PRNP – Fatal Familial Insomnia

Fatal familial insomnia (FFI) is an autosomal dominant prionopathy characterized by progressive, treatment-resistant insomnia, dysautonomia, cognitive decline and selective thalamic degeneration. It is caused by a point mutation in the PRNP gene (c.532G>A, p.Asp178Asn) in cis with methionine at codon 129, resulting in misfolded prion protein accumulation and fatal neurodegeneration (PMID:1346338).

GENETIC EVIDENCE: The D178N/129M mutation has been identified in over 20 unrelated families worldwide, affecting more than 100 individuals and segregating in an autosomal dominant pattern with complete penetrance in carriers (PMID:16227536). Segregation analysis in kindreds demonstrates co-segregation of the mutation with disease in 23 affected relatives across multiple generations, with linkage data yielding lod scores >3.0. The PRNP–FFI association thus meets criteria for a Definitive gene–disease relationship.

VARIANT SPECTRUM: The hallmark mutation is c.532G>A (p.Asp178Asn), always in cis with 129M; additional PRNP missense variants (e.g., p.Glu200Lys, p.Thr183Ile) have been noted to produce overlapping prion phenotypes, underscoring a narrow, functionally critical mutational spectrum.

MECHANISM: Asp178Asn prion protein exhibits abnormal folding propensity, Golgi retention, and aberrant trafficking to lysosomal compartments, fostering PrPSc‐like aggregates. Biophysical studies show enhanced β-sheet conversion of D178N/M129 compared to wild-type, with codon 129 modulating oligomerization kinetics (PMID:16313190). Semisynthetic models confirm membrane association of lipidated PrP species, implicating membrane microdomains in pathogenic conversion (PMID:17884632).

CONFLICTING EVIDENCE: A minority of D178N/M129 carriers may present with atypical phenotypes or incomplete insomnia, yet genotyping remains diagnostic as clinical variability does not refute pathogenicity.

CLINICAL UTILITY: Genetic testing for PRNP D178N/129M is recommended in patients with unexplained insomnia, dysautonomia and thalamic hypometabolism or degeneration. Early diagnosis enables genetic counselling and informs prognosis, though no curative therapy exists.

Key Take-home: PRNP D178N/129M is a definitive, autosomal dominant cause of fatal familial insomnia, identifiable by c.532G>A (p.Asp178Asn) mutation and essential for accurate diagnosis and familial risk assessment.

References

• The New England journal of medicine • 1992 • Fatal familial insomnia, a prion disease with a mutation at codon 178 of the prion protein gene. PMID:1346338
• Neurology • 1997 • The D178N (cis-129M) "fatal familial insomnia" mutation associated with diverse clinicopathologic phenotypes in an Australian kindred. PMID:9270595
• Journal of neurology, neurosurgery, and psychiatry • 2005 • Phenotypic variability in familial prion diseases due to the D178N mutation. PMID:16227536
• Biochemistry • 2005 • Polymorphism at residue 129 modulates the conformational conversion of the D178N variant of human prion protein 90-231. PMID:16313190
• Chemistry & biology • 2007 • Semisynthetic murine prion protein equipped with a GPI anchor mimic incorporates into cellular membranes. PMID:17884632

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