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Glycogen storage disease types I and II: treatment updates.

ABSTRACT: Prior to 2006 therapy for glycogen storage diseases consisted primarily of dietary interventions, which in the case of glycogen storage disease (GSD) type II (GSD II; Pompe disease) remained essentially palliative. Despite improved survival and growth, long-term complications of GSD type I (GSD I) have not responded to dietary therapy with uncooked cornstarch or continuous gastric feeding. The recognized significant risk of renal disease and liver malignancy in GSD I has prompted efforts towards curative therapy, including organ transplantation, in those deemed at risk. Results of clinical trials in infantile Pompe disease with alglucosidase alfa (Myozyme) showed prolonged survival reversal of cardiomyopathy, and motor gains. This resulted in broad label approval of Myozyme for Pompe disease in 2006. Furthermore, the development of experimental therapies, such as adeno-associated virus (AAV) vector-mediated gene therapy, holds promise for the availability of curative therapy in GSD I and GSD II/Pompe disease in the future.

SUBMITTER: Koeberl DD

PROVIDER: S-EPMC2692363 | biostudies-literature | 2007 Apr

REPOSITORIES: biostudies-literature

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Glycogen storage disease types I and II: treatment updates.

Koeberl D D DD Kishnani P S PS Chen Y T YT

Journal of inherited metabolic disease 20070216 2

Prior to 2006 therapy for glycogen storage diseases consisted primarily of dietary interventions, which in the case of glycogen storage disease (GSD) type II (GSD II; Pompe disease) remained essentially palliative. Despite improved survival and growth, long-term complications of GSD type I (GSD I) have not responded to dietary therapy with uncooked cornstarch or continuous gastric feeding. The recognized significant risk of renal disease and liver malignancy in GSD I has prompted efforts towards ...[more]

PMID: 17308886

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Project description:Glycogen storage diseases (GSD) encompass a group of rare inherited diseases due dysfunction of glycogen metabolism. Hypoglycemia is the most common primary manifestation of GSD, and disturbances in glucose metabolism can cause neurological damage. The aims of this study were to first investigate the metabolic, genetic, and neurological profiles of children with GSD, and to test the hypothesis whether GSD type I would have greater neurological impact than GSD type IX. A cross-sectional study was conducted with 12 children diagnosed with GSD [Types: Ia (n=5); 1, Ib (n=1); 4, IXa (n=5); and 1, IXb (n=1)]. Genetic testing was conducted for the following genes using multigene panel analysis. The biochemical data and magnetic resonance imaging of the brain presented by the patients were evaluated. The criteria of adequate metabolic control were adopted based on the European Study on Glycogen Storage Disease type I consensus. Pathogenic mutations were identified using multigene panel analyses. The mutations and clinical chronology were related to the disease course and neuroimaging findings. Adequate metabolic control was achieved in 67% of patients (GSD I, 43%; GSD IX, 100%). Fourteen different mutations were detected, and only two co-occurring mutations were observed across families (G6PC c.247C>T and c.1039C>T). Six previously unreported variants were identified (5 PHKA2; 1 PHKB). The proportion of GSD IX was higher in our cohort compared to other studies. Brain imaging abnormalities were more frequent among patients with GSD I, early-symptom onset, longer hospitalization, and inadequate metabolic control. The frequency of mutations was similar to that observed among the North American and European populations. None of the mutations observed in PHKA2 have been described previously. Therefore, current study reports six GSD variants previously unknown, and neurological consequences of GSD I. The principal neurological impact of GSD appeared to be related to inadequate metabolic control, especially hypoglycemia.

Project description:BackgroundGlycogen storage disease type 1b (GSD1b) is an ultra-rare autosomal recessive disorder, caused by mutations in SLC37A4 gene. Affected patients present with episodes of fasting hypoglycemia and lactic acidosis, hepatomegaly, growth retardation, hyperlipidemia and renal impairment. In addition, patients present neutropenia, neutrophil dysfunction and oral, and skin infections as well as a significant predisposition to develop inflammatory bowel disease (IBD). Low neutrophil counts and function is related to the toxic accumulation of 1,5-anhydroglucitol-6-phosphate (1,5-AG6P). Recently, several reports have shown that off-label treatment with empagliflozin (EMPA), an inhibitor of the renal glucose transporter SGLT2, decreased blood 1,5-anhydroglucitol (1,5-AG), and neutrophil 1,5-AG6P, thus resulting in a new therapeutic option for neutropenia and neutrophil dysfunction in patients.MethodsOff-label treatment with EMPA was established in two GSD1b patients after signed informed consent. The patients were followed clinically. We monitored neutrophil counts and function, 1,5-AG levels in plasma and its renal clearance before and during EMPA treatment.ResultsA 17 year-old girl who had long standing oral ulcers and developed IBD, requiring systemic steroid and regular granulocyte colony-stimulating factor (GCSF) therapy and an 8 year-old boy who had steady non healing oral lesions were treated with empagliflozin during 18-24 months. Treatment led to increase of neutrophil counts and function with substantial clinical improvement. This included remission of IBD in the first patient which allowed to discontinue both GCSF and steroid therapy and resolution of oral lesions in both patients. The concentration of 1,5-AG in blood was greatly decreased within two weeks of treatment and remained stable thereafter.ConclusionsRepurposing of empagliflozin to treat neutropenia in two GSD1b patients was safe and resulted in the urinary excretion of 1,5-AG, the normalization of neutrophil function, and a remarkable improvement of neutropenia-related clinical traits. We showed for the first time that empagliflozin increases concomitantly the renal clearance of both 1,5-anhydroglucitol and glucose in GSD1b patients.

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Glycogen storage disease types I and II: treatment updates.

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Glycogen storage disease types I and II: treatment updates.

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