Other disorders of glycogen metabolism: GLUT2 deficiency and aldolase A deficiency
- William J Craigen, MD, PhD
William J Craigen, MD, PhD
- Professor of Molecular and Human Genetics
- Baylor College of Medicine
- Basil T Darras, MD
Basil T Darras, MD
- Professor of Neurology
- Harvard Medical School
Glycogen is the stored form of glucose and serves as a buffer for glucose needs. It is composed of long polymers of a 1,4-linked glucose, interrupted by a 1,6-linked branch point every 4 to 10 residues. Glycogen is formed in periods of dietary carbohydrate loading and broken down when glucose demand is high or dietary availability is low (figure 1).
There are a number of inborn errors of glycogen metabolism that result from mutations in genes for virtually all of the proteins involved in glycogen synthesis, degradation, or regulation (figure 1). Those disorders that result in abnormal storage of glycogen are known as glycogen storage diseases (GSDs) (table 1).
Glycogen is most abundant in liver and muscle. The major manifestations of disorders of glycogen metabolism affecting the liver are hypoglycemia and hepatomegaly, and the primary features of those defects that affect muscle are muscle cramps, exercise intolerance, easy fatigability, and progressive weakness.
This topic will review two disorders of glycogen metabolism: glucose transporter 2 (GLUT2) deficiency and aldolase A deficiency. An overview of GSDs is presented separately. (See "Overview of inherited disorders of glucose and glycogen metabolism".)
GLUT2 deficiency (MIM #227810), also known as Fanconi-Bickel syndrome, is a rare disorder of glucose homeostasis that leads to accumulation of glycogen in the liver and kidney and glucose and galactose intolerance. GLUT2 is a facilitative, bidirectional transporter. It passively transports intracellular glucose and galactose across the basolateral membrane of cells including hepatocytes, pancreatic beta cells, renal tubular cells, and intestinal epithelial cells by moving the carbohydrate molecule down its concentration gradient . Transient expression of induced apical membrane GLUT2 plays a role separate from sodium-glucose transporter 1 (SGLT1 or SLC5A1) in the absorption of simple sugars in the intestinal mucosa and is a potential target for modulating carbohydrate absorption . Glycogen accumulation in patients with GLUT2 deficiency occurs due to a failure to adequately export glucose generated by glycogen degradation. This inadequate export leads to a marked increase in intracellular glucose that inhibits glycogen degradation. (See "Pancreatic beta cell function", section on 'Role of glucose'.)To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Brown GK. Glucose transporters: structure, function and consequences of deficiency. J Inherit Metab Dis 2000; 23:237.
- Kellett GL, Brot-Laroche E, Mace OJ, Leturque A. Sugar absorption in the intestine: the role of GLUT2. Annu Rev Nutr 2008; 28:35.
- Santer R, Schneppenheim R, Dombrowski A, et al. Mutations in GLUT2, the gene for the liver-type glucose transporter, in patients with Fanconi-Bickel syndrome. Nat Genet 1997; 17:324.
- Santer R, Steinmann B, Schaub J. Fanconi-Bickel syndrome--a congenital defect of facilitative glucose transport. Curr Mol Med 2002; 2:213.
- Sansbury FH, Flanagan SE, Houghton JA, et al. SLC2A2 mutations can cause neonatal diabetes, suggesting GLUT2 may have a role in human insulin secretion. Diabetologia 2012; 55:2381.
- Taha D, Al-Harbi N, Al-Sabban E. Hyperglycemia and hypoinsulinemia in patients with Fanconi-Bickel syndrome. J Pediatr Endocrinol Metab 2008; 21:581.
- Berry GT, Baker L, Kaplan FS, Witzleben CL. Diabetes-like renal glomerular disease in Fanconi-Bickel syndrome. Pediatr Nephrol 1995; 9:287.
- Manz F, Bickel H, Brodehl J, et al. Fanconi-Bickel syndrome. Pediatr Nephrol 1987; 1:509.
- Dunger DB, Holder AT, Leonard JV, et al. Growth and endocrine changes in the hepatic glycogenoses. Eur J Pediatr 1982; 138:226.
- Mannstadt M, Magen D, Segawa H, et al. Fanconi-Bickel syndrome and autosomal recessive proximal tubulopathy with hypercalciuria (ARPTH) are allelic variants caused by GLUT2 mutations. J Clin Endocrinol Metab 2012; 97:E1978.
- Paesold-Burda P, Baumgartner MR, Santer R, et al. Elevated serum biotinidase activity in hepatic glycogen storage disorders--a convenient biomarker. J Inherit Metab Dis 2007; 30:896.
- Müller D, Santer R, Krawinkel M, et al. Fanconi-Bickel syndrome presenting in neonatal screening for galactosaemia. J Inherit Metab Dis 1997; 20:607.
- Lee PJ, Van't Hoff WG, Leonard JV. Catch-up growth in Fanconi-Bickel syndrome with uncooked cornstarch. J Inherit Metab Dis 1995; 18:153.
- Kikuta A, Yoshida MC, Sakakibara M, et al. Molecular gene mapping for the structural gene for human aldolase A (ALDOA) to chromosome 22. Cytogenet Cell Genet 1985; 40:674 (Abstract).
- Serero S, Maire P, Nguyen VC, et al. Localization of the active gene of aldolase on chromosome 16, and two aldolase A pseudogenes on chromosomes 3 and 10. Hum Genet 1988; 78:167.
- Kreuder J, Borkhardt A, Repp R, et al. Brief report: inherited metabolic myopathy and hemolysis due to a mutation in aldolase A. N Engl J Med 1996; 334:1100.
- Yao DC, Tolan DR, Murray MF, et al. Hemolytic anemia and severe rhabdomyolysis caused by compound heterozygous mutations of the gene for erythrocyte/muscle isozyme of aldolase, ALDOA(Arg303X/Cys338Tyr). Blood 2004; 103:2401.
- Esposito G, Vitagliano L, Costanzo P, et al. Human aldolase A natural mutants: relationship between flexibility of the C-terminal region and enzyme function. Biochem J 2004; 380:51.
- Mamoune A, Bahuau M, Hamel Y, et al. A thermolabile aldolase A mutant causes fever-induced recurrent rhabdomyolysis without hemolytic anemia. PLoS Genet 2014; 10:e1004711.