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Carbohydrate Metabolism Disorders

by Chin-To Fong, MD

Glycogen Storage Diseases

Glycogen storage diseases (GSDs) are caused by deficiencies of enzymes involved in glycogen synthesis or breakdown; the deficiencies may occur in the liver or muscles and cause hypoglycemia or deposition of abnormal amounts or types of glycogen (or its intermediate metabolites) in tissues.

Inheritance for GSDs is autosomal recessive except for GSD type VIII/IX, which is X-linked. Incidence is estimated at about 1/25,000 births, which may be an underestimate because milder subclinical forms may be undiagnosed. For a more complete listing of glycogen storage diseases, see Table Glycogen Storage Diseases and Disorders of Gluconeogenesis.

Glycogen Storage Diseases and Disorders of Gluconeogenesis

Disease (OMIM Number)

Defective Proteins or Enzymes

Defective Gene or Genes (Chromosomal Location)

Comments

GSD I (Von Gierke’s disease)

Most common type of GSD I: Ia (> 80%)

Onset: Before 1 yr

Clinical features: Before 1 yr, severe hypoglycemia, lactic acidosis, and hepatomegaly; later, hepatic adenomas, renomegaly with progressive renal insufficiency and hypertension, short stature, hypertriglyceridemia, hyperuricemia, platelet dysfunction with epistaxis, and anemia

In type Ib, less severe but including neutropenia, neutrophil dysfunction with recurrent infections, and inflammatory bowel disease

Treatment: Uncooked cornstarch 1.5–2.5 g/kg po q 4–6 h or lactose-free formula with maltodextrin to maintain normoglycemia; nocturnal feedings (important); fructose and galactose restriction; for lactic acidosis, bicarbonate 0.25 to 0.5 mmol/kg qid; allopurinol to keep uric acid to < 6.4 mg/dL; liver and kidney transplantation (may be successful)

For type Ib patients with neutropenia, G-CSF

Type Ia (232200)

Glucose-6-phosphatase

G6PC (17q21)*

Type Ib (232220)

Glucose-6-phosphate translocase

G6PT1 (11q23)*

Type Ic (232240)

Microsomal phosphate or pyrophosphate transporter

G6PT1 (11q23)*

Type Id

Microsomal glucose transporter

Probably same as Ic

GSD II (Pompe’s disease, 232300)

Onset: Infancy, childhood, or adulthood; residual enzyme activity in child and adult forms

Clinical features: In infantile form, cardiomyopathy with heart failure, severe hypotonia, macroglossia

In juvenile and adult forms, skeletal myopathy with delayed motor development, progressive peripheral and respiratory muscle weakness

In type IIb, intellectual disability

Treatment: None known

For cardiomyopathy, heart transplantation

Type IIa

Lysosomal acid α-glucosidase

GAA (17q25)*

Type IIb (Danon)

Lysosomal membrane protein-2

LAMP2 (Xq24)*

GSD III (Forbes’ disease, Cori’s disease, limit dextrinosis; 232400)

Frequency: IIIa, 85%; IIIb, 15%; IIIc and IIId, rare

Onset: Infancy or childhood

Clinical features: In type IIIa, liver and muscle involvement with features of type Ia and II

In type IIIb, only liver involvement plus features of type Ia

In types IIIc and IIId, various features depending on tissue affected

Treatment: Uncooked cornstarch and continuous feeding to maintain normoglycemia, high-protein diet to stimulate gluconeogenesis

Types IIIa and IIIb

Debrancher enzyme (amyloglucosidase and oligoglucanotransferase)

AGL (1p21)*

Type IIIc

Amyloglucosidase only

Type IIId

Oligoglucanotransferase only

GSD IV (Andersen’s disease; 232500)

Branching enzyme

GBE1 (3p12)*

Onset: Early infancy; rarely, the neonatal period, late childhood, or adulthood (manifesting as a variant nonprogressive or a neuromuscular form)

Clinical features: Hepatomegaly with progressive cirrhosis and hypoglycemia, esophageal varices, and ascites; splenomegaly; failure to thrive

In neuromuscular forms, hypotonia and muscle atrophy

Treatment: None known

For cirrhosis, liver transplantation

GSD V (McArdle disease; 232600)

Muscle phosphorylase

PYGM (11q13)*

Onset: Adolescence or early adulthood

Clinical features: Exercise intolerance due to muscle cramps, rhabdomyolysis

Treatment: Carbohydrate administration before exercise, high-protein diet

GSD VI (Hers’ disease; 232700)

Liver phosphorylase

PYGL (14q21-q22)*

Frequency: Rare

Onset: Early childhood

Clinical features: Benign course with symptoms lessening with aging; growth retardation, hepatomegaly, hypoglycemia, hyperlipidemia, ketosis

Treatment: None necessary

GSD VII (Tarui’s disease; 232800)

Phosphofructokinase

PFKM (12q13.3)*

Onset: Middle childhood

Clinical features: Exercise intolerance due to muscle cramps, rhabdomyolysis, hemolysis

Treatment: Nonspecific, avoidance of exercise

GSD VIII/IX (306000, 172490, 604549, 311870)

Onset: Heterogeneous

Clinical features: Heterogeneous; hepatomegaly, growth retardation, muscle hypotonia, hypercholesterolemia

Treatment: Nonspecific

Type VIII/IXa:

X-linked phosphorylase kinase

PHKA2 (Xp22)*

Type IXb

Liver and muscle phosphorylase kinase

PHKB (16q12-q13)*

Type IXc

Liver phosphorylase kinase

PHKG2 (16p12.1-p11.2)*

Type IXd

Muscle phosphorylase kinase

PHKA1 (Xq13)*

GSD O (240600)

Glycogen synthase

GYS2 (12p12)*

Onset: Variable but often after cessation of nighttime feedings or intercurrent illness

Clinical features: Fasting hypoglycemia and ketosis, postprandial lactic acidosis

Treatment: Frequent protein-rich meals, uncooked cornstarch at bedtime

Fanconi-Bickel syndrome (227810)

Glucose transporter-2

GLUT2 (3q26)*

Onset: Infancy

Clinical features: Failure to thrive, abdominal distention, hepatomegaly, renomegaly, mild fasting hypoglycemia and hyperlipidemia, glucose intolerance, renal Fanconi syndrome

Treatment: Diet similar to that for diabetes, replacement of renally lost electrolytes, vitamin D

Fructose 1,6-diphosphatase deficiency (229700)

Fructose 1,6-diphosphatase

FBP1 (9q22)*

Onset: Infancy or early childhood

Clinical features: Episodic hyperventilation, apnea, hypoglycemia, ketosis, or lactic acidosis; episodes provoked by fasting, febrile infection, or ingestion of fructose, sorbitol, or glycerol

Treatment: Avoidance of fasting and fructose, sorbitol, and glycerol; uncooked cornstarch

Phosphoenolpyruvate carboxykinase deficiency (261680)

Phosphoenolpyruvate carboxykinase

PCK1 (20q13.31)*

Onset: Childhood

Clinical features: Failure to thrive, hypotonia, hepatomegaly, lactic acidosis, hypoglycemia

Treatment: Avoidance of fasting, uncooked cornstarch

*Gene has been identified, and molecular basis has been elucidated.

G-CSF = granulocyte colony-stimulating factor; GSD = glycogen storage disease; OMIM = online mendelian inheritance in man (see database at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM ).

Age of onset, clinical manifestations, and severity vary by type, but symptoms and signs are most commonly those of hypoglycemia and myopathy. Diagnosis is suspected by history, examination, and detection of glycogen and intermediate metabolites in tissues by MRI or biopsy.

Diagnosis is confirmed by significant decrease of enzyme activity in liver (types I, III, VI, and VIII/IX), muscle (types IIb, III, VII, and VIII/IX), skin fibroblasts (types IIa and IV), or RBCs (type VII) or by lack of an increase in venous lactate with forearm activity/ischemia (types V and VII). Prognosis and treatment vary by type, but treatment typically includes dietary supplementation with cornstarch to provide a sustained source of glucose for the hepatic forms of GSD and exercise avoidance for the muscle forms.

Defects in glycolysis (rare) may cause syndromes similar to GSDs. Deficiencies of phosphoglycerate kinase, phosphoglycerate mutase, and lactate dehydrogenase mimic the myopathies of GSD types V and VII; deficiencies of glucose transport protein 2 (Fanconi-Bickel syndrome) mimic the hepatopathy of other GSD types (eg, I, III, IV, VI).

Galactosemia

Galactosemia is caused by inherited deficiencies in enzymes that convert galactose to glucose. Symptoms and signs include hepatic and renal dysfunction, cognitive deficits, cataracts, and premature ovarian failure. Diagnosis is by enzyme analysis of RBCs. Treatment is dietary elimination of galactose. Physical prognosis is good with treatment, but cognitive and performance parameters are often subnormal.

Galactose is found in dairy products, fruits, and vegetables. Autosomal recessive enzyme deficiencies cause 3 clinical syndromes.

Galactose-1-phosphate uridyl transferase deficiency

This deficiency causes classic galactosemia. Incidence is 1/62,000 births; carrier frequency is 1/125. Infants become anorectic and jaundiced within a few days or weeks of consuming breast milk or lactose-containing formula. Vomiting, hepatomegaly, poor growth, lethargy, diarrhea, and septicemia (usually Escherichia coli) develop, as does renal dysfunction (eg, proteinuria, aminoaciduria, Fanconi syndrome), leading to metabolic acidosis and edema. Hemolytic anemia may also occur. Without treatment, children remain short and develop cognitive, speech, gait, and balance deficits in their teenage years; many also have cataracts, osteomalacia (caused by hypercalciuria), and premature ovarian failure. Patients with the Duarte variant have a much milder phenotype.


Galactokinase deficiency

Patients develop cataracts from production of galactitol, which osmotically damages lens fibers; idiopathic intracranial hypertension (pseudotumor cerebri) is rare. Incidence is 1/40,000 births.


Uridine diphosphate galactose 4-epimerase deficiency

There are benign and severe phenotypes. Incidence of the benign form is 1/23,000 births in Japan; no incidence data are available for the more severe form. The benign form is restricted to RBCs and WBCs and causes no clinical abnormalities. The severe form causes a syndrome indistinguishable from classic galactosemia, although sometimes with hearing loss.


Diagnosis

  • Galactose levels

  • Enzyme analysis

Diagnosis is suggested clinically and supported by elevated galactose levels and the presence of reducing substances other than glucose (eg, galactose, galactose 1-phosphate) in the urine; it is confirmed by enzyme analysis of RBCs, hepatic tissue, or both. Most states require that neonates be screened for galactose-1-phosphate uridyl transferase deficiency.


Treatment

  • Dietary galactose restriction

Treatment is elimination of all sources of galactose in the diet, most notably lactose, which is a source of galactose present in all dairy products, including milk-based infant formulas and a sweetener used in many foods. A lactose-free diet prevents acute toxicity and reverses some manifestations (eg, cataracts) but may not prevent neurocognitive deficits. Many patients require supplemental Ca and vitamins. For patients with epimerase deficiency, some galactose intake is critical to ensure a supply of uridine-5-diphosphate-galactose (UDP-galactose) for various metabolic processes.


Disorders of Fructose Metabolism

Deficiency of enzymes that metabolize fructose may be asymptomatic or cause hypoglycemia.

Fructose is a monosaccharide that is present in high concentrations in fruit and honey and is a constituent of sucrose and sorbitol.

Fructose 1-phosphate aldolase (aldolase B) deficiency

This deficiency causes the clinical syndrome of hereditary fructose intolerance. Inheritance is autosomal recessive; incidence is estimated at 1/20,000 births. Infants are healthy until they ingest fructose; fructose 1-phosphate then accumulates, causing hypoglycemia, nausea and vomiting, abdominal pain, sweating, tremors, confusion, lethargy, seizures, and coma. Prolonged ingestion may cause cirrhosis, mental deterioration, and proximal renal tubular acidosis with urinary loss of phosphate and glucose.

Diagnosis is suggested by symptoms in relation to recent fructose intake and is confirmed by enzyme analysis of liver biopsy tissue or by induction of hypoglycemia by fructose infusion 200 mg/kg IV. Diagnosis and identification of heterozygous carriers of the mutated gene can also be made by direct DNA analysis.

Short-term treatment is glucose for hypoglycemia; long-term treatment is exclusion of dietary fructose, sucrose, and sorbitol. Many patients develop a natural aversion to fructose-containing food. Prognosis is excellent with treatment.


Fructokinase deficiency

This deficiency causes benign elevation of blood and urine fructose levels (benign fructosuria). Inheritance is autosomal recessive; incidence is about 1/130,000 births.

The condition is asymptomatic and diagnosed accidentally when a non-glucose reducing substance is detected in urine.


Deficiency of fructose-1,6-bisphosphatase

This deficiency compromises gluconeogenesis and results in fasting hypoglycemia, ketosis, and acidosis. This deficiency can be fatal in neonates. Inheritance is autosomal recessive; incidence is unknown. Febrile illness can trigger episodes.

Acute treatment is oral or IV glucose. Tolerance to fasting generally increases with age.


Disorders of Pyruvate Metabolism

Inability to metabolize pyruvate causes lactic acidosis and a variety of CNS abnormalities.

Pyruvate is an important substrate in carbohydrate metabolism.

Pyruvate dehydrogenase deficiency

Pyruvate dehydrogenase is a multi-enzyme complex responsible for the generation of acetyl CoA from pyruvate for the Krebs cycle. Deficiency results in elevation of pyruvate and thus elevation of lactic acid levels. Inheritance is X-linked or autosomal recessive.

Clinical manifestations vary in severity but include lactic acidosis and CNS malformations and other postnatal changes, including cystic lesions of the cerebral cortex, brain stem, and basal ganglia; ataxia; and psychomotor retardation.

Diagnosis is confirmed by enzyme analysis of skin fibroblasts, DNA testing, or both.

There is no clearly effective treatment, although a low-carbohydrate or ketogenic diet and dietary thiamin supplementation have been beneficial for some patients.


Pyruvate carboxylase deficiency

Pyruvate carboxylase is an enzyme important for gluconeogenesis from pyruvate and alanine generated in muscle. Deficiency may be primary, or secondary to deficiency of holocarboxylase synthetase, biotin, or biotinidase; inheritance for both is autosomal recessive, and both result in lactic acidosis.

Primary deficiency incidence is < 1/250,000 births but may be higher in certain American Indian populations. Psychomotor retardation with seizures and spasticity are the major clinical manifestations. Laboratory abnormalities include hyperammonemia; lactic acidosis; ketoacidosis; elevated levels of plasma lysine, citrulline, alanine, and proline; and increased excretion of α-ketoglutarate. Diagnosis is confirmed by enzyme analysis of cultured skin fibroblasts.

Secondary deficiency is clinically similar, with failure to thrive, seizures, and other organic aciduria.

There is no effective treatment, but some patients with primary deficiency and all those with secondary deficiencies should be given biotin supplementation 5 to 20 mg po once/day.


Other Disorders of Carbohydrate Metabolism

Phosphoenolpyruvate carboxykinase deficiency impairs gluconeogenesis and results in symptoms and signs similar to the hepatic forms of glycogen storage disease but without hepatic glycogen accumulation.

Other deficiencies include those of glycolytic enzymes or enzymes in the pentose phosphate pathway. Common examples are pyruvate kinase deficiency (see Embden-Meyerhof Pathway Defects) and glucose-6-phosphate dehydrogenase (G6PD) deficiency (see Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency), both of which may result in hemolytic anemia. Wernicke-Korsakoff syndrome (see Symptoms and Signs) is caused by a partial deficiency of transketolase, which is an enzyme for the pentose phosphate pathway that requires thiamin as a cofactor.

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