Clinical Guidance

Although some PRNP pathogenic variants are associated with specific neuropathologic phenotypes , evidence also suggests that heterozygotes for the same variant in the same family may develop distinct clinicopathologic phenotypes . Note that the phenotype may be modified by the presence of the polymorphic codon 129 (p.Asp178Asn) on the same allele as the PRNP variant. The phenotype in individuals with the p.Asp178Asn pathogenic variant typically depends on which variant – Met129 or Val129 – is on the same allele as 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 .

Source: GeneReviews — "Genetic Prion Disease"

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 and 100% in Libyan Jewish families .

Source: GeneReviews — "Genetic Prion Disease"

Diagnostic Criteria

Suggestive Findings

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

Clinical

Genetic 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 C...

Source: GeneReviews — "Genetic Prion Disease"

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 .

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) | GBA1 (GBA)SNCASNCB

Source: GeneReviews — "Genetic Prion Disease"

Management Guidelines

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

• 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 .

Source: GeneReviews — "Genetic Prion Disease"

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.

Source: GeneReviews — "Genetic Prion Disease"

Surveillance Guidelines

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.

Source: GeneReviews — "Genetic Prion Disease"