Abstract Details

XMEN (X-linked MAGT1 deficiency with increased susceptibility to Epstein-Barr virus (EBV) infection, and N-linked glycosylation defect) is a rare disease resulting from loss-of-function (LOF) mutations in MAGT1 encoding the multi-pass transmembrane and ER protein MAGT1 that is both a magnesium transporter and a subunit of the oligosaccharyltransferase (OST) complex.  XMEN is a combined immunodeficiency often associated with persistent EBV viremia and propensity to EBV-driven malignancies.  XMEN has been recognized as a congenital disorder of glycosylation (CDG).  Functionally, MAGT1 is complemented by its paralog TUSC3, another member of the OST complex.  Differences in MAGT1 and TUSC3's tissue-specific expression account for their diverging clinical phenotypes.

We evaluated two men with adult-onset progressive behavioral and neurodegenerative symptoms as part of XMEN.  Patient 1 (age 32) had a  history of gait abnormalities and dysarthria.  Patient 2 (age 33) had psychiatric and cerebellar symptoms, and a family history of B-cell lymphoma.  Multidisciplinary evaluations were undertaken under NIH protocols 14-HG-0071, 15-HG-0130, and/or 93-I-0119.

LOF mutations in MAGT1 were present in both.  Neurological histories were unrevealing until the onset of behavioral and cognitive symptoms as young adults including parkinsonism, cerebellar ataxia, and profound cerebral and spinal atrophy.  Both patients had abnormal glycosylation profiles consistent with type I CDG and both had EBV viremia.

XMEN patients may experience adult-onset neurodegeneration.  How MAGT1 directly or indirectly contributes to neurodegeneration is unknown but it is a relevant topic to other XMEN patients and to patients with common neurodegenerative disorders.