What Are the New Directions in Gerstmann-Sträussler-Scheinker Syndrome?

A Misfolded Protein

Prion diseases, also known as transmissible spongiform encephalopathies, are a unique group of neurodegenerative disorders. They are caused by deposition of the pathologically altered (“infectious”) prion protein (PrP^Sc) in brain tissue, leading to progressive neuronal loss and irreversible brain damage. Clinically, patients experience gradual decline in motor and cognitive functions, ultimately resulting in death.

GSS is inherited in an autosomal dominant manner. If one parent carries a PRNP mutation, their child has a 50% chance of inheriting the syndrome. Families with this mutation often face the distressing knowledge that the disease may reappear and must make difficult ethical decisions about genetic testing.

PRNP —⁠ the Gene That Determines Neuronal Fate

GSS is caused by mutations in the PRNP gene, which encodes the prion protein (PrP). This protein is normally present in the brain and other tissues, and although its full physiological role is unclear, it is thought to help protect neurons and participate in signal transmission. Problems arise when the protein becomes misfolded.

The mutated prion protein gains the ability to convert normal PrP molecules into the pathological form, which accumulates in the brain and forms deposits that damage nervous tissue. This process acts like an avalanche: one misfolded molecule “infects” others, eventually causing widespread neurodegeneration.

From Unsteady Gait to Dementia

The first typical symptom of GSS is cerebellar ataxia —⁠ a progressive disorder of coordination and balance that gradually impairs walking and fine motor skills. Cognitive decline leading to dementia follows. The disease usually appears after age 50. Besides the classic phenotype, three other forms have been described: initial areflexia and paresthesias followed by ataxia and dementia; early-onset GSS around age 35 with predominant dementia and later ataxia; and simultaneous onset of ataxia and dementia with rapid progression.

Why Is Diagnosis So Difficult?

The variability of symptoms often complicates diagnosis, and the disease may initially be mistaken for other neurodegenerative or movement disorders. Imaging and cerebrospinal fluid analysis usually provide only indirect signs. Therefore, PRNP gene testing is crucial for confirming the diagnosis.

Unlike other prion diseases such as Creutzfeldt-Jakob disease, GSS may progress more slowly, paradoxically making diagnosis even harder —⁠ the symptoms develop gradually and may resemble Parkinson’s disease or spinocerebellar ataxias.

Hope for Early Intervention

Recent prion research is exploring new strategies targeting the pathogenic mechanisms of the disease. Experimental approaches focus mainly on blocking pathological prion protein misfolding or on immunotherapies directed against its abnormal forms.

One example is the monoclonal antibody PRN100, tested for the first time in humans in a pilot study involving six patients with Creutzfeldt-Jakob disease. The therapy appeared safe and achieved encouraging concentrations in cerebrospinal fluid and brain tissue.

Another promising approach is the antisense oligonucleotide ION717, designed to suppress expression of the prion protein gene. The goal is to reduce production of normal PrP, thereby limiting the substrate required for misfolding. An international phase 1/2a clinical trial using intrathecal administration is currently ongoing; patient enrolment was completed in 2024 and treatment is underway.

There is growing hope that it will one day be possible to intervene before irreversible brain damage occurs, underscoring the critical importance of early and accurate diagnosis.

Editorial Team, Medscope.pro

Sources:

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3. Jiang A. A., Longardner K., Dickson D. et al. Gerstmann-Sträussler-Scheinker syndrome misdiagnosed as conversion disorder. BMJ Case Rep 2019; 12 (8): e229729, doi: 10.1136/bcr-2019-229729.

4. Mead S., Khalili-Shirazi A., Potter C., et al. Prion protein monoclonal antibody (PRN100) therapy for Creutzfeldt-Jakob disease: evaluation of a first-in-human treatment programme. Lancet Neurol. 2022; 21 (4): 342–354, doi:10.1016/S1474-4422(22)00082-5.

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