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PGM3 mutations linked to severe atopy, immune deficiency, neurocognitive impairment

Autosomal recessive hypomorphic PGM3 mutations were linked to severe atopy, immune deficiency, autoimmunity, and neurocognitive impairment, according to researchers.

“Our findings suggest that altered glycosylation might be important in the pathophysiology of allergic diseases in the general population,” Yu Zhang, PhD, of the National Institutes of Allergy and Infectious Diseases at the NIH, and colleagues wrote.

The researchers reported the discovery of a genetic defect in glycosylation precursor synthesis causing a novel disease in eight patients from two families. The patients demonstrated severe atopy with markedly increased serum IgE levels, recurrent bacterial and viral infections, and motor and neurocognitive impairment; associated with hypomyelination, according to researchers.

They conducted brain MRI and sensory examinations, peripheral lymphocyte flow cytometry, measured antibody responses, and T-cell cytokine production. In addition, whole-exome sequencing was used to identify disease-causing mutations; molecular consequences of the mutations were determined based on other analyses, researchers wrote.

Marked atopy and autoimmunity were associated with increased Th2 and Th17 cytokine production by cluster of differentiation 4 (CD4)⁺ T cells, according to data. The likelihood of bacterial and viral infections were calculated in addition to T-cell lymphopenia, particularly of CD8⁺ T cells, and reduced memory beta cell numbers, researchers wrote.

“Finally, neurologic impairment was evident from early life in all patients,” researchers wrote.

Specifically, brain hypomyelination resulted in markedly delayed evoked potentials and may have contributed to the neurologic impairment, they added.

They found that N-acetyl glucosamine (GlcNAc) supplementation restored intracellular uridine diphosphate N-acetyl glucosamine (UDP-GlcNAc) levels in PGM3-deficient cells, according to data.

“Thus exogenous nondiabetogenic sugars might be used to bypass the metabolic defect and treat these patients,” they wrote.

The researchers concluded that clinical implications may define a new congenital disorder of glycosylation.  

Disclosure: Researchers Mie Ichikawa, BSc, and Hudson H. Freeze, PhD, report research support from the National Institutes of Health and support from the Rocket Fund. Joshua McElwee, PhD, reports employment by Merck and stock/stock options as part of his compensation. All other researchers report no relevant financial disclosures.