Two neurologic facets of CTLA4-related haploinsufficiency

Abstract

ObjectiveTo describe the clinical and radiologic neurologic characteristics of patients with cytotoxic T-lymphocyte antigen-4 (CTLA4) haploinsufficiency.MethodsThree patients from 2 families had neurologic manifestations in the context of CTLA4 haploinsufficiency. Their clinical and MRI findings are presented.ResultsA 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).ConclusionsThese 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.

Comprehensive comparison between 222 CTLA-4 haploinsufficiency and 212 LRBA deficiency patients: a systematic review

“…There are 73 distinct mutations among 222 patients (124 families) suffering from CHAI, including 37 (50·7%) missense, 14 (19·2%) insertion/deletion frameshift, 10 (13·7%) nonsense, eight (11%) splice‐site, three (4·1%) large insertion/deletion and one (1·4%) start codon mutation. Among patients diagnosed with CHAI, the mutation has not been reported for four patients [20–23]. To find a better estimation of penetrance we restricted our assessment to families with available mutation analyses in the proband and family members (at least parents).…”

Persisting brain inflammation: a neurological whodunnit

“…Neurological features associated with this condition develop in approximately 30% of affected individuals and usually comprise multifocal inflammatory brain lesions and autoimmune encephalitis; however, a wide variety of neurological conditions has been described 6 9 10. Histological changes on brain biopsy can show chronic inflammatory lymphocytic infiltration with predominance of CD4+ and CD8+ T cells and areas of granuloma formation 11…”

“…Typically, treatment with standard immunosuppressive medications is not fully effective 10. Targeted therapy involves treatment with abatacept, a humanised CTLA-4 immunoglobulin G fusion protein used to treat rheumatoid arthritis 12.…”

“…Targeted therapy involves treatment with abatacept, a humanised CTLA-4 immunoglobulin G fusion protein used to treat rheumatoid arthritis 12. This decreases T-cell proliferation and has is effective even in cases with neurological involvement 9 10. An alternative is belatacept, another CTLA-4-Ig, or sirolimus, an inhibitor of the mechanistic target of rapamycin 6.…”

“Time to recharge”

“…Neurologic manifestations have been reported in approximately 30% of cases, including autoimmune encephalitis or encephalomyelitis with perivascular lymphocytic infiltration, inflammatory demyelinating processes, and optic neuritis, among others. Ayrignac et al 2 add to this list in their case descriptions of 3 patients. Two of the patients were siblings who had symptom onset during childhood, including recurrent episodes of brain or spinal cord inflammatory processes, as has been described before.…”