SLC37A4 – Glycogen storage disease Ib

Glycogen storage disease type Ib (GSD1b) is an autosomal recessive inborn error of metabolism caused by biallelic mutations in the glucose-6-phosphate translocase gene, SLC37A4. Patients present with fasting hypoglycemia, hepatomegaly, neutropenia, inflammatory bowel disease and growth retardation. The causal relationship between SLC37A4 and Glycogen storage disease Ib has been established by decades of genetic, biochemical and clinical studies.

Autosomal recessive inheritance of SLC37A4 variants has been reported in large cohorts, including 113 Chinese patients (PMID:40009380) and 25 Italian patients (PMID:15906092), for a total of 138 probands with documented biallelic pathogenic alleles. Multi-family segregation analyses, including consanguineous pedigrees with three affected siblings, further confirm Mendelian transmission of disease-causing variants.

The SLC37A4 mutation spectrum comprises at least 91 distinct pathogenic alleles, including 39 missense variants and numerous loss-of-function changes (PMID:24745989). Representative variants include c.70T>C (p.Tyr24His) (PMID:12409273), which was identified as a novel missense mutation in a compound heterozygous patient, and c.443C>T (p.Ala148Val) reported in Korean GSD1b cases.

Loss of SLC37A4 function impairs glucose-6-phosphate transport into the endoplasmic reticulum, disrupting glycogenolysis and gluconeogenesis and triggering endoplasmic reticulum stress and unfolded protein response in hematopoietic cells (PMID:30951856). Prenatal molecular diagnosis using DHPLC has enabled early detection of homozygous mutations without invasive liver biopsy (PMID:11015710).

Therapeutic studies have repurposed SGLT2 inhibitors such as empagliflozin to lower intracellular 1,5-anhydroglucitol-6-phosphate, normalizing neutrophil counts and function in multiple patients (PMID:36507137; PMID:32838757). These clinical interventions highlight the mechanistic link between SLC37A4 deficiency and neutrophil dysfunction, offering a targeted approach to reduce infection rates and improve inflammatory bowel outcomes.

ClinGen classifies the SLC37A4–GSD1b association as Definitive based on consistent autosomal recessive segregation, over 138 probands, and concordant functional data spanning >20 years. Genetic testing of SLC37A4 is essential for diagnostic confirmation, carrier screening and prenatal decision-making. Key take-home: SLC37A4 molecular analysis guides clinical management and emerging SGLT2 inhibitors provide a novel therapeutic avenue for neutropenia in GSD1b.

References

• Prenatal diagnosis • 2000 • Prenatal diagnosis of glycogen storage disease type 1b using denaturing high performance liquid chromatography. PMID:11015710
• Molecular genetics and metabolism • 2002 • Novel missense mutation (Y24H) in the G6PT1 gene causing glycogen storage disease type 1b. PMID:12409273
• Current topics in membranes • 2014 • The SLC37 family of sugar-phosphate/phosphate exchangers. PMID:24745989
• European journal of pediatrics • 2005 • Genotype/phenotype correlation in glycogen storage disease type 1b: a multicentre study and review of the literature. PMID:15906092
• JAMA network open • 2025 • Genetic Variants and Clinical Features of Patients With Glycogen Storage Disease Type Ib. PMID:40009380
• Gene • 2019 • CRISPR/Cas9 genome editing of SLC37A4 gene elucidates the role of molecular markers of endoplasmic reticulum stress and apoptosis in renal involvement in glycogen storage disease type Ib. PMID:30951856
• Orphanet journal of rare diseases • 2020 • Improved inflammatory bowel disease, wound healing and normal oxidative burst under treatment with empagliflozin in glycogen storage disease type Ib. PMID:32838757
• Frontiers in pediatrics • 2022 • Favorable outcome of empagliflozin treatment in two pediatric glycogen storage disease type 1b patients. PMID:36507137
• Pediatrics and neonatology • 2009 • Glycogen storage disease type Ib: the first case in Taiwan. PMID:19579760
• Molecular genetics and genomic medicine • 2021 • A novel SLC37A4 missense mutation in GSD-Ib without hepatomegaly causes enhanced leukocytes endoplasmic reticulum stress and apoptosis. PMID:33280276
• Molecular genetics and metabolism • 2004 • Genetic testing of glycogen storage disease type Ib in Japan: five novel G6PT1 mutations and a rapid detection method for a prevalent mutation W118R. PMID:15059622
• Current opinion in hematology • 2019 • Neutropenia in glycogen storage disease Ib: outcomes for patients treated with granulocyte colony-stimulating factor. PMID:30451720
• Journal of inherited metabolic disease • 2005 • Mutation spectrum of type I glycogen storage disease in Hungary. PMID:16435186
• Journal of inherited metabolic disease • 2000 • Quantitative analysis of glucose-6-phosphate translocase gene expression in various human tissues and haematopoietic progenitor cells. PMID:11032333

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