Aim: The NLR family pyrin domain containing 3-associated autoinflammatory disease (NLRP3-AID) is a rare and heterogeneous hereditary inflammatory disorder caused by variants in the NLRP3 gene on chromosome 1q44. This condition encompasses a broad spectrum of clinical phenotypes, including urticarial rash, fever, ocular disorders, hearing loss, and musculoskeletal and central nervous system (CNS) involvement. This study reports the clinical features and newly identified NLRP3 gene variants in two Chinese Han patients with NLRP3-AID presenting with leukoencephalopathy.

Case Presentation: The study includes two adult male patients aged 25 and 24 years. Both patients experienced recurrent fevers with elevated C-reactive protein levels during febrile episodes, which normalized during asymptomatic intervals. Elevated cerebrospinal fluid protein levels and magnetic resonance imaging (MRI) findings of intracranial calcification and white matter damage were observed in both cases. Genetic testing revealed novel heterozygous NLRP3 variants: p.L798M in Patient 1 and p.K829T in Patient 2. Both patients received treatment with adalimumab and canakinumab, resulting in significant clinical improvement.

Results: The clinical and genetic features of two NLRP3-AID patients were characterized. Functional studies demonstrated overactivation of the NLRP3 inflammasome in these patients.

Conclusions: Neurological involvement in NLRP3-AID patients is variable. This study expands the clinical spectrum of CNS damage in NLRP3-AID to include intracranial calcification and leukoencephalopathy. Additionally, two novel NLRP3 variants, L798M and K829T, were identified and associated with the disease.