The natural history of glycogen storage disease type Ib in England: A multisite survey

Halligan, Rebecca; White, Fiona J.; Schwahn, Bernd; Stępień, Karolina M.; Jaman, Nazreen Kamarus; McSweeney, Mel; Kitchen, Steve; Gribben, Joanna; Dawson, Charlotte; Lewis, Katherine; Cregeen, David; Mundy, Helen; Santra, Saikat

doi:10.1002/jmd2.12200

Cited by 10 publications

(8 citation statements)

References 28 publications

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“…However, improvement clinically and in neutrophil function tests enabled us to wean and ultimately cease GCSF in all patients. Formation of a gastrostomy for enteral feeding has been contraindicated in GSD Ib patients due to poor wound healing; however, two of our patients have now successfully undergone this procedure [ 6 ]. We performed sophisticated immune response studies on 4 of our patients; however, these are expensive and not readily available and we do not feel that they add much to the clinical evaluation.…”

Section: Discussionmentioning

confidence: 99%

“…GSD Ib patients have neutropaenia and neutrophil dysfunction causing recurrent infections, periodontal inflammation and inflammatory bowel disease (IBD) [ 5 ]. The neutropaenia and neutrophil dysfunction in GSD Ib persists throughout life, and is not ameliorated by liver transplantation [ 6 – 9 ]. This is likely to impact on quality of life (QoL) with studies finding that patients with GSD Ib typically reported a lower QoL than patients with GSD Ia [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Understanding the role of SGLT2 inhibitors in glycogen storage disease type Ib: the experience of one UK centre

Halligan

Dalton

Turner

et al. 2022

Orphanet J Rare Dis

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Background Glycogen storage disease type Ib (GSD Ib) is a severe disorder of carbohydrate metabolism due to bi-allelic variants in SLC37A4. It is associated with neutropaenia and neutrophil dysfunction, which has recently been attributed to the accumulation of 1,5-anhydroglucitol-6-phosphate (1,5AG6P) within neutrophils. Treatment with sodium-glucose co-transporter-2 (SGLT2) inhibitors, such as empagliflozin, is a novel therapy that reduces 1,5-anhydroglucitol (1,5AG) in plasma. Results We report our experience in treating 8 paediatric GSD Ib patients with empagliflozin with a cumulative treatment time greater than 12 years. Treatment with a median dose of 5 mg (0.22 mg/kg height weight) of empagliflozin resulted in improvement in bowel health, growth, and laboratory parameters. Plasma 1,5AG levels reduced by a median of 78%. Baseline 1,5AG levels in our cohort were higher than in adult patients with GSD Ib. Hypoglycaemia on empagliflozin treatment occurred in 50% of our cohort. Conclusion We report the largest single centre cohort of GSD Ib patients treated with empagliflozin to date. Treatment with SGLT2 inhibitors is a novel and favourable treatment option for neutropaenia and neutrophil dysfunction in GSD Ib. We suggest a low starting dose of empagliflozin with careful titration due to the risk of hypoglycaemia. The interpretation of 1,5AG levels and their role in treatment monitoring is yet to be established, and requires ongoing research.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Understanding the role of SGLT2 inhibitors in glycogen storage disease type Ib: the experience of one UK centre

Halligan

Dalton

Turner

et al. 2022

Orphanet J Rare Dis

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“…Neutropenia and neutrophil dysfunction resulting in recurrent infections, perioral and perianal infections, and abscesses are the hallmark features of GSD Ib [ 2 ]. The administration of granulocyte colony-stimulating factor (G-CSF) improves the neutrophil count but not dysfunction and increases the risk of myelodysplasia and acute myeloid leukemia [ 1 ].…”

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confidence: 99%

The overall benefits of empagliflozin treatment in adult siblings with glycogen storage disease type Ib: one year experience

2022

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IntroductionRecently published case reports suggest the benefit of empagliflozin use in subjects with glycogen storage disease Ib (GSD Ib).Material and methodsWe present the clinical and laboratory data of 2 adult brothers with GSD Ib treated with empagliflozin for 12 months.ResultsThere was no severe infection during administration of empagliflozin. The improvement of clinical symptoms of inflammatory bowel disease and arthritis along with reduction in serum CRP levels and urinary albumin excretion were noted. Neutrophil count increased allowing for reduction or temporary withdrawal of G-CSF treatment.ConclusionsEmpagliflozin may be new safe treatment in GSD Ib patients with advanced stage of the disease.

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“…72 A 2021 review details the current management options, burden, and unmet needs in GSD Ia, 73 providing support for clinical trials targeting GSD Ia. Findings from a retrospective, observational study on individuals with GSD Ib in England (N = 35) was published in 2021, 74 and key findings include the impact of GSD Ib on growth, fasting tolerance, bone health, as well as renal, endocrine, and gastrointestinal manifestations. That study was limited in conclusions it could draw on the natural history in adulthood due to limited adult cases (N = 7).…”

Section: Gsd Ia and Ibmentioning

confidence: 99%

Gene therapy for glycogen storage diseases

Koeberl

Koch

Lim

et al. 2023

J of Inher Metab Disea

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Glycogen storage disorders (GSDs) are inherited disorders of metabolism resulting from the deficiency of individual enzymes involved in the synthesis, transport, and degradation of glycogen. This literature review summarizes the development of gene therapy for the GSDs. The abnormal accumulation of glycogen and deficiency of glucose production in GSDs lead to unique symptoms based upon the enzyme step and tissues involved, such as liver and kidney involvement associated with severe hypoglycemia during fasting and the risk of long‐term complications including hepatic adenoma/carcinoma and end stage kidney disease in GSD Ia from glucose‐6‐phosphatase deficiency, and cardiac/skeletal/smooth muscle involvement associated with myopathy +/− cardiomyopathy and the risk for cardiorespiratory failure in Pompe disease. These symptoms are present to a variable degree in animal models for the GSDs, which have been utilized to evaluate new therapies including gene therapy and genome editing. Gene therapy for Pompe disease and GSD Ia has progressed to Phase I and Phase III clinical trials, respectively, and are evaluating the safety and bioactivity of adeno‐associated virus vectors. Clinical research to understand the natural history and progression of the GSDs provides invaluable outcome measures that serve as endpoints to evaluate benefits in clinical trials. While promising, gene therapy and genome editing face challenges with regard to clinical implementation, including immune responses and toxicities that have been revealed during clinical trials of gene therapy that are underway. Gene therapy for the glycogen storage diseases is under development, addressing an unmet need for specific, stable therapy for these conditions.

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The natural history of glycogen storage disease type Ib in England: A multisite survey

Cited by 10 publications

References 28 publications

Understanding the role of SGLT2 inhibitors in glycogen storage disease type Ib: the experience of one UK centre

Understanding the role of SGLT2 inhibitors in glycogen storage disease type Ib: the experience of one UK centre

The overall benefits of empagliflozin treatment in adult siblings with glycogen storage disease type Ib: one year experience

Gene therapy for glycogen storage diseases

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