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Abstract: Background The PRNP p.Asp178Asn (D178N) mutation on a methionine-bearing codon-129 allele is classically associated with fatal familial insomnia (FFI), but some carriers develop a Creutzfeldt-Jakob disease (CJD)-like phenotype. Case presentation and findings We report a 59-year-old woman with two months of rapidly progressive cognitive-language decline, caregiver-observed nocturnal sitting-up and sleep talking, weight loss, extensive cortical diffusion-weighted imaging (DWI) ribboning, positive cerebrospinal fluid 14–3-3, and positive multisite skin real-time quaking-induced conversion. Electroencephalography showed diffuse slowing without periodic sharp-wave complexes. PRNP sequencing identified D178N with methionine homozygosity at codon 129. A focused literature review identified six previously reported individual D178N-129MM cases with prion-compatible cortical or cortical-striatal DWI abnormalities. Because these reports were selectively ascertained by imaging and used heterogeneous clinical assessments, they were not treated as a clinical series or compared numerically with MRI-negative cohorts. Other D178N-129MM reports show normal DWI in non-insomnia cognitive or motor presentations, objective sleep abnormalities preceding insomnia, and occasional cortical DWI hyperintensity in FFI cohorts. Conclusion D178N-129MM disease shows substantial phenotypic and imaging heterogeneity. Marked CJD-like cortical ribboning can occur in an initially non-sleep-dominant presentation and should not exclude an FFI-associated genotype. MRI pattern alone should not be used to infer a specific clinical phenotype; PRNP sequencing and objective sleep assessment remain important when clinically appropriate.