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Genetic Prion Diseases

Synonym: Transmissible Spongiform Encephalopathies (TSEs)
, MD, PhD
Associate Professor, Department of Neurology
Director, Center for Comprehensive Care and Research on Memory Disorders
Committee of Neurobiology
University of Chicago
The Helen McLoraine Neuroscience Investigator of the Brain Research Foundation
Chicago, Illinois

Initial Posting: ; Last Update: January 2, 2014.

Summary

Disease characteristics. Genetic prion diseases generally manifest with cognitive difficulties, ataxia, and myoclonus (abrupt jerking movements of muscle groups and/or entire limbs). The order of appearance and/or predominance of these features and other associated neurologic and psychiatric findings vary. Familial Creutzfeldt-Jakob disease (fCJD), Gerstmann-Sträussler-Scheinker (GSS) syndrome, and fatal familial insomnia (FFI) represent the core phenotypes of genetic prion disease. Note: A fourth clinical phenotype, known as Huntington disease like-1 (HDL-1) has been proposed, but this is based on a single report, and the underlying pathologic features would categorize it as GSS. Although it is clear that these four subtypes display overlapping clinical and pathologic features, recognition of these phenotypes can be useful when providing affected individuals and their families with information about the expected clinical course. The age at onset ranges from the third to ninth decade of life. The course ranges from a few months to several years (typically 5-7 years; in rare instances, >10 years).

Diagnosis/testing. PRNP is the only gene in which mutations are known to cause genetic prion disease. The presence of a PRNP mutation is necessary to establish the diagnosis of genetic prion disease in a symptomatic individual. Sequence analysis of PRNP may not detect all disease-causing mutations; thus, the absence of a PRNP disease-causing mutation does not rule out the diagnosis of genetic human prion disease.

Management. Treatment of manifestations: Antiepileptic drugs (AEDs) including diphenylhydantoin or carbamazepine for seizures; clonazepam for myoclonus; use of a permanent feeding tube for dysphagia on a case by case basis; involvement of a social worker to assist the family in management planning.

Prevention of secondary complications: Caution is advised for any affected individual undergoing a surgical procedure, including endoscopy, brain biopsy, etc., as the surgical instruments used must be properly decontaminated or discarded, to reduce the possibility of transmission of prion disease to other persons.

Surveillance: Examination at regular intervals for complications (related to, e.g., swallowing difficulties, intercurrent infections, and other disease manifestations).

Agents/circumstances to avoid: There are no known substances that are reported to specifically worsen prion diseases, but as with any dementia, anticholinergics and antihistamines with high anticholinergic potential should be avoided.

Therapies under investigation: Clinical trials of quinacrine were unsuccessful in proving benefit for CJD. Several experimental therapies (antibodies against PrP, gene silencing with RNA inhibitors, and anti-amyloids) are being tested in animal models.

Genetic counseling. Genetic prion disease is inherited in an autosomal dominant manner. Most individuals diagnosed with genetic prion disease have an affected parent. However, a proband with genetic prion disease may have the disorder as the result of a de novo gene mutation. The proportion of cases caused by de novo gene mutations is unknown. Each child of an individual with a disease-causing PRNP mutation has a 50% chance of inheriting the mutation. Prenatal testing for pregnancies at increased risk of having a PRNP mutation is possible if the mutation in the family has been identified.

GeneReview Scope

Genetic Prion Diseases: Included Disorders
  • Familial Creutzfeldt-Jakob disease (fCJD)
  • Gerstmann-Sträussler-Scheinker disease
  • Fatal familial insomnia

For synonyms and outdated names see Nomenclature.

Diagnosis

Clinical Diagnosis

Genetic prion diseases constitute a continuum of clinical manifestations, originally labeled as familial Creutzfeldt-Jakob disease (fCJD), Gerstmann-Sträussler-Scheinker (GSS) syndrome, and fatal familial insomnia (FFI). Note: A fourth clinical phenotype, known as Huntington disease like-1 (HDL-1), has been proposed, but this is based on a limited number of cases, and the underlying pathologic features would categorize it as GSS [Moore et al 2001]. It is now known that these phenotypes are not distinct entities but rather constitute a spectrum of clinical and pathologic manifestations of genetic prion disease; nonetheless, certain aspects of these phenotypes are useful in diagnosis and care. There are no formal diagnostic criteria established for the genetic forms of disease, although criteria do exist for the non-genetic form of CJD (see end of this section), which can be used as a general framework for approaching these diseases.

The diagnosis of genetic prion disease requires a combination of the following:

  • Clinical features comprising varying combinations of adult-onset neurologic signs and symptoms, including:
    • Dementia
    • Psychiatric symptoms
    • Dyscoordination of movements (ataxia, dysarthria)
    • Myoclonus (muscle jerks)
    • Weakness and/or spasticity
    • Chorea
    • Stroke-like episodes
    • Seizures
    • Autonomic disturbances
  • Neuropathologic findings include:
    • Spongiform degeneration and astrogliosis diffusely distributed throughout the cortex and deep nuclei of the brain (fCJD)
    • Multiple amyloid plaques to which anti-prion protein (PrP) antibodies bind (GSS)
    • A relative lack of spongiform degeneration and presence of neuronal dropout and gliosis primarily within the thalamus and inferior olivary nucleus of the brain stem (FFI) [DeArmond & Prusiner 1997]
  • Family history consistent with autosomal dominant inheritance

Other studies including electroencephalogram (EEG), brain imaging, or examination of cerebrospinal fluid (CSF) may be helpful in supporting the diagnosis, but none is diagnostic on its own. Often such studies are performed to evaluate for other potentially treatable diseases of the central nervous system (see Differential Diagnosis). It should be emphasized that these tests have been best studied and are most helpful in the diagnosis of non-genetic prion disease (i.e., sporadic CJD). Reliance, therefore, on such studies for the diagnosis of genetic prion disease is cautioned.

  • EEG. Characteristic EEG findings of periodic sharp wave complexes (PSWCs), consisting of triphasic or sharp wave bursts every 0.5 to 2.0 seconds, can suggest the diagnosis of prion disease. Although PSWCs are observed in a relatively small percentage of individuals with genetic prion disease, their presence appears to be highly dependent on the associated causal mutation and resultant clinical phenotype; those mutations that produce a CJD-like clinical phenotype and spongiform degeneration pathology appear more likely to have a positive EEG.

    Note: Initially, the PSWCs may be unilateral, but with disease progression, they typically spread to both brain hemispheres. In late stages of the disease, the periodic activity may disappear.
  • Brain imaging
    • Magnetic resonance imaging (MRI) may show mild to moderate generalized atrophy at the time of presentation or within a short interval after presentation. FLAIR and T2-weighted images may demonstrate hyperintensity of the basal ganglia.
    • Diffusion-weighted MRI (DWI) shows signal hyperintensity within the cortical ribbon and/or basal ganglia (caudate and putamen) in more than 90% of individuals with sCJD and a limited number of reports suggest similar findings in a much smaller percentage of genetic prion disease phenotypes. Those who present with CJD-like phenotypes appear to be more likely to display the MRI findings.
    • PET or SPECT scanning, with the exception of FFI, appears to be of limited usefulness in diagnosing genetic prion disease, as the findings show nonspecific and diffuse cortical hypometabolic activity, sometimes with frontal predominance.

      Note: (1) In some reports, a reduction in perfusion to specific brain regions correlates with the clinical symptoms observed in the individual (e.g., left frontal or occipital cortex affected in language or visual deficits, respectively). (2) In the FFI phenotype the PET scan demonstrates a significant and selective reduction in activity within the thalamus, often early in the disease.
  • CSF (cerebrospinal fluid). An elevation of CSF protein concentration by approximately 10% is common, and may be attributed at least in part to release of the normal neuronal 14-3-3 protein into the CSF following neuronal death; however, this finding is not specific for prion disease.

    Note: (1) Because a significant number of neurons die in individuals with prion disease, the concentration of the 14-3-3 protein in CSF may increase substantially in some but not all cases. (2) Because of the generally slower rate of progression of genetic prion disease, the detection of the 14-3-3 protein in the CSF of these individuals appears less consistent than with sporadic CJD, suggesting that the increased rate of neuronal death leads to the measurable increase in 14-3-3 protein. (3) The 14-3-3 protein is released into the CSF in herpes encephalitis and hypoxic brain damage resulting from stroke, Hashimoto's encephalopathy, Alzheimer disease, and, on occasion, multiple sclerosis [Zerr et al 1998, Satoh et al 1999, Huang et al 2003]. (4) Van Everbroeck et al [2005] reported a more specific antibody to the gamma isoform of 14-3-3 that is more reliable against false positive tests. (5) Recent studies comparing the level of 14-3-3 protein with the levels of neuron-specific enolase (NSE) and total tau suggest that each are generally comparable in their elevations in non-genetic prion disease, with some reports favoring tau protein as more specific [Coulthart et al 2011, Polymenidou et al 2011]; however, data are not sufficient to draw conclusions about genetic prion disease [Sanchez-Juan et al 2006].

Modified WHO criteria for diagnosis of sporadic CJD. See Figure 1.

Figure 1

Figure

Figure 1. Modified WHO criteria for diagnosis of sporadic JCD

Molecular Genetic Testing

Gene. PRNP is the only gene in which mutations are known to cause genetically transmissible human prion disease.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in the Diagnosis of Genetic Prion Diseases

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
PRNPSequence analysis 4Sequence variantsUnknown 5
Targeted mutation analysisDuplication of 1 to 9 additional octapeptide repeats (Pro-His-Gly-Gly-Gly-Trp-Gly-Gln)Unknown

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. By definition, "genetically transmissible" prion disease requires the presence of a disease-causing PRNP mutation; however, it is possible that sequence analysis of the coding and flanking intronic regions does not detect all disease-causing mutations. Thus, the absence of a disease-causing mutation does not rule out the diagnosis.

Interpretation of test results. Because identification of a PRNP mutation is required to make the diagnosis of a genetically transmissible human prion disease, it is important to consider possible outcomes of sequence analysis.

Testing Strategy

To confirm/establish the diagnosis of genetically transmissible prion disease in a proband, a PRNP mutation must be identified through either targeted mutation analysis or full gene sequencing of PRNP.

Clinical Description

Natural History

Genetic prion diseases generally manifest with cognitive difficulties, ataxia, and myoclonus (abrupt jerking movements of muscle groups and/or entire limbs); however, the order of presentation and/or predominance of these features and associated neurologic and psychiatric findings vary with genetic prion disease subtype and/or PRNP mutation. The age at onset ranges from the third to ninth decade of life. Of note, a 13-year-old with a p.Pro105Thr mutation developed symptoms suggestive of prion disease; however, pathology has not been reported [Rogaeva et al 2006]. Since this initial report, another family was identified in which the symptoms developed in the fifth and sixth decade, and the neuropathologic findings were reported as CJD-like, with diffuse spongiform degeneration and some unicentric plaque-like deposits [Polymenidou et al 2011].

The course ranges from a few months to several years (typically 5-7 years, but in rare cases >10 years). Death often results from infection, either by pneumonia (typically from aspiration) or urosepsis.

The classic phenotypes associated with genetic prion disease (fCJD, GSS, and FFI), were defined by clinical and neuropathologic findings long before the molecular basis of this group of disorders was discovered. The recognition that some families with clinical features of Huntington disease had a PRNP mutation has expanded the clinical spectrum of prion disease. While it is recognized that these phenotypes are part of a continuum and have overlapping features, it can be helpful to think of genetic human prion disease at least in part in terms of these phenotypes when providing individuals and families with information about the expected clinical course.

Familial Creutzfeldt-Jakob disease (fCJD). Progressive confusion and memory impairment occur first, followed by ataxia and myoclonus. The disease typically manifests between ages 30 and 50 years, although a few individuals present before age 30 years or as late as the upper 80s. The course from onset to death ranges from a few months to five years. At the end stage of disease, the individual is generally bed-bound, mute, and immobile (akinetic), except for myoclonic jerks.

The cognitive impairment observed may initially be mild confusion or it may be specific for a particular cortical function, such as language or constructional abilities; however, the resultant picture is one of global dementia. As the disease progresses, neurobehavioral symptoms may vary considerably. Psychiatric features, including delusions and hallucinations, may also occur.

Ataxia may be either truncal or appendicular, manifesting either as an unsteady gait, clumsiness while carrying out commonly performed tasks (e.g., picking up the salt shaker while dining), or progressive dysarthria (slurred speech). As the ataxia progresses, the individual may fall repeatedly, necessitating the use of a wheelchair to prevent injury.

Myoclonus generally, but not always, occurs after cognitive impairment is evident. Myoclonus may begin focally in a single limb but eventually becomes generalized. "Startle myoclonus" may be elicited by simple acts such as clapping the hands or turning on the room lights. Even if warned of an impending noise, the individual cannot suppress the startle response.

Other neurologic signs and symptoms such as focal or generalized weakness, rigidity, bradykinesia, tremor, chorea, alien hand syndrome, stroke-like symptoms, visual disturbances, and seizures have been reported.

Gerstmann-Sträussler-Scheinker syndrome (GSS) typically begins in the fourth to sixth decade with the insidious onset of cerebellar dysfunction, manifest as unsteady gait and mild dysarthria. Cognitive dysfunction is generally not apparent early on; however, with progression, bradyphrenia (slowness of thought processing) may become evident. Pyramidal involvement with spasticity and/or extrapyramidal involvement with bradykinesia, increased muscle tone with or without cogwheeling, and masked facies are also common. Psychiatric or behavioral symptoms are atypical. The disease progresses at a relatively slow but relentless pace over the course of a few to seven or more years. Cerebellar dysfunction results in severe dysarthria, gait and appendicular ataxia, ocular dysmetria, and lack of coordination in swallowing. A decline in cognitive abilities, particularly of concentration and focus, becomes apparent with progression into the late stage of disease. In the terminal stage, the individual is bedridden from the disabling ataxia, unable to eat because of severe lack of coordination in swallowing, and unable to communicate because of the profound dysarthria; yet insight into his/her condition may remain. This pattern of progression relates to the cerebellar nature of this disease, with progression into the brain stem and eventually the cerebrum.

Fatal familial insomnia (FFI) typically presents in midlife (40s to 50s) with the insidious or subacute onset of insomnia, initially manifest as a mild, then more severe, reduction in overall sleep time. When sleep is achieved, vivid dreams are common. A disturbance in autonomic function then emerges; it may manifest as elevated blood pressure, episodic hyperventilation, excessive lacrimation, sexual and urinary tract dysfunction, and/or a change in basal body temperature. Signs of brain stem involvement including decreased ability to gaze upward, double vision, jerky eye pursuit movements, or dysarthric speech may also appear in some individuals. With continued progression over the next few months, individuals develop truncal and/or appendicular ataxia.

The speed of thought processing may be reduced, as is common in subcortical dementing states, and memory impairment may be variable; however, compared with other more prominent features of disease, cognitive capacity is relatively spared until late in the course. Advancing disease results in progressively greater loss of total sleep time, worsening ataxia, and more profound confusion, leading ultimately to an awake but stuporous state as death approaches. As with other forms of prion disease, debilitation leading to feeding difficulties and loss of airway protection is the most common immediate cause of death. The typical duration of disease is 12 to 16 months, with a range of a few months to five years.

Neuropathology. The various genetic prion disease syndromes have relatively characteristic neuropathologic changes including abundant deposition of amyloid plaques that are stained by PrP antibodies in GSS, focal thalamic neuronal loss and gliosis in FFI, and diffusely distributed spongiform change with neuronal destruction in fCJD. Note that HDL-1 associated pathology suggests a variable picture, with prion protein-containing plaque deposits present in some and spongiform degeneration in others. This phenotype is not well characterized at this time.

Although characteristic of each syndrome, the neuropathology is not 100% specific and variations from case to case are apparent [Gambetti et al 1999, Kovacs et al 2002, Liberski et al 2005].

Genotype-Phenotype Correlations

Detailed phenotype-genotype correlations of the various genetic prion syndromes can be found in Mastrianni [1998], Gambetti et al [1999], and Kovacs et al [2002].

Familial CJD (fCJD) phenotype. Several PRNP point mutations cause the fCJD phenotype (p.Asp178Asn with normal variant p.Val129, and mutations p.Val180Ile, p.Thr183Ala, p.Glu200Lys, p.Arg208His, p.Val210Ile, p.Met232Arg). See Table 2.

GSS phenotype. Causal mutations may include p.Pro102Leu, p.Pro105Leu, p.Ala117Val, p.Tyr145Ter, p.Gln160Ter, p.Phe198Ser, and p.Gln217Arg. See Table 2.

FFI phenotype. Only one haplotype causes FFI (p.Asp178Asn + normal variant p.Met129).

p.His187Arg. Early onset and long duration of disease that includes neuropsychiatric disturbances and frontotemporal-like symptoms have been associated with the p.His187Arg mutation [Hall et al 2005].

Insertional mutations are associated with the fCJD phenotype and the GSS phenotype. These insertions all lie within an unstable region of PRNP that is rich in proline, glycine, and glutamine (see Molecular Genetics). Normal PRNP alleles have one nonapeptide followed by four octapeptide repeat sequences each of which comprises the following amino acids: Pro-(His/Gln)-Gly-Gly-Gly-(-/Trp)-Gly-Gln. Because the nucleotide sequence encoding the octapeptide may vary, the repeat is described typically as an octapeptide rather than as a 24-nucleotide repeat.

From one to nine additional octapeptide repeat segments have been detected in familial forms of genetic prion disease. A correlation between the number of extra octapeptide repeats and phenotype seems to exist:

  • Two to seven additional repeats are typically associated with the fCJD pathologic phenotype, but clinical presentation varies remarkably.
  • Eight or nine extra repeats are associated with the GSS pathologic phenotype.

Of note, some families with octapeptide repeat insertions show significant phenotypic variability among affected individuals [Mead et al 2006].

Normal/disease-modifying variant at codon 129. The common normal variant at codon 129 of PRNP (c.385A>G) codes for either the amino acid methionine (Met; p.Met129) or valine (Val; p.Val129). Approximately 50% of affected individuals of northern European descent are homozygous at this variation for either Met or Val, although 80%-90% of individuals with sporadic CJD are homozygotes.

  • In general, the onset of genetic prion disease is earlier and its course shorter in individuals homozygous for p.Met129 compared to either heterozygotes for p.Met129Val or homozygotes for p.Val129.
  • For alleles with the p.Asp178Asn mutation, the presence of p.Met129 vs p.Val129 modifies the phenotype of disease.
    • If Val is encoded, the phenotype is almost always typical fCJD.
    • If Met is encoded, the phenotype is almost always FFI.
    • Even in nonfamilial forms of CJD, the p.Met129Val variant appears to have an effect on disease phenotype such that individuals with Met homozygosity present most often with dementia and a more rapid disease course, whereas those with a Val on one or both alleles display ataxia at onset and a slower disease course [Parchi et al 1999b].

Penetrance

The p.Glu200Lys and p.Val210Ile mutations of PRNP are commonly associated with a variable but generally age-dependent penetrance such that the older the individual, the greater likelihood of his/her manifesting the disease. Thus, it is not uncommon to encounter a situation in which the parents and other relatives of an affected individual may be unaffected but have a PRNP mutation [Kovacs et al 2005]. Interestingly, the p.Val180Ile mutation appears to occur almost exclusively in individuals presenting with CJD in later life [Kovacs et al 2005].

Most other PRNP mutations demonstrate complete penetrance and symptoms present well under the age of 65.

Anticipation

Genetic anticipation has not been documented.

Nomenclature

Spastic pseudosclerosis is an older term used to describe a more fulminant course of CJD, as it appeared to have features suggestive of multiple sclerosis, with spasticity of gait and limbs.

Heidenhain’s variant is a term used to describe a specific presentation of CJD that occurs in about 10% of non-genetic forms. It begins with visual symptoms that may manifest as visual loss, blurring, and/or visual distortions (e.g., bending in the walls), related to the early involvement of the occipital lobes of the brain. Diffusion-weighted MRI may show hyperintensities primarily within the occipital cortex in this subtype.

Prevalence

Genetic prion diseases are rare. The general worldwide yearly incidence of genetic and non-genetic prion disease is between 1 and 1.5 cases per million people. Thus, in the US, slightly more than 300 new cases of prion disease are expected per year. The genetic forms of prion disease represent approximately 10% of the total number of cases of prion disease.

The most common disease-associated mutations of PRNP are p.Glu200Lys, the largest focus being present in the Middle East (Libyan Jews) and Eastern Europe (Slovakia), and p.Asp178Asn, which is found worldwide. Other mutations are relatively rare [Kovacs et al 2005].

In Italy nearly 18% of all cases of recorded prion disease were found to involve a PRNP mutation, with p.Val210Ile and p.Glu200Lys being the most common mutations observed [Ladogana et al 2005].

Differential Diagnosis

Other prion diseases. About 10% of prion diseases are genetically transmissible, while the remainder occur from unknown risk factors or are acquired through infection with prions; these include sporadic Creutzfeldt-Jakob disease (sCJD), iatrogenic CJD (iCJD), variant CJD (vCJD), sporadic fatal insomnia (sFI), and most recently, variably protease-sensitive prionopathy (VPSPr) [Gambetti et al 2008]. Kuru, a prion disease associated with the practice of cannibalism in a primitive culture in New Guinea, is primarily of historical significance.

  • Sporadic CJD. The clinical and pathologic features of sCJD are the same as in fCJD; however, the duration of disease is typically much shorter (on average ≤6 months) and the age at onset is later (typically age >60 years).
  • Sporadic FI. The phenotype is the same as in FFI, including age at onset and duration of disease [Mastrianni et al 1999, Parchi et al 1999a]; sFI is much less common than FFI.
  • Iatrogenic CJD. Diagnosis of this form of prion disease requires the identification or strong association with exposure to a biologic extract or tissue contaminated with prions. Such sources have included human growth hormone (used prior to 1980), improperly decontaminated depth electrodes previously used in individuals with CJD, transplantation of corneas obtained from individuals with CJD, dura mater grafts, and various poorly documented neurosurgical procedures [Mastrianni & Roos 2000].
  • Variant CJD. This form of CJD is acquired by ingestion of beef or beef products contaminated with bovine spongiform encephalopathy (BSE), the prion disease of cattle (commonly known as mad cow disease). The typical clinical picture is that of a young adult or teen who develops behavioral changes (apathy and depression) and/or pain in the lower extremities, eventually leading to a progressive dementia with ataxia and myoclonus [Will et al 2000]. The course is about 1.5 years. The EEG is often diffusively slow rather than periodic, and the 14-3-3 CSF protein test is more often negative than positive. The head MRI in this form of CJD shows hyperintensities of the pulvinar nucleus of the thalamus, rather than the basal ganglia, which is a key distinction between variant CJD and sCJD. Neuropathology reveals spongiform change spread diffusely throughout the brain and dense amyloid plaque deposition surrounded by a halo of vacuolation described as "florid plaques" [Ironside 1998].
  • Variably protease-sensitive prionopathy. This form of prion disease has been recognized in a small but growing number of individuals [Gambetti et al 2008]. Individuals with this condition have variable presentations (aphasia and behavioral symptoms being most common) but are best recognized by the histopathology, which reveals a generally greater sensitivity of the pathogenic prion protein to protease digestion, compared with that from typical CJD. The histopathology consists primarily of punctate and globular collections of prion protein.

Other. Prion disease should always be considered a possible diagnosis in an individual with a progressive cognitive decline, either in isolation or when combined with a movement disorder. The rapidity of progression may be a helpful clue; however, some prion diseases, especially genetically based ones, often progress slowly, over the course of several years, especially those with insertional mutations and those associated with GSS. Genetic prion diseases may be easily confused with several other neurodegenerative diseases such as Alzheimer disease, dementia with Lewy bodies, Huntington disease, progressive supranuclear palsy, the inherited ataxias, and the frontotemporal dementias including progressive subcortical gliosis, dementia with motor neuron disease, Pick disease, and FTD with parkinsonism (chromosome 17-linked FTD) [Allen et al 2007], inclusion body myopathy with Paget disease of bone and/or frontotemporal dementia, CHMP2B-related frontotemporal dementia, and GRN-related frontotemporal dementia.

Autoimmune diseases such as Hashimoto's thyroiditis with related encephalopathy, paraneoplastic syndromes such as limbic encephalitis, and/or systemic CNS vasculitides, multiple sclerosis, toxins (heavy metals, including bismuth), and metabolic abnormalities must also be considered.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with genetic prion disease, the following evaluations are recommended:

  • Physical examination with focus on the neurologic features of cognition, motor function, and coordination
  • Medical genetics consultation

Treatment of Manifestations

Therapy is aimed at controlling symptoms that may cause discomfort.

  • If present, seizures may be treated with antiepileptic drugs (AEDs) such as diphenylhydantoin or carbamazepine.
  • Myoclonus can sometimes be mitigated by clonazepam.
  • Issues related to dysphagia are often difficult to resolve. Since the disease is terminal, families are often faced with the decision of whether or not to place a permanent feeding tube. The timing of this decision differs depending on the type of prion disease. In general, placement of a feeding tube should be discouraged in those with late-developing dysphagia, as it may make it difficult for families to eventually withdraw feeding.

Evaluation by a social worker is mandatory to assist the family in management planning, as many decisions are required during the course of disease and at the end of the disease process. Autopsy to confirm the diagnosis should always be a consideration, as accurate information is important for family members.

Prevention of Secondary Complications

Similar to the non-genetic forms of prion disease, some genetic forms of prion disease can also be environmentally transmitted to others. Therefore, caution is advised for any affected individual undergoing a surgical procedure (e.g., endoscopy, brain biopsy): surgical instruments used must be properly decontaminated or discarded to reduce the possibility of transmission of prion disease to other persons.

Surveillance

Affected individuals are examined at regular intervals for complications related to swallowing difficulties, intercurrent infections, and other disease manifestations.

Agents/Circumstances to Avoid

There are no known substances that are reported to specifically worsen prion diseases, but as with any dementia, anticholinergics and antihistamines with high anticholinergic potential, should be avoided.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

No cases of pregnant women affected with prion disease have been documented; if such a situation were to arise, clinical judgment regarding the safety and viability of the fetus and the life expectancy of the mother (which can be estimated based on the gene mutation and time of onset of symptoms) should be used in determining the best course of action during the pregnancy.

Therapies Under Investigation

The drug quinacrine, an antimalarial agent that showed promise in tissue culture, was studied in both the US and the UK as a possible therapy, but in both cases it was found not to significantly affect the progression or symptoms of disease.

Several experimental therapies, including antibodies against PrP, gene silencing with RNA inhibitors, and anti-amyloids (such as Anle138b [Wagner et al 2013]) are being tested in animal models.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

The National Prion Disease Surveillance Center is charged with collecting and recording all cases of prion disease in the US. They should be notified regarding all cases of suspected prion disease.

Individuals with genetic prion disease do NOT need to be quarantined. While all prion diseases are potentially transmissible through ingestion or injection of infectious tissue (neural), they are not contagious by typical means of close contact with affected individuals. It is advisable, however, that body fluids of symptomatic individuals be handled as biohazard waste.

Antiviral therapies have been tested and anecdotal reports do not support them to be efficacious.

In rodent studies, amphotericin B, pentosan polysulfate, and various other agents displayed promise when administered prior to infecting animals with prions; however, no successful clinical results have been reported.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Genetic human prion disease is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with genetic human prion disease have an affected parent. However, a proband with a genetic human prion disease may have the disorder as the result of a de novo gene mutation.
  • The proportion of cases caused by de novo gene mutations is unknown.
  • In addition, families in which penetrance appears to be reduced have been observed; thus the parent with a disease-causing mutation is unaffected while the child is affected.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected or has a disease-causing PRNP mutation, the risk to each sib of inheriting the allele is 50%.
  • If the parents are clinically unaffected and do not have a PRNP disease-causing mutation, the risk to the sibs of a proband appears to be low.
  • If a PRNP mutation cannot be detected in the DNA of either parent, it is presumed that the proband has a de novo gene mutation and the risk to the sibs of the proband depends on the spontaneous mutation rate of PRNP and the probability of germline mosaicism. Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband. Each child of an individual with a disease-causing PRNP mutation has a 50% chance of inheriting the mutation.

Other family members

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent is affected or has a disease-causing PRNP mutation, his or her family members are at risk.

Related Genetic Counseling Issues

Molecular genetic testing of symptomatic individuals from families with no history of neurologic disease. Goldman et al [2004] stress the importance of pretest counseling for families of symptomatic individuals with no family history of neurologic disease to better prepare families and to allow them to make informed decisions about receiving genetic test results.

Testing of at-risk asymptomatic adults for genetic human prion diseases is possible using the techniques described in Molecular Genetic Testing. Such testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. When testing at-risk individuals for genetic prion diseases, an affected family member must be tested first to confirm the molecular diagnosis in the family.

Testing for the disease-causing mutation in the absence of definite symptoms of the disease is predictive testing. At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations including simply the "need to know." Testing of asymptomatic at-risk adult family members usually involves pre-test interviews in which the motives for requesting the test, the individual's knowledge of genetic prion diseases, the possible impact of positive and negative test results, and neurologic status are assessed. Those seeking testing should be counseled about possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow-up and evaluations.

Testing of at-risk individuals younger than age 18 years. Consensus holds that individuals younger than age 18 years who are at risk for adult-onset disorders should not have testing in the absence of symptoms. The principal arguments against testing asymptomatic individuals during childhood are that it removes their choice to know or not know this information, it raises the possibility of stigmatization within the family and in other social settings, and it could have serious educational and career implications. In addition, no preventive treatment for prion diseases is available.

See also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available either through a clinical laboratory or a laboratory offering custom prenatal testing.

Requests for prenatal testing for late-onset conditions such as genetic prion diseases are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Creutzfeldt-Jakob Disease Foundation, Inc.
    341 West 38th Street
    Suite 501
    New York City NY 10018
    Phone: 800-659-1991; 212-719-5900
  • National Library of Medicine Genetics Home Reference

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Genetic Prion Diseases: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Genetic Prion Diseases (View All in OMIM)

123400CREUTZFELDT-JAKOB DISEASE; CJD
137440GERSTMANN-STRAUSSLER DISEASE; GSD
176640PRION PROTEIN; PRNP
245300KURU, SUSCEPTIBILITY TO
600072FATAL FAMILIAL INSOMNIA; FFI
603218HUNTINGTON DISEASE-LIKE 1; HDL1

Gene structure. Normal PRNP has a coding region of 756 nucleotides in two exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. Several PRNP variants not associated with an enhanced susceptibility to prion disease have been detected; however, these variants may play a role in altering the phenotype of disease from either sporadic or genetic forms of prion disease (see Table 2). They include p.Met129Val (see Genotype-Phenotype Correlations), p.Glu219Lys, p.Asn171Ser, and a deletion of a single octapeptide repeat segment [Palmer et al 1993]. While these variants do not appear in and of themselves to promote disease, homozygosity at codon 129 appears to increase disease susceptibility, and depending on the substitution, this polymorphic site appears to affect the phenotype of disease. The p.Glu219Lys variant has been reported as protective, although this change would seem to be limited to the Japanese population. The p.Asn171Ser change has recently been reported to influence the phenotype of fCJD caused by the p.Asn178Asp mutation, resulting in a phenotype with prominent psychiatric features [Appleby et al 2010].

Normal alleles have a repeat region between amino acid residues 51 and 91 comprising one nonapeptide unit that begins at residue 51 and encodes the following nine amino acids: Pro-Gln-Gly-Gly-Gly-Gly-Trp-Gly-Gln. This is followed by four octapeptide units beginning at residue 60 encoding the following eight amino acids: Pro-His-Gly-Gly-Gly-Trp-Gly-Gln. The octapeptide units can be unstable and are duplicated in pathogenic variants. Because the nucleotide sequence encoding the octapeptide units can vary slightly, the specific sequences for normal and pathogenic alleles in this region are often not specified.

Pathogenic allelic variants. A host of pathogenic variants (see Genotype-Phenotype Correlations) are known. Three major types of pathogenic mutations have been described:

  • Nucleotide substitutions that result in an amino-acid substitution (see Table 2). All of the mutations associated with pathology are in-frame heterozygous mutations with the exception of one report of an individual homozygous for the p.Glu200Lys mutation.
  • An insertion (also called a duplication) of one or more octapeptide repeat segment(s), which results in an extended PrP. These mutations involve the insertion of one or more octapeptide repeat segments between codons 51 and 90. Each repeat adds 24 nucleotides to the gene, or eight amino acids to the protein. From one to nine additional octapeptide repeats (Pro-His-Gly-Gly-Gly-Trp-Gly-Gln) have been associated with disease.
  • The generation of an early stop signal that results in a truncated PrP. The substitutions that result in an early stop signal are p.Tyr145Ter and p.Gln160Ter.

Table 2. Selected PRNP Variants

Variant ClassDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
Benign/disease modifying24-bp deletionDeletion of one octapeptide repeatNM_000311​.3
NP​_000302
c.385A>Gp.Met129Val
c.512A>Gp.Asn171Ser
c.655G>Ap.Glu219Lys
PathogenicDuplication of an octapeptide repeat
c.305C>Tp.Pro102Leu
c.314C>Tp.Pro105Leu
c.313C>Tp.Pro105Ser
c.313C>Ap.Pro105Thr
c.350C>Tp.Ala117Val
c.435T>Gp.Tyr145Ter
c.478C>Tp.Gln160Ter
c.532G>Ap.Asp178Asn
c.538G>Ap.Val180Ile
c.547A>Gp.Thr183Ala
c.560A>Gp.His187Arg
c.593G>Cp.Phe198Ser
c.598G>Ap.Glu200Lys
c.623G>Ap.Arg208His
c.628G>Ap.Val210Ile
c.650A>Gp.Gln217Arg
c.695T>Gp.Met232Arg 1

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. See Genetically Related Disorders.

Normal gene product. The prion protein is translocated into the endoplasmic reticulum (ER) during translation, as a 253-amino acid protein. Once within the ER lumen, the first 23 amino acids (which constitute a signal sequence) are cleaved, as are the last 23 amino acids, which signal the attachment of a glycosyl-phosphatidylinositol anchor, by which the protein is attached to the cell surface. An octapeptide repeat segment is present between amino acids 51 and 90. Two asparagine-linked glycosylation sites are present. The normal function of the protein is unknown, although roles in synapse formation, delivery of copper to cells, and cell signaling have been proposed. Two major isoforms of the prion protein exist: the non-pathogenic (cellular) form (PrPC) and the pathogenic (scrapie-inducing) form (PrPSc) [Prusiner 1998]. Although the amino acid sequence is the same in the two, their biochemical properties differ: PrPC is α-helical, PrPSc is at least 40% β-pleated sheet; PrPC is soluble in non-denaturing detergents, PrPSc is insoluble; PrPC is completely degraded by proteases, PrPSc has a relative resistance to proteases.

Abnormal gene product. The normal protein product is presumably destabilized by the presence of a pathogenic mutation, which enhances the propensity for the protein to attain the PrPSc state. PrPSc then behaves as a conformational template that complexes with non-pathogenic PrPC. The manner in which the accumulation of PrPSc is toxic to the cell is unknown.

References

Published Guidelines/Consensus Statements

  1. American Society of Human Genetics and American College of Medical Genetics. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Available online. 1995. Accessed 6-16-14. [PMC free article: PMC1801355] [PubMed: 7485175]
  2. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2012. Accessed 6-16-14.

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Suggested Reading

  1. Gambetti P, Parchi P, Chen SG. Hereditary Creutzfeldt-Jakob disease and fatal familial insomnia. Clin Lab Med. 2003;23:43–64. [PubMed: 12733424]
  2. Knight R, Brazier M, Collins SJ. Human prion diseases: cause, clinical and diagnostic aspects. Contrib Microbiol. 2004;11:72–97. [PubMed: 15077404]
  3. Knight RS, Will RG. Prion diseases. J Neurol Neurosurg Psychiatry. 2004;75 Suppl 1:i36–42. [PMC free article: PMC1765647] [PubMed: 14978149]
  4. Prusiner SB. Prion diseases. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 224. Available online. 2014. Accessed 6-16-14.

Chapter Notes

Author Notes

University of Chicago Memory Center Web site: memorycenter.bsd.uchicago.edu

Revision History

  • 2 January 2014 (me) Comprehensive update posted live
  • 7 September 2010 (cd) Revision: prenatal testing available clinically
  • 18 December 2008 (me) Comprehensive update posted live
  • 7 October 2005 (cd) Revision: targeted mutation analysis for common mutations no longer clinically available
  • 16 May 2005 (me) Comprehensive update posted to live Web site
  • 4 March 2004 (cd) Revisions: Testing
  • 27 March 2003 (me) Review posted to live Web site
  • 12 April 2002 (jm) Original submission
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