>To: [log in to unmask]
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>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.
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