Wondering about pruritus in the fatal familial insomnia

Objective: Fatal Familial Insomnia (FFI) is an intractable and rare inherited prion disease characterized by sleep disturbances, rapidly progressive dementia, and dysautonomic symptoms. We aimed to estimate the prevalence of “pruritus” as a symptom onset of the disease. Materials and Method: Data from FFI cases visited at the Istituto Besta and referred to the period 2018-2024 were retrieved. A literature search was conducted on February 19th 2025 via PubMed, utilizing the search string: “(FFI OR fatal familial insomnia) AND (case report OR case series OR case history OR registry)”. Results: Pruritus has been reported at onset in 3 patients: in 2 cases it occurred with insomnia, myoclonus, and cognitive decline, while in one case it was isolated. The symptom was experienced by 3 females belonging to 2 different families. In all situations, pruritus started from the head, becoming then widespread and presenting, in one case, a migrant distribution. Due to the enrollment in a clinical trial (NCT04846335, Sponsor Negri Institute, Collaborator Telethon), all cases experienced a long-term administration of Doxycycline. In two cases, pruritus occurred in association with neuropathic pain) and with the M/M genotype at codon 129 in the PRNP gene. From Pubmed, 241 results were retrieved including 180 cases, 8 of them experiencing pruritus. In particular, 3 out of 23 cases were reported in a German cohort (1). Discussion: Pruritus occurs rarely in FFI, however, since this symptom may characterize the prodromal phase, it is of particular interest. Three main hypotheses have been proposed to explain its origin: it may be caused by a deposition of the abnormal prion protein 1.in the skin, 2.in the peripheral nerves/dorsal root ganglia, 3.in the central pathways. Finally, considering the long-term assumption of Doxycycline, a “toxic / skin sensitization” pathogenesis may also be hypothesized. The “central hypothesis” is the most probable, supported by brain imaging findings. However, pathological prion protein has been detected in nerve fibers within the skin in familial Creutzfeldt-Jakob Disease (2), suggesting a neuronally mediated centrifugal spread of prions from the fibers to the skin. Thus, a skin biopsy is expected to be indicative of prion disease only in later stages of the disease. Conclusion: Performing a skin biopsy at onset and analyzing the tissue using amplification techniques (PMCA and RT-QuIC) to detect pathological prion protein, could pave the way to disentangle the underlying the pathogenesis of pruritus in FFI. References: (1) Krasnianski A, Bartl M, Sanchez Juan PJ, Heinemann U, Meissner B, Varges D, Schulze-Sturm U, Kretzschmar HA, Schulz-Schaeffer WJ, Zerr I. Fatal familial insomnia: Clinical features and early identification. Ann Neurol. 2008 May;63(5):658-61. doi: 10.1002/ana.21358 (2) Cohen OS, Chapman J, Lee H, Nitsan Z, Appel S, Hoffman C, Rosenmann H, Korczyn AD, Prohovnik I. Pruritus in familial Creutzfeldt-Jakob disease: a common symptom associated with central nervous system pathology. J Neurol. 2011 Jan;258(1):89-95. doi: 10.1007/s00415-010-5694-1.