Genetics of progressive multifocal leukoencephalopathy: update on case reports with an inborn error of immunity and...

Area of Science:

• Immunology
• Genetics
• Neurology

Background:

• Progressive multifocal leukoencephalopathy (PML) risk is increasingly linked to genetic factors, specifically inborn errors of immunity (IEI).
• The number of IEI genes associated with PML has risen significantly, with a high overlap (92%) between PML-linked IEI genes and those causing hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).
• JC virus infection in individuals with pathogenic variants in HLH-linked IEI genes may increase PML risk, mirroring associations between Epstein-Barr virus and HLH.

Purpose of the Study:

• To increase awareness among researchers and clinicians about the critical role of patient genetics in PML risk.
• To highlight the genetic overlap between PML and HLH/MAS, suggesting shared etiological pathways.
• To advocate for genetic screening of PML risk variants in patients considered for PML-associated therapies.

Main Methods:

• Review of case reports and genetic data linking inborn errors of immunity (IEI) to progressive multifocal leukoencephalopathy (PML).
• Analysis of gene associations between PML, HLH/MAS, and susceptibility to viral infections.
• Examination of recently identified PML risk variants and their correlation with HLH-linked genes.

Main Results:

• Over 26 IEI genes are now linked to PML, a substantial increase over the past decade.
• A majority (92%) of PML-associated IEI genes are also implicated in HLH/MAS.
• Two of the four identified PML risk variants are associated with HLH, underscoring the genetic connection.

Conclusions:

• Patient genetics represent a key risk factor for developing PML.
• Genetic screening for PML risk variants should be considered before initiating therapies associated with PML.
• Understanding the genetic basis of PML can inform risk stratification and preventative strategies.