Monogenic Mimics of Neuroinflammatory Phenotypes in Children and Young Adults: An Evolving Landscape

A recent explosion in genomic testing has led to the identification of several genetic disorders that mimic CNS-specific autoimmune disorders. Such monogenic disorders, although rare, represent a diagnostic challenge because of their diverse phenotypes and overlapping features. Early recognition of these disorders is crucial not only to prevent overtreatment with immunotherapy but also to ensure that targeted treatments are available for many of these disorders. This review explores some of the monogenic disorders that can masquerade as neuroinflammatory phenotypes. These clinical vignettes are stratified according to neuroanatomical localization along the neuroaxis: supratentorial white matter, gray matter, brainstem, and spinal cord involvement. Through these cases, we discuss how clinical, laboratory, and neuroimaging red flags, such as early onset, relentless progression despite immunotherapy, and lack of CSF markers of inflammation, can guide specific diagnostic workup. In the next section, we highlight the approach to genetic testing in identifying monogenic mimickers. Finally, we discuss a selected list of currently available and emerging therapeutic strategies for some of these disorders. These include JAK inhibitors for Aicardi-Goutières syndrome, anti-TNF therapy for adenosine deaminase 2 deficiency (DADA2), and gene replacement therapy for X-linked adrenoleukodystrophy. By providing a comprehensive and systematic clinical approach, this review aims to equip neurologists with a framework to navigate diagnostic evaluations for such monogenic disorders.