Inborn errors of carbohydrate metabolism

Inborn errors of metabolism can affect the catabolism and anabolism of carbohydrates, such as in lactose intolerance. Carbohydrates account for a major portion of the human diet. These carbohydrates are composed of three principal monosaccharides: glucose, fructose and galactose; in addition, glycogen is the storage form of carbohydrates in humans. The failure to effectively use these molecules accounts for the majority of the inborn errors of human carbohydrates metabolism.

By 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.
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; unabsorbed lactose can cause abdominal pain, bloating, diarrhea, gas, and nausea.
In most mammals, production of lactase diminishes after infants are weaned from maternal milk. However, 5% to 90% of the human population possess an advantageous autosomal mutation in which lactase production persists after infancy. The geographic distribution of lactase persistence is concordant with areas of high milk intake. Lactase non-persistence is common in tropical and subtropical countries. Individuals with lactase non-persistency may experience nausea, bloating and diarrhea after ingesting dairy.

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, mental retardation, 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.

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 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 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.

By affected system

Glucose metabolism

Glycolysis

The metabolic pathway glycolysis is used by cells to break down carbohydrates like glucose in order to extract energy from them. During glycolysis ATP, NADH 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 ; 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.

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		Hypoglycemia due to hyperinsulinemia.
Step 1	Glucokinase	GCK		Pancreatic beta cells	Maturity onset diabetes of the young type II		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	NLM/GHR:	Hemolytic anemia.
Step 3	Phosphofructokinase 1	PFKM		Muscle, also RBCs	Phosphofructokinase deficiency	NLM/GHR:	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. Severe symptoms from classic type are absent. Infantile form: Rare. Often floppy infant syndrome, 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. Increased rise of ammonia.	No specific treatment. General advice is avoidance of vigorous exercise and of high-carbohydrate meals.
Step 3	Phosphofructokinase 1	PFKL		Liver, also RBCs	Phosphofructokinase deficiency	NLM/GHR:	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. Severe symptoms from classic type are absent. Infantile form: Rare. Often floppy infant syndrome, 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. Increased rise of ammonia.	No specific treatment. General advice is avoidance of vigorous exercise and of high-carbohydrate meals.
Step 4	Aldolase A	ALDOA		Muscle, also liver and RBCs	Aldolase A 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.
Step 4	Aldolase B	ALDOB		Liver	Hereditary fructose intolerance		Hypoglycemia. Hepatic and renal dysfunction.
Step 4	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	NLM/GHR:	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.
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	NLM/GHR:	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	NLM/GHR:	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 9	Enolase 1	ENO1		Red blood cells	Enolase deficiency		Hemolytic anemia.
Step 9	Enolase 1	ENO1		Red blood cells	Unclear role in: Severe asthma Behçet's disease Hashimoto's encephalopathy Juvenile idiopathic arthritis		Autoimmunity, unclear role.	See respective conditions.	See respective conditions
Step 9	Enolase 3	ENO3		Muscle	GSD type XIII		Myopathy. Exercise-induced myalgias, generalized muscle weakness and fatigability.	Exercise test: No rise of lactate. Biopsy: Focal sarcoplasmic accumulation of glycogen-beta particles. Immunohistochemistry and immunoblotting show reduced beta-enolase protein.	No treatment information in references given.
Step 10	Pyruvate kinase	PKLR		Red blood cells, liver	Pyruvate kinase deficiency	NLM/GHR:	Hemolytic anemia.

Related to glycolysis

The pyruvate created by glycolysis is transported to the mitochondrion for further energy extraction.
Under anaerobic conditions most if not all of the pyruvate is converted into lactate.
Under aerobic conditions only part of the pyruvate is converted to lactate; the pyruvate not converted feeds the citric acid cycle (CAC); both via pyruvate dehydrogenase and via pyruvate decarboxylation - this will create further ATP and NADH for the cell's use.
The pentose phosphate pathway (HMP Shunt) is connected to the glycolysis pathway, and can convert substrates to and from the glycolysis pathway. It generates NADPH and pentoses as well as ribose 5-phosphate, a precursor for the synthesis of nucleotides. While the pentose phosphate pathway does involve oxidation of glucose, its primary role is anabolic rather than catabolic. The pathway is especially important in red blood cells.
Transport proteins move substrates through cellular membranes. A glucose transporter (GLUT) protein is needed to assist glucose into the cell. De Vivo disease is a deficiency of GLUT1, which is needed to transport glucose across the blood-brain barrier. Fanconi-Bickel syndrome is a deficiency of GLUT2, which is needed for the transport of glucose between liver and blood.
Mitochondrial pyruvate carrier deficiency (MPYCD) is a metabolic disorder, in which the transport of pyruvate from the cytosol to the mitochondria is affected ; the deficiency is characterized by delayed psychomotor development and lactic acidosis with a normal lactate/pyruvate ratio resulting from impaired mitochondrial pyruvate oxidation. A similar disease is also seen in mutations of gene SLC54A2/BRP44/MPC2.
The gene SLC16A1/MCT1 is responsible for transporting lactate across membranes. Mutations in the monocarboxylate transporter 1 gene have been associated with three diseases: hyperinsulinemic hypoglycemia, familial 7 ; monocarboxylate transporter 1 deficiency (MCTD1); and erythrocyte lactate transporter defect.

Glycogen metabolism

Glycogenesis

Glycogenesis is the metabolic pathway in which glycogen is created. Glycogen, which consists of branched long chains made out of the simple sugar glucose, is an energy storage form for carbohydrates in many human cells; this is most important in liver, muscle and certain brain cells.
The monosaccharide glucose-6-phosphate is typically the input substance for glycogenesis. G-6-P is most commonly created from glucose by the action of the enzymes glucokinase or hexokinase.
Through the action of several enzymes glycogen is built up:

G-6-P is converted into glucose-1-phosphate by the action of phosphoglucomutase, passing through the obligatory intermediate glucose-1,6-bisphosphate.
G-1-P is converted into UDP-glucose by the action of the enzyme UDP-glucose pyrophosphorylase.
The enzyme glycogenin is needed to create initial short glycogen chains, which are lengthened and branched by the other enzymes of glycogenesis.
Once eight glucose have been added to the glycogen chain, then glycogen synthase can bind to the growing glycogen chain and add UDP-glucose to lengthen the glucogen chain.
Branches are made by glycogen branching enzyme, which transfers the end of the chain onto an earlier part, forming branches; these grow further grow by addition of more units.

On an alternative metabolic pathway the simple sugar galactose is converted by the enzyme galactokinase to galactose-1-phosphate, which in turn is converted by the enzyme galactose-1-phosphate uridylyltransferase to glucose-1-phosphate, which can also serve as input for glycogenesis – this bypasses the first step of glycogenesis.
Errors in glycogenesis can have different consequences on a cellular level:

Too little glycogen is produced, e.g. in GSD 0.
The glycogen is badly formed and inaccessible, typically accumulating in the affected cells.

Depending on the affected cells and the extent of the deficiency, a wide range of symptoms and severities are the result.

Glycogenolysis

To access the energy stored as glycogen, cells use the metabolic pathway glycogenolysis ; this produces the simple sugar glucose-6-phosphate, from which cells can extract energy or build other substances.
G-6-P acts as an input substance for:

An alternative to glycolysis is the Pentose phosphate pathway : Depending on cellular conditions the PPP can produce NADPH or synthesize riboses - the PPP is for example important in red blood cells.
If glycogenolysis is taking place in the liver, G-6-P can be converted to glucose by the enzyme glucose 6-phosphatase ; the glucose produced in the liver is then released to the bloodstream for use in other organs. Muscle cells in contrast do not have the enzyme glucose 6-phosphatase, so they cannot share their glycogen stores with the rest of the body.
In addition to glycogen breakdown with the glycogen debranching enzyme and the glycogen phosphorylase enzyme, cells also use the enzyme acid alpha-glucosidase in lysosomes to degrade glycogen.
A deficiency of an involved enzyme results in:

Accumulation of glycogen in the cells
Lack of cellular energy negatively affects the involved organs

Myophosphorylase comes in two forms: form 'a' is phosphorylated by phosphorylase kinase, form 'b' is not phosphorylated. Form 'a' is de-phosphorylated into form 'b' by the enzyme phosphoprotein phosphatase, which is activated by elevated insulin.
Both forms 'a' and 'b' of myophosphorylase have two conformational states: active and inactive. When either form 'a' or 'b' are in the active state, then the enzyme converts glycogen into glucose-1-phosphate.
Myophosphorylase-b is allosterically activated by elevated AMP within the cell, and allosterically inactivated by elevated ATP and/or glucose-6-phosphate. Myophosphorylase-a is active, unless allosterically inactivated by elevated glucose within the cell. In this way, myophosphorylase-a is the more active of the two forms as it will continue to convert glycogen into glucose-1-phosphate even with high levels of glycogen-6-phosphate and ATP..

Related to glycogenolysis

Mutations in the PRKAG2 gene have been traced to fatal congenital nonlysosomal cardiac glycogenosis; PRKAG2 is a noncatalytic gamma subunit of AMP-activated protein kinase, which affects the release of G-1-P by phosphorylase kinase during nonlysosomal glycogenolysis.