The natural history of glycogen storage disease type Ib in England: A multisite survey.
Ontology highlight
ABSTRACT:
SUBMITTER: Halligan R
PROVIDER: S-EPMC8100392 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Glycogen storage disease type IIIa (GSD IIIa) is caused by a deficiency of glycogen debranching enzyme activity. Hepatomegaly, muscle degeneration, and hypoglycemia occur in human patients at an early age. Long-term complications include liver cirrhosis, hepatic adenomas, and generalized myopathy. A naturally occurring canine model of GSD IIIa that mimics the human disease has been described, with progressive liver disease and skeletal muscle damage likely due to excess glycogen deposition. In the current study, long-term follow-up of previously described GSD IIIa dogs until 32 mo of age (n = 4) and of family-owned GSD IIIa dogs until 11 to 12 y of age (n = 2) revealed that elevated concentrations of liver and muscle enzyme (AST, ALT, ALP, and creatine phosphokinase) decreased over time, consistent with hepatic cirrhosis and muscle fibrosis. Glycogen deposition in many skeletal muscles; the tongue, diaphragm, and heart; and the phrenic and sciatic nerves occurred also. Furthermore, the urinary biomarker Glc4, which has been described in many types of GSD, was first elevated and then decreased later in life. This urinary biomarker demonstrated a similar trend as AST and ALT in GSD IIIa dogs, indicating that Glc4 might be a less invasive biomarker of hepatocellular disease. Finally, the current study further demonstrates that the canine GSD IIIa model adheres to the clinical course in human patients with this disorder and is an appropriate model for developing novel therapies.
| S-EPMC4752035 | biostudies-literature
Project description:We report on liver transplantation in two patients with GSD Ib on treatment with empagliflozin. The use of this SGLT2 inhibitor resulted in a marked decrease of 1,5-anhydroglucitol which has an important role in the development of neutropenia in this condition. As intended, this caused a significant rise of neutrophil numbers. Liver transplantation alone did not produce the desired effect and our observation argues for continuing SGLT2 inhibitor treatment after transplantation.
| S-EPMC10233270 | biostudies-literature
Project description:Glycogen storage disease type Ib (GSD-Ib) is caused by a deficiency in the glucose-6-phosphate (G6P) transporter (G6PT) that works with a liver/kidney/intestine-restricted glucose-6-phosphatase-alpha (G6Pase-alpha) to maintain glucose homeostasis between meals. Clinically, GSD-Ib patients manifest disturbed glucose homeostasis and neutrophil dysfunctions but the cause of the latter is unclear. Neutrophils express the ubiquitously expressed G6PT and G6Pase-beta that together transport G6P into the endoplasmic reticulum (ER) lumen and hydrolyze it to glucose. Because we expected G6PT-deficient neutrophils to be unable to produce endogenous glucose, we hypothesized this would lead to ER stress and increased apoptosis. Using GSD-Ib mice, we showed that GSD-Ib neutrophils exhibited increased production of ER chaperones and oxidative stress, consistent with ER stress, increased annexin V binding and caspase-3 activation, consistent with an increased rate of apoptosis. Bax activation, mitochondrial release of proapoptotic effectors, and caspase-9 activation demonstrated the involvement of the intrinsic mitochondrial pathway in these processes. The results demonstrate that G6P translocation and hydrolysis are required for normal neutrophil functions and support the hypothesis that neutrophil dysfunction in GSD-Ib is due, at least in part, to ER stress and increased apoptosis.
| S-EPMC2424162 | biostudies-other
Project description:Glycogenosis type Ib (GSD1B) causes not only hypoglycemia but also infections and "Crohn's disease like" inflammatory bowel disease (IBD) that can significantly impair patient's quality of life. We retrospectively evaluated infectious and digestive complications in 9 French patients (3 girls, 6 boys) diagnosed at 0.8 years on average, with a mean follow-up of 19.1 years. Infections occurred earlier than IBD, at mean ages of 1.7 and 3.8 years, respectively. The number of acute hospitalizations was 0.7/year due to infectious (0.4/year) or digestive symptoms (0.4/year). Clinical presentations allowed separating patients into mild (n = 5) and severe (n = 4) intestinal involvement. Patients in the severe group had more serious digestive symptoms but also earlier neutropenia (median 0.3 vs. 1.5 years, p =0 .046) with a tendency to a lower neutrophil count (NC) during follow-up, and a higher number of acute hospitalizations (median 1.3/year vs. 0.2/year, p =0 .014) due to digestive symptoms (median 0.6/year vs. 0.05/year, p = 0,012) and infections (median 0.8/year vs. 0.2/year, p =0 .014). Treatments included G-CSF and cotrimoxazole (n = 7), 5-aminosalicylic acid (n = 2), and a polymeric solution enriched in the anti-inflammatory cytokine TGF-? (n = 4, "severe" group), and immunomodulatory treatment (n = 1). In conclusion, infections and IBD are rare but severe complications in GSD1B. Neutropenia tended to be more prevalent in the severe IBD group than in the mild IBD group. Dietetic treatment with specific anti-inflammatory solutions seems particularly appropriate in these patients.
| S-EPMC7152669 | biostudies-literature
Project description:Neutropenia and neutrophil dysfunction cause serious infections and inflammatory bowel disease in glycogen storage disease type Ib (GSD-Ib). Our discovery that accumulating 1,5-anhydroglucitol-6-phosphate (1,5AG6P) caused neutropenia in a glucose-6-phosphatase 3 (G6PC3)-deficient mouse model and in 2 rare diseases (GSD-Ib and G6PC3 deficiency) led us to repurpose the widely used antidiabetic drug empagliflozin, an inhibitor of the renal glucose cotransporter sodium glucose cotransporter 2 (SGLT2). Off-label use of empagliflozin in 4 GSD-Ib patients with incomplete response to granulocyte colony-stimulating factor (GCSF) treatment decreased serum 1,5AG and neutrophil 1,5AG6P levels within 1 month. Clinically, symptoms of frequent infections, mucosal lesions, and inflammatory bowel disease resolved, and no symptomatic hypoglycemia was observed. GCSF could be discontinued in 2 patients and tapered by 57% and 81%, respectively, in the other 2. The fluctuating neutrophil numbers in all patients were increased and stabilized. We further demonstrated improved neutrophil function: normal oxidative burst (in 3 of 3 patients tested), corrected protein glycosylation (2 of 2), and normal neutrophil chemotaxis (1 of 1), and bactericidal activity (1 of 1) under treatment. In summary, the glucose-lowering SGLT2 inhibitor empagliflozin, used for type 2 diabetes, was successfully repurposed for treating neutropenia and neutrophil dysfunction in the rare inherited metabolic disorder GSD-Ib without causing symptomatic hypoglycemia. We ascribe this to an improvement in neutrophil function resulting from the reduction of the intracellular concentration of 1,5AG6P.
| S-EPMC7530374 | biostudies-literature
Project description:In patients with glycogen storage disease type Ib (GSD Ib), quality of life is severely hampered by neutropenia and neutropenia-associated symptoms. SGLT2 inhibitors are a new treatment option and have shown improved medical outcomes in more than 120 patients so far. The aim of this international questionnaire study was to assess patient-reported outcomes of this new treatment in GSD Ib patients. Patients and caregivers of pediatric patients were invited to complete a web-based questionnaire. This was designed to evaluate treatment effects of the SGLT2 inhibitor empagliflozin on clinical symptoms and important aspects of daily life including physical performance, sleep, social and work life, traveling, socioeconomic aspects, and quality of life. The questionnaire was completed by 73 respondents from 17 different countries. The mean duration of treatment was 15 months, the cumulative treatment time was 94.8 years. More than 80% of patients reported an improved quality of life. The number of hospitalizations was reduced (66% of patients), as well as the number of days absent from school or work. Granulocyte colony-stimulating factor (G-CSF) treatment could be stopped in 49% of patients and reduced in another 42%. Clear improvement of neutropenia and all neutropenia-associated symptoms was reported by the majority of patients. Additionally, patients or caregivers reported positive effects on appetite (63%), level of activity (75%), overall well-being (96%), and sleep (63%). Empagliflozin positively impacts many aspects of daily life including work and social life and thereby significantly improves quality of life of patients and caregivers.
| S-EPMC10159866 | biostudies-literature
Project description:BackgroundMolecular techniques are fundamental for establishing an accurate diagnosis and therapeutic approach of glycogen storage diseases (GSDs). We aimed to evaluate SLC37A4 mutation spectrum in Korean GSD Ib patients.MethodsNine Korean patients from eight unrelated families with GSD Ib were included. SLC37A4 mutations were detected in all patients with direct sequencing using a PCR method and/or whole-exome sequencing. A comprehensive review of previously reported SLC37A4 mutations was also conducted.ResultsNine different pathogenic SLC37A4 mutations were identified in the nine patients with GSD Ib. Among them, four novel mutations were identified: c.148G>A (pGly50Arg), c.320G>A (p.Trp107*), c.412T>C (p.Trp138Arg), and c.818G>A (p.Gly273Asp). The most common mutation type was missense mutations (66.7%, 6/9), followed by nonsense mutations (22.2%, 2/9) and small deletion mutations (11.1%, 1/9). The most common mutation identified in the Korean population was c.443C>T (p.Ala148Val), which comprised 39.9% (7/18) of all tested alleles. This mutation has not been reported in GSD Ib patients in other ethnic populations.ConclusionsThis study expands knowledge of the SLC37A4 mutation spectrum in Korean patients with GSD Ib.
| S-EPMC5339099 | biostudies-literature
Project description:Glycogen storage disease (GSD) Ib is a rare genetic metabolic disorder caused by gene mutation in the glucose 6-phosphate transport gene SLC37A4 (OMIM# 602671). This study aimed to explore the association between a novel lipoprotein lipase (LPL) mutation and severe hypertriglyceridemia in a GSD Ib infant with severe hypertriglyceridemia. A 5-month-old girl was admitted to our hospital because of repeated episodes of low-grade fever over the past month and because of neutropenia. The patient was diagnosed with GSD Ib and severe hypertriglyceridemia based on clinical manifestations and laboratory test results. Next-generation sequencing and Sanger sequencing were then applied to DNA from the peripheral blood of the patient and her parents to analyze gene mutations. Pathogenicity prediction analysis was performed using Sorting Intolerant From Tolerant (SIFT) and PolyPhen-2 platforms. The results revealed that this infant carried a compound heterozygous variation in the SLC37A4 gene, a c.1043T > C (p.L348P) mutation derived from her mother and a c.572C > T (p.P191L) mutation derived from her father. In addition, a novel c.483delA (p. A162Pfs*10) frameshift mutation was found in the patient's LPL gene exon 4, which was derived from the heterozygous carrier of her father. The SIFT and PolyPhen-2 prediction programs indicated that these mutations were likely harmful. Medium-chain triglyceride milk and granulocyte colony-stimulating factor subcutaneous injection alleviated the symptoms. Our findings identified a novel LPL gene frameshift mutation combined with SLC37A4 gene compound heterozygous mutations in a GSD Ib infant with severe hypertriglyceridemia.
| S-EPMC8416156 | biostudies-literature
Project description:BackgroundGlycogen storage disease type I (GSD I) is a rare autosomal recessive disorder of carbohydate metabolism characterized by recurrent hypoglycaemia and hepatomegaly. Management of GSD I is demanding and comprises a diet with defined carbohydrate intake and the use of complex carbohydrates, nocturnal tube feeding or night-time uncooked cornstarch intake, regular blood glucose monitoring and the handling of emergency situations. With improved treatment, most patients nowadays survive into adulthood. Little research has been performed on the impact of GSD I on daily life, especially in adult patients.ResultsIn this multi-centre study we assessed the impact of GSD I on adult daily life in 34 GSD I patients (27 GSD Ia, 7 GSD Ib) between 17 and 54 years (median 26 years) using a self-designed questionnaire that specifically focused on different aspects of daily life, such as job situation, social life, sports, travelling, composition of the household, night-time and day-time dietary management and disease monitoring as well as the patient's attitude towards the disease. At the time of investigation, the majority of patients either attended school or university or were employed, while 3 patients (9%) were out of work. Most patients ranked GSD I as a disease with moderate severity and disease burden. Dietary treatment was considered challenging by many, but the vast majority of patients considered life with GSD I as well-manageable.ConclusionsAlthough the management of GSD I poses a significant burden on daily life, most patients live an independent adult life, have a positive attitude towards their disease and seem to cope well with their situation.
| S-EPMC8414849 | biostudies-literature
Project description:IntroductionRecently published case reports suggest the benefit of empagliflozin use in subjects with glycogen storage disease Ib (GSD Ib).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 was noted. Neutrophil count increased, allowing for reduction or temporary withdrawal of G-CSF treatment.ConclusionsEmpagliflozin may be a new safe treatment in GSD Ib patients with an advanced stage of the disease.
| S-EPMC9266796 | biostudies-literature