some families the genetic basis is still unknown. The authors report two pedigrees with FTDP-17 harboring a novel mutation (K317M) in exon 11 in the MAPT gene. METHODS: The authors identified two apparently unrelated pedigrees with an autosomal dominant neurodegenerative condition. Thirteen patients were examined and eight autopsies were performed. RESULTS: Mean age at onset was 48 years. Mean disease duration was 6 years. Dysarthria often heralded the disease. All cases had parkinsonism and pyramidalism and half of them had amyotrophy. Behavioral or personality changes were not a prominent feature. Cognitive decline appeared late in the evolution. Neuropathologically, a massive degeneration of the substantia nigra without Lewy bodies was a constant finding. A variable degree of frontotemporal atrophy was found. Corticospinal tract degeneration and anterior horn neuron loss were present in six of seven autopsies in which the spinal cord was examined. An extensive deposition of abnormal tau protein in a mixed pattern (neuronal, glial) was observed. Pick's bodies were not seen. Biochemical analysis of tau revealed two bands of 64 and 68 kDa. CONCLUSION: Genetic analysis revealed the same novel mutation (K317M) in exon 11 of the MAPT gene in both pedigrees. A common haplotype between members of the two pedigrees suggests that they belong to the same family.

Dementia, amyotrophy, and periodic complexes on the electroencephalogram: a diagnostic challenge.

BACKGROUND: The clinical diagnosis of neurodegenerative diseases is a challenge to the neurologist. In many cases the diagnosis becomes neuropathological only after the autopsy. Several consensus criteria have been defined for the clinical diagnosis of different neurodegenerative diseases, among them the various types of dementia as well as prion-induced diseases. When compared with neuropathological findings, these criteria have proved to be reasonably accurate for regular practice, research, and epidemiological studies. The problem arises when a combination of complementary and clinical data are obtained that do not easily match these diagnostic criteria. CASE DESCRIPTION: We describe a patient with dementia and periodic complexes on an electroencephalogram, suggesting a diagnosis of sporadic Creutzfeldt-Jakob disease. RESULTS: When the condition progressed, signs and symptoms of a motoneuron disease appeared. Thus, 2 different diagnoses were proposed: (1) an amyotrophic variant of a prion-induced disease; or (2) an ELA dementia syndrome with periodic complexes on the electroencephalogram, a finding that previously has not been described.

Value of limited necropsy in HIV-positive patients.

We performed limited autopsy with histological examination of tissue cores obtained percutaneously using the Tru-Cut needle and the Jamshidi trocar in 150 adult HIV-positive patients. Data were compared retrospectively with the antemortem clinical diagnosis. Eighty-one percent of the patients were male, and 78% were intravenous drug users. Specimens were obtained from the brain, liver, lung, bone marrow, and kidney of most patients. The main findings included liver cirrhosis in 22 cases (associated with HCV infection in 81%), Pneumocystis carinii pneumonia in 21, Cytomegalovirus (CMV) infection in 19, Mycobacterium avium-intracellulaire (MAI) infection in 17, bacterial pneumonia in 14, tuberculosis in 12, and lymphoma in 13 cases. Forty-six (30.6%) patients had at least one clinical diagnosis that was confirmed by autopsy, i.e., there was 40.6% agreement between pre- and postmortem findings. Forty-six (30.6%) patients had at least one clinical diagnosis that was not confirmed at autopsy, whereas 41 (27.3%) had at least one AIDS-related or unrelated disease that was not suspected clinically. The results obtained by limited autopsy are principally comparable to those achieved by full necropsy, with the advantages of decreasing the contagious risk, saving cost and time, including a rapid final diagnosis, and easily obtaining the consent for postmortem examination so that necropsy studies may be performed on a larger number of patients, thus contributing to a better understanding of the spectrum of HIV infection in our environment.