Partial correction of neutrophil dysfunction by oral galactose therapy in glycogen storage disease type Ib

Letkemann, Rudolf; Wittkowski, Helmut; Antonopoulos, Aristotelis; Podskabi, Teodor; Haslam, Stuart M.; Föll, D.; Dell, Anne; Marquardt, Thorsten

doi:10.1016/j.intimp.2017.01.020

Cited by 8 publications

(12 citation statements)

References 38 publications

(1 reference statement)

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“…To determine whether our findings could lead to a rational treatment of AP, we focused our attention specifically on the possibility that galactose might be helpful, as this sugar has already been included as part of human trials for the treatment of glycogen storage disease type 1b (Fabry’s disease), nephrotic syndrome, and congenital disorders of glycosylation and has not been shown to have any negative effects (30–33). Galactose, an essential component of human breast milk (up to 70 mM during the first month; ref.…”

Section: Resultsmentioning

confidence: 99%

Galactose protects against cell damage in mouse models of acute pancreatitis

Peng¹,

Gerasimenko²,

Tsugorka³

et al. 2018

Journal of Clinical Investigation

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Acute pancreatitis (AP), a human disease in which the pancreas digests itself, has substantial mortality with no specific therapy. The major causes of AP are alcohol abuse and gallstone complications, but it also occurs as an important side effect of the standard asparaginase-based therapy for childhood acute lymphoblastic leukemia. Previous investigations into the mechanisms underlying pancreatic acinar cell death induced by alcohol metabolites, bile acids, or asparaginase indicated that loss of intracellular ATP generation is an important factor. We now report that, in isolated mouse pancreatic acinar cells or cell clusters, removal of extracellular glucose had little effect on this ATP loss, suggesting that glucose metabolism was severely inhibited under these conditions. Surprisingly, we show that replacing glucose with galactose prevented or markedly reduced the loss of ATP and any subsequent necrosis. Addition of pyruvate had a similar protective effect. We also studied the effect of galactose in vivo in mouse models of AP induced either by a combination of fatty acids and ethanol or asparaginase. In both cases, galactose markedly reduced acinar necrosis and inflammation. Based on these data, we suggest that galactose feeding may be used to protect against AP.

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Section: Resultsmentioning

confidence: 99%

Galactose protects against cell damage in mouse models of acute pancreatitis

Peng¹,

Gerasimenko²,

Tsugorka³

et al. 2018

Journal of Clinical Investigation

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“…This results in low respiratory burst, impaired calcium import and sequestration as well as chemotaxis defects, probably contributing to neutrophil dysfunction . Galactose supplementation in a patient led to significant clinical improvement which suggests that the glycosylation defects play a significant immunopathological role …”

Section: The Immunological Impact Of Glycosylation Defects—an Update mentioning

confidence: 99%

“…Antibiotics—via IV or oral administration—have also been extensively used both as a preventive and curative measure. In general, a good response to antibiotic therapy (alone or in combination with Igs replacement therapy) has been observed …”

Section: Immunomodulatory Therapeutic Avenues In Cdgmentioning

confidence: 99%

“…The exceptions are: (1) fucose administration in SLC35C1‐CDG patients with well‐defined mutations which significantly improved leucocyte migration defects, leukocytosis and resolved infections; and (2) galactose supplementation in combination with G‐CSF in a SLC37A4‐CDG patient that ceased infections and abscesses. These targeted approaches underpin the glycosylation defect as the underlying cause of the immune‐related alterations observed in patients and reinforce the necessity of targeted and more effective immune‐therapies for CDG patients …”

Section: Immunomodulatory Therapeutic Avenues In Cdgmentioning

confidence: 99%

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CDG and immune response: From bedside to bench and back

Pascoal

Francisco

Ferro

et al. 2019

J of Inher Metab Disea

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Glycosylation is an essential biological process that adds structural and functional diversity to cells and molecules, participating in physiological processes such as immunity. The immune response is driven and modulated by protein‐attached glycans that mediate cell‐cell interactions, pathogen recognition and cell activation. Therefore, abnormal glycosylation can be associated with deranged immune responses. Within human diseases presenting immunological defects are congenital disorders of glycosylation (CDG), a family of around 130 rare and complex genetic diseases. In this review, we have identified 23 CDG with immunological involvement, characterized by an increased propensity to—often life‐threatening—infection. Inflammatory and autoimmune complications were found in 7 CDG types. CDG natural history(ies) and the mechanisms behind the immunological anomalies are still poorly understood. However, in some cases, alterations in pathogen recognition and intracellular signaling (eg, TGF‐β1, NFAT, and NF‐κB) have been suggested. Targeted therapies to restore immune defects are only available for PGM3‐CDG and SLC35C1‐CDG. Fostering research on glycoimmunology may elucidate the involved pathophysiological mechanisms and open new therapeutic avenues, thus improving CDG patients' quality of life.

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“…A recent study has evidenced a partial improvement of neutrophil respiratory burst activity in a GSD-Ib patient by oral administration of galactose, even though the role of galactose in sugar metabolism of GSD-Ib neutrophils remains to be clarified (Letkemann et al, 2017 ).…”

Section: Therapeutic Approaches For Slc37a4 Defectmentioning

confidence: 99%

The Physiopathological Role of the Exchangers Belonging to the SLC37 Family

et al. 2018

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The human SLC37 gene family includes four proteins SLC37A1-4, localized in the endoplasmic reticulum (ER) membrane. They have been grouped into the SLC37 family due to their sequence homology to the bacterial organophosphate/phosphate (Pi) antiporter. SLC37A1-3 are the less characterized isoforms. SLC37A1 and SLC37A2 are Pi-linked glucose-6-phosphate (G6P) antiporters, catalyzing both homologous (Pi/Pi) and heterologous (G6P/Pi) exchanges, whereas SLC37A3 transport properties remain to be clarified. Furthermore, SLC37A1 is highly homologous to the bacterial glycerol 3-phosphate permeases, so it is supposed to transport also glycerol-3-phosphate. The physiological role of SLC37A1-3 is yet to be further investigated. SLC37A1 seems to be required for lipid biosynthesis in cancer cell lines, SLC37A2 has been proposed as a vitamin D and a phospho-progesterone receptor target gene, while mutations in the SLC37A3 gene appear to be associated with congenital hyperinsulinism of infancy. SLC37A4, also known as glucose-6-phosphate translocase (G6PT), transports G6P from the cytoplasm into the ER lumen, working in complex with either glucose-6-phosphatase-α (G6Pase-α) or G6Pase-β to hydrolyze intraluminal G6P to Pi and glucose. G6PT and G6Pase-β are ubiquitously expressed, whereas G6Pase-α is specifically expressed in the liver, kidney and intestine. G6PT/G6Pase-α complex activity regulates fasting blood glucose levels, whereas G6PT/G6Pase-β is required for neutrophil functions. G6PT deficiency is responsible for glycogen storage disease type Ib (GSD-Ib), an autosomal recessive disorder associated with both defective metabolic and myeloid phenotypes. Several kinds of mutations have been identified in the SLC37A4 gene, affecting G6PT function. An increased autoimmunity risk for GSD-Ib patients has also been reported, moreover, SLC37A4 seems to be involved in autophagy.

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Partial correction of neutrophil dysfunction by oral galactose therapy in glycogen storage disease type Ib

Cited by 8 publications

References 38 publications

Galactose protects against cell damage in mouse models of acute pancreatitis

Galactose protects against cell damage in mouse models of acute pancreatitis

CDG and immune response: From bedside to bench and back

The Physiopathological Role of the Exchangers Belonging to the SLC37 Family

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