Biallelic IRAK4 Variants Associated with Severe Neurological Autoinflammation: An Expansion of the Clinical Phenotype

Rare biallelic variants in IRAK4, a Myddosome-pathway kinase mediating IL-1 and Toll-like receptor signalling, leading to pathological activation of innate immunity.

IRAK4 encodes a Myddosome-pathway kinase mediating IL-1 and Toll-like receptor signalling; biallelic loss-of-function variants classically cause immunodeficiency, but recent reports implicate biallelic variants in severe neuro- and systemic autoinflammation (NASA). The authors reanalysed genome sequencing from individuals in the Myelin Disorders Biorepository Project with unexplained autoinflammatory leukoencephalopathy, interrogating splicing consequences by short-read and targeted long-read RNA sequencing and assessing nonsense-mediated decay. Six patients from five unrelated families carried rare biallelic IRAK4 variants (two homozygous, three compound heterozygous) with severe persistent autoinflammation and no immunodeficiency. All shared a concordant clinical and radiological syndrome: episodic waxing-waning encephalopathy with refractory seizures, transient white matter oedema evolving to gliosis, marked calcifications and subsequent cerebral atrophy; median age at neurological onset was 12.96 years (IQR 9.44). Immunosuppressive therapy gave only partial benefit, with ongoing seizures and progressive neuroinflammation in most patients, and loss of life without treatment.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This is a medRxiv preprint that has not undergone peer review, so its conclusions remain provisional. The series is descriptive — six patients, with no functional demonstration of variant effect beyond splicing and nonsense-mediated decay analysis — and recruitment from a leukoencephalopathy biorepository mechanically selects a homogeneous phenotype, which may make the syndrome look more uniform than it is. In practice, considering IRAK4 in autoinflammatory encephalopathy with calcifications is mainly a matter of reinterpreting genomes that have already been sequenced.

Analysis by Dr Thibaut Benquey