Recurrent Demyelinating Episodes as Sole Manifestation of Inherited CD59 Deficiency

Abstract

Defects in the regulatory components of the complement system can lead to inflammatory diseases. We present a patient who had four episodes of demyelination in the central nervous system as the only manifestation of inherited CD59 deficiency. Relapsing encephalopathy partially responsive to intravenous immunoglobulin and steroid treatments on the background of parental consanguinity suggested an inherited immune dysregulation. Next generation sequencing revealed homozygous mutation in the CD59 gene, confirmed by lack of CD59 expression on flow cytometry. Inherited CD59 deficiency is a rare autosomal recessive condition characterized by chronic hemolysis, recurrent strokes, and relapsing peripheral demyelinating neuropathy mimicking Guillain–Barré syndrome or chronic inflammatory demyelinating polyneuropathy. Recurrent central nervous system demyelinating episodes as the only manifestation has not been reported to date in inherited CD59 deficiency. This entity should be considered in the differential diagnosis of patients with early-onset recurrent neurological diseases with central or peripheral origin.

Recurrent Blistering Skin Lesions and Reversible Monocular Abducens Paralysis in a Patient with CD59 Deficiency

“…5 6 The spectrum of neurologic findings was further expanded with the reporting of Moyamoya syndrome, progressive stenosis of cerebral arteries with recurrent infarctions, acute-onset immune-mediated cerebellitis, hemorrhagic myelitis, acute disseminated encephalomyelitis-like demyelination, or recurrent demyelination in the central nervous system. 7 8 9 Acquired monocular abducens nerve palsy has not been previously described in CD59 deficiency. Our patient had isolated monocular abducens paralysis and a pontine lesion consistent with the clinical findings was detected on brain MRI.…”

Association of Blood Group Antigen CD59 with Disease

“…Improvement of neurological disease was seen with all patients treated with eculizumab. The ability to swallow returned [112,113], muscle strength improved [14,[111][112][113], and some children learned to stand with support [14,113]. We hopefully will learn about the long-term effect of C5blocking therapy in these children, including breakthrough events and impaired defence against bacterial infections.…”

“…Demyelination of peripheral sensory and motor nerves led to weak reflexes or areflexia, muscle weakness and difficulties or inability to walk, and they required mechanical ventilation [12,13,112]. Further, peripheral hypoaesthesia [14] and urinary incontinence [111] were observed. Demyelinating processes in the central nervous system, ischaemic infarctions or haemorrhagic events impaired the cognitive abilities and mental development including speech.…”

“…It is the only membrane-bound inhibitor of the terminal pathway of the complement system; no other molecule providing a backup function exists. CD59 protein variants with impaired function have not been described so far [11][12][13][14][15]. Low density of membrane-anchored CD59 was thought to generate unprotected areas on the cell membrane, which expose the cells or tissues to complement-mediated damage, a concept that has been deduced from paroxysmal nocturnal haemoglobinuria (PNH) where the lack of CD59 on PNH cells causes disease [16,17].…”

Cd59 and inflammation orchestrate Schwann cell development

“…Though the precise function is unknown, it is clear that CD59 does impact human nervous system development. Patients with CD59 dysfunction, such as those with congenital CD59 deficiency (Haliloglu et al, 2015;Höchsmann and Schrezenmeier, 2015;Karbian et al, 2018;Solmaz et al, 2020) or germline paroxysmal nocturnal hemoglobinuria (Johnston et al, 2012), present with polyneuropathies during infancy and continue to have nervous system dysfunction throughout their lives. Intriguingly, these neurological symptoms persist even with complement inhibition, the most common treatment for congenital CD59 deficiency (Höchsmann and Schrezenmeier, 2015).…”