133: Genetic Prion Disease

Key Points

• Disease summary:

  • Rare neurodegenerative diseases typically associated with rapidly progressive dementia and ataxia.

  • Disease subtypes—Sporadic (s) and familial (f) forms of Creutzfeldt-Jakob disease (sCJD and fCJD) and fatal insomnia (sFI and fFI). Gerstmann-Sträussler-Scheinker disease (GSS) is always genetic. Rarer forms caused by exposure to prions, include variant CJD (vCJD) and kuru. A new phenotype, labeled Variably Protease-Sensitive Prionopathy, has recently been recognized in a small number of patients.

  • Transmissible properties—Prions are misfolded isoforms of prion protein (PrP) that can interact with and convert normal prion protein (PrP^C) to the misfolded pathogenic isoform (PrP^Sc). Nervous tissues from affected patients with any subtype of prion disease can potentially transfer disease to healthy individuals, if directly introduced.

  • Diagnostic tests—For sCJD, brain magnetic resonance imaging (MRI) diffusion-weighted imaging (DWI) sequences often show hyperintensity of the cortical ribbon or basal ganglia, and electroencephalography (EEG) may demonstrate periodic sharp waves complexes of approximately 1 per second. Cerebrospinal fluid (CSF) may show elevation of 14-3-3 and/or extremely elevated tau protein. In FI, positron emission tomography (PET) scan of brain shows a hypometabolic thalamus. Genetic testing assists with diagnosis of familial forms of prion disease.

• Hereditary basis:

  • About 10% to 15% of all cases result from an autosomal dominant mutation of the PrP gene (PRNP). Homozygosity at the common polymorphic codon 129 of PRNP is more common in cases of sCJD and vCJD. Codon 129 genotype may influence the phenotype of some genetic prion diseases. No other genes are directly causal.

• Differential diagnosis:

  • Other neurodegenerative conditions, including Alzheimer disease, Huntington disease, frontotemporal lobar dementias, spinocerebellar ataxia, and dementia with Lewy bodies, among others. CNS viral and bacterial infections, paraneoplastic syndromes, Hashimoto encephalopathy, and Whipple disease are important considerations in the workup.

Diagnostic Criteria and Clinical Characteristics

• World Health Organization (WHO) criteria exists only for sporadic (s) CJD, which includes the following

• Probable sCJDRapidly progressive dementia and at least two of the following

  1. Myoclonus

  2. Visual or cerebellar signs

  3. Pyramidal or extrapyramidal signs

  4. Akinetic mutism

And a positive result from at least one of the following

1. Periodic EEG

2. Positive CSF 14-3-3 (*or significantly elevated tau protein >1200 pg/mL) in patients with disease under 2 years duration

3. MRI of brain with high-signal abnormalities in basal ganglia (*or cortical ribbon) by DWI or fluid attenuated inversion recovery (FLAIR)

And the absence of

• Routine investigations indicating an alternative diagnosis

  (*indicate author’s modification of the WHO—levels may be greater than 3000 pg/mL)

Possible sCJD Progressive dementia and at least two of the following features

1. Myoclonus

2. Visual or cerebellar signs

3. Pyramidal or extrapyramidal signs

4. Akinetic mutism

And, the absence of a positive result [or unavailability of results] for any of the three tests described for probable CJD (a-c, earlier)

And, duration of illness ...