Modifier-Sensitive Phenotypic Divergence in XMEN Disease (MAGT1 Deficiency): Neurodegenerative and Immuno-Hematologic...

Area of Science:

• Immunology
• Genetics
• Neurology

Background:

• X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection, and neoplasia (XMEN) disease is a rare primary immunodeficiency.
• Caused by MAGT1 mutations, it impairs N-linked glycosylation and is associated with chronic EBV viremia.
• Mechanisms of XMEN disease's clinical heterogeneity are poorly understood.

Purpose of the Study:

• To investigate the clinical, immunological, and genetic basis of intrafamilial heterogeneity in XMEN disease.
• To characterize the phenotypes of two siblings with a pathogenic MAGT1 variant.
• To propose a conceptual classification for neurological manifestations in XMEN disease.

Main Methods:

• In-depth clinical, immunological, and genetic characterization of two siblings with a MAGT1 variant.
• Whole-exome sequencing and multiparametric flow cytometry (NKG2D expression).
• Longitudinal clinical follow-up and comparative immunophenotyping.

Main Results:

• Siblings with identical MAGT1 variant and NKG2D absence showed divergent phenotypes: neurodegeneration vs. immuno-hematologic issues (Hodgkin lymphoma, autoimmune cytopenias, thrombotic microangiopathy).
• Shared B-cell maturation defects but distinct T-cell differentiation patterns were observed.
• A novel association of lymphoma with thrombotic microangiopathy in XMEN disease was identified.

Conclusions:

• Profound intrafamilial heterogeneity in XMEN disease exists, influenced by modifier-sensitive factors affecting organ-specific expression.
• Lymphoma-associated thrombotic microangiopathy is a notable finding.
• A descriptive neurological classification framework is proposed to guide multidisciplinary surveillance.