Neutropenia and impaired neutrophil migration in type IB glycogen storage disease

Beaudet, Arthur L.; Anderson, Donald C.; Michels, Virginia V.; Arion, William J.; Lange, Alex J.

doi:10.1016/s0022-3476(80)80418-5

Cited by 146 publications

(73 citation statements)

References 20 publications

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“…A second, less prevalent form of GSD-I, GSD-Ib, exhibits identical metabolic abnormalities, but is caused by mutations of the G6P transporter (1). GSD-Ib patients exhibit additional clinical manifestations of neutropenia and myeloid dysfunctions (1)(2)(3)(4). In the last two and half decades, effective dietary therapies (5,6) have significantly alleviated the metabolic abnormalities of GSD-I.…”

Section: Introductionmentioning

confidence: 99%

Necrotic foci, elevated chemokines and infiltrating neutrophils in the liver of glycogen storage disease type Ia

Kim

Weinstein

Starost

et al. 2008

Journal of Hepatology

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Background/Aims-Glycogen storage disease type Ia (GSD-Ia) patients manifest the long-term complication of hepatocellular adenoma (HCA) of unknown etiology. We showed previously that GSD-Ia mice exhibit neutrophilia and elevated serum cytokine levels. This study was conducted to evaluate whether human GSD-Ia patients exhibit analogous increases and whether in GSD-Ia mice a correlation exists between immune abnormalities and, biochemical and histological alterations in the liver.Methods-Differential leukocyte counts and cytokine levels were investigated in GSD-Ia patients. Hepatic chemokine production, neutrophil infiltration, and histological abnormalities were investigated in GSD-Ia mice.Results-We show that GSD-Ia patients exhibit increased peripheral neutrophil counts and serum interleukin-8 (IL-8). Compared to normal subjects, HCA-bearing GSD-Ia patients have a 2.8-fold higher serum IL8 concentration, while GSD-Ia patients without HCA have a 1.4-fold higher concentration. Hepatic injury in GSD-Ia mice is evidenced by necrotic foci, markedly elevated infiltrating neutrophils, and increased hepatic production of chemokines.Conclusion-Peripheral neutrophilia and elevated serum chemokines are characteristic of GSDIa with HCA-bearing GSD-Ia patients having the highest serum IL-8. In GSD-Ia mice these elevations correlate with elevated hepatic chemokine levels, neutrophil infiltration, and necrosis. Taken together, peripheral neutrophilia and increased serum chemokines may indicate hepatic injuries in GSD-Ia

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Section: Introductionmentioning

confidence: 99%

Necrotic foci, elevated chemokines and infiltrating neutrophils in the liver of glycogen storage disease type Ia

Kim

Weinstein

Starost

et al. 2008

Journal of Hepatology

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“…Since then, there have been several reports in which a defect of the G-6-P transport system was confirmed (7,9,12,20). We observed three patients with GSD type l b including two siblings.…”

Section: Discussionmentioning

confidence: 63%

“…The clinical symptoms in the siblings were severe compared to most patients with GSD type l b reported in the literature (6-9, 16, 19, 21, 22), indicating an early onset and rapid development of hypoglycemia. The patients had neutropenia (15), which was common in cases of GSD type l b (1, 6,7,13,17,18). On the other hand, the adult patient (Y.M.)…”

Section: Discussionmentioning

confidence: 99%

Glycogen Storage Disease Type 1b: Microsomal Glucose-6-Phosphatase System in Two Patients with Different Clinical Findings

et al. 1983

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“…In addition, GSD-Ib patients manifest neutropenia along with myeloid dysfunctions in Ca 2+ mobilization, respiratory burst, and chemotaxis [Beaudet et al, 1980;Gitzelmann and Bosshard 1993;Visser et al, 2002;Chou and Mansfield 2003]. Oral and intestinal mucosal ulcerations are common in GSD-Ib, and most patients also suffer from chronic inflammatory bowel disease [Roe et al, 1986;Visser et al, 2002].…”

Section: Gsd-ibmentioning

confidence: 99%

“…Additional accumulation of fat droplets in the liver also contributes significantly to the hepatomegaly. Unlike the GSD-Ia patients, GSD-Ib patients manifest additional symptoms of neutropenia and myeloid dysfunctions [Beaudet et al, 1980;Gitzelmann and Bosshard 1993;Visser et al, 2002;Chou and Mansfield 2003] that are not obviously related to metabolism in the gluconeogenic tissues. In examining the potential roles of G6PT outside of the gluconeogenic tissues, a recent bone marrow transplantation study established that G6PT expression in the bone marrow is required for normal neutrophil and myeloid functions [Kim et al, 2006].…”

Section: Introductionmentioning

confidence: 96%

Gene Therapy for Type I Glycogen Storage Diseases

Chou¹,

Mansfield²

2007

CGT

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The type I glycogen storage diseases (GSD-I) are a group of related diseases caused by a deficiency in the glucose-6-phosphatase-α (G6Pase-α) system, a key enzyme complex that is essential for the maintenance of blood glucose homeostasis between meals. The complex consists of a glucose-6-phosphate transporter (G6PT) that translocates glucose-6-phosphate from the cytoplasm into the lumen of the endoplasmic reticulum, and a G6Pase-α catalytic unit that hydrolyses the glucose-6-phosphate into glucose and phosphate. A deficiency in G6Pase-α causes GSD type Ia (GSD-Ia) and a deficiency in G6PT causes GSD type Ib (GSD-Ib). Both GSD-Ia and GSD-Ib patients manifest a disturbed glucose homeostasis, while GSD-Ib patients also suffer symptoms of neutropenia and myeloid dysfunctions. G6Pase-α and G6PT are both hydrophobic endoplasmic reticulum-associated transmembrane proteins that can not expressed in soluble active forms. Therefore protein replacement therapy of GSD-I is not an option. Animal models of GSD-Ia and GSD-Ib that mimic the human disorders are available. Both adenovirus-and adeno-associated virus (AAV)-mediated gene therapies have been evaluated for GSD-Ia in these model systems. While adenoviral therapy produces only short term corrections and only impacts liver expression of the gene, AAV-mediated therapy delivers the transgene to both the liver and kidney, achieving longer term correction of the GSD-Ia disorder, although there are substantial differences in efficacy depending on the AAV serotype used. Gene therapy for GSD-Ib in the animal model is still in its infancy, although an adenoviral construct has improved the metabolic profile and myeloid function. Taken together further refinements in gene therapy may hold long term benefits for the treatment of type I GSD disorders.

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Neutropenia and impaired neutrophil migration in type IB glycogen storage disease

Cited by 146 publications

References 20 publications

Necrotic foci, elevated chemokines and infiltrating neutrophils in the liver of glycogen storage disease type Ia

Necrotic foci, elevated chemokines and infiltrating neutrophils in the liver of glycogen storage disease type Ia

Glycogen Storage Disease Type 1b: Microsomal Glucose-6-Phosphatase System in Two Patients with Different Clinical Findings

Gene Therapy for Type I Glycogen Storage Diseases

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