NORD Gratefully acknowledges Pawel P. Liberski, MD, PhD, Department of Molecular Pathology and Neuropathology, Medical University of Lodz, Lodz, Poland, for assistance in the preparation of this report.
Gerstmann-Sträussler-Scheinker (GSS) disease is a rare genetic degenerative brain disorder. The symptoms, the progression of the disorder, and the overall severity can vary greatly among affected families and individuals. This is true even among members of the same family. A common symptom is a progressive loss of coordination that may present as unsteadiness of gait, difficulty walking, and clumsiness. As the disease progresses, other symptoms become apparent including dementia, in which there are worsening problems with thought, cognition, memory, language, and behavior. In all instances, GSS is caused by an abnormal variant of the prion protein (PRPN) gene. The PRNP gene encodes the human prion protein (PrPc). Alterations in this gene lead to the generation of abnormally-shaped (misfolded) prion protein (PrPSc), also known simply as a “prion”, which is toxic to the body. In GSS, the abnormal prions build up primarily within the brain. This leads to the progressive loss of nerve cells (neurons) and the various symptoms associated with this disorder. The disorder most often affects people in their 40s through 50s. There is no cure, but investigators are researching ways to best treat and manage GSS.
GSS is classified as a transmissible spongiform encephalopathy (TSE) or a prion disease. Prion diseases are caused by the accumulation of misfolded prion protein in the brain. Two other prion diseases, Creutzfeldt-Jakob disease (CJD) and fatal familial insomnia (FFI), may also occur as a result of variations of the PRNP gene, although some prion diseases occur in the absence of a genetic variation. Generally, prion disorders are characterized by long incubation periods and short clinical duration, which means the abnormal prions may be build up for many years (long incubation period), but once symptoms begin the disorder rapidly worsens.
The initial symptoms associated with Gerstmann-Sträussler-Scheinker disease are progressive loss of coordination and mild difficulty with speech (dysarthria). Loss of coordination may present as unsteadiness, difficulty walking, and clumsiness. Affected may have problems coordinating voluntary movements (ataxia). Speech problems may present as slurred speech and progress to severe dysarthria in which people have difficulty speaking and other people have difficulties understanding what they are trying to say. There may be problems with swallowing (dysphagia) due to lack of coordination of the muscles needed for swallowing.
Additional early signs include diminished reflexes (hyporeflexia), progressive weakness in the legs, and a sensation of burning, tingling or discomfort under the skin (dysesthesia). As the disorder progresses, affected individuals develop a condition called spasticity. Spasticity is characterized by rigid muscle tone and progressive muscle stiffness and weakness, causing abnormal, writhing movements, abnormal slowness of movement (bradykinesia). Some affected individuals exhibit a reduced degree of facial expression called hypomimia or masked facies. Hypomimia means that affected individuals are often do not show much expression or emotion.
Some affected individuals develop rapid, involuntary eye movements (nystagmus) and have difficulties judging distance or scale (ocular dysmetria), and problems with vision. Sometimes, eye problems can progress to blindness. Less commonly, hearing loss or deafness will develop.
Additional symptoms that sometimes occur include seizures, paralysis (palsy) of certain cranial nerves, and movements disorders like jerky, muscle spasms (myoclonus) or slow, writhing, involuntary movements (athetosis).
Eventually, affected individual develop problems with cognition, which is thinking, remembering, reasoning, imagining and processing thoughts. Concentration and focus are particularly affected, and some individuals exhibit slowness of thought processing (bradyphrenia). As the disease progresses, other symptoms become apparent including dementia, in which there are worsening problems with thought, cognition, memory, language, and behavior. Initially, the signs may be subtle and include unintended weight loss, forgetfulness, inattentiveness, problems concentrating, or speech problems. Episodes of confusion or hallucinations can eventually occur.
GSS causes slowly progressive physical and mental deterioration, although more rapid progression can occur. Eventually, affected individuals become bedridden, unable to eat unassisted, and unable to communicate. The disease ultimately progresses to coma and death.
GSS is caused by an abnormal variant (gene mutation) of the PRNP gene. Genes provide instructions for encoding proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.
In rare instances, the change (variation) in the PRPN gene in individuals with GSS occurs spontaneously, without a family history of the disease. This is called a new or de novo variant. The gene variation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. The disorder is usually not inherited from or “carried” by a healthy parent. However, the person who has this de novo variant could pass on the variant gene to their offspring in an autosomal dominant manner.
Researchers believe that GSS is associated with almost complete penetrance, which means that virtually all individuals who have a disease-causing variation in the PRPN gene will eventually develop signs and symptoms of the disorder.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Disorders inherited in a dominant pattern occur when only a single copy of an abnormal gene is necessary for the appearance of the disorder. The abnormal gene can be inherited from either parent, or it can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
The PRNP gene encodes for a protein called prion protein, a cellular variant or PrPc. The exact function of PrPc in the body is not fully understood. However, because of the variant gene, the PrPSc that is produced develops an abnormal 3-dimensional shape that is described simply as “misfolded”. The misfolded PrPSc is toxic to the body, especially cells of the nervous system. In GSS, misfolded PrPSc is found in many brain structures, mostly the cerebellum and also in the thalamus, which is a structure deep within the brain that helps to regulate many functions of the body including sleep, appetite, and body temperature. As the misfolded PrPSc builds up, it results in a progressive destruction of nerve cells (neurons), which leads to the symptoms of the disorder. The damage to brain tissue may appear as sponge-like cavities or spaces (vacuoles) when examined under a microscope, which is why prion diseases like GSS are called transmissible spongiform encephalopathies.
The term “prion” was coined to designate a “proteinaceous infectious agent” to explain the protein-only nature of the infectious agent. Extensive research has shown that a prion is essentially the misfolded PrPSc. However, it is important to know that GSS is not contagious in the traditional sense because the only way to transmit prion disease to a healthy individual is through direct exposure to disease-affected brain tissue, for instance by injection. If a person without an underlying genetic defect develops a prion disease by transmission from another prion disease, they are said to have an ‘acquired’ form. For example, variant Creutzfeldt-Jakob disease occurred in the United Kingdom when people ate prion-contaminated beef. A lesser known example is kuru. Kuru is a virtually extinct prion disease that occurred in the Fore people of Papua New Guinea. The disease spread throughout this population because of the villagers’ practice of eating the brains of deceased kuru-affected tribesmen (ritualistic cannibalism).
Investigators have determined that the PRNP gene is located on the short arm (p) of chromosome 20 (20p13). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual.
The exact incidence or prevalence of GSS is unknown. Estimates range from 1 to 10 in 100,000,000 people in the general population. CJD affects about 1 in 1,000,000 people in the general population per year. Genetic prion diseases are believed to make up about 15% of all individuals with prion diseases. Because rare diseases often go undiagnosed or misdiagnosed, it is difficult to determine their true frequency in the general population. GSS affects men and women in equal numbers. The average age of onset is 35-50 years old, the youngest describe occurrence was in a 10-year-old child.
A diagnosis of GSS is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A diagnosis of GSS cannot be confirmed through laboratory tests or imaging studies.
Clinical Testing and Workup
Molecular genetic testing can confirm a diagnosis. Molecular genetic testing can detect an abnormal variant in the PRPN gene known to cause the disorder, but such testing is available only as a diagnostic service at specialized laboratories.
Physicians may recommend an electroencephalogram (EEG), which is a test that measures the electrical activity of the brain and may show changes in brain function and slowing of background activity. An EEG can also be used to help to detect seizures.
Advanced imaging techniques include computerized tomography (CT) scanning and magnetic resonance imaging (MRI) may be conducted. CT scanning is not useful in the diagnosis of GSS or prion disease, while the MRI can show some abnormalities in the scan that may support prion disease, although its application to diagnose GSS is not well characterized. However, MRI and CT may be helpful in ruling out other conditions that may mimic GSS or prion disease. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and body tissues.
Single photon emission computed tomography (SPECT) is a specialized form of CT scanning that may show reduced blood flow in the brain in some individuals GSS, particularly early in the disease. SPECT is able to show how blood flows to tissues and organs. SPECT uses a radioactive material called a tracer. This chemical tracer is injected into the body and emits gamma rays that are recorded by the computer. Sometimes, this test can demonstrate slow or inadequate flow of blood through blood vessels (hypoperfusion), potentially resulting in decreased blood flow resulting in oxygen and nutrients.
The treatment of GSS is directed toward the management of specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Neurologists, psychiatrists, psychologists, pain specialists, social workers and other healthcare professionals may need to systematically and comprehensively plan treatment. Psychosocial support for the entire family is essential as well. Genetic counseling may be of benefit for affected individuals and their families.
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with GSS.
Affected individuals may receive standard treatments for any associated symptoms. Antiseizure medications, known as anti-epileptics or anti-convulsants, may be prescribed for seizures. A drug called clonazepam may be used to treat myoclonus.
If swallowing problems be severe enough, families can consider the option a feeding tube. A feeding tube is a device that is inserted through a small surgical cut in the abdominal wall directly into the stomach. This ensures that affected individuals receive sufficient calories and nutrients.
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