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>To: [log in to unmask] > >From: [log in to unmask] (DR. LLOYD STEWART) >Subject: Creutzfeldt-Jacob > >PRION DISEASES > >INTRODUCTION > >Although traditionally included in discussions of viral diseases of the CNS, a substantial and rapidly accumulating body of research suggests that the transmissible neurodegenerative diseases (TNDs), e.g., kuru, Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker (GSS) syndrome, are not viral diseases at all. The leading hypothesis for the etiology of these diseases suggests that they are caused by a proteinaceous infectious particle (prion) devoid of nucleic acid that is encoded by a single-copy host gene (designated PRNP) present on the short arm of chromosome 20. The function of the normal cellular isoform of the PRNP gene (PrPc) is unknown, although both membrane-associated and secreted forms exist. Neurons contain high concentrations of PrPc, which is developmentally regulated. Substantial amino acid homology exists between PrPc and a chicken protein (ARIA) produced by motor neurons that induces acetylcholine receptor activity. > >A modified form, PrPSc, which is resistant to proteolytic digestion and spontaneously aggregates to produce rodlike or fibrillary particles (scrapie-associated fibrils, prion rods) can be isolated from the brains of animals and humans with TNDs. The exact mechanism by which the normal cellular protein (PrPc) is modified to its pathologic isoform (PrPSc), the method by which PrPSc replicates itself, and the way PrPSc accumulation leads to neuronal degeneration remain unknown. > >Epidemiologic and clinical studies indicate that human TNDs can be sporadic (Creutzfeldt-Jakob disease), infectious (kuru, rare cases of Creutzfeldt-Jakob), or genetic (GSS syndrome, familial Creutzfeldt-Jakob disease) in origin. The basic clinical features of each of these diseases are discussed below. > >KURU > >This disease was previously endemic among members of the Fore linguistic tribal group of the Eastern Highlands area of Papua New Guinea. At its peak, the disease affected close to 1 percent of the population, although currently less than 10 cases per year are reported. The cardinal features of the illness were severe cerebellar ataxia with associated involuntary movements, including choreoathetosis, myoclonus, and tremor. These were associated with the subsequent development of mental impairment and frontal release signs. Brain material from affected individuals transmits the disease to primates. No new cases of the disease have been reported among individuals born since the cessation of ritual cannibalism in the affected areas. It has been suggested that ingestion of infected brain material during these rituals was responsible for disease transmission. > >CREUTZFELDT-JAKOB DISEASE > >Most cases are sporadic in nature, although 5 to 15 percent are familial with an autosomal dominant pattern of inheritance. Regions of high incidence and prevalence are scattered throughout the world, most prominently in parts of Libya and North Africa and in Slovakia. Creutzfeldt-Jakob disease is not contagious, but person-to-person spread of the disease has occurred following transplantation of corneas or dural grafts obtained from infected individuals. Isolated cases also have been attributed to improperly decontaminated neurosurgical instruments and stereotactic intracerebral depth electrodes. Approximately 25 cases have been reported in patients with panhypopituitarism who received supplemental cadaveric human growth hormone therapy and in patients who received cadaveric human gonadotropins for treatment of infertility. > >Creutzfeldt-Jakob disease typically presents as a rapidly progressive dementia with prominent associated myoclonus. Clinical manifestations are protean and often include combinations of severe and progressive dementia, pyramidal and extrapyramidal motor disturbances, and signs and symptoms of cerebellar dysfunction. Clinical and pathologic subtypes with predominant involvement of specific regions of the brain have been described (e.g., occipital, thalamic, and cerebellar types). Early signs of mental impairment may be manifested as slowness in thinking, difficulty concentrating, impaired judgment, and memory loss. Mood changes and emotional lability may be combined with visual or other types of hallucinations. About a third of patients present initially with prominent cerebellar or visual disturbances, which may initially overshadow the mental impairment. Myoclonus occurs in more than 90 percent of patients and may be provoked or aggravated by startle. Additional motor signs and symptoms can include tremor, clumsiness, and choreoathetosis. As the disease progresses, about two-thirds of patients will develop a parkinsonian extrapyramidal syndrome with hypokinesia and rigidity. Hyperreflexia, spasticity, and extensor plantar responses occur in about half of patients. The clinical presentation of Creutzfeldt-Jakob disease associated with use of cadaveric human pituitary hormone therapy may differ from that of classic Creutzfeldt-Jakob disease. Patients are typically younger and often present with a kuru-like illness in which cerebellar features may be more prominent initially than dementia. > >Laboratory tests are helpful in excluding other causes of rapidly progressing dementia. The CSF is typically unremarkable, although the protein level may be mildly elevated. A pleocytosis is unusual and should prompt a thorough search for other processes. It has been suggested recently that two-dimensional isoelectric focusing of CSF proteins may show abnormal protein species, two of which (proteins designated 130 and 131) may be typical of Creutzfeldt-Jakob disease. This test has recently become commercially available; however, additional studies of sensitivity and specificity will be required to establish its diagnostic utility. CT and MRI may show evidence of generalized cortical atrophy, but more typically the degree of clinical dementia appears disproportionate to the amount of tissue loss seen on CT and MRI. In some patients, sequential studies performed at biweekly or monthly intervals may show rapidly progressive loss of brain tissue and ex vacuo ventricular enlargement. The EEG may be quite useful in suggesting the diagnosis. The typical pattern of periodic sharp wave complexes consists of a generalized slow background interrupted by bilaterally synchronous sharp wave complexes occurring at intervals of 0.5 to 2.5 s and lasting for 200 to 600 ms. The classic EEG pattern is found in 75 to 95 percent of cases, although it may not be present very early or in the terminal stages of the disease. Sequential EEG studies may be useful if the initial recording fails to reveal the typical pattern. > >The gold standard for diagnosis remains the histologic study of brain material obtained at biopsy or necropsy and the subsequent demonstration of transmissibility to susceptible rodents. The pathologic hallmarks of Creutzfeldt-Jakob disease are spongiform changes (small round vacuoles) within the neuropil, neuronal loss, hypertrophy and proliferation of glial cells, and absence of significant inflammation or white matter involvement. Pathologic changes are maximal in the cortex but are often prominent in the basal ganglia, cerebellum, and thalamus. The brainstem and spinal cord are usually spared. Recent studies suggest that the demonstration of prion proteins in immunoblots of brain material is a sensitive and apparently specific marker for the presence of Creutzfeldt-Jakob disease or related TNDs. The finding of prion rods or scrapie-associated fibrils which may be seen in electron micrographs of prepared brain material also appears to be pathognomonic for TNDs. > >Creutzfeldt-Jakob disease is invariably fatal, and no specific therapy is available. A number of drugs, including amantadine, have been reported to slow disease progression in isolated anecdotal case reports; however, the results have not been consistently reproducible. > >Recent molecular genetic studies have established an unequivocal linkage between mutations in the PRNP gene and familial cases of Creutzfeldt-Jakob disease. Several mutations have been described, which may correlate with variations in the clinical phenotype of the disease in individual familial clusters. Among the commonly reported mutations are a Lys for Glu substitution in codon 200 and an Asn for Asp substitution in codon 178. Inserts in the PRNP gene also occur in several families with Creutzfeldt-Jakob disease. No consistent PRNP gene mutation has been identified in cases of sporadic Creutzfeldt-Jakob disease. Some recent reports suggest that homozygosity at a polymorphic amino acid residue at codon 129 of the PRNP gene occurs with greater than expected frequency in cases of sporadic and iatrogenic Creutzfeldt-Jakob disease and kuru, although this requires further confirmation. >