Genetic Prion Disease

Genetic Prion Diseases make up about 10 to 15 percent of all cases of human prion diseases. 

Genetic Prion Disease mutations are inherited in autosomal dominant pattern. Therefore, if one parent carries the mutation, there is 50-50 chance for each child to inherit the gene. However, the likelihood of developing disease in a mutation carrier (i.e., penetrance) depends on the specific mutation and can vary widely. Most cases of genetic prion disease have a family history, but some do not because the disease was not properly recognized in a family member, or because the mutation has low penetrance.

If a blood relative has had a genetic prion disease confirmed by autopsy or blood testing, family members (blood relatives who are 18 years of age or older) can be genetically tested for a prion disease mutation. Genetic testing can be performed on blood samples sent to the NPDPSC and we strongly encourage the involvement of genetic counseling.

Type Genetic CJD (gCJD)
What is it? The most common form of genetic prion disease and most closely resembles sCJD. gCJD is a rapidly progressive prion disease typically marked by rapid neurological and cognitive deterioration. Genetic CJD is caused by an inherited genetic mutation of the prion gene.
Symptoms Personality changes, anxiety, depression, memory loss, impaired thinking, vision abnormalities, insomnia, difficulty speaking, difficulty swallowing, myoclonus (sudden jerky movements), impaired balance and falling, tremors and weakness.
Duration Generally a few months to 2 years.
Age of Onset Usually mid-life, 40s, 50s, 60s; often starts at an earlier age than Sporadic CJD
Diagnosis Clinical examination, genetic testing, MRI, EEG, Spinal Tap (14-3-3, tau, RT-QuIC test).

 

Type Fatal Familial Insomnia (FFI)
What is it? A genetic prion disease with symptoms including insomnia, mental deterioration, and loss of coordination. It predominantly affects the thalamus. Fatal Familial Insomnia (FFI) is inherited through the D178N-129M mutation on the prion gene. It is the rarest named genetic prion disease with only 25 known families.
Symptoms< Severe insomnia that progressively worsens over time, accompanied by ataxia and mental confusion. Later symptoms include dementia and weight loss, but also may include unsteady gait, jerky eye movements, double vision, dysarthria, high blood pressure, and hallucinations.
Duration A few months to 5 years.
Age of Onset Mid-life, typically 30s, 40s, 50s.
Diagnosis Family history, genetic testing, polysomnography (sleep study) and brain positron emission tomography. EEG, brain MRI, and spinal fluid tests typically used to diagnose prion disease are usually negative in FFI.

 

Type Gerstmann-Sträussler-Scheinker disease (GSS)
What is it? This is an extremely rare and genetic neurodegenerative brain disorder caused by prion (proteins) that misfold in the brain, primarily in the cerebellum. GSS is inherited through several mutations, the most common include P102L and A117V.
Symptoms< Severe insomnia that progressively worsens over time, accompanied by ataxia and mental confusion. Later symptoms include dementia and weight loss, but also may include unsteady gait, jerky eye movements, double vision, dysarthria, high blood pressure, and hallucinations.
Duration 2-10+ years.
Age of Onset Mid-life, typically 30s, 40s, 50s.
Diagnosis Family history, genetic testing, brain MRI, spinal fluid testing (RT-QuIC). It is not uncommon for EEG, brain MRI, and spinal fluid tests used to diagnose prion disease to be negative in specific GSS mutations.
Mutations Prion Disease Average Age at Onset Average Duration(mo) Lifetime Risk of Illness in Mutation Carriers Clinical Features
E200K gCJD 30s-60s 2-41 ~60-90% Similar to typical sCJD.
V210I gCJD 40s-70 3-5 ~10% Like typical sCJD.
D178N (129V) gCJD 20s-50s 9-51 Near 100% Dementia, ataxia, myclonus, extrapyramidal and pyramidal signs.
D178N (129M) FFI 20-70 6-33 Near 100% Severe loss of sleep (insomnia), enacted dreams, sympathetic hyperactivity, myoclonus, ataxia; late dementia.
P102L (129M) GSS 30s-60 1-10 Near 100% Slowly progressive cerebellar syndrome with late dementia, extrapyramidal and pyramidal signs.
P102L (129V) GSS 33 12(years) Near 100% Seizures, numbness, gait difficulties, dysarthria, long tract signs; no dementia.
A117V GSS 20-64 1-11(years) Near 100% Dementia, parkinsonism, pyramidal signs, occasional cerebellar signs.
T188R gCJD 50s-70s 1-10 Unclear Progressive dementia and prominent behavioral changes, gait difficulties, and speech problems.
F198S GSS 34-71 3-11(years) Unclear Slowly progressive cerebellar syndrome with late dementia.
H187R GSS 35-50 8-19(years) Unclear Early progressive cognitive impairment, cerebellar ataxia, myoclonus, seizures, pyramidal and extrapyramidal signs.
V180I gCJD 66-85 1-2(years) ~1% Similar to typical sCJD, but with a much slower progression.

Octapeptide Repeat Insertion Mutations: One to twelve additional octapeptide repeat insertions (OPRI) have been detected in patients with prion disease. OPRI mutations have a significant phenotypic variability, including the rate of progression of dementia, the presence of other symptoms, age at onset and duration of the disease. In some examples of OPRI mutations, a presymptopmatic phase, which includes agressiveness, frontal lobe involvement has been recognized.

OPRI mutations of 2 or less have been reported in small numbers, with a clinical and histopathologic phenotype similar to CJD, raising questions as to whether these are true mutations or merely incidental polymorphisms in cases of sCJD.

OPRI Mutation Average Age at Onset Average Duration(mo) Penetrance Clinical Features
OPRI 4 or fewer repeats 62 6 Low Rapidly progressive dementia, ataxia, myoclonus, and visual disturbance. CJD-like
OPRI 5 or more repeats 32 6(years) High Slowly progressive syndrome with mental deterioration, cerebellar and extrapyramidal signs. Dementia does not appear until later in the disease. GSS-like.