Gerstmann-Straussler-Scheinker disease (GSS) is an extremely rare, neurodegenerative brain disorder. It is almost always inherited and is found in only a few families around the world. The disease usually begins between the ages of 35 and 55.

In the early stages, people with GSS may experience varying levels of ataxia (lack of muscle coordination), including clumsiness, unsteadiness, and difficulty walking. As the disease progresses, the ataxia becomes more pronounced, and most people develop dementia.

Other symptoms may include

• Dysarthria (slurring of speech)
• Nystagmus (involuntary movements of the eyes)
• Spasticity (rigid muscle tone)
• Visual disturbances, sometimes leading to blindness

Deafness also can occur. In some families, parkinsonian features are present. GSS belongs to a family of human and animal diseases known as the transmissible spongiform encephalopathies (TSEs). Other TSEs include Creutzfeldt-Jakob disease, kuru, and fatal familial insomnia.

There is no cure for GSS, nor are there any known treatments to slow progression of the disease. Current therapies are aimed at alleviating symptoms. GSS is a slowly progressive condition usually lasting from two to 10 years. The disease ultimately causes severe disability and finally death.

Normal Function

The PRNP gene provides instructions for making a protein called prion protein (PrP), which is active in the brain and several other tissues. Although the precise function of this protein is unknown, researchers have proposed roles in several important processes. These include the transport of copper into cells and protection of brain cells (neurons) from injury (neuroprotection). Studies have also suggested a role for PrP in the formation of synapses, which are the junctions between nerve cells (neurons) where cell-to-cell communication occurs.

Different forms of PrP have been identified. The normal version is often designated PrPC to distinguish it from abnormal forms of the protein, which are generally designated PrPSc.

Health Conditions Related to Genetic Changes

Huntington's disease-like syndrome

A particular type of variant (also called a mutation) in the PRNP gene has been found to cause signs and symptoms that resemble those of Huntington's disease, including uncontrolled movements, emotional problems, and loss of thinking ability. Researchers have proposed that this condition be called Huntington's disease-like 1 (HDL1).

The PRNP gene variants associated with HDL1 involve a segment of DNA called an octapeptide repeat. This segment provides instructions for making eight protein building blocks (amino acids) that are linked to form a protein fragment called a peptide. The octapeptide repeat is normally repeated five times in the PRNP gene. In people with HDL1, this segment is repeated eleven or thirteen times. An increase in the size of the octapeptide repeat leads to the production of an abnormally long version of PrP. It is unclear how the abnormal protein damages and ultimately destroys neurons, leading to the characteristic features of HDL1.

Prion disease

Many variants in the PRNP gene have been identified in people with familial forms of prion disease, including Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), and fatal familial insomnia (FFI). The major features of these diseases include changes in memory, personality, and behavior; a decline in intellectual function (dementia); and abnormal movements, particularly difficulty with coordinating movements (ataxia). The signs and symptoms worsen over time, ultimately leading to death.

Some of the PRNP gene variants that cause familial prion disease change single amino acids in PrP. Other variants insert additional amino acids into the protein or result in an unusually short version of the protein. These changes alter the structure of PrP, leading to the production of an abnormally shaped protein, known as PrPSc, from one copy of the PRNP gene. In a process that is not fully understood, PrPSc can attach (bind) to PrPC and promote its transformation into PrPSc. The abnormal protein builds up in the brain, forming clumps that damage or destroy neurons. The loss of these cells creates microscopic sponge-like holes (vacuoles) in the brain, which leads to the signs and symptoms of prion disease.

Researchers have identified several common variations (polymorphisms) in the PRNP gene that affect single amino acids in PrP. These polymorphisms do not cause prion disease, but they may affect a person's risk of developing these disorders. Studies have focused on the effects of a polymorphism at position 129 of PrP. At this position, people can have either the amino acid methionine (Met) or the amino acid valine (Val). This polymorphism is written as Met129Val or M129V. Because people inherit one copy of the PRNP gene from each parent, at position 129 an individual can receive methionine from both parents (Met/Met), valine from both parents (Val/Val), or methionine from one parent and valine from the other (Met/Val).

The Met129Val polymorphism appears to influence the risk of developing prion disease. Most affected individuals have the same amino acid at position 129 (Met/Met or Val/Val) instead of different amino acids (Met/Val). Having Met/Met at position 129 is also associated with an earlier age of onset and a more rapid worsening of the disease's signs and symptoms.

Wilson disease

The Met129Val polymorphism has been reported to influence the onset of Wilson disease, an inherited disorder in which excessive amounts of copper accumulate in the body. Wilson disease is caused by variants in the ATP7B gene, but studies suggest that symptoms of Wilson disease begin several years later in people who have Met/Met at position 129 in PrP compared with those who have Met/Val or Val/Val. Other research findings indicate that this polymorphism may also affect the type of symptoms that develop in people with Wilson disease. Having Met/Met at position 129 appears to be associated with an increased occurrence of symptoms that affect the nervous system, particularly tremors.

Other disorders

The Met129Val variation has been associated with differences in performance on long-term memory tasks among healthy young adults. In one study, people who had either Met/Met or Met/Val at position 129 performed better at long-term memory tasks than those who had Val/Val. It is unclear how these differences may be related to memory.

Other Names for This Gene

• AltPrP
• ASCR
• CD230 antigen
• CJD
• GSS
• MGC26679
• PRIO_HUMAN
• prion protein (p27-30) (Creutzfeldt-Jakob disease, Gerstmann-Strausler-Scheinker syndrome, fatal familial insomnia)
• PRIP
• PrP
• PrP27-30
• PrP33-35C
• PrPc
• PrPSc

Genomic Location

• Progressive ataxia, including clumsiness, unsteadiness, and difficulty walking
• Cognitive dysfunction leading to bradyphrenia (slowness of thought processing) and dementia of different degrees
• Dysarthria (slurred speech)
• Nystagmus (abnormal eye movements)
• Spasticity (rigid muscle tone)
• Visual disturbances, sometimes leading to blindness
• Lack of coordination in swallowing
• Deafness
• Parkinsonian features (present in some families).

• Characteristic signs and symptoms
• Nervous system findings including multiple amyloid plaques (clumps which form in the brain and cause the death of nerve cells and the progressive symptoms of the disease)
• A family history consistent with autosomal dominant inheritance
• Genetic test showing a disease-causing mutation of the PRNP gene (establishes and confirms the diagnosis).