A Rare Central Nervous System Involvement Due to CTLA-4 Gene Defect

Area of Science:

• Immunology
• Genetics
• Neurology

Background:

• Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a critical immune checkpoint inhibitor.
• CTLA-4 haploinsufficiency leads to immune dysregulation and primary immunodeficiency.
• Common variable immunodeficiency (CVID) can present with complex autoimmune and inflammatory manifestations.

Observation:

• A 26-year-old female with a history of autoimmune disorders presented with progressive neurological deficits including gait impairment and bowel/bladder dysfunction.
• Neuroimaging revealed extensive inflammatory lesions in the brain and spinal cord.
• Biopsies indicated lymphoproliferation consistent with Lymphomatoid granulomatosis, and laboratory analyses confirmed CVID.

Findings:

• Next-generation sequencing identified a heterozygous CTLA-4 mutation (c.436G>A(p.G146R)) as the underlying cause.
• The patient exhibited a complex phenotype involving autoimmune phenomena, lymphoproliferation, and neurological involvement.
• The identified CTLA-4 mutation confirmed the diagnosis of CTLA-4 haploinsufficiency.

Implications:

• This case highlights the importance of considering CTLA-4 haploinsufficiency in patients with CVID and severe immune dysregulation.
• Molecular diagnosis is crucial for identifying the specific genetic defect.
• Targeted therapy with abatacept, alongside immunoglobulin replacement, represents a viable treatment strategy for CTLA-4 haploinsufficiency.