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A Case of Neuromyelitis Optica Spectrum Disorder in ARCN1-related Congenital Disorder of Glycosylation: A Rare Autoimmune Phenotype

Biochemical/Metabolic and Therapeutics
  • Primary Categories:
    • Metabolic Genetics
  • Secondary Categories:
    • Metabolic Genetics
Introduction
ARCN1-related Congenital Disorder of Glycosylation (CDG) is a rare disorder caused by heterozygous loss of function variants in ARCN1, which encodes the delta subunit of COAT protein complex I (COPI), involved in intracellular protein transport. The syndrome is characterized by intrauterine growth restriction, short stature, micrognathia, microcephaly, rhizomelia, prematurity, genitourinary anomalies, cataracts, liver dysfunction, and intermittent glycosylation defects.  The first case of neuromyelitis optica spectrum disorder (NMOSD) in ARCN1-CDG was recently reported in a 7-year-old male. NMOSD is a rare antibody-mediated inflammatory disease of the central nervous system primarily affecting the optic nerves and spinal cord. We present the second known case of this unusual phenotype in a 5-year-old male with ARCN1-CDG who subsequently presented with NMOSD, confirming a rare disease association.

Case Presentation
A 5-year-old former 38-week gestation male with a history of severe IUGR, micrognathia, short stature, microcephaly, hypospadias, and history of Haemophilus influenzae type b (Hib) meningitis in infancy presented with subacute blurry vision, loss of color perception, and headaches. The physical exam was notable for microcephaly, short stature, and microretrognathia. The patient had previously undergone exome sequencing (ES) as an infant for IUGR and micrognathia that identified a heterozygous de novo variant of uncertain significance (VUS) in ARCN1 (c.934C>T; p.Arg312*), a then candidate gene.

Diagnostic Workup
Initial ophthalmologic evaluation demonstrated poor visual acuity, loss of color perception, and a relative afferent pupillary defect in the left eye. MRI brain demonstrated signal abnormality and enhancement of the bilateral optic nerves, optic chiasm, and hypothalamus. Serum aquaporin-4 (AQP4) antibodies were positive, consistent with a diagnosis of NMOSD. The Genetics team was consulted to determine the relevance of his prior ARCN1 VUS, which was reclassified as a pathogenic variant and explained his congenital anomalies, short stature, microcephaly, and an incidentally noted transaminitis. Given the associated glycosylation defects in ARCN1-CDG, an N-glycan profile and carbohydrate deficient transferrin analysis were sent and within normal limits.

Treatment and Management
The patient was treated acutely with a course of intravenous methylprednisolone, 7 cycles of plasma exchange, and intravenous immunoglobulin. He was then started on monthly tocilizumab infusions for prevention of relapse.

Outcome and Follow-Up
Visual acuity remains poor over 1 year from the initial onset of symptoms. He remains on disease modifying therapy with monthly tocilizumab infusions and has not had a relapse of NMOSD.

Discussion
While the pathogenesis behind an increased risk for NMOSD in ARCN1-CDG is not completely understood, COPI is involved in the intracellular protein transport between the endoplasmic reticulum (ER) and the Golgi apparatus. ARCN1 knockdown (KD) cell lines have shown evidence of ER stress, a risk factor for autoimmunity. Autoimmunity has also been implicated in a related monogenic disorder caused by pathogenic variants of COPA, encoding the alpha subunit of COPI, and leading to autoimmune-mediated lung disease and arthritis. Patient derived B-lymphoblastoid cell lines with COPA variants were similarly found to have evidence of ER stress as well as increased expression of cytokines that prime for a T helper type 17 (TH17) response, also implicated in autoimmunity. Finally, dysregulated immune function is a common feature of many CDGs.

Conclusion
We report the second known case of NMOSD in a pediatric patient with ARCN1-CDG, demonstrating a rare disease association and expanding our evidence of dysregulated immune function in CDGs. From a clinical perspective, visual and neurologic changes in patients with ARCN1-CDG necessitate prompt evaluation and consideration of NMOSD.

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