A deadly prion disease: fatal familial insomnia.
Subject: Insomnia (Research)
Authors: Sundstrom, Dianne G.
Dreher, H. Michael
Pub Date: 12/01/2003
Publication: Name: Journal of Neuroscience Nursing Publisher: American Association of Neuroscience Nurses Audience: Professional Format: Magazine/Journal Subject: Health care industry Copyright: COPYRIGHT 2003 American Association of Neuroscience Nurses ISSN: 0888-0395
Issue: Date: Dec, 2003 Source Volume: 35 Source Issue: 6
Topic: Event Code: 310 Science & research
Accession Number: 111854929
Full Text: Abstract: Fatal familial insomnia (FFI) is an inherited disease caused by a mutation in the protein prion gene. Symptoms of FFI closely resemble those of familial Creutzfeldt-Jakob disease, making genetic testing and histological examination of brain tissue the only means to determine a definitive diagnosis. The disease is rare--approximately 60 cases have been detected worldwide since 1986. Incubation time of the disease may be as long as 30 years; death generally occurs within 1 year of the onset of symptoms. There is no known procedure or treatment for delaying the onset of symptoms or modifying the disease course. Nurses who confront patients with FFI will be challenged to provide care to a patient and family who are facing certain death.

Neurodegenerative diseases usually surface in middle age or later and are characterized by similar pathology: degeneration of neurons, accumulation of protein deposits, and enlargement of glial cells that support and nourish nerve cells (Prusiner, 1995). The most common neurodegenerative diseases are Parkinson's and Alzheimer's. Less common are the transmissible spongiform encephalopathies (TSEs), including Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker disease (GSSD), and fatal familial insomnia (FFI).

Spongiform encephalopathies were first described in sheep and goats more than 200 years ago (Johnson & Gibbs, 1998). Affected animals developed progressive ataxia, became irritable, and sometimes developed an intense itch causing them to scrape off their wool, hence the term "scrapie" (Prusiner, 1995). In 1985, bovine spongiform encephalopathy (BSE) made a dramatic entrance onto the world stage with the appearance of "mad cow disease." Since 1985, more than 170,000 cases of BSE have been confirmed in the United Kingdom; the likely source is feed that contained material from scrapie-infected sheep. Regulatory changes in the production of animal feed have reduced the number of BSE cases. Interestingly, a new variant form of human CJD (vCJD) has surfaced (Johnson & Gibbs). Since 1994, more than 100 cases of vCJD have been reported, and laboratory studies have demonstrated convincing evidence linking vCJD and BSE (Prusiner, 2001). Extensive media coverage of these events has heightened general interest in transmissible spongiform encephalopathies, but they do remain rare, complex, and deadly diseases.

The scientific community has taken quantum leaps in unraveling the mysteries of these diseases through breakthroughs in genetic research. These discoveries have provided the foundation for identifying the cause of human TSE, a mutation in the protein prion gene, and for elucidating and identifying subtypes of TSE (Elbourn, 1999; Gambetti et al., 1993).

A rapidly fatal disease, FFI is caused by aberrant prion proteins that wreak havoc with the nervous system. Although the number of worldwide cases of FFI is small, neuroscience nurses may be the first to encounter these patients as they find their way into physician offices, clinics, and hospitals. In this regard, neuroscience nurses are uniquely positioned to grasp the complex characteristics of the disease and coordinate the extensive physical, psychological, and social support these patients and their families require. This article provides a historical perspective on the development of prion diseases as well as a review of what is currently known about FFI. Information is provided to assist nurses, if they confront the disease, in understanding the pathology of the disease as well as their role in supporting patients and families through this complex and devastating illness.

Prions

Although CJD, the first spongiform encephalopathy, was described as early as 1921, it was not until 1982 that Prusiner proposed that proteinaceous infectious particles or "prions" might be the agent responsible for causing these diseases in mammals. Prusiner proposed that these prions might (a) consist of protein and nothing else, (b) underlie inherited as well as communicable diseases, and (c) multiply by converting normal protein into dangerous protein simply by inducing the normal protein to change shape (Prusiner, 1995). At the time, all three ideas were looked upon with skepticism because conventional wisdom held that conveyers of transmissible diseases required genetic material (either DNA or RNA) in order to infect a host. Even the simplest form of life required DNA or RNA for survival and replication.

Early studies by Alper and colleagues in England (as cited in Prusiner, 1995) found that the TSE agent in sheep and goats, commonly called scrapie, retained infectivity when treated with ultraviolet or ionizing radiation. Because nucleic acid is usually destroyed by radiation, it was assumed that scrapie did not contain nucleic acid and was therefore not a virus or any other known type of infectious agent. Prusiner and colleagues (1995) replicated this finding and subsequently determined that the scrapie prion or infectious particle contained a single protein, a "prion protein" (PrP). After Prusiner and colleagues identified some of the amino acids at the end of the PrP, scientists at the University of Zurich and the NIH Rocky Mountain Laboratories isolated the gene for PrP. Subjecting both infected and normal PrP to cellular enzymes called proteases, enzymes that degrade proteins fairly easily, they demonstrated that the infected form of PrP resisted degradation while normal PrP did not (Prusiner, 1995). These findings were critical to establishing that there is both a normal and a disease-causing form of PrP.

The normal product of the prion gene, Pr[P.sup.c] (for proteinaceous infectious particle and the superscript "c" for cellular), contains about 250 amino acids with mainly alpha helices. Pr[P.sup.c] is found to be expressed in most cell types with the highest concentration in brain tissue as well as is ganglia and nerves of the peripheral nervous system (Elbourn, 1999). The infectious prion protein, Pr[P.sup.sc] (the superscript "sc" for scrapie), was found to be composed of mostly beta pleated sheets and approximately 142 amino acids (Prusiner, 2001). The prion hypothesis, developed by Prusiner, asserts that infectivity results from changes in protein conformation of Pr[P.sup.c] to Pr[P.sup.sc] in a "recruitment reaction" within which Pr[P.sup.sc] acts as a catalyst for further conversion (Cashman, 1997). Although the exact mechanism of this conformational reaction is not known, this structural transition is the fundamental event underlying prion diseases (Fig 1).

[FIGURE 1 OMITTED]

Genetic Mutations of the Protein Prion Gene

In humans, the protein prion gene (PRNP) is located on the short arm of chromosome 20. Many mutations of the gene have been identified, with specific mutations linked to different phenotypes or observable characteristics of TSE. In FFI, a mutation at codon 178 of the PRNP results in the substitution of the amino acid, asparagine, for aspartic acid. This mutation, when coupled with methionine at codon 129 of the mutant allele of the PRNP and either methionine or valine at the normal allele of codon 129, results in the genotype for FFI. Methionine/methionine results in a homozygote and methionine/valine in a heterozygote (Johnson, Vnencak-Jones, & McLean, 1998). The duration of the disease is significantly shorter and the severity of clinical symptoms worse in homozygotes than in heterozygotes (Elbourn, 1999). Reports of a small number of patients presenting with FFI type symptoms but without mutations in the PRNP raise the possibility of a sporadic form of fatal insomnia, one with no familial link (Gambetti et al., 1993; Mastrianni et al., 1999). Familial prion diseases are autosomal and dominant, meaning that if a parent develops the disease, there is a 50% chance that a child of either sex will develop the disease (Prusiner, 2001). Prion diseases may incubate in humans for 30 years or more before becoming symptomatic (Prusiner, 1995).

The Family of Prion Diseases

In humans, prion diseases are CJD, GSSD, Kuru, and FFI, with inherited forms of the diseases accounting for approximately 10% of all cases. As of 2000, there were 400 reported cases of prion diseases in the United States (Prusiner, 2001). The clinical presentation of prion diseases is devastating. The most common prion disease, CJD, first described in 1921, typically produces dementia accompanied by weakness and dysarthria, ataxia, spasticity, rigidity, tremors, myoclonus, and aphasia. Occasionally, involvement of the occipital lobes produces cortical blindness. Death is rapid, usually occurring within 3 to 12 months of onset (Cashman, 1997; Gambetti et al., 1993). First observed in 1928, GSSD was described as a progressive ataxia of 2 to 10 years duration with various degrees of mental deterioration. In 1957, a strange "laughing death" disease named Kuru was described among the Fore peoples of Papua, New Guinea. Kuru was marked by ataxia and later by dementia and was apparently acquired through ritual cannibalism: the Fore tribe honored their dead by eating their brains. The practice has since stopped, and Kuru has virtually disappeared (Gambetti et al., 1993; Prusiner, 1995). Almost another 30 years elapsed before FFI, another prion disease, was recognized and described in the medical literature.

The Emergence of Fatal Familial Insomnia

Fatal familial insomnia is an illness hauntingly similar to the lethal insomnia of Rebecca, a character in the Nobel prize winner One Hundred Years of Solitude by Gabriel Garcia Marquez. It was first described in 1986 by Lugaresi, an Italian sleep researcher, and his colleagues (Sghirlanzoni & Carella, 2000). The patient was a 53-year-old man referred to Lugaresi and colleagues by a physician family member who had been investigating a "peculiar, fatal disorder of sleep" in the family. The patient had an unremarkable history except for high blood pressure but described symptoms that began with nocturnal insomnia, loss of libido, and impotence. These symptoms were followed by difficulty urinating, constipation, and episodes of salivation, rhinorrhea, lacrimation, diaphoresis, and pyrexia. Three months after the onset of symptoms, the patient described an inability to sleep and increasing periods of a dream-like state. Symptoms progressed to include dysarthria, severe fatigue, tremor, and myoclonus. Breathing irregularities, ataxia, and tremors developed, and the patient fell into a coma and died 9 months after symptom onset (Lugaresi et al., 1986).

FFI is rare--only about 60 cases from 28 families have been reported around the world including Italy, United States, Germany, Australia, and Japan. Presentation of the disease closely resembles that of CJD, making diagnosis difficult. However, unlike CJD, which attacks primarily the cerebral cortex, FFI attacks the thalamus, specifically the anterior and medial thalamic nuclei. CJD causes widespread cerebral cortex spongiosis, whereas FFI causes severe thalamic neuronal loss or atrophy and gliosis (Gambetti et al., 1993; Guterman, 2002). Damage to the thalamus interferes with the transmission of sensory signals to the brain and control of voluntary motor activity. Consciousness and sensory awareness are also affected (Sherwood, 2001).

Onset of the disease typically occurs in middle age, between 40 and 60 years, with a 20-year-old male being the youngest reported patient (Gambetti et al., 1993; Silburn et al., 1996). Initial symptoms can vary significantly but usually include progressive insomnia, depression, deteriorating memory, and fatigue. In studies by Nagayama, Shinohara, Furukawa, and Kitamoto (1996) and by Zerr and colleagues (1998), none of 10 patients complained of insomnia in the early stages of the disease, although relatives later recalled sleep alterations. In the initial stages of the disease, intelligence is often left intact, so patients are acutely aware of symptom progression. With progressive illness, however, patients are unable to sustain attention and persist in tasks. They may experience visual hallucinations and dream-like states. Gait worsens with shuffling, postural tremors, and unsteadiness. Excessive sweating, hyperthermia, tachycardia, hypertension, and pyramidal tract signs, such as extensor plantar responses and generalized hyperreflexia, appear. Symptoms eventually progress to severe insomnia, continuous myoclonic jerks, confusion, and ultimately coma. Death typically occurs within 1 year of the first symptoms (Gallassi et al., 1996; Padovani et al., 1998; Prusiner, 1995; Silburn et al., 1996).

Although polysomnographic (i.e., sleep) studies are not consistently reported in the literature, Zerr et al. (1998) described a complete disruption of the sleep cycle with a nearly complete absence of REM (rapid eye movement) sleep in one patient. Johnson et al. (1998) reported similar results on another patient monitored 11 months after symptom onset. On an overnight polysomnogram, the patient experienced 8.9 minutes of total sleep time with no REM or slow wave sleep noted. In another case study report by Reder et al. (1995), a 7-hour nighttime study performed on a patient 12 months after onset of symptoms indicated the patient slept only 1 hour, with 6 minutes of REM sleep. EEG monitoring by Lugaresi et al. (1986) found that patterns of sleep such as spindles, K complexes, and delta activity were missing. Some investigators reported abnormal blood, cerebrospinal fluid, or urine results, but no consistent pattern of abnormality was noted among patients. A broad compendium of tests performed by Mastrianni et al. (1999), including spinal fluid, urine and blood, were all normal.

Molecular genetic testing of blood and histological examination of brain tissue are the only means of diagnosing FFI and distinguishing it from other neurodegenerative diseases. Definitive diagnosis of FFI can be accomplished through blood restriction endonuclease analysis of the PRNP gene and is associated with the genotype 17[8.sup.Asn] 12[9.sup.Met]. Microscopic examination (Fig 2) of the anterior and dorsomedial nuclei of the thalamus typically shows a severe reduction in the number of neurons and gliosis (Gambetti et al., 1993; Silburn et al., 1996).

[FIGURE 2 OMITTED]

Implications for Nursing

Recognizing Prion Diseases

Neurodegenerative diseases include Parkinson's disease, motor neuron diseases, dementias (including Alzheimer's), cerebellar degenerations, Huntington's disease, and the prion diseases. Neurodegeneration can also be a factor in many diseases not usually classified as degenerative, for example, multiple sclerosis, epilepsy, schizophrenia, and even tumors. Some of the conditions have an underlying genetic mutation, and some have both genetic and environmental risk factors. For others, the underlying cause is unknown. A common feature of these diseases is a long period of latency followed by a cascade of symptoms over months to years with increasing disability leading to death. The key characteristics of these conditions are that progressive degeneration occurs long before symptoms and that the degeneration is selective to a certain group of neurons. Onset of disease and clinical symptoms across the spectrum of classic degenerative diseases can be similar and therefore diagnostically confusing (Williams, 2002).

Among the prion diseases, CJD and FFI are the most similar and share many clinical symptoms (Table 1). However, FFI patients maintain global intelligence until late in the disease, and it may be this hallmark that is most helpful in differentiating FFI from CJD. Genetic testing should be used to confirm the FFI PRNP genotype. Although brain biopsy can also provide pertinent data, it is difficult to recommend as a routine diagnostic tool in view of the risk of complications and the possibility of sampling an area of brain unaffected by the pathological process (Will & Zidler, 1996).

Gambetti et al. (1993) outlined the characteristics needed to establish a probable diagnosis and those required for a definitive diagnosis of FFI. The characteristics are (a) autosomal dominant disease, onset at adult age, and duration of 6 to 32 months; (b) presence of untreatable insomnia, dysautonomia, memory impairment, ataxia and/or myoclonus, and pyramidal and extrapyramidal signs; (c) decrease or loss of sleep-related EEG activities; (d) preferential hypometabolism in the thalamic region using PET; (e) preferential thalamic atrophy; and (f) 12[9.sup.Met], 17[8,sup.Asn] PRNP genotype. Any combination of criteria (a) through (e) makes the diagnosis of FFI probable; criterion (f) in combination with any one of the other criteria makes the diagnosis definitive.

Treatment

After 20 years of research on prion diseases, scientists have now begun to focus on treatment and potential cure. Because a conversion of normal PrP to abnormal PrP is associated with disease, research has focused on blocking the ability of the prion protein to assume an abnormal shape. Scientists from the U.S. National Institute of Allergy and Infectious Diseases and their colleagues in France and the United Kingdom have demonstrated that adding a peptide derived from the core of the normal prion protein dramatically reduced the generation of abnormal PrP associated with prion disease in rodent species (Chabry et al., 1999). Promising findings have also been reported using two older tricyclic compounds: quinacrine, approved to treat malaria and giardiasis, and chlorpromazine, approved to treat schizophrenia and other psychotic conditions. The drugs were found to inhibit the propagation of prions in a mouse neuroblastoma cell culture line (Josefson, 2001). Preliminary trials using quinacrine in patients with both new variant CJD and sporadic CJD apparently reduced symptoms early in treatment but failed to cure the disease (Wilson, 2002).

Another approach involves strategies for preventing disease. In mice, it appears that the protein prion gene that encodes normal protein is redundant and, if made dysfunctional, protects the mice from experimental infection with scrapie. If the human gene is similarly redundant, it could be ablated or otherwise neutralized. This strategy could have application to familial prion diseases. Development and use of a vaccine would be ideal, but because the antigen target is a conformational rather than a chemical form, the body does not recognize it as foreign (Brown, 2002).

Nursing Care

As with all neurodegenerative diseases, patients and families affected by FFI or any of the prion diseases will most benefit from supportive care combined with psychological counseling and support. Preserving patients' sense of well-being and maintaining and improving quality of life should be the objectives of a treatment program. Educating and counseling caregivers and family members is also of paramount importance (Findley & Baker, 2002).

Genetic Testing and Screening

Patients who present with neurodegenerative symptoms, in particular those associated with prion diseases such as FFI, may be asked to undergo diagnostic genetic testing to confirm a clinical diagnosis. Immediate family members may be encouraged or may desire to undergo presymptomatic genetic screening to assess their own risk for developing the disease. However, such screening raises difficult issues because FFI is fatal and there are no current treatments. There is also no known procedure for delaying the onset or modifying the disease course.

Nurses must become more knowledgeable about genetic science and technology to educate and support patients and effectively collaborate with other healthcare providers. Nurses can play a critical role in guiding patients and families through the complexities of genetic testing; they can bridge the gap between the technological aspect of testing and the more pragmatic issues created by testing. Genetic testing, nonetheless, has broad ramifications beyond the test itself, and issues such as privacy and confidentiality, informed consent, counseling, referral, and patient advocacy must be considered (Foley & Sommers, 1998). Also, the cost of genetic testing can exceed $1,000, including physician visits and counseling, and may not be covered by health insurance plans. Patients must be counseled about the purpose, risks, and benefits of testing; the reasons for accepting or declining testing; alternative interventions or treatments; and posttest considerations (Lea & Williams, 2002). Nurses can also help patients understand genetic conditions and their management and support patients in coping with a changing health status.

Summary

The last 20 years have resulted in remarkable scientific progress in understanding the cause of prion diseases. FFI is a devastating and deadly neurodegenerative disease caused by a mutation in the human prion gene. This mutation ultimately causes normal prion protein to transform into an abnormal form that causes severe degeneration of neurons in the thalamic region of the brain. Initial symptoms can vary significantly but usually include progressive insomnia, depression, deteriorating memory, and fatigue. In middle age, when symptoms usually appear, patients begin a rapid decline towards certain death. Although studies are under way to examine the efficacy of drug therapy in treating prion diseases, there is no effective treatment for FFI. As nurses encounter patients with neurodegenerative diseases, they should be alert to the myriad symptoms that occur in prion diseases. Certainly the neuroscience nurse will most likely be faced with discriminating between CJD and FFI. And while FFI is rare, if confronted with it, neuroscience nurses will be challenged to provide care to a patient and family who are facing certain death. Care should focus on preserving patients' sense of well-being and supporting individual quality-of-life decisions.

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Dianne G. Sundstrom, BSN RN, is an independent nursing consultant in Long Beach, CA.
Table 1. Comparison of Creutzfeldt-Jakob Disease and Fatal Familial
Insomnia

Parameter               CJD *

Age of onset (years)    31-88 (M = 66)

Duration (months)       3-12 (M = 5)

Sleep and Vigilance     Fatigue; disordered sleep;
                        coma in terminal stages

Cognitive Functions     Confusion; uncharacteristic
                        behavior; rapid, progressive
                        dementia, memory loss

Clinical Symptoms       Weakness, dysarthria, ataxia;
                        myoclonus; spasticity; rigidity;
                        tremors; hemiparesis; aphasia;
                        occipital lobe involvement may
                        produce cortical blindness:
                        reduced appetite

EEG                     May be normal early
                        in disease; slowing and
                        periodic sharp wave complexes

Histopathology          Widespread cerebral cortex
                        spongiosis with neuronal loss
                        and gliosis

Brain Imaging           Normal in early stages; generalized
                        atrophy later; hyperactive signals
                        in basal ganglia on MRI

Parameter                   FFI

Age of onset (years)   40-60 (M = 51)

Duration (months)      7-18 (M = 14)

Sleep and Vigilance    Progressive insomnia; loss of vigilance;
                       progressive dream states and hallucinations;
                       fatigue; stupor and coma in
                       terminal stages

Cognitive Functions    Impairment of working memory;
                       deficit of attention; depression;
                       preservation of global intelligence; late
                       dementia

Clinical Symptoms      Hyperhidrosis; tachycardia; pyrexia;
                       hypertension; irregular breathing;
                       dysarthria; dysphagia; ataxia;
                       myoclonus: hyperreflexia

EEG                    Loss of delta activity during sleep; loss
                       of REM phase; progressive flattening
                       and slowing during wakefulness

Histopathology         Severe ventral and mediodorsal
                       thalamic neuronal loss and atrophy;
                       gliosis

Brain Imaging          MRI normal; uptake in thalamus
                       reduced on PET

* The phenotype or clinical presentation of CJD may vary depending on
the genotype. A new variant form of CJD
caused by bovine spongiform encephalopathy (BSE) has been identified.
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