Glycogen storage disease (GSD) Type Ib is a group of inherited metabolic disorders caused by variants in the SLC37A4 gene, with an incidence of approximately 1/500 000. Fewer than 250 cases of type Ib patients have been reported, much less than type Ia, with the most reports in China, Japan, South Korea, Iran and Serbia (7, 8).
The human SLC37A4 gene is located on chromosome 11q23, consists of 9 exons, spans approximately 5.3 kb of genomic DNA, and is expressed ubiquitously in liver, kidney, intestine, blood and skeletal muscle (9). SLC37A4 gene encodes G6PT, G6PT transports G6P from the cytoplasm to the lumen of the endoplasmic reticulum and delivers it to the catalytic site of G6Pase-α or G6Pase-β. G6Pase-α and G6Pase-β are G6P hydrolases in the endoplasmic reticulum membrane, which in turn hydrolyze G6P to glucose and inorganic phosphate (10). Among them, G6Pase‑α and G6PT are coupled functionally, rather than physically, to maintain the interprandial (between meals) glucose homeostasis. A detrimental variant in the SLC37A4 gene can cause G6PT deficiency or dysfunction, failing to complete the transport of G6P and resulting in disturbed glucose homeostasis, and then leading to hyperlipemia, lactic acidosis, hyperuricemia, and other metabolic abnormalities. Whereas G6Pase-β couples functionally with G6PT to maintain neutrophil function and homeostasis. Consequently, G6PT is essential to maintain both interprandial glucose homeostasis and myeloid cell energy homeostasis (11). Although G6Pase-α and G6Pase-β are similar in structure and function, patients with G6Pase-β deficiency do not exhibit the metabolic phenotypes of GSD I patients. In contrast, these individuals only present with severe congenital neutropenia syndrome, reflecting the differences between the presentations of GSD Ia and GSD Ib.
So far, there are 115 pathogenic variants in the SLC37A4 gene that have been identified, including missense variants, nonsense variants, frameshift variants, splice site variants, and deletion variants, etc. There are ethnic variability in variant types and proportions (8, 12). Previous studies have demonstrated that one of the most common types of variants is c.1042_1043del (p.Leu348Valfs* 53), which has been repeatedly reported in Germans (32%) and mixed Caucasians (27–31%) (2). In the Korean population, the most common variant is c.443C > T (p.Ala148Val), which is found in 55.6% of GSD Ib patients and 38.9% of alleles. Since it has not been reported in other races, the author speculates that the variant may be unique to Koreans (12). The common variant type in Japanese is c.352T > C (p.Trp118Arg), accounting for 37–50% (12). No strict genotype-phenotype correlation has been determined in previous studies (13–16). In our study, 5 variant types of SLC37A4 gene were detected in 3 patients. Among them, c.680G > A is a novel variant, the c.572C > T (p.Pro191Leu) variant is the most common and only reported in the Chinese population (17–19). We speculate that c.572C > T may be a Chinese race-specific variant.
The typical clinical manifestations of GSD Ib are similar to those of type Ia, including impaired glucose homeostasis such as liver enlargement and growth retardation. By contrast, neutropenia and neutrophil dysfunction are major clinical phenotypes of patients with GSD Ib. GSD Ib patients are often accompanied by neutropenia and are prone to frequent infectious diseases, such as recurrent upper respiratory tract infections, oral ulcers, enterocolitis and inflammatory bowel disease (IBD). There are also reports of GSD Ib combined with Crohn's disease (20). The exact mechanism of recurrent infections and IBD due to neutropenia and neutrophil dysfunction is still unclear. Studies have demonstrated that it may be related to impaired functions such as cell chemotaxis, calcium mobilization, respiratory burst, and leukocyte phagocytosis (21). In addition, studies have shown that patients with GSD Ib are at increased risk of autoimmune diseases (including IBD, thyroid autoimmune diseases and myasthenia gravis, etc.). Melis et al. found that this may be related to a reduced engagement in T cell glycolysis and an impaired regulatory T cell function (22). Therefore, GSD Ib caused by SLC37A4 gene variants is both a metabolic and an immune disorder (1).
A decreased number of neutrophils in peripheral blood is an important feature that distinguishes GSD Ib from GSD Ia. It is worth mentioning that not all patients diagnosed with GSD Ib based on metabolic phenotypes and genetic testing develop neutropenia, which may be related to the residual transport activity of G6PT (1). According to reports from different regions, the prevalence of neutropenia in GSD Ib patients is above 94%, and some patients may develop periodic neutropenia (1, 10, 12, 13). There are scattered reports of atypical GSD Ib patients without neutropenia or infectious diseases (23, 24). Neutropenia may also be observed in a subset of GSD Ia patients (25). Therefore, it is not possible to distinguish between type Ib and Ia based on the decrease in the number of neutrophils alone.
The current treatment of GSD Ib is mainly symptomatic. As a serious metabolic and immune multisystem disorder, if not actively treated, it may cause the patient to be fatal in adolescence. Clinically, diet therapy (raw cornstarch, etc.) can maintain the patient's glucose stability and reduce the early symptoms of the disease (10, 21). Those with poor diet control compliance often have obvious abnormalities in metabolic indicators, and death is mainly caused by metabolic disorders. Granulocyte colony stimulating factor (G-CSF) can improve neutropenia and IBD, but the underlying pathological process of the disease has not been corrected, and the specific mechanism is unknown (1, 2). For type Ib patients with both IBD and neutropenia, G-CSF and 5-aminosalicylic acid can be used in combination (1). In addition, GSD Ib patients receiving G-CSF treatment may have side effects such as splenomegaly, which is dose-dependent, and a few patients have myelodysplastic/acute myeloid leukemia (21, 26). There is also a case report of severe hypertriglyceridemia (triglyceride 80 mmol/L) in a GSD Ib infant with a significant decrease in blood lipid levels after plasma exchange (15). Another way to correct metabolic abnormalities in GSDI patients is liver transplantation or combined liver/kidney transplantation, while correction of bone marrow dysfunction in patients with GSD Ib can be achieved by bone marrow transplantation. However, many researchers believe that liver transplantation is a last resort, because the death rate associated with transplantation is higher than most other medical treatments (1). Studies have reported that bone marrow transplantation for GSD Ib patients with severe IBD and repeated infections, although their neutropenia persists, neutrophil function and IBD are improved (27). Although this is a case report, it offers hope for GSD Ib patients with severe myeloid complications. Since protein replacement therapy is not suitable for hydrophobic transmembrane proteins (such as G6PT), somatic gene therapy is a promising treatment for patients with type Ib. Effective use of gene therapy is very promising for correcting the metabolic abnormalities in GSD Ib patients, but to solve the problems of metabolic abnormalities and bone marrow complications at the same time, it may be necessary to construct either a vector with a wider range of tissue transduction specificity or a multivector approach (21).
The 3 patients in our study all had typical clinical manifestations such as elevated liver enzymes, fasting hypoglycemia, hyperlipidemia, hyperlactacidemia, lactic acidosis, and decreased neutrophil count, accompanied by hepatomegaly, growth retardation, and repeated infections. With increasing age, ANC of the 3 patients decreased progressively. Among them, the condition of patient 1 was poorly controlled, G-CSF was used irregularly, and the effect was not good, with secondary IBD and frequent hospitalizations due to infection. The other 2 patients were effectively controlled with age, and the number of infections was significantly decreased. Therefore, the clinical manifestations of patients with GSD Ib have certain heterogeneity.