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. Author manuscript; available in PMC: 2022 Jan 1.
Published in final edited form as: Am J Med Genet A. 2020 Oct 12;185(1):213–218. doi: 10.1002/ajmg.a.61914

Immune dysfunction in MGAT2-CDG: A clinical report and review of the literature

Sheri A Poskanzer 1, Matthew J Schultz 2, Coleman T Turgeon 2, Noemi Vidal-Folch 2, Kris Liedtke 2, Devin Oglesbee 2, Dimitar K Gavrilov 2, Silvia Tortorelli 2, Dietrich Matern 2, Piero Rinaldo 2, James T Bennett 1,3, Jenny M Thies 4, Irene J Chang 1,4, Anita E Beck 1,4, Kimiyo Raymond 2, Eric J Allenspach 1,5, Christina Lam 1,4
PMCID: PMC8098812  NIHMSID: NIHMS1692138  PMID: 33044030

Abstract

Glycosylation is a critical post/peri-translational modification required for the appropriate development and function of the immune system. As an example, abnormalities in glycosylation can cause antibody deficiency and reduced lymphocyte signaling, although the phenotype can be complex given the diverse roles of glycosylation. Human MGAT2 encodes N-acetylglucosaminyltransferase II, which is a critical enzyme in the processing of oligomannose to complex N-glycans. Complex N-glycans are essential for immune system functionality, but only one individual with MGAT2-CDG has been described to have an abnormal immunologic evaluation. MGAT2-CDG (CDG-IIa) is a congenital disorder of glycosylation (CDG) associated with profound global developmental disability, hypotonia, early onset epilepsy, and other multisystem manifestations. Here, we report a 4-year old female with MGAT2-CDG due to a novel homozygous pathogenic variant in MGAT2, a 4-base pair deletion, c.1006_1009delGACA. In addition to clinical features previously described in MGAT2-CDG, she experienced episodic asystole, persistent hypogammaglobulinemia, and defective ex vivo mitogen and antigen proliferative responses, but intact specific vaccine antibody titers. Her infection history has been mild despite the testing abnormalities. We compare this patient to the 15 previously reported patients in the literature, thus expanding both the genotypic and phenotypic spectrum for MGAT2-CDG.

Keywords: arrhythmia, CDG, hypogammaglobinemia, immunodeficiency, MGAT2

1 ∣. INTRODUCTION

Congenital disorders of glycosylation (CDG) encompass a rapidly growing and heterogeneous group of individually rare genetic metabolic disorders that involve impairment of proper glycan synthesis, modification, and attachment to specific proteins or lipids. There are currently over 150 CDG described, each of which has a unique phenotypic spectrum with broad multisystem clinical and laboratory manifestations (Brucker et al., 2020; Chang, He, & Lam, 2018; Ferreira et al., 2018; Makhamreh, Cottingham, Ferreira, Berger, & Al-Kouatly, 2020; Pascoal et al., 2020; Verheijen, Tahata, Kozicz, Witters, & Morava, 2020).

MGAT2-CDG, previously known as CDG-IIa, is an autosomal recessive CDG with biallelic pathogenic variants in MGAT2. MGAT2 encodes the enzyme N-acetylglucosaminyltransferase II, which catalyzes a step in the N-linked glycan synthetic pathway (Figure S1A). MGAT2-CDG shows a type II carbohydrate-deficient transferrin profile (CDT) and is confirmed with molecular testing (Tan et al., 1996; Chang et al., 2018; Cormier-Daire et al., 2000). Affected individuals with MGAT2-CDG typically have a severe neurologic phenotype that includes profound global developmental delay, psychomotor disability, hypotonia, and early onset epilepsy. Individuals generally have a normal cerebellum and lack peripheral neuropathy. Other multisystem features can include congenital heart disease, scoliosis, osteopenia, endocrine abnormalities, and clotting factor deficiency (primarily factor XI) (Table S1; Alsubhi et al., 2017; de Cock and Jaeken., 2009; Jaeken et al., 1994; Tan, Dunn, Jaeken, & Schachter, 1996; van Geet et al., 2001; Ramaekers, Stibler, Kint, & Jaeken, 1991; Alazami et al., 2012; Alkuraya, 2010; Cormier-Daire et al., 2000).

Major immunological defects have been observed with several CDG (Francisco et al., 2020; Pascoal et al., 2020). The specific immunologic phenotype and the degree of severity can vary between individuals within the same CDG as well as between different CDG. Complex N-linked glycans have a central role in T-cell function and serum proteins; however, patient phenotypes can vary depending upon the specific enzyme defect in each CDG and degree of residual enzyme activity. One published patient with MGAT2-CDG has had a detailed immunologic assessment. This individual was noted to have normal IgM and IgA levels, but decreased IgG levels until the age of 6 years, when the deficiency resolved spontaneously (Jaeken et al., 1994, personal communication). He did not have a history of frequent infections. Two separately reported individuals from Saudi Arabia have been noted to have scalp psoriasis (Alkuraya, 2010; Alsubhi et al., 2017). Mice carrying a myeloid-specific knockout of the Mgat2 gene, resulting in myeloid glycosylation defects, have been described to have deficient IgG antibody production in response to infection and vaccination, as well as an induced, autoimmune-mediated depletion of naïve T-cells and decreased T-cell activity (Ryan, Abbott, & Cobb, 2014; Ryan, Leal Jr., Abbott, Pearlman, & Cobb, 2014). Here, we present a patient with MGAT2-CDG with both persistent hypogammaglobulinemia and T-cell proliferation abnormalities.

2 ∣. CLINICAL REPORT

Our patient is a 4-year-old female of Iraqi ancestry, who initially presented with respiratory distress and dysmorphic facial features. She was born via vaginal delivery at 32 weeks and 6 days gestation to a 23-year-old G3P3 mother. Birth weight, birth length, and head circumference were appropriate for gestational age. She spent 2 months in the Neonatal Intensive Care Unit with numerous life-threatening episodes of cyanosis and difficulty breathing requiring respiratory support via positive pressure ventilation and high-flow oxygen. She had hypotonia and a ventricular septal defect. A SNP chromosomal microarray revealed 8.5% runs of homozygosity (ROH), consistent with the level of consanguinity reported by the family. A Prader-Willi/Angelman syndrome methylation study was normal. Her newborn screen indicated an increased risk for cystic fibrosis, but follow-up sweat chloride testing was normal.

Around 6 months of age, she had a gastrostomy tube placed due to persistent feeding difficulties and faltering growth. Postoperation, she was diagnosed with seizures characterized as hypsarrhythmia and infantile spasms by EEG. A biochemical work-up included urine organic acids, plasma amino acids, acylcarnitine profile, and very long chain fatty acids. A carbohydrate-deficient transferrin (CDT) profile was performed due to the presence of inverted nipples, a finding in some patients with CDG (Ferreira et al., 2018).

Of the biochemical testing, only the CDT profile was abnormal, revealing a marked increase of abnormally glycosylated transferrin with incomplete glycan processing and minimal amounts of the fully glycosylated protein. Complete glycosylation of transferrin results in bi-antennary glycans at two asparagine residues (N-linked glycosylation) with glycan structure of NeuAcα2-6Galβ1-4GlcNAcβ1-2Manα1-6 (NeuAcα2-6Galβ1-4GlcNAcβ1-2Manα1-3)Manβ1-4GlcNAcβ1-4 GlcNAcβ1-4-Asn (Figure 1a). The mass spectrometry analysis of the abnormally glycosylated transferrin was consistent with both sites harboring a glycan with incomplete processing of one antenna (Lacey, Bergen, Magera, Naylor, & O'Brien, 2001). This was consistent with a type II carbohydrate deficient transferrin pattern. The predicted glycan structure from the mass observed was Manα1-6(NeuAcα2-6Galβ1-4GlcNAcβ1-2Manα1-3)Manβ1-4GlcNAcβ1-4 GlcNAcβ1-4-Asn, where each glycan has one complete antenna and one antenna lacking an N-acetylglucosamine, galactose, and terminal sialic acid (Figure 1b). Serum N-glycan profiling substantiated this result and demonstrated similarly abnormal N-linked glycosylation on serum proteins compared with an unaffected individual (Figure 1c,d; Li, Raihan, Reynoso, & He, 20i5). This predicted glycan structure would result from deficiency of alpha-1,-6-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase, sugg esting MGAT2-CDG.

FIGURE 1.

FIGURE 1

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Biochemical testing. (a) Transferrin profile of an individual without a CDG. Illustration represents protein with bi-antennary glycans at both N-linked sites. (b) Our patient's transferrin profiling showing near absence of normally glycosylated transferrin and accumulation of an abnormally processed glycan. (c) Serum N-glycan profile of an individual without a CDG. (d) Our patient's serum N-glycan profile demonstrates accumulation of the abnormal glycan on serum proteins. Blue square, N-acetylglucosamine; green circle, mannose; yellow circle, galactose; pink diamond, sialic acid; m/z ratio, mass to charge ratio; Da, dalton

The MGAT2 gene encoding this glycosyltransferase was within a 9.4 Mb run of homozygosity noted on this patient's chromosomal microarray. Targeted sequencing of MGAT2 revealed homozygosity for a 4 bp deletion, c.1006_1009delGACA (p.Asp336LeufsTer17), NM_002408.3. This deletion alters the reading frame of the transcript and is a predicted null variant. This variant has been previously reported once in the heterozygous state in population databases (a single Latino individual in gnomAD [v2.2.1] and no carriers present in the Saudi Genome Project database) and this patient constitutes the only entry in ClinVar at the time of the writing of this manuscript. This variant is also classified as pathogenic by the American College of Medical Genetics and Genomics and Association of Molecular Pathology variant classification criteria (Richards et al., 2015).

Subsequent medical concerns for this patient have included cortical blindness with persistent pupillary membranes, bilateral sensorineural hearing loss (mild to moderate in her right ear, moderate to moderately severe in her left ear), chronic respiratory failure with nocturnal BiPAP dependence, cyanotic episodes possibly secondary to excessive secretions leading to aspiration and bronchospasm, delayed gastric emptying with gastroesophageal reflux disease, gastrojejunostomy tube dependence, global developmental disability, diffuse hypotonia, seizures, scoliosis, kyphosis, and mildly decreased factor XI (Table S1). Around 11 months of age, she was found to have asystolic pauses, initially treated with glycopyrrolate. Electrocardiogram and Holter monitor evaluations did not reveal an intrinsic conduction defect. At 15 months of age, more frequent pauses were recorded on telemetry, the longest being 22 seconds in duration. An implantable epicardial pacemaker was placed just before her second birthday and actively continues to discharge infrequently. Her dysmorphic features include acquired microcephaly, dolichocephaly, down-slanting palpebral fissures, long eyelashes, mild hypertelorism, low-set posteriorly rotated ears with a very prominent antihelix and overfolded earlobe, and a significantly beaked nose with overhanging columella (Figure S2). She has widely set hypoplastic and inverted nipples. Her score on the Nijmegen Pediatric CDG Rating Scale (NPCRS) at age 3 was 52 and at age 4 was 44. The improvement was primarily accounted for in the Systemic Specific Involvement and Current Clinical Assessment categories (Achouitar et al., 2011).

Detailed immunologic evaluation was performed at 2 years of age following several viral respiratory infections, including human meta-pneumovirus, rhinovirus/enterovirus, and parainfluenza type 3. She also had a history of Clostridium difficile infection and cellulitis. She previously (at 7 months) had abnormal QuantiFERON Gold testing, suggesting a problem with lymphocyte proliferation control. Absolute T and B cell counts were normal (absolute CD3 2,574/mm3; CD4: CD8 ratio 1.95; absolute CD19 1,069/mm3) and had normal naïve to memory ratios (CD4: CD45RA+ 68%;CD45RO+ 14%; CD8: CD45RA+ 92%; CD45RO+ 3%). Despite normal T-cell numbers, proliferative responses to phytohemagglutinin (PHA) was <1% (Table S2). Given the known PHA dependence on complex N-glycans, other lectins were also tested and she was noted to have extremely low responses to concanavalin A (ConA) and pokeweed mitogen (PWM). Evaluation of her antigen-specific responses revealed reduced tetanus response, but notably enhanced Candida proliferative response. She did not have issues with Candida infections. Given the poor proliferative responses, she was started on trimethoprim-sulfamethoxazole prophylaxis.

Hypogammaglobulinemia was another consistent feature. She demonstrated a mildly decreased IgG level (439 mg/dl, reference range 468–1,196 mg/dl at 2 years old), with normal IgM and IgA levels (198 mg/dl, reference range 47–200 mg/dl and 101 mg/dl, reference range 21–117 mg/dl, respectively). She tolerated all age-appropriate vaccinations without complication, including one dose each of MMR and varicella vaccines, and she has had positive antibody titers to rubella, varicella, tetanus, and pneumococcus serotypes 16/22 (including 11 of 12 PCV13 vaccine serotypes tested; Table S2). Secondary to the risk for aspiration from her other medical concerns and the laboratory evidence of a combined immunodeficiency, she was started on intravenous immunoglobulin (IVIG) replacement therapy at 2 years 8 months old. Measurements of IgG levels were repeated over time and continued to decline to 188 mg/dl, demonstrating ongoing loss of IgG, so she was provided with an additional IVIG infusion. She has received eight IVIG infusions with normalization of IgG levels immediately following infusions. Infusions have been paused and her IgG levels have trended downwards over 6 months to 234 mg/dl (reference range 574–1,309 mg/dl; Figure 2).

FIGURE 2.

FIGURE 2

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Immunoglobulin G levels over time. Arrows indicate administration of IVIG. Mg/dl, milligrams per deciliter; IVIG, intravenous immunoglobulin

There are no other affected relatives in this patient's family with MGAT2-CDG or with evidence of an immunodeficiency. Family history is notable for intellectual disability and small for gestational age (SGA) in her mother, and global developmental delay, dysmorphic features, a history of febrile seizures, and multiple episodes of syncope of uncertain etiology in her full brother. Her brother's cardiac workup, including echocardiogram and long-term home telemetry, did not reveal a cardiac cause for syncope. Both relatives had targeted variant testing and both are heterozygous for the c.1006_1009delGACA variant in MGAT2. The patient's father and an additional full brother are healthy.

3 ∣. DISCUSSION

This clinical report of MGAT2-CDG highlights a novel pathogenic variant in MGAT2, c.1006_1009delGACA, and expands the phenotype to include cardiac arrhythmia, specifically episodic asystole requiring epicardial pacemaker placement, and combined immunodeficiency. We present the first comprehensive immunologic evaluation of a patient with MGAT2-CDG and demonstrate the presence of both persistent hypogammaglobulinemia and T-cell proliferation abnormalities.

Interestingly, and fortunately, this individual has lacked any serious illnesses or infections, although this may be confounded by the fact that she lives in a residential medical facility, where there are minimal infectious exposures. Of note, the individual described by de Cock and Jaeken (2009) also had MGAT2-CDG and low IgG without significant infections. A similar paradox of hypogammaglobulinemia and lack of frequent or severe infections was noted in the two children with MOGS-CDG described by Sadat et al. (2014), who explored multiple mechanisms to determine the etiology of their individuals' hypogammaglobulinemia. They determined that the individuals had normal IgG synthesis, secretion, and stability in vitro, but reduced IgG half-life in vivo when infused into Rag1−/− mice when compared to unaffected controls. The authors acknowledged that they were not able to provide a precise etiology for why the children did not have significant bacterial infections despite the low IgG. Further investigation is needed to determine if the mechanism is the same in MGAT2-CDG.

A prominent difference between the individuals with MOGS-CDG and our patient is that our patient demonstrated a protective antibody response to live vaccines for rubella and varicella (enveloped viruses), while the two individuals with MOGS-CDG did not respond adequately to any live virus vaccines. Since these viruses rely on host protein glycosylation for entry and active viral replication, the intrinsic defect in N-glycosylation in MOGS-CDG was proposed as the etiology for reduced susceptibility to viral infection. Francisco et al. (2020) also reported three patients with MOGS-CDG who did not identify viral infection as the most common infectious agent. However, MGAT2-CDG is also a disorder of N-glycosylation, potentially providing evidence against this theory. Alternatively, this difference in vaccine response could be related to the individual locations of these two enzymes in the N-glycosylation pathway. Mannosyl-oligosaccharide glucosidase, encoded by MOGS, acts on the glycan precursor upstream of MGAT2 activity and glycan processing to a complex N-glycan. Therefore, all complex N-glycans would be expected to be reduced in MOGS-CDG, whereas complex glycans distal to MOGS, but proximal to the MGAT2, would be predicted to be spared in MGAT2-CDG.

Our patient demonstrates diagnostic evidence for impaired cellular immunity despite normal specific antibody responses. Very low proliferative responses were observed to multiple lectins, including PHA, ConA, and PWM. These lectins are plant mitogens that stimulate cell proliferation and function by binding to glycosylated surface proteins (Miller, 1983). Since one of PHA's lectin binding sites incorporates a mature glycan that is dependent on MGAT2 for formation (Carlson et al., 2017; Bonnardel et al., 2019; Figure S1B), our patient’s absent PHA response was expected. However, her extremely low responses to ConA and PWM were unexpected. One of the lectin binding sites for ConA is GlcNAc(β1-2)Man(α1-3)[GlcNAc(β1-2)Man (α1-6)]Man (Figure S1C), whose formation is also dependent on MGAT2, which could be the reason for the low response to ConA. However, ConA appears to have a higher affinity for the (Man(α1-3) [Man(α1-6)]Man) component of the glycan (Bonnardel et al., 2019; Moothoo& Naismith, 1998; Naismith & Field, 1996, Figure S1D), and high mannose moieties upstream of MGAT2 would still be present with MGAT2 deficiency, providing a limitation to this theory. Another possible mechanism of extremely low response to ConA and PWM could be generalized hyper-reactivity to mitogens similar to what is seen in PGM3-CDG (Carlson et al., 2017). As standard diagnostic proliferative assays are based upon thymidine incorporation, the assay does not distinguish between reduced proliferation and activation-induced cell death. In support of a hyperactive response, the measured proliferation to Candida, a known poor stimulatory antigen, was consistently 5–6 fold higher in our patient's cells compared to controls. Finally, there is the possibility that the low lectin responses are a consequence of the assay itself as opposed to a true in vivo deficiency. Future studies will be needed to distinguish these possibilities.

The information provided in our clinical report is limited by the current lack of a unifying diagnosis for our patient's full brother, who has a history of global developmental delay, dysmorphic features, and episodes of syncope. With the presence of significant ROH in the setting of known consanguinity and the presence of only heterozygosity for the familial MGAT2 variant in her brother, there is possibly an additional autosomal recessive disorder in the family that could be confounding our patient's phenotype. Untargeted genetic testing, such as exome sequencing in this family, could be helpful in providing additional genotypic information, though this has not been possible at the time of this report. However, neither her mother nor her brother are known to have clinical features that would indicate concern for an underlying immunodeficiency and her brother has had a negative cardiac evaluation for his episodes of syncope, which supports the association of these abnormal immunologic and cardiac phenotypes with MGAT2-CDG.

In conclusion, this clinical report expands the phenotype of MGAT2-CDG and highlights a novel pathogenic variant causative of the disorder. As the number of individuals with different CDG continues to rise due to improved awareness, leading to increased biochemical screening and expanded use of large scale molecular testing such as exome sequencing, further natural history and novel variants will be revealed, including in additional individuals with MGAT2-CDG.

Supplementary Material

ajmga61914-sup mat

ACKNOWLEDGMENTS

We would like to thank Dr. Jaak Jaeken and Dr. Jonathan Lyons for their useful communications and insights into this disorder. This project was partially supported (C.L.) by the NINDS/NCATS Frontiers in Congenital Disorders of Glycosylation Grant (1U54NS115198-01) and the Rare Disorders Consortium Disease Network. This project was also partially supported (P.R.) by the T. Denny Sanford Professorship Fund.

Funding information

National Center for Advancing Translational Sciences (NCATS)/ National Institute of Neurological Disorders and Stroke (NINDS) Frontiers in Congenital Disorders of Glycosylation, Grant/Award Number: 1U54NS115198-01; Rare Disorders Consortium Disease Network; T. Denny Sanford Professorship Fund

Footnotes

CONFLICT OF INTEREST

The authors declare no conflict of interest.

SUPPORTING INFORMATION

Additional supporting information may be found online in the Supporting Information section at the end of this article.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. The novel variant reported in the manuscript has been previously reported once in the heterozygous state in population databases (a single Latino individual in gnomAD [v2.2.1] and no carriers in the Saudi Genome Project database). This patient constitutes the only entry in ClinVar at the time of the writing of this manuscript.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ajmga61914-sup mat
NIHMS1692138-supplement-ajmga61914-sup_mat.pdf (283.8KB, pdf)

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. The novel variant reported in the manuscript has been previously reported once in the heterozygous state in population databases (a single Latino individual in gnomAD [v2.2.1] and no carriers in the Saudi Genome Project database). This patient constitutes the only entry in ClinVar at the time of the writing of this manuscript.

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