On this page
Glycogen storage disease type Ib
GSD Ib is a rare inherited disorder impacting glucose metabolism, causing low blood sugar (hypoglycaemia) and liver enlargement. It typically presents in infancy or early childhood and requires careful dietary management to prevent serious complications.
Available at Jeen Health
Clinical tests that include this
Overview
Glycogen Storage Disease Type Ib (GSD Ib) is a rare, inherited metabolic condition that affects how the body stores and uses glycogen. Glycogen is the main way the body stores glucose, a type of sugar, for energy. In GSD Ib, the body has difficulty releasing glucose from these stores, particularly during periods without food, which can lead to dangerously low blood sugar levels (hypoglycaemia) [PMID:31252037]. This condition is one of several types of glycogen storage diseases, each caused by different genetic changes affecting specific enzymes or transport proteins involved in glycogen metabolism.
Individuals with GSD Ib often experience symptoms from infancy or early childhood. The condition can impact several organs, most notably the liver, kidneys, and intestines. Lifelong management, primarily through dietary adjustments, is crucial to maintain stable blood sugar and reduce the risk of long-term complications.
Symptoms & clinical features
Symptoms of GSD Ib typically emerge in infancy. A key feature is persistent low blood sugar, especially between meals or overnight, which can lead to tiredness, irritability, and, in severe cases, seizures. The liver often becomes enlarged (hepatomegaly) due to the accumulation of unprocessed glycogen [PMID:31252037].
Other common symptoms include delayed growth and short stature. Many individuals with GSD Ib also experience recurrent infections due to a type of white blood cell dysfunction, as well as inflammatory bowel disease-like symptoms, such as abdominal pain and diarrhoea. Kidney involvement can lead to problems with kidney stone formation or kidney dysfunction over time [PMID:20301389].
Video: Genetics 101
Affected organs
GSD Ib primarily affects the liver, where glycogen is stored and processed. The liver can become significantly enlarged due to the build-up of glycogen. The kidneys are also commonly affected, potentially leading to issues with their function over time.
The digestive system, particularly the intestines, can be impacted, leading to chronic inflammatory conditions similar to inflammatory bowel disease. Additionally, the immune system is often compromised, increasing susceptibility to infections. In some cases, bone health may be affected, potentially contributing to bone thinning (osteopenia or osteoporosis) later in life.
Risks & severity
The severity of GSD Ib can vary, but it is generally a serious condition requiring ongoing medical attention. Persistent low blood sugar poses a significant risk, particularly in infants and young children, as it can lead to brain damage if not managed effectively. The chronic inflammation and recurrent infections can also lead to significant health challenges.
Without appropriate management, GSD Ib can lead to severe complications such as growth failure, kidney disease, liver tumours (adenomas or hepatocellular carcinoma), and neutropenia-related infections. However, with consistent dietary intervention and medical oversight, many individuals can achieve good health outcomes and a near-normal life expectancy.
Genetic causes
Glycogen Storage Disease Type Ib is caused by pathogenic variants in the SLC37A4 gene. This gene provides instructions for making a protein called glucose-6-phosphate translocase, which is essential for the final step in converting glycogen to glucose in the liver and kidneys. Specifically, this protein transports glucose-6-phosphate from the cell's cytoplasm into a structure called the endoplasmic reticulum, where it can be further processed into glucose.
When the SLC37A4 gene has a pathogenic variant, the glucose-6-phosphate translocase protein is either absent or doesn't function correctly. This prevents the normal release of glucose from glycogen stores, leading to the accumulation of glycogen in the liver and kidneys, and the characteristic low blood sugar levels [PMID:20301389]. Variants in SLC37A4 can also affect neutrophil function, contributing to immune system problems seen in GSD Ib.
- SLC37A4 solute carrier family 37 member 4
Inheritance pattern
GSD Ib is inherited in an autosomal recessive pattern. This means that a person must inherit two copies of the altered SLC37A4 gene - one from each parent - to develop the condition. Individuals who inherit only one copy of the altered gene are known as carriers. Carriers typically do not show any symptoms of GSD Ib but can pass the altered gene on to their children.
If both parents are carriers of a pathogenic SLC37A4 variant, there is a 1 in 4 (25%) chance with each pregnancy that their child will inherit two altered copies and develop GSD Ib. There is a 2 in 4 (50%) chance that their child will be a carrier, and a 1 in 4 (25%) chance that their child will inherit two unaffected copies of the gene and not be affected or a carrier.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
Diagnosis of GSD Ib often begins with the recognition of typical clinical symptoms such as recurrent low blood sugar, an enlarged liver, and failure to thrive. Blood tests may show characteristic metabolic changes, including low blood glucose, elevated levels of lactate, uric acid, and lipids.
Confirmation of GSD Ib is primarily achieved through genetic testing, which looks for pathogenic variants in the SLC37A4 gene. In the UK, genetic testing for GSD Ib is available through the NHS Genomic Medicine Service (GMS) as part of the rare disease testing pathway (R-code R146). Referrals for genetic testing are typically made by paediatricians or metabolic specialists, often after initial biochemical investigations suggest a glycogen storage disorder. A clinical geneticist or genetic counsellor can discuss the testing process and implications.
Management & lifestyle
Management for GSD Ib focuses on maintaining stable blood glucose levels and preventing complications. This primarily involves a strict dietary regimen, often including frequent small meals high in complex carbohydrates, and uncooked cornstarch given between meals or overnight [PMID:31252037]. Uncooked cornstarch slowly releases glucose, helping to prevent episodes of low blood sugar. In infants, continuous nocturnal feeding via a nasogastric tube may be necessary.
Regular monitoring of blood glucose, liver function, and kidney function is essential. Medications may be prescribed to manage elevated uric acid or lipid levels. Given the increased risk of infections, individuals with GSD Ib may receive prophylactic antibiotics or granulocyte colony-stimulating factor (G-CSF) to improve immune function. An NHS metabolic dietitian, working alongside a multidisciplinary team, will provide ongoing guidance on dietary management and overall care, with regular follow-up appointments at specialist centres.
UK care pathway
In the UK, individuals suspected of having GSD Ib are typically referred through their GP or paediatrician to a specialist metabolic centre. The NHS Genomic Medicine Service (GMS) provides access to genetic testing for rare diseases, including GSD Ib (NHS R-code R146). A clinical geneticist or genetic counsellor can guide families through the diagnostic process and discuss the implications of a diagnosis. Ongoing care involves a multidisciplinary team, usually including a metabolic consultant, dietitian, and other specialists as needed, ensuring comprehensive management within the NHS framework.
Frequently asked questions
What is the main difference between GSD Ia and GSD Ib?
Both GSD Ia and GSD Ib cause low blood sugar and an enlarged liver. However, GSD Ib also involves immune system problems, leading to recurrent infections, and often features inflammatory bowel disease-like symptoms, which are not typically seen in GSD Ia.
Will my child need to follow a special diet forever?
Yes, dietary management is a lifelong necessity for individuals with GSD Ib. A specialised diet, often including uncooked cornstarch, helps to maintain stable blood sugar levels and prevent complications. Regular consultation with a metabolic dietitian is crucial.
Can GSD Ib be cured?
Currently, there is no cure for GSD Ib. However, with strict dietary management and regular medical oversight, many individuals with GSD Ib can lead healthy and active lives, managing their symptoms and preventing serious complications.
What are the long-term health concerns for someone with GSD Ib?
With careful management, many long-term complications can be avoided. However, potential long-term concerns may include kidney problems, bone thinning, and, rarely, liver tumours. Regular monitoring by a specialist team helps to identify and manage these risks early.
How common is GSD Ib?
GSD Ib is a rare condition, affecting approximately 1 in 100,000 individuals worldwide. Because it is so rare, diagnosis may sometimes be delayed.
References
- Grünert SC, Derks TGJ, Mundy H. Treatment recommendations for glycogen storage disease type IB- associated neutropenia and neutrophil dysfunction with empagliflozin: Consensus from an international workshop. Molecular genetics and metabolism. 2024. PMID: 38277989
- Lava SAG, Laurence C, Di Deo A. Dapagliflozin and Empagliflozin in Paediatric Indications: A Systematic Review. Paediatric drugs. 2024. PMID: 38635113
- Sim SW, Weinstein DA, Lee YM. Glycogen storage disease type Ib: role of glucose-6-phosphate transporter in cell metabolism and function. FEBS letters. 2020. PMID: 31705665
- Kim GY, Lee YM, Kwon JH. Glycogen storage disease type Ib neutrophils exhibit impaired cell adhesion and migration. Biochemical and biophysical research communications. 2017. PMID: 27864142
- Chou JY, Cho JH, Kim GY. Molecular biology and gene therapy for glycogen storage disease type Ib. Journal of inherited metabolic disease. 2018. PMID: 29663270
- Lan J, Zhang Y, Jin C. Gut Dysbiosis Drives Inflammatory Bowel Disease Through the CCL4L2-VSIR Axis in Glycogen Storage Disease. Advanced science (Weinheim, Baden-Wurttemberg, Germany). 2024. PMID: 38889269
- Wicker C, Roda C, Perry A. Infectious and digestive complications in glycogen storage disease type Ib: Study of a French cohort. Molecular genetics and metabolism reports. 2020. PMID: 32300528
- Veiga-da-Cunha M, Van Schaftingen E, Bommer GT. Inborn errors of metabolite repair. Journal of inherited metabolic disease. 2020. PMID: 31691304