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Disorders of Carbohydrate Metabolism
Disorders of Carbohydrate Metabolism PS Kishnani and Y-T Chen, Duke University Medical Center, Durham, NC, USA ã 2014 Elsevier Inc. All rights reserved.
Inborn errors of carbohydrate metabolism covered in this chapter include disaccharidase deficiencies, disorders of monosaccharide metabolism, glycogen storage diseases (GSDs), and gluconeogenic disorders. A number of strides have been made in understanding the clinical course, variability, molecular dissection, and treatment interventions for these disorders. This chapter focuses mainly on clinical aspects, genetics and current treatments pertaining to inborn errors of carbohydrate metabolism. Disaccharidase deficiencies are characterized by the defective digestion of dietary sugars, starch, lactose and sucrose. Congenital lactase deficiency is a rare autosomal recessive disorder where infants, as a result of being unable to break down lactose in milk or other foods due to absence of the enzyme lactase, present with severe gastrointestinal symptoms. Late-onset or adult-type lactase deficiency (hypolactasia) is quite common in comparison to lactase persistence. Sucrase-isomaltase deficiency usually causes severe symptoms in younger children who ingest sucrose-containing foods. Dietary modification results in successful treatment outcome. Several disorders arise due to transport defects, including Fanconi–Bickel syndrome and arterial tortuosity syndrome. Glucosegalactose malabsorption marks a defect in the SGLT 1 gene, which codes for concentrative glucose transporter proteins. Defects in GLUT genes, however, mark abnormalities in facilitative glucose transporters. GLUT1, GLUT2 (Fanconi-Bickel syndrome), and GLUT10 (arterial tortuosity syndrome) are clinically significant. Disorders of galactose metabolism stem from defects in the three main galactose enzymes involved in the Leloir pathway. Galactokinase deficiency usually results in cataracts and pseudotumor cerebri. Galactose-1-phosphate uridyltransferase deficiency (classic galactosemia) is the most severe disorder. If not diagnosed early, galactosemia can result in hypotonia, hepatomegaly, jaundice, cataracts, reduced immune function, hypergonadotropic hypogonadism in women, physical retardation and mental delay. Elimination of dietary galactose with calcium supplementation can significantly alter outcome. Finally, uridine diphosphate galactose-4-epimerase deficiency (epimerase deficiency) presents in both a benign and a rare but severe form that elicit symptoms similar to those in classic galactosemia. Fructose metabolism disorders include essential fructosuria, a generally benign condition, and hereditary fructose intolerance, a deficiency of liver fructose-1-phosphate aldolase. Hereditary fructose intolerance results in generalized aminoaciduria, hypoglycemia, and a range of clinical manifestations dependent upon age and amount of fructose or sucrose ingested. Dehydrogenases fructose-6-phosphate and glucose-6-phosphate are products of pentose metabolism, a process in the minor hexose monophosphate pathway of glucose metabolism. Glucose-6-phosphate dehydrogenase deficiency, the most prominent genetic disorder in humans, is a well-known cause of hemolytic anemia (Perl et al., 2011). All 10 individuals from six families identified as having transaldolase deficiency (TALDO) presented with liver disease (Balasubramaniam et al., 2011). TALDO has broad phenotypic heterogeneity, ranging from fetal hydrops to slow-progressing liver cirrhosis. Only one case of ribose-5phosphate isomerase deficiency has been identified, possibly because of its complex molecular etiology (Wamelink et al., 2010). Essential pentosuria is a benign disorder not requiring treatment. To date, there are over 12 glycogenoses, or glycogen metabolism disorders, that have been cataloged. GSDs, a major category of glycogenoses, are categorized by type of tissue involved: primarily liver, muscle, and/or cardiac. In some, there is accumulation of normally structured glycogen while in others (GSD III, IV), the structure of glycogen is abnormal. Hepatic GSDs include types I, III, IV, VI, IX, IX, and XI. Muscle GSDs include types II, III, V, VII and IX. GSD type Ia (Von Gierke disease) results from deficiency of a catalytic subunit of the glucose-6-phosphatase enzyme and causes severe, often life-threatening hypoglycemia when not managed. GSD type Ib, marked by neutropenia and neutrophil dysfunction, is due to the absence of glucose-6-phosphate translocase, T1. GSD III (amylo-1,6-glucosidase (debrancher) deficiency) has two forms: GSD IIIa involving both liver and muscle, and GSD IIIb involving only liver. The defective debranching enzyme, which functions to break down glycogen, causes glycogen buildup in both types and muscle weakness in type IIIa. GSD type VI (hepatic phosphorylase deficiency, Hers disease) results from mutations in PYGL, or the liver isoform of phosphorylase. Type IV GSD (Andersen’s disease, brancher deficiency) has several presentations. The hepatic form is accompanied by hypotonia and fatal liver dysfunction appearing between ages 2 and 4 years. The neuromuscular form of GSD-IV has four forms: the first two causing neonatal death, the second causing late childhood symptoms of myopathy or cardiomyopathy, and the third an adult form characterized by central and peripheral nervous system dysfunction and polyglucosan body disease. GSD XI (Fanconi–Bickel syndrome) involves a mutation in the facilitative glucose transporter GLUT2. GSD II, or Pompe disease, derives from acid alfa-glucosidase deficiency (GAA). The only GSD where glycogen accumulates in the lysosomes, Pompe disease is characterized by a range of phenotypes each including myopathy but differing in age at onset, organ involvement, and clinical severity. The advent of enzyme replacement therapy with alglucosidase alfa has significantly advanced GSD II: infantile patients experience respiratory and cardiac improvement and adult-onset patients experience stabilization of skeletal muscle function and pulmonary disease (Hobson-Webb et al., 2011; Kishnani et al., 2009). GSD V (McArdle disease) appears in late adolescence or in the second decade of life with pain and muscle stiffness due to muscle phosphorylase deficiency. GSD type VII (Tarui disease) has several features in common with McArdle disease but includes an infantile form with neurologic involvement. Muscle phosphorylase kinase deficiency, characterized by muscle weakness and atrophy, is due to mutations in the PHKA1 gene. In addition, two GSDs mimic hypertrophic cardiomyopathy: Glycogen can amalgamate in heart
Reference Module in Biomedical Research
http://dx.doi.org/10.1016/B978-0-12-801238-3.05565-3
1
2
Disorders of Carbohydrate Metabolism
and skeletal muscle due to malfunctioning lysosomal associated membrane 2 proteins (LAMP2, classified as Danon’s disease) and AMP-activated kinase gamma 2 proteins (PRKAG2). Two rare disorders – hepatic and muscle glycogen synthase deficiencies – are caused by a lack of glycogen synthase. Although both appear in the glycogen storage disorders section, neither involves excessive glycogen storage but rather the lack of due to synthase deficiency. Hepatic glycogen synthase deficiency is also called GSD type 0. Muscle glycogen synthase deficiency (GYS1) has only been reported in four children. If diagnosed early on, it can be managed. The final section covers gluconeogenic disorders associated with lactic acidosis, for, in fasting conditions, blood glucose is derived mainly from glycogen breakdown (glycogenolysis) and from the conversion of lactic acid and certain amino acids to glucose (gluconeogenesis). These gluconeogenic disorders include fructose-1,6-diphosphatase deficiency, pyruvate carboxylase deficiency, phosphoenolpyruvate carboxykinase deficiency, and pyruvate dehydrogenase complex deficiencies. Fructose-1,6diphosphatase deficiency and pyruvate dehydrogenase complex deficiencies often cause cognitive difficulties. Hypoglycemia can present in all four gluconeogenic disorders, whereas hypotonia is seen primarily in pyruvate carboxylase deficiency, phosphoenolpyruvate carboxykinase deficiency, and pyruvate dehydrogenase complex deficiencies.
References Balasubramaniam S, Wamelink M, Ngu L, Talib A, Salomons G, et al. (2011) Novel heterozygous mutations in TALDO1 gene causing transaldolase deficiency and early infantile liver failure. Journal of Pediatric Gastroenterology and Nutrition 52: 113–116. Hobson-Webb LD, DeArmey S, and Kishnani PS (2011) The clinical and electrodiagnostic characteristics of pompe disease with post-enzyme replacement therapy findings. Clinical Neurophysiology 122(11): 2312–2317. Kishnani P, Corzo D, Leslie ND, Gruskin D, Van der Ploeg A, Clancy JP, Parini R, Morin G, Beck M, Bauer MS, et al. (2009) Early treatment with alglucosidase alpha prolongs longterm survival of infants with pompe disease. Pediatric Research 66: 329–335. Perl A, Hanczko R, Telarico T, Oaks Z, and Landas S (2011) Oxidative stress, inflammation and carcinogenesis are controlled through the pentose phosphate pathway by transaldolase. Trends in Molecular Medicine 17(7): 395–403. Wamelink M, Gru¨ning N-M, Jansen E, Bluemlein K, Lehrach H, et al. (2010) The difference between rare and exceptionally rare: Molecular characterization of ribose 5-phosphate isomerase deficiency. Journal of Molecular Medicine 88: 931–939.
Inborn errors of carbohydrate metabolism covered in this chapter include disaccharidase deficiencies, disorders of monosaccharide metabolism, glycogen storage diseases (GSDs), and gluconeogenic disorders. A number of strides have been made in understanding the clinical course, variability, molecular dissection, and treatment interventions for these disorders. This chapter focuses mainly on clinical aspects, genetics and current treatments pertaining to inborn errors of carbohydrate metabolism. Disaccharidase deficiencies are characterized by the defective digestion of dietary sugars, starch, lactose and sucrose. Congenital lactase deficiency is a rare autosomal recessive disorder where infants, as a result of being unable to break down lactose in milk or other foods due to absence of the enzyme lactase, present with severe gastrointestinal symptoms. Late-onset or adult-type lactase deficiency (hypolactasia) is quite common in comparison to lactase persistence. Sucrase-isomaltase deficiency usually causes severe symptoms in younger children who ingest sucrose-containing foods. Dietary modification results in successful treatment outcome. Several disorders arise due to transport defects, including Fanconi–Bickel syndrome and arterial tortuosity syndrome. Glucosegalactose malabsorption marks a defect in the SGLT 1 gene, which codes for concentrative glucose transporter proteins. Defects in GLUT genes, however, mark abnormalities in facilitative glucose transporters. GLUT1, GLUT2 (Fanconi-Bickel syndrome), and GLUT10 (arterial tortuosity syndrome) are clinically significant. Disorders of galactose metabolism stem from defects in the three main galactose enzymes involved in the Leloir pathway. Galactokinase deficiency usually results in cataracts and pseudotumor cerebri. Galactose-1-phosphate uridyltransferase deficiency (classic galactosemia) is the most severe disorder. If not diagnosed early, galactosemia can result in hypotonia, hepatomegaly, jaundice, cataracts, reduced immune function, hypergonadotropic hypogonadism in women, physical retardation and mental delay. Elimination of dietary galactose with calcium supplementation can significantly alter outcome. Finally, uridine diphosphate galactose-4-epimerase deficiency (epimerase deficiency) presents in both a benign and a rare but severe form that elicit symptoms similar to those in classic galactosemia. Fructose metabolism disorders include essential fructosuria, a generally benign condition, and hereditary fructose intolerance, a deficiency of liver fructose-1-phosphate aldolase. Hereditary fructose intolerance results in generalized aminoaciduria, hypoglycemia, and a range of clinical manifestations dependent upon age and amount of fructose or sucrose ingested. Dehydrogenases fructose-6-phosphate and glucose-6-phosphate are products of pentose metabolism, a process in the minor hexose monophosphate pathway of glucose metabolism. Glucose-6-phosphate dehydrogenase deficiency, the most prominent genetic disorder in humans, is a well-known cause of hemolytic anemia (Perl et al., 2011). All 10 individuals from six families identified as having transaldolase deficiency (TALDO) presented with liver disease (Balasubramaniam et al., 2011). TALDO has broad phenotypic heterogeneity, ranging from fetal hydrops to slow-progressing liver cirrhosis. Only one case of ribose-5phosphate isomerase deficiency has been identified, possibly because of its complex molecular etiology (Wamelink et al., 2010). Essential pentosuria is a benign disorder not requiring treatment. To date, there are over 12 glycogenoses, or glycogen metabolism disorders, that have been cataloged. GSDs, a major category of glycogenoses, are categorized by type of tissue involved: primarily liver, muscle, and/or cardiac. In some, there is accumulation of normally structured glycogen while in others (GSD III, IV), the structure of glycogen is abnormal. Hepatic GSDs include types I, III, IV, VI, IX, IX, and XI. Muscle GSDs include types II, III, V, VII and IX. GSD type Ia (Von Gierke disease) results from deficiency of a catalytic subunit of the glucose-6-phosphatase enzyme and causes severe, often life-threatening hypoglycemia when not managed. GSD type Ib, marked by neutropenia and neutrophil dysfunction, is due to the absence of glucose-6-phosphate translocase, T1. GSD III (amylo-1,6-glucosidase (debrancher) deficiency) has two forms: GSD IIIa involving both liver and muscle, and GSD IIIb involving only liver. The defective debranching enzyme, which functions to break down glycogen, causes glycogen buildup in both types and muscle weakness in type IIIa. GSD type VI (hepatic phosphorylase deficiency, Hers disease) results from mutations in PYGL, or the liver isoform of phosphorylase. Type IV GSD (Andersen’s disease, brancher deficiency) has several presentations. The hepatic form is accompanied by hypotonia and fatal liver dysfunction appearing between ages 2 and 4 years. The neuromuscular form of GSD-IV has four forms: the first two causing neonatal death, the second causing late childhood symptoms of myopathy or cardiomyopathy, and the third an adult form characterized by central and peripheral nervous system dysfunction and polyglucosan body disease. GSD XI (Fanconi–Bickel syndrome) involves a mutation in the facilitative glucose transporter GLUT2. GSD II, or Pompe disease, derives from acid alfa-glucosidase deficiency (GAA). The only GSD where glycogen accumulates in the lysosomes, Pompe disease is characterized by a range of phenotypes each including myopathy but differing in age at onset, organ involvement, and clinical severity. The advent of enzyme replacement therapy with alglucosidase alfa has significantly advanced GSD II: infantile patients experience respiratory and cardiac improvement and adult-onset patients experience stabilization of skeletal muscle function and pulmonary disease (Hobson-Webb et al., 2011; Kishnani et al., 2009). GSD V (McArdle disease) appears in late adolescence or in the second decade of life with pain and muscle stiffness due to muscle phosphorylase deficiency. GSD type VII (Tarui disease) has several features in common with McArdle disease but includes an infantile form with neurologic involvement. Muscle phosphorylase kinase deficiency, characterized by muscle weakness and atrophy, is due to mutations in the PHKA1 gene. In addition, two GSDs mimic hypertrophic cardiomyopathy: Glycogen can amalgamate in heart
Reference Module in Biomedical Research
http://dx.doi.org/10.1016/B978-0-12-801238-3.05565-3
1
2
Disorders of Carbohydrate Metabolism
and skeletal muscle due to malfunctioning lysosomal associated membrane 2 proteins (LAMP2, classified as Danon’s disease) and AMP-activated kinase gamma 2 proteins (PRKAG2). Two rare disorders – hepatic and muscle glycogen synthase deficiencies – are caused by a lack of glycogen synthase. Although both appear in the glycogen storage disorders section, neither involves excessive glycogen storage but rather the lack of due to synthase deficiency. Hepatic glycogen synthase deficiency is also called GSD type 0. Muscle glycogen synthase deficiency (GYS1) has only been reported in four children. If diagnosed early on, it can be managed. The final section covers gluconeogenic disorders associated with lactic acidosis, for, in fasting conditions, blood glucose is derived mainly from glycogen breakdown (glycogenolysis) and from the conversion of lactic acid and certain amino acids to glucose (gluconeogenesis). These gluconeogenic disorders include fructose-1,6-diphosphatase deficiency, pyruvate carboxylase deficiency, phosphoenolpyruvate carboxykinase deficiency, and pyruvate dehydrogenase complex deficiencies. Fructose-1,6diphosphatase deficiency and pyruvate dehydrogenase complex deficiencies often cause cognitive difficulties. Hypoglycemia can present in all four gluconeogenic disorders, whereas hypotonia is seen primarily in pyruvate carboxylase deficiency, phosphoenolpyruvate carboxykinase deficiency, and pyruvate dehydrogenase complex deficiencies.
References Balasubramaniam S, Wamelink M, Ngu L, Talib A, Salomons G, et al. (2011) Novel heterozygous mutations in TALDO1 gene causing transaldolase deficiency and early infantile liver failure. Journal of Pediatric Gastroenterology and Nutrition 52: 113–116. Hobson-Webb LD, DeArmey S, and Kishnani PS (2011) The clinical and electrodiagnostic characteristics of pompe disease with post-enzyme replacement therapy findings. Clinical Neurophysiology 122(11): 2312–2317. Kishnani P, Corzo D, Leslie ND, Gruskin D, Van der Ploeg A, Clancy JP, Parini R, Morin G, Beck M, Bauer MS, et al. (2009) Early treatment with alglucosidase alpha prolongs longterm survival of infants with pompe disease. Pediatric Research 66: 329–335. Perl A, Hanczko R, Telarico T, Oaks Z, and Landas S (2011) Oxidative stress, inflammation and carcinogenesis are controlled through the pentose phosphate pathway by transaldolase. Trends in Molecular Medicine 17(7): 395–403. Wamelink M, Gru¨ning N-M, Jansen E, Bluemlein K, Lehrach H, et al. (2010) The difference between rare and exceptionally rare: Molecular characterization of ribose 5-phosphate isomerase deficiency. Journal of Molecular Medicine 88: 931–939.