INTRODUCTION — 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 — 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 [1]. 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 [2]. 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'.)
Genetics — The disorder is due to pathogenic variants in the gene for the glucose transporter GLUT2 (solute carrier family 2 member 2 [SLC2A2]), located at 3q26 [3]. Inheritance is autosomal recessive. Many cases occur in consanguineous families [4].
Clinical features — Affected patients typically present in infancy with hepatomegaly secondary to glycogen accumulation, severe failure to thrive, and rickets [5]. Neonatal diabetes, either transient or persistent, has also been observed. In a study of 104 neonates with diabetes in whom other genetic causes of neonatal diabetes had been excluded, five were found to have pathogenic variants in SLC2A2 [6]. Aberrant hepatocyte glucose transport results in postprandial hyperglycemia followed by fasting hypoglycemia. Glucose-stimulated insulin release is diminished and contributes to poor glucose control. Hemoglobin A1c (HgbA1c) is normal, and fasting hypoglycemia and postprandial hyperglycemia appear to improve with age [7].
Patients have a characteristic tubular nephropathy, with glucosuria, phosphaturia, bicarbonate wasting, and a generalized amino aciduria, leading to rickets [5,8]. Osmotic diuresis leads to polyuria. Short stature persists through adulthood [9]. (See "Overview of rickets in children".)
Intellectual development is normal in patients with GLUT2 deficiency. Linear growth and puberty are delayed. While the underlying mechanisms have not been well documented in GLUT2 deficiency, endocrine abnormalities have been documented in other forms of hepatic glycogenoses that may be operative in GLUT2 deficiency [10].
Clinical features of GLUT2 deficiency have considerable overlap with glycogen storage disease Ia (GSD Ia; glucose 6-phosphatase deficiency). However, severe hypoglycemia, lactic acidemia, or hyperuricemia are not present in GLUT2 deficiency, and renal tubulopathy is seen only in GLUT2 deficiency. Conversely, autosomal-recessive proximal tubulopathy and hypercalciuria (ARPTH), which may present with hypophosphatemic rickets, is allelic with Fanconi-Bickel syndrome [11]. Reminiscent of GSD Ia (a form of glucose-6-phosphate deficiency), hepatocellular carcinoma was reported in a six-year-old affected child [12].
Diagnosis — The diagnosis of GLUT2 deficiency should be considered in a child with the symptoms described plus altered glucose homeostasis, accumulation of glycogen in the liver, and a Fanconi-type tubulopathy. Tests of glucose and galactose tolerance and kidney function are abnormal. Serum biotinidase activity may be increased, as is observed in other GSDs [13]. Liver biopsy reveals increased glycogen content without significant inflammation or fibrosis. The diagnosis is confirmed by DNA analysis. The disorder may be detected by a newborn screening test that is positive for galactosemia if the basis for screening is the direct measurement of galactose and not measurement of galactose-1-phosphate uridyl transferase (GALT) activity [14].
Treatment — No specific treatment is available. Management of the kidney disease consists of supplementation of water and electrolytes, L-carnitine supplements, vitamin D supplements (ergocalciferol or cholecalciferol), and restriction of galactose. Frequent, small meals with adequate caloric intake may improve growth. Treatment with uncooked cornstarch, a complex glucose polymer that is digested over several hours, before bedtime may help maintain glucose levels during sleep [15]. Nocturnal enteral nutrition and/or uncooked cornstarch may normalize growth in a subset of children [16]. Young infants (less than six months) treated with cornstarch may develop gastrointestinal distress (colicky symptoms or diarrhea) since pancreatic amylase has not reached adult levels.
ALDOLASE A DEFICIENCY — Aldolase A deficiency (also called glycogen storage disease XII [GSD XII]; MIM #611881) is a rare GSD associated with hereditary hemolytic anemia.
Pathogenesis — In the glycolytic pathway, three isozymes of aldolase (A, B, and C) are responsible for the conversion of fructose-1,6-biphosphate into glyceraldehyde-3-phosphate and dihydroxyacetone phosphate and are encoded by distinct genes. Aldolase A in humans is encoded by a single gene on chromosome 16p11.2 and is a homotetrameric enzyme [17,18]. Aldolase A is the only isozyme present in both red blood cells and skeletal muscle.
Clinical and laboratory findings — To date, only a few patients have been reported with both hemolysis and myopathic symptoms. Five patients developed rhabdomyolysis during a febrile illness [19-23]. Additional manifestations during the acute illness included myopathic symptoms, hemolytic anemia, jaundice, increased ferritin levels, and hyperkalemia. One of these children had initially presented with increasing muscle weakness and transfusion-dependent hemolytic anemia that was reversed following splenectomy [20]. There is also a report of a family with three affected siblings in whom recurrent rhabdomyolysis without hemolytic anemia was observed [24]. Episodes of rhabdomyolysis began in infancy and occurred during febrile illnesses. Mild intellectual disability, short stature, microcephaly, and possibly related dermatologic abnormalities have been reported as well [19,23].
Laboratory findings in one of the two children first reported included a highly elevated serum creatine kinase and markers of hemolysis, mild hemoglobinuria, and myoglobinuria [19]. Biochemical assays showed a profound reduction in red blood cell and skeletal muscle aldolase A level and also diminished thermostability of the residual enzyme. A third child with suspected hemolytic anemia had associated myopathic symptoms at birth, as well as arthrogryposis multiplex congenita and pituitary ectopia [21].
Despite its rare occurrence, a history of hemolytic anemia and the development of myopathic symptoms and/or myoglobinuria in the setting of fever and/or overexertion, which may also elevate core body temperature [22], should alert the clinician to the possibility of aldolase A deficiency. (See "Rare RBC enzyme disorders".)
Diagnosis — Aldolase A activity is diminished in erythrocytes and muscle biopsy tissue of patients with aldolase A deficiency. Hence, an enzymatic assay is typically used to make the diagnosis. The detection of a homozygous pathogenic variant or two heterozygous variants in the aldolase, fructose-bisphosphate A (ALDOA) gene by sequence analysis can also confirm the diagnosis.
Treatment — Treatment of aldolase A deficiency remains supportive. Enzyme replacement therapy is not available. Patients are usually assessed first by a hematologist regarding the diagnosis and management of hemolytic anemia. During febrile episodes, patients with confirmed enzymatic and/or molecular diagnosis should be treated aggressively with antipyretics to diminish the risk of hemolysis and rhabdomyolysis. (See "Overview of hemolytic anemias in children", section on 'Enzyme deficiencies'.)
SUMMARY
●Inborn errors of glycogen metabolism include the inherited glycogen storage diseases (GSDs) (table 1). 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 and easy fatigability, and progressive weakness. (See 'Introduction' above and "Overview of inherited disorders of glucose and glycogen metabolism".)
●Glucose transporter 2 (GLUT2) deficiency, 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. Affected patients typically present in infancy with hepatomegaly secondary to glycogen accumulation, severe failure to thrive, and rickets. No specific treatment is available, other than dietary management. (See 'GLUT2 deficiency' above.)
●Aldolase A deficiency, also called GSD XII, is a rare GSD associated with hereditary hemolytic anemia. The most common findings are myopathic symptoms and hemolytic anemia. Rhabdomyolysis can occur during a febrile illness. Treatment of aldolase A deficiency includes management of hemolytic anemia and antipyretics during febrile episodes to decrease the risk of hemolysis and rhabdomyolysis. (See 'Aldolase A deficiency' above.)
