Sage Journals: Discover world-class research

Abstract

Glycogen storage disease type 1b (GSD1b) is a rare genetic disorder, resulting from mutations in the SLC37A4 gene located on chromosome 11q23.3. Although the SLC37A4 gene has been identified as the pathogenic gene for GSD1b, the complete variant spectrum of this gene remains to be fully elucidated. In this study, we present three patients diagnosed with GSD1b through genetic testing. We detected five variants of the SLC37A4 gene in these three patients, with three of these mutations (p. L382Pfs*15, p. G117fs*28, and p. T312Sfs*13) being novel variants not previously reported in the literature. We also present a literature review and general overview of the currently reported SLC37A4 gene variants. Our study expands the mutation spectrum of SLC37A4, which may help enable genetic testing to facilitate prompt diagnosis, appropriate intervention, and genetic counseling for affected families.

Keywords

Glycogen storage disease type 1b SLC37A4 gene hypoglycemia neutropenia inflammatory bowel disease genetic variant

Introduction

Glycogen storage disease 1b (GSD1b OMIM 232220) is an autosomal recessive metabolic disorder distinguished by a deficiency of glucose 6-phosphate translocase (G6PT). The incidence rate of GSD1b is approximately 1 in 500,000 live births.¹ The SLC37A4 gene, which encodes G6PT, is found on chromosome 11 at 11q23.3. This gene spans 4.5 kb, comprises nine exons, and codes for a predominantly hydrophobic protein with 10 transmembrane domains.² G6PT plays a pivotal role in the translocation of glucose-6-phosphate (G6P) from the cytoplasm into the endoplasmic reticulum (ER) lumen. Subsequently, G6P undergoes hydrolysis to convert into glucose in the ER membrane. Additionally, G6PT expression is crucial for maintaining energy homeostasis in neutrophils.³

The absence of G6PT activity leads to the buildup of glycogen and other metabolic intermediates in the liver, kidney, and intestines. This accumulation results in a variety of clinical manifestations.⁴ The predominant clinical symptoms of GSD1b include hepatomegaly, hypoglycemia, lactic acidemia, hyperlipidemia, hyperuricemia, and growth retardation. Notably, G6PT is abundantly expressed in hematopoietic progenitor cells⁵ and has a pivotal role in neutrophil homeostasis and its functional dynamics.⁶ Defective G6PT can cause reduced glucose absorption that leads to a drop in the intracellular levels of G6P, ATP, lactate, and NADPH.³ Thus, GSD1b in G6PT brings about neutropenia and neutrophil dysfunction and a higher susceptibility to various infectious diseases, including recurrent bacterial infections and inflammatory bowel disease (IBD).⁷

Since the SLC37A4 gene was first identified, more than 100 variants have been reported, with the missense mutation being the most common variant.⁸ Further analysis of the SLC37A4 gene may provide an important clinical strategy for patients with GSD1b. Despite the identification of SLC37A4 as the pathogenic gene for GSD1b, a comprehensive understanding of the complete spectrum of its genetic variants remains to be fully elucidated. In this study, we have identified three novel SLC37A4 variants. We then systematically review the literature pertaining to reported variants to further clarify the full variant spectrum of SLC37A4.

Case presentations

Patient 1

Patient 1 (male) was admitted to the hospital at the age of 17 months from the presence of abdominal distension. He had a medical history characterized by recurrent episodes of pneumonia, bronchitis, and hypoglycemic attacks since the age of 3 months. Additionally, he experienced chronic diarrhea from birth until the age of 1 year. Upon admission, the patient's height measured 69 cm, corresponding to a height-for-age z-score of −4.9 (0.1st percentile). His weight was 9 kg, resulting in a weight-for-age z-score of −1.8 (4th percentile). A physical analysis revealed the presence of hepatomegaly. Notably, the fasting glucose, lactic acid, and blood triglyceride (TG) levels were found to be abnormal (measuring 1.6 mmol/L, 12.35 mmol/L, and 12.35 mmol/L, respectively). Moreover, urine ketone bodies tested positive. An abdominal ultrasound analysis confirmed the presence of hepatosplenomegaly. Subsequent genetic analysis identified a compound heterozygous variant on the SLC37A4 gene, consisting of a c.1145_1163del TGGGAGGTGCCACACAAGT (p. L382Pfs*15) variant in exon 11 and a c.572C>T (p. Pro191Leu) variant in exon 6. The former variant was inherited from the patient's mother, while the latter variant was inherited from the patient's father. Importantly, the c.1145_1163del variant has not been previously reported. According to the American College of Medical Genetics and Genomics (ACMG), this variant is classified as a “variant of uncertain significance” (PVS1_moderate, PM2_Supporting). Additional analysis using Sanger sequencing confirmed that the patient's mother was heterozygous for this variant, while the patient's father did not exhibit any variant at this site (Figure 1a). The Sorting Intolerant From Tolerant (SIFT) and PolyPhen-2 prediction programs indicated that the variant is likely harmful, as the L382Pfs*15 variant represents a frameshift mutation that may affect the structure and function of the SLC37A4 protein. Subsequently, the patient's treatment plan involved the administration of lactose-free milk powder and four daily doses of oral uncooked cornstarch at a dosage of 1.5 g/kg, as well as adhering to a sucrose and fructose-free diet. Despite this therapeutic regimen, the patient continued to experience recurrent infections, averaging five to eight episodes per year between the ages of 1 and 2 years. Moreover, the patient's peripheral blood neutrophil count exhibited fluctuations (0.48–0.85 × 10⁹/L) and he frequently experienced poorly healing oral ulcers. Notably, the patient did not receive granulocyte colony-stimulating factor (G-CSF) injections or adhere to the prescribed cornstarch regimen. At the age of 9 years, the patient was readmitted to the hospital because of recurrent diarrhea and abdominal pain. Laboratory test results revealed abnormalities in blood routine parameters (white blood cell (WBC) 2.8 × 10⁹/L, neutrophil (NE) 0.99 × 10⁹/L), liver function (alanine aminotransferase (ALT) 6 U/L, aspartate aminotransferase (AST) 12 U/L, total bile acid (TBA) 3.6 μmol/L, y-glutamyl transpeptidase (GGT) 11 U/L, direct bilirubin (DBil) 1.4 μmol/L, total bilirubin (TBil) 2.7 μmol/L, albumin (Alb) 38.5 g/L, total protein (TP) 74.6 g/L), and blood lipid levels (TG 1.79 mmol/L, total cholesterol (TC) 2.59 mmol/L). Stool analysis did not detect the presence of red blood cells or leukocytes. Colonoscopy revealed the presence of an ulcer in the ileocecal region, accompanied by a swollen surrounding mucosa. Additionally, mucosal congestion was observed in the rectum, sigmoid colon, descending colon, transverse colon, and ascending colon (Figure 2a, b). Following regular treatment with uncooked cornstarch and G-CSF (3.5 μg/kg/day), the patient's condition improved, leading to his subsequent discharge.

Figure 1.

Sanger sequencing results and sequence conservation analysis. (a) The novel variant c.1145_1163del TGGGAGGTGCCACACAAGT was detected in Patient 1, which was derived from his mother. Patient 1 also carried the c.572C>T variant, with the Sanger sequencing results indicating that it was inherited from his father. (b) The c.1042_1043delCT in Patient 2 was from his father, while the novel variant c.351delC was confirmed by Sanger sequencing to be from his mother and (c) Patient 3 and his father both had the heterozygous deletion mutation of c.935_936delCTG, while his mother was normal. Patient 3 was a carrier of c.572C>T, which was derived from his mother

Figure 2.

Endoscopy images of Patient 1 (a, b) and Patient 2 (c, d). (a) An ileocecal ulcer in the ileocecal area. (b) Hyperemia and edema of the ascending colon. (c) A large ulcer in the ileocecal area and (d) Mucosal erosion in the transverse colon

Patient 2

At the age of 2 months, a male patient was admitted to the hospital from pneumonia and poor spirit. During his hospitalization, the patient presented with a hypoglycemic state, with low blood glucose levels of 2.0 mmol/L and high blood lactic acid levels of 7.7 mmol/L. Considering the clinical symptoms, it was suspected that the patient harbored inborn errors of metabolism. We then performed genetic testing, which confirmed that the patient had a compound heterozygous variation of c.1042_1043delCT (p.L348Vfs*53) in exon 10 and c.351delC (p. G117fs*28) in exon 4 of the SLC37A4 gene. The former variation was inherited from the father, while the latter was inherited from the mother (Figure 1b). The c.351delC variant was a previously unreported mutation. Using the ACMG criteria, the variant was categorized as “likely pathogenic” (PVS1+ PM2_supporting). Sanger sequencing revealed that the mother carried this variant in a heterozygous state at this site, while the father did not exhibit any variant at this site (Figure 1b). The SIFT and PolyPhen-2 prediction programs indicated that the variant was likely harmful, with p.G117fs*28 representing a frameshift variant that could potentially impact the structure and function of the SLC37A4 protein. To manage this condition, the patient was administered lactose-free milk powder and his feeding frequency was augmented. At the age of 16 months, he commenced oral intake of uncooked cornstarch at a dosage of 2 g/kg/day every 6 hours. However, despite these interventions, his blood glucose levels remained unstable, plummeting to 3.1 mmol/L. Additionally, the patient experienced recurrent oral ulcers and gingivitis approximately three to five times per year, starting at the age of 2.5 years. These oral lesions persisted for a month and exhibited a protracted healing process. The patient also suffered from respiratory tract infections three to five times per year, which exhibited improvement upon antibiotic therapy. At the age of 3 years and 5 months, the patient presented with mucopurulent bloody stool and an increased frequency of defecation. During his subsequent hospitalization, laboratory test results revealed normal liver function but an abnormal blood routine (WBC 5.2 × 10⁹/L, NE 0.61 × 10⁹/L, platelet (PLT) 438 × 10⁹/L). However, colonoscopy unveiled edema of the ileocecal valve and appendicular ostium, accompanied by mucosal erosion and a sizable ulceration, as well as erosions in the transverse colon (Figure 2c, d).

After G-CSF treatment, the patient's WBC count increased and the ANC returned to normal. Two months later, his appetite improved, the daily stool frequency reduced to once per day, and the mucopurulent bloody stool disappeared. His weight increased by 3 kg. The medication was self-discontinued. At 2 years and 6 months old, abnormal bowel movements occurred six to seven times daily, without blood or mucus. Recurrent oral aphthous ulcers with slow healing were also present.

At the age of 6 years, the patient presented with recurring episodes of vomiting, chronic diarrhea, and oral ulcerations. In addition, he displayed an inability to maintain neutrophil levels in the normal range. Therefore, the patient was prescribed empagliflozin at a dosage of 10 mg/day (0.4 mg/kg/day) and administered uncooked cornstarch at a dosage of 48 mg (2 mg/kg/day) every 4 hours. Following a 2-month course of treatment, the neutrophil levels gradually trended towards normalcy. Concurrently, his symptoms of diarrhea and vomiting significantly abated and the occurrence of recurrent oral ulcerations ceased. The patient's height measured 115 cm, corresponding to a height-for-age z-score of −1.17. Additionally, the patient's weight was recorded as 24 kg, yielding a weight-for-age z-score of 0.32.

Patient 3

A 5-month-old boy was admitted to the hospital with pneumonia and diarrhea. The patient had experienced diarrhea since the age of 2 months, with six to seven loose stool episodes per day, but received no medication. Prior to admission, the patient had a fever and cough for 10 days. He had a height of 63 cm and weight of 7.5 kg, with a weight-for-length z-score of 1.2 (88th percentile). The patient presented with a fever exceeding 39°C, tachycardia of 200 beats per minute, tachypnea of 64 breaths per minute, bilateral wheezing and rhonchi in the lungs, hepatomegaly measuring 8 cm below the right costal margin, and splenomegaly measuring 2 cm below the left costal margin.

The blood tests revealed a base excess of −20.4 and a cHCO₃- level of 0.5 mmol/L. His fasting blood glucose measured 2.52 mmol/L, lactate was recorded at 5.33 mmol/L, and urine ketone test yielded a positive result. The AST and ALT levels were elevated, with values of 266 U/L and 240 U/L, respectively. Pneumonia-related indications were observed in the chest X-ray. Throughout the hospitalization period, the lowest recorded blood glucose level was 1.8 mmol/L. Sanger sequencing of all the exons and exon-intron boundaries of the SLC37A4 gene (NM_001164277) in the proband detected a compound heterozygous variant, including c.935_936delCTG (p.T312Sfs*13) in exon 9 inherited from the father and c.572C>T (p.Pro191Leu) in exon 6 inherited from the mother. The c.935_936delCTG has not previously been reported. Using the ACMG guidelines, the present variation was initially classified as a suspected pathogenic variant (PVS1+PM2_Supporting). Sanger sequencing revealed that the father was heterozygous for this site, while the mother did not possess any variant at this site (Figure 1c). The SIFT and PolyPhen-2 prediction programs indicated that the variant was likely harmful, with the p.T312sfs*13 mutation representing a frameshift mutation that may affect the structure and function of the SLC37A4 protein. Subsequent treatment for the patient involved the administration of antibiotics and oral uncooked cornstarch. This intervention led to an improvement in clinical symptoms, thus resulting in the patient's discharge.

Table 1 presents the analysis results of all three patients during their initial hospitalization. Verbal informed consent and treatment consent were obtained from the parents of all patients. The reporting of this study adheres to the CARE guidelines.⁹

Table 1.

Examination results of the patients at first hospitalization.

	Patient 1	Patient 2	Patient 3
Onset age (months)	3	2	5
WBC (×10⁹)	8.28	5.70	6.0
ANC (×10⁹)	0.82	2.8	2.54
PLT (×10⁹)	417	409	844
AST (U/L)	53	65	240
ALT (U/L)	39	53	266
TG (mmol/L)	12.35	3.21	1.70
TC (mmol/L)	2.59	5.3	1.94
Fasting glucose (mmol/L)	1.6	2.8	2.52
Lactic acid (mmol/L)	12.35	7.26	5.33
Uric acid (μmol/L)	428	189	150
Abdominal ultrasound findings
Liver size (cm)	8	3	8
Kidney	Normal	Normal	Normal

WBC, white blood cell; ANC, absolute neutrophil count; PLT, platelet; AST, aspartate aminotransferase; ALT, alanine aminotransferase; TG, triglyceride; TC, total cholesterol.

Normal range: WBC, 4.0–10.0 × 10⁹/L; ANC > 1.5 × 10⁹/L; PLT, 150–400 × 10⁹/L; ALT, 4–41 U/L; AST, 4–40 U/L; TG, 0.05–1.7 mmol/L; TC, 2.9–5.68 mmol/L; fasting glucose, 3.61–6.61 mmol/L; lactic acid, 0.50–2.20 mmol/L; uric acid, 202.3–416.5 μmol/L.

Literature review

A literature review was conducted to retrieve all previously published SLC37A4 variants in GSD1b from 1978 to 2023 from the MEDLINE, PubMed, and Web of Science databases. Upon reviewing the literature, a total of 134 mutations were identified for the SLC37A4 gene (Table 2). Among these variants, the most prevalent one was the c.1042_1043delCT (p. Leu348Vfs*53) mutation (Table 2). Additionally, 25 variants have been reported in the Chinese population, with the c.572C>T (p. Pro191Leu) variant being the most frequent. The overall spectrum of SLC37A4 variants is summarized in Table 2, which includes references not cited in the main text.

Table 2.

The spectrum of SLC37A4 variants

Nucleotide change	Amino acid change	Ethnicity	Reference(s)
c.1042_1043delCT	p.Leu348Valfs*53	China, South Korea, Hungary, NM, Serbia, Brazil, Iran	^22–28
c.343G>A	p.Gly115Arg	China	^22,29–31
c.572C>T	p.Pro191Leu	China	^{22,29,32–34}
c.870 + 5G>A	p.Arg291fs*34	China	^22,29,35
c.1043T>C	p.Leu348Pro	NM, China	^23,34
c.446G>A	p.Gly149Glu	China, Brazil	^22,25,29
c.68T>G	p.Leu23Arg	China	^22,31
c.784 + 1G>A	–	China	²²
c.842G>A	p.Gly281Val	China	²²
c.1014_1120del107	p.Phe338Leufs*30	China	²²
c.1243C>T	p.Arg415*	China	²²
c.1243C>G	p.Arg415Gly	China	²²
c.959_960insT	p.Val320fs*104	China	²⁹
c.365C>T	p.Pro119Leu	China, Iran	^27,36
c.1016G>A	p.Gly339Asp	China	³⁴
c.310insT	p.Ala104fs*	China	³⁷
c.359C>T	p.Pro120Leu	China	^32,38
IVS8 + 1_4delGTAA	–	China	²⁸
c.680G>A	p.Trp227*	China	³⁵
c.1014_1120del107	–	China	³⁸
c.70C>T	p.Tyr24His	Hong Kong	³⁹
g.1689C>T	p.Pro191Leu	Hong Kong	⁴⁰
g.1563G>A	p.Gly149Glu	Hong Kong	⁴⁰
c.354_355insC	p.Trp118fs*12	Taiwan, China	⁴¹
c.736T>C	p.Trp246Arg	Taiwan, China	⁴¹
c.521T>A	p.Trp118Arg	Japan, France	^14,33,42,43
IVS1 + 1G>A	–	Japan	⁴³
IVS7 + 1G>T	–	Japan	⁴³
c.del1094GGTG/ins TC	–	Japan	⁴³
c.72C>T	p.Gln73*	Japan	⁴²
c.1013_1029del	p.Gly281Arg	Japan	⁴²
c.1412C>T	p.Arg415*	Japan	^42,44
c.202delT	–	Japan	⁴²
c.679delCCTA	–	Japan	⁴²
c.166G>T	p.Arg116Leu	Japan	⁴²
c.1211_1212delCT	–	Japan, Turkey, Italy, France, NM	^{31,33,42,45,46}
c.1185G>A	p.Gly339Asp	Japan, France	^15,47
c.794G>A	–	Japan	⁴⁴
c.354G>T	p.Trp118Cys	Japan	⁴⁸
c.1179G>A	p.Trp393*	Japan, Korea	^15,42
703_705delGTG	delV235	Japan, Brazil	⁴⁹
c.149_2A>C	–	Japan	³
c.149G>A	p.Gly50Glu	Korea	^15,50
c.83G>A	p.Arg28His	Korea, NM	^15,51
c.320G>A	p.Trp107*	Korea	¹⁵
c.818G>A	p.Gly273Asp	Korea	¹⁵
c.412T>C	P.Trp138Arg	Korea	¹⁵
c.148G>A	p.Gly50Arg	Korea	¹⁵
c.443C>T	p.Ala148Val	Korea	^15,52
c.381 + 1G>C	–	Turkey	⁴⁷
c.1004G>A	p.Gly335Glu	Turkey	⁵³
c.752T>C	p.Leu251pro	Oman	⁵⁴
c.365G>A	p.Gly122Glu	Iran	²⁷
c.985_1G>C	–	Argentina	⁵⁵
g.118895235_11891	p.946del	Iran, Argentina	^27,55
c.24T>G	p.Tyr8*	Iran	⁵⁶
c.785-3_786del5	–	NM	²³
c.817G>A	p.Gly273Ser	NM	²³
c.595delC	p.Leu199Trpfs*13	NM	²³
c.572C>G	p.Pro191Arg	NM	²³
c.1024T>C	p.Ser342Pro	NM	²³
NM00164279.1delC	–	India	⁵⁷
c.467C>T	p.Ala156Val	NM	²³
–	p.Gly50Glu	Sri Lanka	⁵⁸
c.81T>A	p.Asn27Lys	Serbia	²⁴
c.162C>A	p.Ser54Arg	Serbia	²⁴
c.785G>A	p.Ser263Glyfs*33	Serbia	²⁴
c.654G>A	p.Gly149Glu	Brazil	⁵⁰
c.1076_28C>T	–	Brazil	⁵⁰
c.1287G>A	–	Brazil	⁵⁰
c.92_94delTCT	p.Phe31_Ser32del	Brazil	²⁵
c.547T>C	p.Cys183Arg	Brazil, Hungary	^25,26
c.59G>A	p.Gly20Asp	Brazil	²⁵
c.344_345dupGG	p.Leu116Glyfs	Brazil	²⁵
c.899G>A	p.Arg300His	Brazil	²⁵
c.557T>C	p.Leu186Pro	Brazil	⁵⁹
c.260_262delTT	p.Phe31Del	Brazil	⁴⁵
c.795_1G>A	–	Italy	¹¹
c.1154_2A>G	–	Italy	¹¹
c.911C>T	–	Italy	⁴⁵
c.1338_1339insT	–	Italy	⁵⁰
c.1124_2del	–	Italy	⁶⁰
c.202G>A	p.Gly68Arg	Italy	⁶¹
c.1393G>A	silent	Italy	⁶¹
c.524del4	p.201*	Italy	⁶¹
c.625G>A	Exon3 skipping	Italy	⁶¹
c.550 + 1G>T	–	America	¹¹
T695C	p.Cys176Arg	America	¹¹
A170G	p.Met1Val	America, England	¹¹
T716C	p.Cys183Arg	America, France	¹¹
G1393A	–	America, Australian, German, England	¹¹
c.359_360insC	p.Cys121fs*10	France	⁶²
c.1099G>A	p.Ala367Thr	France	⁶²
c.352T>C	p.Trp118Arg	France	⁶²
c.686T>C	p.Leu229Pro	France	⁶²
c.263G>A	p.Gly88Asp	France	⁶²
G339C	–	France, Australian, England	¹¹
c.228G>A	p.Gly20Asp	France	³³
c.250T>A	p.N27K	France	³³
c.251C>T	p.Arg28Cys	France	³³
c.855T>C	p.Leu229Pro	France	³³
c.1068G>A	p.Arg300His	France	³³
c.1184G>T	p.Gly339Cys	France	³³
c.1268G>A	p.Ala367Thr	France	³³
c.514_515insGC	–	France	³³
c.528insC	–	France	³³
c.550 + 2T>G	–	France	¹¹
c.1063G>A	p.Glu355*	France, NM	^11,13
c.1245G>A	p.Trp415*	Germany	³⁰
c.81T>A	p.Asn27Lys	Serbia	³³
c.162C>A	p.Ser54Arg	Serbia	³³
c.248G>A	p.Gly83Glu	Serbia	³³
c.404G>A	p.Gly135Asp	Serbia	³³
p.785G>A	p.Ser263Glyfs*33	Serbia	³³
c.742delC	p.Gln248fs*	England	⁶³
c.1123 + 1G>T	–	England	⁶³
c.1051G>A	p.Gly339Cys	England	⁶³
c.1051G>T	p.Gly339Cys	England	⁶³
c.285del	p.Trp96fs*	England	⁶³
c.1155C>T	p.Ser385Arg	England	⁶³
c.381 + 5G>C	–	England	⁶³
c.1175del	p.Ser392fs*	England	⁶³
c.92_94delTCT	p.Phe31del	England	^25,63
c.936dupA	p.Val313Serfs*13	England	⁶³
c.1105_1106insA	p.Val369Aspfs*33	England	⁶³
c.1123 + 3_1123 + 6del		England	⁶³
c.169_175del	p.Ser57fs*	England	⁶³
c.55G>A	p.Gly19Arg	England	⁶³
c.1123 + 2dup	–	England	⁶³
c.214G>A	p.Asp72Asn	England	⁶³
c.514insG	p.Ser130fs*	England	⁶³
c.923_934dup12	p.Met308_Met311dup	England	⁶³
c.248G>A	p.Gly83Glu	Serbia	²⁴
c.404G>A	p.Gly135Asp	Serbia	²⁴
c.1145_1163del	p.382_388del	China	Patient 1
c.351delC	p.G117fs*28	China	Patient 2
c.935_936delCTG	P.T312Sfs*13	China	Patient 3

Patient 1, Patient 2, and Patient 3 are included in our article.

Discussion and conclusions

GSD1 comprises a group of rare hereditary disorders resulting from an insufficiency in the glucose-6-phosphatase (G6Pase) system. This system plays a crucial role in maintaining glucose homeostasis by facilitating the hydrolysis of G6P into glucose and inorganic phosphate (Pi).¹⁰ Of the two types of GSD1, glycogen storage disease type 1a (GSD1a) is the most prevalent, accounting for approximately 80% of GSD1 patients. It is caused by variants in the G6Pase gene, while the remaining 20% of GSD1 cases are diagnosed as GSD1b.¹¹

GSD1b arises from a deficiency in G6PT.¹² The SLC37A4 gene encodes G6PT, which facilitates the transport of G6P from the cytoplasm to the ER lumen and subsequently delivers it to the catalytic site of G6Pase. Situated on human chromosome 11q23.3, the SLC37A4 gene comprises nine exons, spans approximately 5.3 kb of genomic DNA, and exhibits high expression in the liver, kidney, intestines, and skeletal muscle. Firstly, Gerin et al. identified the p.W118R variant in the putative G6P transporter in two patients,¹³ a finding later corroborated by Kure et al.¹⁴ To date, a total of 132 pathogenic variants have been characterized in the SLC37A4 gene, all of which are associated with GSD1b. The most prevalent variant, c.1042_1043delCT (p. Leu348Valfs*53), has been frequently observed in mixed Caucasian (27% to 31%) and German (32%) populations. Consistent with previous reports, Patient 1 in our study also had this variant. The literature has indicated that the type and proportion of variants in GSD1b may vary across different ethnic groups. In the Korean population, the most common variant is c.443C > T (p. Ala148Val), present in 55.6% of GSD1b patients and 38.9% of alleles.¹⁵ In the Japanese population, the predominant variant is c.352 T > C (p. Trp118Arg), detected in 37% to 50% of GSD1b patients.⁷ Among the Chinese population, 25 variants have been identified, with c.572C>T (p. Pro191Leu) being the most frequent, accounting for 18.8% of alleles. Notably, this variant has not been reported in other ethnic groups with GSD1b, suggesting its potential significance as a diagnostic marker specifically for GSD1b in the Chinese population.

The clinical features of GSD1 include hypoglycemia, growth retardation, hyperlipidemia, and lactic acidemia.⁷ Additionally, individuals with GSD1b may exhibit neutropenia, neutrophil dysfunction, recurrent bacterial infections, and IBD.¹⁵ According to reports from various geographical regions, neutropenia affects over 94% of GSD1b patients.³ In these cases, neutropenia was observed in all three patients. Among GSD1b patients, IBD is regarded as one of the most severe complications. The incidence of IBD is on the rise, with the mean age at initial diagnosis being 8.7 years.¹⁶ Nearly all patients experienced abdominal pain or symptoms indicative of intestinal obstruction, with 60% of them presenting with ileal or colonic strictures, necessitating surgical resection or endoscopic dilatation in 50% of cases.¹⁶ Research by Mikami et al. revealed that 28% of patients had confirmed IBD, while an additional 22% exhibited symptoms highly suggestive of IBD, which significantly impacted their quality of life and overall well-being.¹⁷ Many GSD1b patients with IBD manifest chronic gastrointestinal inflammation, characterized by recurrent abdominal pain, emesis, frequent or persistent diarrhea, or the presence of draining fistulas. In our cases, all three patients presented with gastrointestinal symptoms, and two of them were diagnosed with IBD. At the age of ten, Patient 1 experienced recurrent diarrhea and abdominal pain 8 years after his GSD1b diagnosis. Patient 2, at 3 years and 5 months old, exhibited mucopurulent bloody stool with an increased frequency of defecation three years after his GSD1b diagnosis. Patient 3 sought medical attention at our hospital following a 3-month history of diarrhea. Colonoscopy and pathological analysis confirmed the diagnosis of IBD in Patient 1 and Patient 2. The underlying cause of IBD in GSD1b patients may be attributed to neutrophil dysfunction and reduced neutrophil count. The absence of neutrophils in the intestinal mucosa renders the gastrointestinal tract susceptible to pathogenic and commensal bacteria, thus leading to IBD development.¹⁸

For therapy, the metabolic abnormalities in GSD1b can be managed through dietary interventions aimed at maintaining normoglycemia and alleviating symptoms. However, these interventions have limited efficacy in preventing long-term complications such as renal disease and hepatocellular adenoma/carcinoma. Traditional treatment involving subcutaneous injections of G-CSF has been shown to enhance neutrophil numbers but not their functions, and may even elevate the risk of developing monoclonal malignancies, including myelodysplasia and acute myeloid leukemia.¹⁹ Recent studies have indicated that empagliflozin, a sodium glucose co-transporter 2 inhibitor, represents a safe and promising alternative for treating neutropenia in individuals with GSD1b, IBD, and neutropenia.²⁰ In this study, empagliflozin was prescribed to Patient 2 at the age of 6 years, leading to a gradual discontinuation of G-CSF. Subsequently, the patient experienced an improvement in gastrointestinal symptoms, with a normal ANC observed during the last follow-up and no reported adverse effects. Notably, no severe adverse events (AE) were documented throughout the treatment period. A retrospective analysis involving 112 patients from 24 countries demonstrated the efficacy of empagliflozin in ameliorating neutropenia and its favorable outcomes in relation to various symptoms associated with neutropenia and neutrophil dysfunction. These symptoms encompassed oral and urogenital mucosal lesions, recurrent infections, skin abscesses, IBD, and anemia. Among the participants, hypoglycemia was the most commonly reported AE, with a prevalence of 18%.²¹ In addition, glycolysis serves as the sole energy source for mature neutrophils. The precursor of toxic 1,5-AG6P, which is the structural analog of G6P, is 1,5-anhydroglucitol (1,5-AG). Its dephosphorylation is facilitated by G6PT. Because of the deficiency of G6PT, the initial step of glycolysis is inhibited, resulting in 1,5-AG6P accumulation in the cytoplasm.⁶ Wortmann et al. observed a four- to five-fold decrease in plasma 1,5-AG levels following daily empagliflozin intake in all patients. This was subsequently followed by the establishment of a new stable 1,5-AG concentration after 2 to 3 weeks. Prior to treatment, only 34% of neutrophils exhibited an oxidative burst response similar to that of the healthy control sample. Surprisingly, after treatment, 96% of neutrophils displayed oxidative bursts, accompanied by a subsidence of IBD symptoms, thereby enabling the gradual discontinuation of G-CSF treatment. Therefore, neutrophil counts were significantly elevated and gradually approached the normal range.¹⁸

In this study, three novel SLC37A4 genetic variants in GSD1b patients were reported, expanding the variant spectrum of this gene and enhancing our understanding of the disease. Genetic analyses may facilitate the diagnostic process for GSD1b, potentially leading to early diagnosis and therapeutic intervention that could possibly improve patient quality of life.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605231216633 - Supplemental material for Three novel SLC37A4 variants in glycogen storage disease type 1b and a literature review

Supplemental material, sj-pdf-1-imr-10.1177_03000605231216633 for Three novel SLC37A4 variants in glycogen storage disease type 1b and a literature review by Zhuolin Wang, Ruiqin Zhao, Xiaoyun Jia, Xiaolei Li, Li Ma and Haiyan Fu in Journal of International Medical Research

Supplemental Material

sj-pdf-2-imr-10.1177_03000605231216633 - Supplemental material for Three novel SLC37A4 variants in glycogen storage disease type 1b and a literature review

Supplemental material, sj-pdf-2-imr-10.1177_03000605231216633 for Three novel SLC37A4 variants in glycogen storage disease type 1b and a literature review by Zhuolin Wang, Ruiqin Zhao, Xiaoyun Jia, Xiaolei Li, Li Ma and Haiyan Fu in Journal of International Medical Research

Footnotes

Acknowledgements

We appreciate the help of all our colleagues in our hospital.

Author contributions

ZW analyzed the data and wrote the first draft of the manuscript. HF designed the research. XJ, XL, and LM analyzed the genetic testing results. RZ edited and reviewed the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Data availability statement

Data are available from the corresponding author upon reasonable request.

Declaration of conflicting interests

All authors declare that there is no conflict of interest.

Ethics approval and consent to participate

The study was approved by the Ethical Committee of the Children’s hospital of Hebei Province in China (Approval No. 2021170). We also obtained informed consent from all patients’ parents.

Funding

This work was supported by the Hebei Province Medical Science Research Project (No. 20210246) and Hebei Provincial Government-Funded Clinical Medicine Talent Training Project (No. ZF2024186).

ORCID iD

Haiyan Fu

References

Chou

Matern

Mansfield

, et al. Type I glycogen storage diseases: disorders of the glucose-6-phosphatase complex. Curr Mol Med 2002; 2: 121–143.

Chou

Jun

Mansfield

BC.

Type I glycogen storage diseases: disorders of the glucose-6-phosphatase/glucose-6-phosphate transporter complexes. J Inherit Metab Dis 2015; 38: 511–519.

Jun

Weinstein

Lee

, et al. Molecular mechanisms of neutrophil dysfunction in glycogen storage disease type Ib. Blood 2014; 123: 2843–2853.

Narisawa

Igarashi

Otomo

, et al. A new variant of glycogen storage disease type I probably due to a defect in the glucose-6-phosphate transport system. Biochem Biophys Res Commun 1978; 83: 1360–1364.

Ihara

Nomura

Hikino

, et al. Quantitative analysis of glucose-6-phosphate translocase gene expression in various human tissues and haematopoietic progenitor cells. J Inherit Metab Dis 2000; 23: 583–592.

Veiga-da-Cunha

Chevalier

Stephenne

, et al. Failure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PT and G6PC3 deficiency. Proc Natl Acad Sci U S A 2019; 116: 1241–1250.

Kishnani

Austin

Abdenur

, et al. Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics. Genet Med 2014; 16: E1.

Chou

Cho

Kim

, et al. Molecular biology and gene therapy for glycogen storage disease type Ib. J Inherit Metab Dis 2018; 41: 1007–1014.

Gagnier

Kienle

Altman

, et al. The CARE guidelines: consensus-based clinical case reporting guideline development. Headache 2013; 53: 1541–1547.

10.

Van Schaftingen

Gerin

The glucose-6-phosphatase system. Biochem J 2002; 362: 513–532.

11.

Veiga-da-Cunha

Gerin

Chen

, et al. The putative glucose 6-phosphate translocase gene is mutated in essentially all cases of glycogen storage disease type I non-a. Eur J Hum Genet 1999; 7: 717–723.

12.

Froissart

Piraud

Boudjemline

, et al. Glucose-6-phosphatase deficiency. Orphanet J Rare Dis 2011; 6: 27.

13.

Gerin

Veiga-da-Cunha

Achouri

, et al. Sequence of a putative glucose 6-phosphate translocase, mutated in glycogen storage disease type Ib. FEBS Lett 1997; 419: 235–238.

14.

Ihara

Kuromaru

Hara

Genomic structure of the human glucose 6-phosphate translocase gene and novel mutations in the gene of a Japanese patient with glycogen storage disease type Ib. Hum Genet 1998; 103: 493–496.

15.

Choi

Park

, et al. Novel SLC37A4 Mutations in Korean Patients With Glycogen Storage Disease Ib. Ann Lab Med 2017; 37: 261–266.

16.

Dieckgraefe

Korzenik

Husain

, et al. Association of glycogen storage disease 1b and Crohn disease: results of a North American survey. Eur J Pediatr 2002; 161: S88–S92.

17.

Mikami

Arai

Mizumoto

Empagliflozin ameliorated neutropenia in a girl with glycogen storage disease Ib. Pediatr Int 2021; 63: 1394–1396.

18.

Wortmann

Van Hove

JLK

Derks

TGJ

, et al. Treating neutropenia and neutrophil dysfunction in glycogen storage disease type Ib with an SGLT2 inhibitor. Blood 2020; 136: 1033–1043.

19.

Visser

Rake

Fernandes

, et al. Neutropenia, neutrophil dysfunction, and inflammatory bowel disease in glycogen storage disease type Ib: results of the European Study on Glycogen Storage Disease type I. J Pediatr 2000; 137: 187–191.

20.

Veiga-da-Cunha

Wortmann

Grünert

, et al. Treatment of the Neutropenia Associated with GSD1b and G6PC3 Deficiency with SGLT2 Inhibitors. Diagnostics (Basel) 2023; 13: 1803.

21.

Grünert

Derks

TGJ

Adrian

, et al. Efficacy and safety of empagliflozin in glycogen storage disease type Ib: Data from an international questionnaire. Genet Med 2022; 24: 1781–1788.

22.

Qiu

Wang

, et al. [Mutation in the SLC37A4 gene of glycogen storage disease type Ib in 15 families of the mainland of China]. Zhonghua Er Ke Za Zhi 2011; 49: 203–208.

23.

Wang

Cui

Lee

, et al. Clinical application of massively parallel sequencing in the molecular diagnosis of glycogen storage diseases of genetically heterogeneous origin. Genet Med 2013; 15: 106–114.

24.

Skakic

Djordjevic

Sarajlija

, et al. Genetic characterization of GSD I in Serbian population revealed unexpectedly high incidence of GSD Ib and 3 novel SLC37A4 variants. Clin Genet 2018; 93: 350–355.

25.

Sperb-Ludwig

Pinheiro

Bettio Soares

, et al. Glycogen storage diseases: Twenty-seven new variants in a cohort of 125 patients. Mol Genet Genomic Med 2019; 7: E877.

26.

Miltenberger-Miltenyi

Szonyi

Balogh

, et al. Mutation spectrum of type I glycogen storage disease in Hungary. J Inherit Metab Dis 2005; 28: 939–944.

27.

Eghbali

Abiri

Talebi

, et al. Genotype-phenotype correlation and description of two novel mutations in Iranian patients with glycogen storage disease 1b (GSD1b). Orphanet J Rare Dis 2020; 15: 35.

28.

Lin

Zheng

[A Chinese patient with glycogen storage disease type Ib caused by mutations in the glucose-6-phosphate translocase gene]. Zhonghua Er Ke Za Zhi 2014; 52: 58–60.

29.

Liang

Liu

Sheng

, et al. [Gene mutations and clinical manifestations in children with glycogen storage disease type Ib]. Zhongguo Dang Dai Er Ke Za Zhi 2013; 15: 661–665.

30.

Meimand

Azizi

Yazdani

, et al. Novel mutation of SLC37A4 in a glycogen storage disease type Ib patient with neutropenia, horseshoe kidney, and arteriovenous malformation: a case report. Immunol Res 2023; 71: 107–111.

31.

Liang

Zhu

Zhang

, et al. Intestinal stricture in a patient with glycogen storage disease type Ib and inflammatory bowel disease. Asian J Surg 2022; 45: 2437–2438.

32.

Zhang

Sun

Wan

Mutation analysis of SLC37A4 in a patient with glycogen storage disease-type Ib. J Int Med Res 2019; 47: 5996–6003.

33.

Trioche

Petit

Francoual

, et al. Allelic heterogeneity of glycogen storage disease type Ib in French patients: a study of 11 cases. J Inherit Metab Dis 2004; 27: 621–623.

34.

Wei

, et al. Clinical analysis and long-term treatment monitoring of 3 patients with glycogen storage disease type Ib. BMC Med Genomics 2021; 14: 81.

35.

Schroeder

Hildebrandt

Mayatepek

, et al. A patient with glycogen storage disease type Ib presenting with acute myeloid leukemia (AML) bearing monosomy 7 and translocation t(3;8)(q26;q24) after 14 years of treatment with granulocyte colony-stimulating factor (G-CSF): a case report. J Med Case Rep 2008; 2: 319.

36.

Wang

Zhou

, et al. A Novel Lipoprotein Lipase Mutation in an Infant With Glycogen Storage Disease Type-Ib and Severe Hypertriglyceridemia. Front Pediatr 2021; 9: 671536.

37.

Lam

Chan

Tong

, et al. A novel missense mutation (P191L) in the glucose-6-phosphate translocase gene identified in a Chinese family with glycogen storage disease 1b. Hum Mutat 2000; 16: 94.

38.

Xiao

Qiu

WJ.

[Crohn's disease in glycogen storage disease type I b: a case report]. Zhonghua Er Ke Za Zhi 2017; 55: 144–145.

39.

Lam

Sin

Lau

, et al. Prenatal diagnosis of glycogen storage disease type 1b using denaturing high performance liquid chromatography. Prenat Diagn 2000; 20: 765–768.

40.

Yuen

Cheng

Tong

, et al. Novel missense mutation (Y24H) in the G6PT1 gene causing glycogen storage disease type 1b. Mol Genet Metab 2002; 77: 249–251.

41.

Hsiao

Chang

Hwu

, et al. Glycogen storage disease type Ib: the first case in Taiwan. Pediatr Neonatol 2009; 50: 125–128.

42.

Kojima

Kure

Kamada

, et al. Genetic testing of glycogen storage disease type Ib in Japan: five novel G6PT1 mutations and a rapid detection method for a prevalent mutation W118R. Mol Genet Metab 2004; 81: 343–346.

43.

Hou

Kure

Suzuki

, et al. Glycogen storage disease type Ib: structural and mutational analysis of the microsomal glucose-6-phosphate transporter gene. Am J Med Genet 1999; 86: 253–257.

44.

Kure

Hou

Suzuki

, et al. Glycogen storage disease type Ib without neutropenia. J Pediatr 2000; 137: 253–256.

45.

Melis

Balivo

Della Casa

, et al. Myasthenia gravis in a patient affected by glycogen storage disease type Ib: a further manifestation of an increased risk for autoimmune disorders? J Inherit Metab Dis 2008; 31: S227–S231.

46.

Melis

Della Casa

Balivo

, et al. Involvement of endocrine system in a patient affected by glycogen storage disease 1b: speculation on the role of autoimmunity. Ital J Pediatr 2014; 40: 30.

47.

Oguz

Aykan

Yilmaz

, et al. Glycogen storage disease type 1b: an early onset severe phenotype associated with a novel mutation (IVS4) in the glucose 6-phosphate translocase (SLC37A4) gene in a Turkish patient. Genet Couns 2014; 25: 389–394.

48.

Sanderson

Bisset

Milla

, et al. Chronic inflammatory bowel disease in glycogen storage disease type 1B. J Inherit Metab Dis 1991; 14: 771–776.

49.

Santer

Rischewski

Block

, et al. Molecular analysis in glycogen storage disease 1 non-A: DHPLC detection of the highly prevalent exon 8 mutations of the G6PT1 gene in German patients. Hum Mutat 2000; 16: 177.

50.

Carlin

Scherrer

De Tommaso

, et al. Determining mutations in G6PC and SLC37A4 genes in a sample of Brazilian patients with glycogen storage disease types Ia and Ib. Genet Mol Biol 2013; 36: 502–506.

51.

Prasad

Estrella

Christodoulou

, et al. A Third Case of Glycogen Storage Disease IB and Giant Cell Tumour of the Mandible: A Disease Association or Iatrogenic Complication of Therapy. JIMD Rep 2018; 42: 5–8.

52.

Han

Lee

, et al. A novel mutation (A148V) in the glucose 6-phosphate translocase (SLC37A4) gene in a Korean patient with glycogen storage disease type 1b. J Korean Med Sci 2005; 20: 499–501.

53.

Çakar

Gezdirici

Topuz

, et al. Novel variants in Turkish patients with glycogen storage disease. Pediatr Int 2020; 62: 1145–1150.

54.

Mameesh

Ganesh

Harikrishna

, et al. Co-inheritance of the membrane frizzled-related protein ocular phenotype and glycogen storage disease type Ib. Ophthalmic Genet 2017; 38: 544–548.

55.

Angaroni

Labrune

Petit

, et al. Glycogen storage disease type Ib without neutropenia generated by a novel splice-site mutation in the glucose-6-phosphate translocase gene. Mol Genet Metab 2006; 88: 96–99.

56.

Annabi

Hiraiwa

Mansfield

, et al. The gene for glycogen-storage disease type 1b maps to chromosome 11q23. Am J Hum Genet 1998; 62: 400–405.

57.

Bhattacharya

Kumar Bn

Panigrahi

, et al. Hepatomegaly with neutropenia: a girl with glycogen storage disease Ib. BMJ Case Rep 2019; 12: E230660.

58.

Dissanayake

Jayasinghe

Thilakaratne

, et al. A novel mutation in SLC37A4 gene in a Sri Lankan boy with glycogen storage disease type Ib associated with very early onset neutropenia. J Mol Genet Med 2011; 5: 262–263.

59.

Lee

Choi

Kim

, et al. Esophageal Stricture Secondary to Candidiasis in a Child with Glycogen Storage Disease 1b. Pediatr Gastroenterol Hepatol Nutr 2016; 19: 71–75.

60.

Zappu

Lilliu

Podda

, et al. Molecular analysis of glycogen storage disease type Ib in Sardinian population: evidence for a founder effect. Genet Test Mol Biomarkers 2010; 14: 399–403.

61.

Beyzaei

Ezgu

Geramizadeh

, et al. Clinical and genetic spectrum of glycogen storage disease in Iranian population using targeted gene sequencing. Sci Rep 2021; 11: 7040.

62.

Yamaguchi

Ihara

Matsumoto

, et al. Inflammatory bowel disease-like colitis in glycogen storage disease type 1b. Inflamm Bowel Dis 2001; 7: 128–132.

63.

Halligan

White

Schwahn

, et al. The natural history of glycogen storage disease type Ib in England: A multisite survey. JIMD Rep 2021; 59: 52–59.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.24 MB

0.11 MB