To describe two cases of young-onset sporadic Creutzfeldt-Jakob disease (sCJD) with prolonged survival and MM2-thalamic pathology, expanding current understanding of the clinical spectrum of this variant.

Sporadic CJD (sCJD) is a rapidly progressive, fatal prion disease typically affecting adults aged 55–75 years, with a median survival of less than one year. Young-onset sCJD is exceedingly rare, often associated with atypical features and extended disease duration. The MM2-thalamic subtype, also known as sporadic fatal insomnia (SFI), shares phenotypic overlap with familial fatal insomnia and is characterized by thalamic and inferior olivary degeneration.

We report a two-patient case series of young-onset sCJD with the MM2-thalamic subtype. Clinical data, neuroimaging, laboratory studies, and neuropathologic findings were reviewed longitudinally and correlated with prion genotyping.

Both patients presented initially with diplopia in adolescence or early adulthood (ages 18 and 28) and later experienced progressive insomnia along with other behavioral and neurologic manifestations. Cerebrospinal fluid biomarkers (14-3-3 protein and RT-QuIC) and EEGs were repeatedly negative or nonspecific, and MRI brain did not demonstrate the typical sCJD pattern of cortical diffusion restriction. FDG-PET in both cases revealed thalamic hypometabolism, consistent with SFI. Disease duration was 7 and 3 years, respectively. Autopsy in both revealed wild-type PRNP with methionine homozygosity at codon 129 (MM2-thalamic), severe neuronal loss with marked cortical and cerebellar atrophy.

These cases illustrate that SFI can present in adolescence which has not previously been reported to our knowledge. They further build on previously documented cases in supporting the typical features of this variant including an unusually prolonged course and disproportionately negative prion biomarkers. The MM2-thalamic subtype should be considered in patients with progressive insomnia, diplopia, and thalamic hypometabolism, even when standard diagnostic tests are unrevealing. Improved recognition of this phenotype may aid in earlier diagnosis, and more accurate prognostication of young-onset prion disease.