Neuroinflammation Associated With Inborn Errors of Immunity

Area of Science:

• Genetics
• Immunology
• Neurology

Background:

• High-throughput sequencing aids genotype-phenotype correlations in congenital diseases, revealing significant phenotypic heterogeneity.
• Neuroinflammation is increasingly observed in inborn errors of immunity, often dominating initial clinical presentations.
• While individually rare, these neuroinflammatory conditions collectively impact a notable proportion of neuropediatric and adult neurology patients.

Purpose of the Study:

• To review signs and symptoms of neuroinflammation associated with pathogenic variants in immune genes.
• To propose a subdivision of neuroinflammatory disorders based on underlying mechanisms.
• To highlight emerging pathogenic themes and the clinical spectrum of monogenic neuroinflammatory diseases.

Main Methods:

• Review of reported signs and symptoms of neuroinflammation in patients with pathogenic variants in immune genes.
• Classification of disorders based on proposed underlying mechanisms: autoinflammatory disorders, tolerance defects, and immunodeficiency disorders.
• Further subdivision of autoinflammatory disorders into IL-1β-mediated disorders, NF-κB dysregulation, type I interferonopathies, and hemophagocytic syndromes.

Main Results:

• Identification of distinct neuroinflammatory patterns within inborn errors of immunity.
• Recognition of autoinflammatory disorders, tolerance defects, and immunodeficiencies as key categories.
• Detailed characterization of IL-1β-mediated disorders, NF-κB dysregulation, type I interferonopathies, and hemophagocytic syndromes.

Conclusions:

• Neuroinflammation in monogenic diseases presents a broad clinical spectrum.
• Genetic diagnosis is essential for managing patients with these conditions.
• Further research is needed to address this under-recognized phenomenon.