Gerstmann-Sträussler-Scheinker Disease

What Causes Gerstmann-Sträussler-Scheinker Disease?

GSS is caused by a protein called a prion. Prions exist in normal cells and are usually harmless. However, in GSS and other diseases called transmissible spongiform encephalopathies (TSEs), abnormally formed prions cause damage to cells in the brain and the central nervous system. These abnormal prions also make other prions develop abnormally, causing the disease to spread and produce progressively worsening symptoms.

GSS is caused by abnormal changes (mutations) in a gene called the PRNP gene. The PRNP gene carries instructions for producing a prion protein, and the mutations cause the resulting prion to be malformed. The misshapen prions accumulate and spread through the brain, causing progressive damage as they affect more and more brain cells.

The damaged tissue often takes on a cavity-riddled, spongy appearance. This is why GSS is called a transmissible spongiform encephalopathy. TSEs are considered transmissible because they may be transmitted through direct contact with affected brain tissue. However, the diseases are not contagious in the same way most other infectious diseases are.

Is Gerstmann-Sträussler-Scheinker Disease Hereditary?

The PRNP mutations that cause GSS are inherited in an autosomal dominant pattern, meaning that children may develop the disorder if they inherit even one copy of the mutated gene from either of their parents. If a parent carries the disorder-causing mutation, they will have a 50 percent chance of having an affected child with each pregnancy. The parent may also develop FFI themselves, but not everyone with a mutated prion gene will develop the disease.

In rare cases, the disease-causing mutation occurs spontaneously during sperm or egg cell production even though either parent does not carry it. In these cases, a person can develop GSS when there is no family history of the disease. Even though the new mutation occurs without being inherited, it may be passed to the patient’s children in an autosomal dominant pattern.

In some TSEs, such as fatal familial insomnia (FFI), the associated PRNP mutations do not always cause the disease. However, when a person carries the GSS mutation, they will almost always develop GSS. This characteristic is called “complete penetrance.”

How Is Gerstmann-Sträussler-Scheinker Disease Detected?

Symptoms of GSS usually appear in middle adulthood, typically between the ages of 35 and 50. The earliest signs of GSS often include:

• Loss of coordination
• Slurred speech
• Problems coordinating movements (clumsiness, unsteadiness, difficulty walking)
• Poor reflexes
• Weakness in the legs
• Tingling or burning sensations under the skin

How Is Gerstmann-Sträussler-Scheinker Disease Diagnosed?

No single test can reliably identify GSS, but some tests and exams can help diagnose the disease and rule out other potential causes of the symptoms. Possible diagnostic steps include:

• Physical and neurological exams
• Magnetic resonance imaging (MRI) to detect the pattern of brain degeneration characteristic of GSS or rule out other brain disorders. Computerized tomography (CT) may also be used to rule out other potential causes of the symptoms.
• Single-photon emission computed tomography (SPECT) to detect reduced blood flow in the brain. This may be a characteristic of early GSS.
• Electroencephalogram (EEG) to measure electrical brain activity.
• Genetic testing to look for the PRNP gene mutations associated with GSS.

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Gerstmann-Sträussler-Scheinker Disease Treated?

GSS has no cure, and no treatment will halt or reverse the progression of symptoms. Treatment options focus on improving the patient’s quality of life as much as possible. Possible treatment options include:

• Anti-convulsant medications for seizures
• Medications to treat muscle spasms
• Feeding assistance such as a feeding tube

How Does Gerstmann-Sträussler-Scheinker Disease Progress?

GSS is progressive, and symptoms worsen slowly. The disease is invariably fatal within 2-10 years after the initial onset of symptoms. On average, death occurs about five years after onset.

Long-term and/or potentially fatal complications of GSS can include:

• Loss of coordination
• Loss of speech
• Loss of the ability to swallow
• Rigid muscles
• Muscle spasms
• Involuntary writhing movements
• Loss of facial expressions
• Visual impairment or blindness
• Hearing loss
• Seizures
• Loss of concentration
• Hallucinations
• Dementia
• Loss of ability to communicate
• Loss of mobility
• Coma
• Respiratory infections such as pneumonia

How Is Gerstmann-Sträussler-Scheinker Disease Prevented?

There is no known way to prevent GSS. However, a genetic counselor can advise those with a family history of GSS about their risk if they plan to have children.

Gerstmann-Sträussler-Scheinker Disease Caregiver Tips

• Take care of yourself. Caregivers for people with a progressive disease like GSS are susceptible to mental and physical health problems if they don’t take care of themselves. Don’t feel guilty for needing occasional time away from the demands of caregiving, and don’t hesitate to ask for help from family and friends.
• Find sources of support. Organizations such as the Creutzfeldt-Jakob Disease Foundation can guide you to educational resources, support groups, and contact with other families affected by GSS and other TSEs

Many people with GSS also suffer from other brain-related issues, a condition called co-morbidity. Here are a few of the disorders commonly associated with GSS:

• People with GSS are likely to suffer from depression.
• Early signs of GSS may include psychotic symptoms resembling schizophrenia.
• Sleep disturbances are often an early symptom of GSS.

Gerstmann-Sträussler-Scheinker Disease Brain Science

Prion proteins are long chains of amino acids that occur in normal cells, especially in nerve cells in the brain. Scientists are not yet sure of the role prions play in healthy brain cells, but when prions become deformed, as they do in GSS and other TSEs, they clump together. These abnormal protein clumps seem to impair brain cell function and lead to cell damage and death.

Prion diseases are infectious and progressive because abnormal prions cling to normal prions and cause the normal prions to become deformed. In this manner, abnormal prions spread through infected tissue and cause progressive brain damage.

In GSS, the damage caused by prions typically affects many different parts of the brain, including the cerebellum and the thalamus, the part of the brain that controls sleep, body temperature, breathing, heart rate, and other automatic and involuntary functions.

Gerstmann-Sträussler-Scheinker Disease Research

Title:  PRION-1: Quinacrine for Human Prion Disease

Stage: Completed

Principal Investigator: John Collinge, MD, FRCP

National Prion Clinic

London, UK

PRION-1 aims to assess the activity and safety of Quinacrine (Mepacrine hydrochloride) in human prion disease. It also seeks to establish an appropriate framework for the clinical assessment of therapeutic options for human prion disease that can be refined or expanded in the future as new agents become available.

The human prion diseases have been traditionally classified into Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker (GSS) disease and kuru. They can alternatively be classified into three causal categories: sporadic, acquired, and inherited. The appearance of a new human prion disease, variant CJD (vCJD), in the United Kingdom from 1995 onwards, and the experimental evidence that this is caused by the same prion strain as that causing bovine spongiform encephalopathy (BSE) in cattle, has raised the possibility that a major epidemic of vCJD will occur in the United Kingdom and other countries as a result of dietary or other exposure to BSE prions. These concerns have led to intensified efforts to develop therapeutic interventions.

Quinacrine has been previously used to treat other diseases such as malaria; however, it was found to have serious side effects and is no longer licensed in the United Kingdom. There is only minimal evidence from laboratory tests for the potential use of quinacrine in human prion disease, and the evidence to date for any possible clinical benefit is very scarce. The PRION-1 trial is being undertaken since no other drugs are currently available that are considered suitable for human evaluation.

Title: The Role of the Coagulation Pathway at the Synapse in Prion Diseases

Stage: Not Yet Recruiting

Principal investigator: Oren Cohen, MD

Sheba Medical Center

Gottingen, Germany

The study hypothesis is that the harmful effect of prions on the brain may be mediated (at least partially) by the activation of serine proteases involved in the coagulation system. If this is true, then measurement of the activity of the coagulation system may be a marker of disease onset (in higher-risk individuals such as E200K* carriers) and for disease progression or activity in affected individuals. In addition, modulation of the coagulation system activity may be a potential tool for therapeutic intervention.

We plan to collect Cerebrospinal fluid (CSF) samples for thrombin activity assay to test whether there is a difference in thrombin activity in the CSF between CJD (Creutzfeldt-Jakob disease) and non-CJD patients. CSF samples will be obtained from two sources 1. Patients with familial or sporadic CJD and control patients with other neurodegenerative disorders (e.g., SDAT**, NPH) will be evaluated in Sheba Medical Center 2. From our collaborating group of Prof. Zerr in the German Prion Referral Center at the University of Gottingen, which has a collection of thousands of CSF samples from patients with familial and sporadic CJD as well as ideal controls with other degenerative brain diseases.

The study has two sections:

Prospective part in which we plan to recruit 25 patients with CJD and 25 patients with other types of dementia from Sheba Medical Center (SMC). Before inclusion in the study, a senior neurologist will interview the patient and will verify that they fully understand the objectives of the study and they are mentally qualified to sign the informed consent form (severely demented patients who will not be able to adequately consider participation in the study will be excluded).

Cognitive performance will be evaluated using the Mini-mental Status Examination and Frontal Assessment Battery scales.

No clinical data other than the cognitive assessment and those needed for the clinical workup will be especially collected for this study.

CSF samples from CJD patients and patients with other types of dementia will be shipped to us from our collaborators in Germany and will be assayed for Thrombin activity. We plan to recruit 100-200 CJD patient CSF samples and an equal number of samples from age-matched controls to this part of the study.

Thrombin activity (for samples from both parts of the study) will be assayed as follows: CSF sample will be placed in a black 96 well dish (10 per well). A fluorometric assay will measure thrombin activity, quantifying the cleavage of the synthetic peptide substrate Boc-Asp(OBzl)-Pro-Arg-AMC*** (I-1560, Bachem, Switzerland, 13 molar final concentration). Measurements will be performed by the Infinite 2000 microplate reader (Tecan, infinite 200, Switzerland) with excitation and emission filters of 360±35 and 460±35 nm, respectively. CSF testing for thrombin activity will be conducted in Professor Chapman’s laboratory in Sheba. This laboratory is actively engaged in research on the role of thrombin and PAR-1 in diseases of the nervous system and is fully equipped to perform the biochemical and protein levels experiments.

The assay has the potential for commercialization as a diagnostic test for CJD. In addition, there is the potential to develop therapeutic agents targeting excessive thrombin activation.