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.

Suggestive Findings

Genetic prion disease should be suspected in individuals with the following clinical, laboratory, and imaging findings and family history.

Establishing the Diagnosis

The diagnosis of genetic prion disease is established in a proband with suggestive findings and a heterozygous PRNP pathogenic (or likely pathogenic) variant identified by molecular genetic testing [Ladogana & Kovacs 2018] (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include any likely pathogenic variants. (2) Identification of a heterozygous PRNP variant of uncertain significance does not establish or rule out the diagnosis of the disorder.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, 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).

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].

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].

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].

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 care must be performed early. They include the following:

• Need for gastrostomy 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.

Mode of Inheritance

Genetic prion disease is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband. Of note, family history of a neurodegenerative disease may be suggestive in a proportion of affected individuals only and the rate of positive family history varies across pathogenic variants and between countries. Probably the most information is available from affected individuals with the E200K or V210I variant. Clusters of affected individuals with E200K variants have been identified from Chile, Israel, Slovakia, Argentina, Australia, Japan, and China. While a positive family history has been reported in all affected individuals from Chile and Israel, in other countries the incidence of a positive family history varies between 44% and 60%. For the V210I variant, a positive family history varies between 12% and 21% [Ladogana & Kovacs 2018].

• Some individuals diagnosed with genetic prion disease have a parent who is heterozygous for a PRNP pathogenic variant. Because PRNP pathogenic variants may be associated with reduced penetrance, a parent who is heterozygous for a PRNP pathogenic variant may or may not have manifestations of genetic prion disease.
• Some individuals with genetic prion disease have the disorder as the result of a de novo PRNP pathogenic variant. The proportion of individuals with genetic prion disease caused by a de novo pathogenic variant is unknown.
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Though theoretically possible, no instances of a proband inheriting a PRNP pathogenic variant from a parent with germline mosaicism have been reported. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• The family history of some individuals diagnosed with genetic prion disease may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, or early death of the parent before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband [Synofzik et al 2009].

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 and/or is known to have a pathogenic PRNP variant, the risk to sibs is 50%.
  • The likelihood that a heterozygous sib will develop manifestations of genetic prion disease varies depending on the specific PRNP pathogenic variant segregating in the family. Some PRNP pathogenic variants (e.g., E200K) are considered highly penetrant whereas other variants (e.g., V210I) are associated with a penetrance as low as approximately 10% [Kim et al 2018].
  • A sib who inherits a familial PRNP pathogenic variant may have a clinicopathologic phenotype that is distinct from that of the proband [Synofzik et al 2009, Ladogana & Kovacs 2018].
• If the proband has a known PRNP pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the PRNP pathogenic variant but are clinically unaffected, sibs are still presumed to be at increased risk for genetic prion disease because of the possibility of age-related penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with a pathogenic variant in PRNP has a 50% chance of inheriting the variant.

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent is affected or has a PRNP pathogenic variant, the parent's family members are at risk.

Related Genetic Counseling Issues

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

• Predictive testing for at-risk relatives is possible once the PRNP pathogenic variant has been identified in an affected family member.
• Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing 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)

• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For more information, see the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

In a family with an established diagnosis of genetic prion disease, it is appropriate to consider testing of symptomatic individuals regardless of age.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

Once the PRNP pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for genetic prion disease are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. For more information, see the National Society of Genetic Counselors position statement on prenatal testing in adult-onset conditions.

Molecular Pathogenesis

PRNP encodes the major prion protein, a glycoprotein (PrPC) that is attached to the plasma membrane. The normal function of PrPC is unknown, although roles in synapse formation, delivery of copper to cells, and cell signaling have been proposed.

Mechanism of disease causation. A PRNP pathogenic variant changes the non-pathogenic (cellular) prion protein (PrPC) to a pathogenic (scrapie-inducing) protein (PrPSc) that is abnormal and misfolded [Prusiner 1998]. The effect of a pathogenic variant is presumed to be destabilization of prion protein, which enhances the propensity for the protein to attain the PrPSc state. PrPSc then behaves as a conformational template, which complexes with non-pathogenic PrPC. The manner in which the accumulation of PrPSc is toxic to the cell is unknown.

PRNP-specific laboratory technical considerations. The first exon of PRNP is noncoding; the prion protein is encoded by a single exon typically designated as exon 2 (NM_000311.3).

The designation of the polymorphic variant at nucleotide 385 will vary depending on the reference sequence used. The PRNP reference sequence NM_000311.3 has an A at the polymorphic nucleotide 385 (c.385A), thereby encoding M129 (p.Met129). Other PRNP reference sequences may have the polymorphic nucleotide c.385G and encode V129 (p.Val129). See rs1799990.

Insertional pathogenic variants are associated with the genetic Creutzfeldt-Jakob disease phenotype and the Gerstmann-Sträussler-Scheinker syndrome phenotype. Insertion variants of one or more octapeptide repeat segments (sometimes designated as a duplication) predict a prion protein extended by additional amino acids. The insertion variants involve one or more additional octapeptide repeat segments between codons 51 and 90, a highly unstable region that is enriched for encoding proline, glycine, and glutamine residues. Each repeat segment adds 24 nucleotides (i.e., 8 amino acids). Typically, these variants are described as an octapeptide repeat rather than a 24-bp nucleotide repeat because the nucleotide sequence encoding the octapeptide varies.

Normal PRNP alleles have one nonapeptide followed by four octapeptide tandem repeat sequences, each of which comprises the following amino acids: Pro-(His/Gln)-Gly-Gly-Gly-(-/Trp)-Gly-Gln. An additional 1-12 repeats has resulted in significant clinical and neuropathologic phenotypes of genetic prion disease [Ladogana & Kovacs 2018].

Author Notes

www.demenzzentrum-goettingen.de

Acknowledgments

This research was funded by the Robert Koch-Institute through funds of the Federal Ministry of Health (grant no 1369-341), cjd-goettingen.de.

Author History

James A Mastrianni, MD, PhD; University of Chicago (2003-2020)
Matthias Schmitz, MD (2021-present)
Inga Zerr, MD (2021-present)

Revision History

• 7 January 2021 (bp) Comprehensive update posted live
• 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 live
• 4 March 2004 (cd) Revisions: Testing
• 27 March 2003 (me) Review posted live
• 12 April 2002 (jm) Original submission

Published Guidelines / Consensus Statements

• Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 1-9-24.
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2018. Accessed 1-9-24.

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