Genetic Prion Disease
Summary
Clinical characteristics.
Genetic prion disease generally manifests 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. The three major phenotypes of genetic prion disease are genetic Creutzfeldt-Jakob disease (gCJD), fatal familial insomnia (FFI), and Gerstmann-Sträussler-Scheinker (GSS) syndrome. Although these phenotypes 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 typically ranges from 50 to 60 years. The disease course ranges from a few months in gCJD and FFI to a few (up to 4, and in rare cases up to 10) years in GSS syndrome.
Diagnosis/testing.
The diagnosis of genetic prion disease is established in a proband with suggestive findings and a heterozygous PRNP pathogenic variant identified by molecular genetic testing.
Management.
Treatment of manifestations: No treatment of the underlying cause of genetic prion disease is available. Supportive care by a multidisciplinary team of specialists including neurologists, psychiatrists, physical therapists, occupational therapists, speech and language therapists, and social workers is recommended.
Surveillance: Because of very rapid disease progression, close periodic monitoring by the multidisciplinary team is needed, typically every 14 days to evaluate needs for symptomatic treatment.
Genetic counseling.
Genetic prion disease is inherited in an autosomal dominant manner. Some individuals diagnosed with genetic prion disease may have a parent who is heterozygous for a PRNP pathogenic variant (some of whom may be asymptomatic because of reduced penetrance). Other individuals with genetic prion disease may have the disorder as the result of a de novo PRNP pathogenic variant. Each child of an individual with a PRNP pathogenic variant has a 50% chance of inheriting the variant. Although predictive testing (i.e., testing of asymptomatic at-risk adults) is possible, the capabilities and limitations of predictive testing as well as possible socioeconomic and medical care issues should be discussed in the context of formal genetic counseling prior to testing. Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals younger than age 18 years) is considered inappropriate.
Diagnosis
Suggestive Findings
Genetic prion disease should be suspected in individuals with the following clinical, laboratory, and imaging findings and family history.
Clinical
Geneic prion disease is a progressive neurodegenerative syndrome with rapid evolution of clinical signs (which reflect involvement of various neuroanatomic structures) – typically, dementia in combination with the following developing within a few months or (rarely) a few years:
- Extrapyramidal/pyramidal involvement
- Ataxia
- Myoclonus
In fatal familial insomnia (FFI) early autonomic disturbances and weight loss are frequent.
Laboratory
Cerebrospinal fluid analysis may be abnormal with high levels of 14-3-3 protein and protein tau.
Abnormally conformed prion protein using aggregation assays (RT QuIC) is typically positive in genetic Creutzfeldt-Jakob disease (gCJD), but not always in FFI or Gerstmann-Sträussler-Scheinker syndrome (GSS).
Imaging
MRI
- In some individuals with genetic CJD, MRI may display high signal abnormalities in the basal ganglia (caudate nucleus) and cortical areas, mostly in diffusion-weighted imaging (DWI), but also T2-weighted-fluid-attenuated inversion recovery (FLAIR) images.
- In individuals with FFI and GSS, MRI is typically not suggestive.
FDG PET (typically displaying hypometabolism in the thalamic areas) may be helpful in individuals FFI.
Family History
Family history is consistent with autosomal dominant inheritance (i.e., multiple affected family members in successive generations or a single affected family member). Absence of a known family history does not preclude the diagnosis.
Establishing the Diagnosis
The diagnosis of genetic prion disease is established in a proband with suggestive findings and a heterozygous PRNP pathogenic variant identified by molecular genetic testing [Ladogana & Kovacs 2018] (see Table 1).
Note: Identification of a heterozygous PRNP variant of uncertain significance does not establish or rule out the diagnosis of this disorder.
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing and multigene panel) and comprehensive genomic testing (exome sequencing or genome sequencing).
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of genetic prion disease has not been considered may be more likely to be diagnosed using genomic testing (see Option 2).
Option 1
Single-gene testing. Sequence analysis of PRNP is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Typically, if no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications; however, to date such variants have not been identified as a cause of this disorder.
Note: Targeted analysis for pathogenic variants can be performed first in individuals of European ancestry; the following five common variants account for approximately 85% of the PRNP pathogenic variants in this population (see Table 4 for details):
- P102L (c.305C>T; p.Pro102Leu)
- D178N (c.532G>A; p.Asp178Asn)
- V180I (c.538G>A; p.Val180Ile)
- E200K (c.598G>A; p.Glu200Lys)
- V210I (c.628G>A; p.Val210Ile)
A multigene panel that includes PRNP and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Genetic Prion Disease
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| PRNP | Sequence analysis 3 | 100% 4 |
| Gene-targeted deletion/duplication analysis 5 | None reported |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Schmitz et al [2017] and Takada et al [2017] include the five pathogenic variants of targeted sequence analysis and the octapeptide insertion/duplication/deletion variants that are detectable by sequence analysis (see Table 4).
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Clinical Characteristics
Clinical Description
Genetic prion disease generally manifests 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. The three major phenotypes of genetic prion disease are genetic Creutzfeldt-Jakob disease (gCJD), fatal familial insomnia (FFI), and Gerstmann-Sträussler-Scheinker (GSS) syndrome. Although these phenotypes 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 typically ranges from ages 50 to 60 years. The disease course ranges from a few months in gCJD and FFI to a few (up to 4, and in rare cases up to 10) years in GSS syndrome.
Table 2 provides information on the frequency of neurologic features in the most frequent genetic prion disease phenotypes that emerge during the disease course. While some PRNP pathogenic variants are associated with specific neuropathologic phenotypes, individuals in the same family who are heterozygous for the same PRNP variant may develop distinct clinicopathologic phenotypes [Cracco et al 2018].
Table 2.
Select Features of Genetic Prion Disease by Phenotype and PRNP Pathogenic Variant
| Feature | % of Persons with Feature by Phenotype & PRNP Variant | ||||
|---|---|---|---|---|---|
| gCJD | FFI | GSS | |||
| E200K | V210I | D178N | P102L | ||
| Dementia | 95% | 92% | 96% | 62% | |
| Ataxia | 100% | 100% | 82% | 100% | |
| Myoclonus | 85% | 92% | 89% | 25% | |
| Extrapyramidal | 65% | 92% | 82% | 50% | |
| Pyramidal | 70% | 71% | 79% | 75% | |
| Visual/Cortical blindness | 70% | 85% | 79% | ||
| Other characteristic features | Dysarthria | Yes | Yes | Yes | Yes |
| Sleep disturbances | Yes | Yes | Yes | ||
| Sensory symptoms | Yes | Yes | |||
| Weight loss | Yes | Yes | |||
| Hyperhidrosis | Yes | ||||
Adapted from Krasnianski et al [2016] (based on 108 affected individuals ascertained by the CJD Surveillance Unit in Göttingen, Germany, from 1993 to 2005)
Genetic Creutzfeldt-Jakob Disease (gCJD)
Genetic prion disease caused by pathogenic variants E200K and V210I frequently resembles the phenotype of sporadic CJD (see Differential Diagnosis). Typical disease onset is in the sixth decade; after a nonspecific prodromal phase with dizziness, fatigue, blurred vision, depressive mood, and weight loss, the disease starts frequently with cognitive decline that progresses over several weeks. Within a few months of progressive neurologic decline, affected individuals become bedridden and akinetic/mute. The advanced disease stage is characterized by rapid involuntary muscle jerks (myoclonus), muscle stiffness (either rigidity or spasticity), and ataxia. The median survival following disease onset is six months.
Fatal Familial Insomnia (FFI)
A prodromal phase with marked autonomic disturbances, hyperhidrosis, weight loss, and sleep disturbances is common. Polysomnography shows complete disruption of the physiologic EEG sleep pattern.
After a nonspecific stage as described for gCJD, affected individuals develop progressive dementia, ataxia, muscle rigidity and involuntary movements. At the end stage of the disease, the clinical manifestations are similar to those of other genetic prion disease phenotypes.
The median age at onset is between 50 and 60 years. The median survival is 16 months. See Genotype-Phenotype Correlations for information on a variant associated with a shorter disease course.
Gerstmann-Sträussler-Scheinker (GSS) Syndrome
The typical clinical manifestations are a rapidly progressive cerebellar syndrome with ataxia at onset followed by cognitive decline and other neurologic signs within a few weeks, or at most a few months.
The typical age at onset, earlier than in the other genetic prion diseases, is early in the sixth decade (51 years) with disease duration typically up to four years.
Tesar et al [2019], who used cluster analysis to address the clinical heterogeneity of GSS syndrome, reported the following four clinical phenotypes:
- Typical GSS syndrome with early ataxia, late dementia, and long disease duration (up to 4 years)
- GSS syndrome beginning with areflexia and paresthesias, and later ataxia and dementia
- Pure dementia GSS syndrome with early onset (age 35 years) with predominant dementia and late ataxia
- Creutzfeldt-Jakob disease-like GSS syndrome with dementia and ataxia at onset and rapid disease progression
Genotype-Phenotype Correlations
Although some PRNP pathogenic variants are associated with specific neuropathologic phenotypes (see Table 2), evidence also suggests that heterozygotes for the same variant in the same family may develop distinct clinicopathologic phenotypes [Cracco et al 2018].
Note that the phenotype may be modified by the presence of the polymorphic codon 129 (p.Asp178Asn) in cis configuration with the PRNP variant. The phenotype in individuals with the p.Asp178Asn pathogenic variant typically depends on which variant – Met129 or Val129 – is in cis configuration with the PRNP variant. In general, the onset of genetic prion disease is earlier and its course shorter (11 months) in individuals homozygous for Met129 compared to either heterozygotes or homozygotes for Val129, in whom the phenotype is usually typical genetic CJD. See Table 4.
Penetrance
The penetrance for genetic prion disease in general is assumed to be 100%; however, only a limited number of studies have been performed to address this issue.
The penetrance for the E200K variant (which has been studied more extensively than for other variants) was 60%-70% in Italian and Slovak families [D'Alessandro et al 1998, Mitrová & Belay 2002] and 100% in Libyan Jewish families [Spudich et al 1995].
Prevalence
Epidemiologic studies utilizing reports of prion disease from centers around the world are frequently consistent with respect to the prevalence of genetic prion disease, as 15% of all individuals with newly diagnosed prion disease have genetic prion disease (i.e., are heterozygous for a PRNP pathogenic variant).
The E200K variant has been identified in populations worldwide, including in Slovakia, in Jewish families from Libya, Chile, and Tunisia, and in individuals of non-Jewish origin in other countries. Studies of ancestral origins by microsatellite markers flanking PRNP on chromosome 20p12-pter and an intragenic single-nucleotide polymorphism at PRNP codon 129 demonstrated that the E200K variant may have originated from a single event, potentially in Spain, and spread to Libya, Tunisia, Chile, and Italy. Families from Slovakia and Poland show similar linked genetic markers as well as those from Germany, Austria, and Sicily; however, in affected individuals from Japan, different linked genetic markers have been identified, suggesting the independent origin of the variants [Lee at al 1999, Ladogana & Kovacs 2018].
Differential Diagnosis
Because of the progressive neurologic decline, the range of neurologic signs, and the heterogeneous presentation of genetic prion disease, the differential diagnosis is broad and needs to include other hereditary neurodegenerative disorders as well as a variety of acquired disorders. Because potential treatment options depend on identification of the underlying cause, autoimmune and paraneoplastic disorders need to be considered (see Table 3).
Table 3.
Disorders Potentially Associated with Rapid Progression of Interest in the Differential Diagnosis of Genetic Prior Disease
| Etiology | Disorder/Comment | Gene(s) |
|---|---|---|
| Hereditary neurodegenerative disorders | CSF1R-related adult-onset leukoencephalopathy w/axonal spheroids & pigmented glia | CSF1R |
| Dementia w/Lewy bodies (OMIM 127750) | GBA SNCA SNCB | |
| Familial Alzheimer disease (See Alzheimer Disease Overview. 1) | APP PSEN1 PSEN2 | |
| Frontotemporal dementia (e.g., ALS/FTD, CHMP2B-FTD, GRN-FTD, IBMPFD) | C9orf72 2 CHMP2B FUS GRN HNRNPA1 HNRNPA2B1 TARDBP 3 VCP | |
| Hereditary ataxia (e.g., SCA1, SCA2, SCA3, SCA6, SCA7, SCA8) 4 | ATXN1 ATXN2 ATXN3 ATXN7 ATXN8 CACNA1A | |
| Huntington disease | HTT | |
| Pick disease (OMIM 172700) | MAPT PSEN1 | |
| Progressive supranuclear palsy (OMIM 601104) | MAPT | |
| Autoimmune | e.g., Hashimoto thyroiditis w/related encephalopathy, multiple sclerosis, antibody-mediated dementia/encephalopathy, CNS lupus, acute disseminated encephalomyelitis | |
| Iatrogenic | e.g., medication toxicity (e.g., lithium, methotrexate, chemotherapy), illicit drug use | |
| Infectious | e.g., viral encephalitis (incl herpes simplex virus), HIV dementia, progressive multifocal leukoencephalopathy | |
| Metastases/ Neoplasm related | e.g., paraneoplastic diseases-limbic encephalopathy, metastases to CNS, primary CNS lymphoma | |
| Systemic/Seizures/ Structural | e.g., sarcoidosis, epilepsy, nonconvulsive status epilepticus | |
| Toxic-metabolic | e.g., heavy metals (incl bismuth), electrolyte disturbances (sodium, calcium, magnesium, phosphorus), endocrine abnormalities (thyroid, parathyroid, adrenal), extrapontine myelinolysis | |
| Vascular/Ischemia | e.g., multi-infarct, thalamic or callosum infarcts, cerebral amyloid angiopathy | |
Adapted from Geschwind [2016], Table 7-4: Partial Differential Diagnosis for Rapidly Progressive Dementias by Etiologic Category
ALS = amyotrophic lateral sclerosis; CNS = central nervous system; FTD = frontotemporal dementia; HIV = human immunodeficiency virus; IBMPFD = inclusion body myopathy associated with Paget disease of bone and/or frontotemporal dementia
- 1.
Listed genes are associated with early-onset familial Alzheimer disease (EOFAD): Alzheimer disease that occurs in multiple members of a family with a mean onset usually before age 65 years. EOFAD represents fewer than 2% of Alzheimer disease cases. Late-onset familial Alzheimer disease (age >60-65 years), representing 15%-25% of Alzheimer disease cases, is thought to be a complex disorder possibly involving multiple susceptibility genes (see Alzheimer Disease Overview).
- 2.
See C9orf72-ALS/FTD.
- 3.
See TARDBP-ALS.
- 4.
The hereditary ataxias are a large group of autosomal dominant, autosomal recessive, and X-linked disorders characterized by slowly progressive incoordination of gait and often associated with poor coordination of hands, speech, and eye movements; see Hereditary Ataxia Overview for molecular genetic and clinical information.
For a detailed review of disorders to consider in an individual with rapidly progressive dementia, see Geschwind [2016].
Other Prion Diseases
Sporadic CJD (i.e., CJD of unknown cause diagnosed in an individual with a negative family history and no pathogenic PRNP variant) is the most common human prion disease. Sporadic CJD is generally regarded as a spontaneous neurodegenerative illness. While genetic CJD caused by the PRNP variants E200K and V210 can be clinically almost indistinguishable from sporadic CJD, some evidence suggests earlier age of onset in genetic CJD (60 years) than in sporadic CJD (65 years).
Iatrogenic CJD has been recognized after exposure of nervous-tissue-contaminated surgical instruments and in dura mater or human growth hormone extracted from cadaveric pituitary glands.
Variant CJD. Following the bovine spongiform encephalopathy (BSE) epidemic in the UK and elsewhere in the 1990s, variant CJD was identified as the only human prion disease with a confirmed zoonotic origin. The clinical syndrome is characterized by early disease onset (frequently before age 30 years) with psychiatric manifestations and prominent paresthesias that are followed by cognitive decline, ataxia, muscle stiffness, myoclonus, and akinetic mutism. In contrast to sporadic CJD, in variant CJD abnormal prion protein deposits are present in the tonsils and appendix. Brain imaging reveals typical high signal intensities in the posterior thalamus ("hockey stick sign") [Zeidler et al 1997].
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with genetic prion disease, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Because of very rapid disease progression and short survival time after the diagnosis, evaluations for supportive patient care must be performed early. They include the following:
- Need for gastric tube feeding for nutrition and to reduce risk of aspiration
- Evaluation for bladder and bowel incontinence
- Need for physical therapy and occupational therapy for mobility and activities of daily living
- Psychiatric manifestations
- Consultation with a social worker (or other medical professional) to determine need for:
- Caregiver support including use of community resources & support/advocacy organizations
- Specific 24-hour/day care assistance
- Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of genetic prion disease in order to facilitate medical and personal decision making
Treatment of Manifestations
No treatment of the underlying cause of genetic prion disease is available. Only a few controlled trials have been performed. Some data point toward slowing of disease progression with doxycycline (100-200 mg/day) when administered early in the disease course [Varges et al 2017].
Supportive care by a multidisciplinary team of specialists including neurologists, psychiatrists, physical therapists, occupational therapists, speech and language therapists, and social workers is recommended.
Symptomatic treatment may include the following:
- For psychiatric manifestations such as depression or psychosis, antidepressant or neuroleptic treatment
- Myoclonic jerks respond well to clonazepam.
- Muscle rigidity may require dopamine or dopaminergic drugs.
- Spasticity may respond to regular antispastic medication.
- Physical therapy for exercises and/or stretching to prevent contractures; durable medical devices for positioning and/or mobility
- Occupational therapy for home adaptation to improve safety and activities of daily living
- Feeding issues addressed by nutritionists, speech pathologists
- Communication (including alternative means of communication) by speech pathologists
Surveillance
Because of very rapid disease progression, close periodic monitoring by the multidisciplinary team is needed, typically every 14 days to evaluate need for treatment of symptoms.
Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.