Abstract
Congenital disorders of glycosylation (CDG) are rare diseases with variable phenotypes and severity. Immunological involvement remains a largely uncharted topic in CDG, mainly due to lack of robust data. To better characterize immune-related manifestations’ prevalence, relevance, and quality-of-life (QoL) impact, we developed electronic questionnaires targeting (1) CDG patients and (2) the general “healthy” population. Two-hundred and nine CDG patients/caregivers and 349 healthy participants were included in this study. PMM2-CDG was the most represented CDG (n = 122/209). About half of these participants (n = 65/122) described relevant infections with a noteworthy prevalence of those affecting the gastrointestinal tract (GI) (63.1%, n = 41/65). Infection burden and QoL impact were shown as infections correlated with more severe clinical phenotypes and with a set of relevant non-immune PMM2-CDG signs. Autoimmune diseases had only a marginal presence in PMM2-CDG (2.5%, n = 3/122), all being GI-related. Allergy prevalence was also low in PMM2-CDG (33%, n = 41/122) except for food allergies (26.8%, n = 11/41, of PMM2-CDG and 10.8%, n = 17/158, of controls). High vaccination compliance with greater perceived ineffectiveness (28.3%, n = 17/60) and more severe adverse reactions were described in PMM2-CDG. This people-centric approach not only confirmed literature findings, but created new insights into immunological involvement in CDG, namely by highlighting the possible link between the immune and GI systems in PMM2-CDG. Finally, our results emphasized the importance of patient/caregiver knowledge and raised several red flags about immunological management.
Highlights
Congenital disorders of glycosylation (CDG) are a diverse and rapidly expanding family of more than 140 genetic diseases caused by defects in the cellular machinery responsible for assembling, trimming, and adding glycans to proteins and lipids
Even though the ubiquitous importance of glycans in the immune system and response is well-established, clear molecular and clinical evidence capable of fully clarifying the immune phenotype of CDG patients, in PMM2-CDG, is lacking [13,14,16,17,50,51,52]. This lack of knowledge regarding immunological involvement is evidenced in this study by: (i) the ~11% of PMM2-CDG patients with unsolved immune status and (ii) the uncertainty or ignorance of PMM2-CDG participants about the presence of specific immune-related manifestations (6.6%, 7.4% and 16.4% related to allergies, infections and autoimmune diseases, respectively)
Immunological involvement in CDG is complex, and this hinders the pathophysiological elucidation of immune-related manifestations
Summary
Congenital disorders of glycosylation (CDG) are a diverse and rapidly expanding family of more than 140 genetic diseases caused by defects in the cellular machinery responsible for assembling, trimming, and adding glycans to proteins and lipids. Most CDG are defects in N- glycosylation, O-glycosylation or both [1,2,3]. PMM2-CDG (MIM: 212065) was the first reported N-glycosylation defect and it is the most common type with approximately 1000 patients reported worldwide [5,11,12]. It shows a broad spectrum of clinical signs and phenotypic severity both among different patients and within the same patient throughout life. Other systems/organs are usually affected, including the gastrointestinal tract (GI) and the immune system [13,14,15]
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