Two neurologic facets of CTLA4-related haploinsufficiency

Abstract

Objective: To describe the clinical and radiologic neurologic characteristics of patients with cytotoxic T-lymphocyte antigen-4 (CTLA4) haploinsufficiency.

Methods: Three patients from 2 families had neurologic manifestations in the context of CTLA4 haploinsufficiency. Their clinical and MRI findings are presented.

Results: A 16-year-old boy with a previous diagnosis of combined immunodeficiency presented with severe recurrent episodes of headaches, motor deficit, and seizures associated with waxing and waning gadolinium-enhancing FLAIR cortical/juxtacortical hyperintensities. His sister, who also had combined immunodeficiency, had a brain MRI when she was aged 13 years due to recent headaches and transient right hemianopsia. It revealed a gadolinium-enhancing left occipital white matter hyperintensity. Another 49-year-old woman had progressive visual loss and cerebellar ataxia in the context of recurrent pulmonary infections. All 3 patients were found to have inherited CTLA4 haploinsufficiency. Patient 1's general condition and neurologic manifestations were completely controlled with abatacept (CTLA4-Ig).

Conclusions: These cases suggest that in addition to the variable clinical penetrance and wide spectrum of CTLA4 haploinsufficiency, its neurologic spectrum is broad, ranging from recurrent tumefactive lesions to progressive deficits including cerebellar ataxia and optic atrophy with leukoencephalopathy. These phenotypes must be recognized, and should lead to a complete immunologic workup, because potentially effective targeted immunotherapy exists.

Figure 1. Family 1

(A) Family 1 pedigree: the arrow indicates patient 1, squares = males, circles = females, black-filled symbol = symptomatic patients, gray-filled symbol = asymptomatic carrier, and strikethrough = deceased patients. (B) Patient's abdominal and pelvic CT showing enlarged liver and lymph nodes (arrow) (left panel), which decreased (respectively from 213 mm to 190 mm and 23 mm to 18 mm) after abatacept therapy (right panel). (C) Regular brain MRI scans repeated from age 16 to 25 years disclosed multiple nodular cortical/juxtacortical FLAIR hyperintensities (C.a–C.d) with gadolinium enhancement (C.e–C.h). (C.i) Spinal cord MRI evidenced diffuse conus medullaris hyperintensities. (D) Patient 1's sister aged 15 years. The MRI showed an infiltrative occipital white matter lesion with gadolinium enhancement.

Figure 2. Patient 3's MRI findings

MRI revealed diffuse white matter and basal ganglia FLAIR hyperintensities (A–C and E–G) and cerebellar atrophy (D and H), which progressively worsened from age 52 years (upper panel) to 56 years (lower panel).