Inborn errors of carbohydrate metabolism can affect the catabolism and anabolism of carbohydrates, causing both minor problems such as lactose intolerance as well as life-threatening diseases such as Von Gierke's Disease.

The carbohydrates that account for a major portion of the human diet are composed of three principal monosaccharides – glucose, fructose, and galactose – with glycogen the storage form of carbohydrates in humans and starch the storage form in plants. The failure to effectively use these carbohydrate molecules accounts for the majority of the inborn errors of human carbohydrate metabolism.

Carbohydrate

Glycogen and glucose

Glycogen storage diseases are deficiencies of enzymes or transport proteins which impair glycogen synthesis, glycogen degradation or glycolysis. The two organs most commonly affected are the liver and the skeletal muscle. Glycogen storage diseases that affect the liver typically cause hepatomegaly and hypoglycemia; those that affect skeletal muscle cause exercise intolerance, progressive weakness and cramping.Jorde, et al. 2006. Carbohydrate metabolism. Medical Genetics. 3rd edition. Chapter 7. Biochemical genetics:Disorders of metabolism. pp139-142.

Glucose-6-phosphate isomerase deficiency affects step 2 of glycolysis. Triosephosphate isomerase deficiency affects step 5 of glycolysis. Phosphoglycerate kinase deficiency affects step 7 of glycolysis. Pyruvate kinase deficiency affects the 10th and last step of glycolysis.

Glucose-6-phosphate dehydrogenase deficiency affects the degradation of glucose in the pentose phosphate pathway, which is especially important in red blood cells.

For further information on inborn errors of glucose metabolism and inborn errors of glycogen metabolism see below.

Lactose

Lactose is a disaccharide sugar composed of galactose and glucose that is found in milk. Lactose can not be absorbed by the intestine and needs to be split in the small intestine into galactose and glucose by the enzyme called lactase; undigested lactose reaches the colon where it is fermented by bacteria. The fermentation process produces H2, CO2, lactic acid, and acetic acid. This process causes digestive disruptions, abdominal pain, bloating, diarrhea, gas, and nausea. Symptoms can be reduced by supplementation of the lactase enzyme.

In most mammals, production of lactase diminishes after infants are weaned from maternal milk. However, around 35% of the human population possess an advantageous autosomal mutation in which lactase production persists throughout adulthood. The geographic distribution of lactase persistence is up to 15% of North Europeans, 80% of Blacks and Latinos and 100% of American Indians and Asians.

Galactose Galactosemia, the inability to metabolize galactose in liver cells, is the most common monogenic disorder of carbohydrate metabolism, affecting 1 in every 55,000 newborns. When galactose in the body is not broken down, it accumulates in tissues. The most common signs are failure to thrive, hepatic insufficiency, cataracts and developmental delay. Long term disabilities include poor growth, mental retardation, and ovarian failure in females.

Galactosemia is caused by mutations in the gene that makes the enzyme galactose-1-phosphate uridylyltransferase. Approximately 70% of galactosemia-causing alleles have a single missense mutation in exon 6. A milder form of galactosemia, called Galactokinase deficiency, is caused a lack of the enzyme uridine diphosphate galactose-4-epimerase which breaks down a byproduct of galactose. This type of is associated with cataracts, but does not cause growth failure, intellectual disability, or hepatic disease. Dietary reduction of galactose is also the treatment but not as severe as in patients with classical galactosemia. This deficiency can be systemic or limited to red blood cells and leukocytes.

Screening is performed by measuring GAL-1-P urydil transferase activity. Early identification affords prompt treatment, which consists largely of eliminating dietary galactose.

Sucrose

Sucrose (table sugar) is a disaccharide consisting of a glucose molecule bound to a fructose molecule. Like lactose, it must be broken into its constituent parts before it can be absorbed.

Rare mutations affecting the sucrase-isomaltase enzyme or damage to the small intestine cause sucrase-isomaltase deficiency. This condition causes lactose intolerance-like reactions to sucrose and starch.

Fructose Fructose malabsorption is a digestive disorder in which absorption of fructose is impaired by deficient fructose carriers in the small intestine's enterocytes.

Three autosomal recessive disorders impair fructose metabolism in liver cells. The most common is caused by mutations in the gene encoding hepatic fructokinase, an enzyme that catalyzes the first step in the metabolism of dietary fructose. Inactivation of the hepatic fructokinase results in asymptomatic fructosuria.

Hereditary fructose intolerance (HFI) results in poor feeding, failure to thrive, chronic liver disease and chronic kidney disease, and death. HFI is caused by a deficiency of fructose 1,6-biphosphate aldolase in the liver, kidney cortex and small intestine. Infants and adults are asymptomatic unless they ingest fructose or sucrose.

Deficiency of hepatic fructose 1,6-biphosphate (FBPase) causes impaired gluconeogenesis, hypoglycemia and severe metabolic acidemia. If patients are adequately supported beyond childhood, growth and development appear to be normal.

Essential fructosuria is a clinically benign condition characterized by the incomplete metabolism of fructose in the liver, leading to its excretion in urine.

Affected system

Glucose metabolism

Glycolysis The metabolic pathway glycolysis is used by cells to break down carbohydrates like glucose (and various other simple sugars) in order to extract energy from them. During glycolysis ATP, NADH (both an energy transport form used inside cells) as well as pyruvate are produced.

Glycolysis is taking place in the cytosol where, under anaerobic conditions, pyruvate is converted to lactate. Under aerobic conditions, the pyruvate is transported from the cytosol to the mitochondrion, where further energy can be extracted through the citric acid cycle (CAC)

The liver can also create glucose (gluconeogenesis, see below); during times of low carbohydrate supply from the digestive system, the liver creates glucose and supplies it to other organs. Most enzymes of glycolysis also participate in gluconeogenesis, as it is mostly the reverse metabolic pathway of glycolysis; a deficiency of these liver enzymes will therefore impact both glycolysis and gluconeogenesis. (Note: gluconeogenesis is taking place only in the liver and not in other cells like e.g. muscle cells.)

Glycolytic step Enzyme Gene OMIM Organ Disease name Disease references Presentation Diagnostic tests Management and treatment Step 1 Glucokinase GCK Pancreatic beta cells Hyperinsulinemic hypoglycemia, familial, 3 (HHF3, hyperinsulinism due to glucokinase deficiency) Hypoglycemia due to hyperinsulinemia. Maturity onset diabetes of the young type II (MODY2, GCK-MODY) Diabetes. Hyperglycemia due to hypoinsulinemia while fasting but some glucose tolerance when consuming carbohydrates. Step 2 Glucose-6-phosphate isomerase GPI Red blood cells Glucose-6-phosphate isomerase deficiency (GPI deficiency, GPID, hemolytic anemia due to glucophosphate isomerase deficiency) NLM/GHR:GPID Hemolytic anemia. Step 3Phosphofructokinase 1 PFKM Muscle, also RBCsPhosphofructokinase deficiency(GSD type VII, GSD 7, Tarui's disease) NLM/GHR:GSD VII Classic form: Symptoms usually appear in early childhood. Myopathy. Exercise-induced muscle cramps, weakness and sometimes rhabdomyolysis. Nausea and vomiting following strenuous exercise. Myoglobinuria, haemolytic anaemia, Hyperuricemia is common. High levels of bilirubin and jaundiced appearance possible. Late-onset form: Presents later in life. Myopathy, weakness and fatigue. Exercise intolerance (more than in GSD 5). Severe symptoms from classic type are absent. Infantile form: Rare. Often floppy infant syndrome (hypotonia), arthrogryposis, encephalopathy, cardiomyopathy and respiratory issues. Also central nervous system manifest possible, usually seizures. Hemolytic form: The defining characteristic is hemolytic anemia. Myopathy not as common. Rhabdomyolysis/myoglobinuria may cause acute renal failure. Exercise test: Late about 3 times increase of lactate (higher than in GSD 5 and lower than in healthy). Increased rise of ammonia. No specific treatment. General advice is avoidance of vigorous exercise and of high-carbohydrate meals. PFKL Liver, also RBCs Step 4 Aldolase A ALDOA Muscle, also liver and RBCs Aldolase A deficiency(GSD type XII, GSD 12, red cell aldolase deficiency) Muscle symptoms: Myopathy. Exercise intolerance, cramps. In some rhabdomyolysis and myoglobinuria. Liver symptoms: Hepatomegaly RBC symptoms: Hemolytic anemia. Rhabdomyolysis/myoglobinuria may cause acute renal failure. Exercise test: ? No treatment information in references given. Aldolase B ALDOB Liver Hereditary fructose intolerance(Aldolase B deficiency, ALDOB deficiency) Hypoglycemia. Hepatic and renal dysfunction. Aldolase C ALDOC Brain Unclear role in: Alzheimer's Mild cognitive impairment Schizophrenia Neurodegeneration, unclear role. See respective conditions. See respective conditions Step 5 Triosephosphate isomerase TPI1 Red blood cells Triosephosphate isomerase deficiency (TPID) NLM/GHR:TPID Hemolytic anemia. Reticulocytosis and hyperbilirubinemia are common. Classical generalized form: Progressive neurologic dysfunction with dystonia, tremor, dyskinesia, pyramidal tract signs, cardiomyopathy and spinal motor neuron involvement with progressive neuromuscular impairment (severe weakness and muscle wasting). Step 6 Glyceraldehyde 3-phosphate dehydrogenase GAPDH Brain Unclear role in: Alzheimer's Huntington's Parkinson's Neurodegeneration, unclear role. See respective conditions See respective conditions Step 7 Phosphoglycerate kinase PGK1 Muscle, red blood cells Phosphoglycerate kinase deficiency (PGK1D, PGK deficiency, GSD due to phosphoglycerate kinase 1 deficiency) NLM/GHR:PGK1D Myopathic form: Progressive muscle weakness, pain, and cramping, particularly with exercise. Myoglobinuria possible. Myoglobinuria may cause acute renal failure. Hemolytic form: Hemolytic anemia.Neurologic form: In some central nervous system manifestation, including hemiplegic migraines, epilepsy, ataxia and tremor. Progressive neurologic impairment in some. Combinations of 1, 2 or all 3 forms have been reported. Exercise test: ? Regular blood transfusions for severe chronic anemia; splenectomy has been shown to be beneficial in some cases. Step 8 Phosphoglycerate mutase PGAM2 Muscle GSD type X (GSD 10, muscle phosphoglycerate mutase deficiency, myopathy due to PGAM deficiency, PGAMD) NLM/GHR:GSD X Myopathy, exercise intolerance. Exercise-induced cramps, myoglobinuria and myalgia. Rhabdomyolysis possible.Rhabdomyolysis/myoglobinuria may cause acute renal failure. Exercise test: ? No treatment information in references given. Step 9Enolase 1ENO1Red blood cells Enolase deficiency Hemolytic anemia. Unclear role in: Severe asthma Behçet's disease Hashimoto's encephalopathy