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Inborn errors of carbohydrate metabolism
Metabolism of common monosaccharides and related reactions (Carbohydrate Metabolism)
Specialty	Medical genetics

Inborn errors of carbohydrate metabolism areinborn errors of metabolism that affect the catabolism and anabolism ofcarbohydrates.

An example islactose intolerance.

Carbohydrates account for a major portion of the human diet. These carbohydrates are composed of three principal monosaccharides:glucose,fructose andgalactose; 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 carbohydratesmetabolism.

Glycogen storage diseases are deficiencies ofenzymes ortransport proteins which impairglycogen synthesis,glycogen degradation orglycolysis. The two organs most commonly affected are the liver and the skeletal muscle. Glycogen storage diseases that affect the liver typically causehepatomegaly andhypoglycemia; those that affect skeletal muscle cause exercise intolerance, progressive weakness and cramping.^[1]

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.^{[citation needed]}

Glucose-6-phosphate dehydrogenase deficiency affects the degradation of glucose in the pentose phosphate pathway, which is especially important in red blood cells.^{[citation needed]}

For further information oninborn errors of glucose metabolism andinborn errors of glycogen metabolism see below.^{[citation needed]}

Lactose is adisaccharide sugar composed ofgalactose 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 calledlactase; unabsorbed lactose can cause abdominal pain, bloating, diarrhea, gas, and nausea.^{[citation needed]}

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.^{[citation needed]}

Galactosemia, the inability to metabolizegalactose in liver cells, is the most common monogenic disorder of carbohydrate metabolism, affecting 1 in every 55,000 newborns.^[2] When galactose in the body is not broken down, it accumulates in tissues. The most common signs arefailure to thrive, hepatic insufficiency, cataracts and developmental delay. Long term disabilities include poor growth,mental retardation, and ovarian failure in females.^[3]

Galactosemia is caused bymutations in thegene that makes theenzymegalactose-1-phosphate uridylyltransferase. Approximately 70% of galactosemia-causing alleles have a singlemissense mutation in exon 6. A milder form of galactosemia, calledGalactokinase deficiency, is caused a lack of the enzymeuridine 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.^{[citation needed]}

Screening is performed by measuring GAL-1-P urydil transferase activity. Early identification affords prompt treatment, which consists largely of eliminating dietary galactose.^{[citation needed]}

Fructose malabsorption is a digestive disorder in which absorption offructose is impaired by deficient fructose carriers in the small intestine's enterocytes.^{[citation needed]}

Three autosomal recessive disorders impairfructose metabolism in liver cells. The most common is caused by mutations in the gene encodinghepatic fructokinase, an enzyme that catalyzes the first step in the metabolism of dietary fructose. Inactivation of the hepatic fructokinase results in asymptomaticfructosuria.^{[citation needed]}

Hereditary fructose intolerance (HFI) results in poor feeding, failure to thrive, chronic liver disease andchronic 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.^{[citation needed]}

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.^{[citation needed]}

Essential fructosuria is a clinically benign condition characterized by the incomplete metabolism of fructose in the liver, leading to its excretion in urine.^{[citation needed]}

Themetabolic pathwayglycolysis is used by cells to break down carbohydrates like glucose (and various othersimple sugars) in order to extract energy from them. During glycolysisATP,NADH (both an energy transport form usedinside cells) as well aspyruvate are produced.^{[citation needed]}

Glycolysis is taking place in thecytosol where, under anaerobic conditions,pyruvate is converted to lactate. Under aerobic conditions, the pyruvate is transported from the cytosol to themitochondrion, where further energy can be extracted through thecitric acid cycle (CAC)^{[citation needed]}

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.^[4] 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.)

Thepyruvate created by glycolysis (in thecytosol) is transported (together with a proton) to themitochondrion for further energy extraction.

Underanaerobic conditions (without the use of oxygen) most if not all of thepyruvate is converted intolactate (furthermore producingNAD⁺ at the same time).

Underaerobic conditions (with the use of oxygen) only part of the pyruvate is converted to lactate; the pyruvate not converted feeds thecitric acid cycle (CAC); both viapyruvate dehydrogenase (PDC, withAcetyl-CoA as intermediate) and viapyruvate decarboxylation - this will create further ATP and NADH for the cell's use.

Thepentose phosphate pathway (HMP Shunt) is connected to the glycolysis pathway, and can convertsubstrates to and from the glycolysis pathway. It generatesNADPH andpentoses (5-carbonsugars) as well asribose 5-phosphate, a precursor for the synthesis ofnucleotides. While the pentose phosphate pathway does involve oxidation ofglucose, its primary role isanabolic rather thancatabolic. The pathway is especially important inred blood cells (erythrocytes).

Transport proteins move substrates through cellular membranes. Aglucose transporter (GLUT) protein is needed to assist glucose into (and in the liver and kidneys, also out of) the cell.De Vivo disease (GLUT1 deficiency) is a deficiency of GLUT1, which is needed to transport glucose across the blood-brain barrier.Fanconi-Bickel syndrome (GLUT2 deficiency, formally known asGSD-XI) 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 (gene SLC54A1/BRP44L/MPC1^[6]); the deficiency is characterized by delayed psychomotor development and lactic acidosis with a normal lactate/pyruvate ratio resulting from impaired mitochondrial pyruvate oxidation.^[7] A similar disease is also seen in mutations of gene SLC54A2/BRP44/MPC2.^[8]

The gene SLC16A1/MCT1 is responsible for transporting lactate across membranes. Mutations in the monocarboxylate transporter 1 (MCT1) gene have been associated with three diseases:hyperinsulinemic hypoglycemia, familial 7 (HHF7);monocarboxylate transporter 1 deficiency (MCTD1); anderythrocyte lactate transporter defect (formerly, myopathy due to lactate transport defect).^[9]

(See alsobioenergetic systems.)

Glycogenesis is themetabolic pathway in whichglycogen is created. Glycogen, which consists of branchedlong chains made out of thesimple sugarglucose, is an energy storage form forcarbohydrates in many human cells; this is most important inliver,muscle andcertain brain cells.

The monosaccharideglucose-6-phosphate (G-6-P) is typically theinput substance for glycogenesis. G-6-P is most commonly created from glucose by the action of theenzymesglucokinase (see glycolysis step 1) orhexokinase.

Through the action of several enzymes glycogen is built up:

• G-6-P is converted intoglucose-1-phosphate (G-1-P) by the action ofphosphoglucomutase (PGM), passing through the obligatory intermediateglucose-1,6-bisphosphate.
• G-1-P is converted intoUDP-glucose by the action of the enzymeUDP-glucose pyrophosphorylase (UGP).
• The enzymeglycogenin (GYG) 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, thenglycogen synthase (GYS) can bind to the growing glycogen chain and add UDP-glucose to lengthen the glucogen chain.
• Branches are made byglycogen branching enzyme (GBE), 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 sugargalactose (Gal, which is typically derived fromlactose) is converted by the enzymegalactokinase (GALK) togalactose-1-phosphate (Gal-1-P), which in turn is converted by the enzymegalactose-1-phosphate uridylyltransferase (GALT) toglucose-1-phosphate (G-1-P), which can also serve as input for glycogenesis – this bypasses the first step of glycogenesis (the enzymephosphoglucomutase PGM).

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 (e.g. polyglucosan bodies).

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

To access the energy stored asglycogen, cells use themetabolic pathwayglycogenolysis (glycogen breakdown); this produces thesimple sugarglucose-6-phosphate (G-6-P), from which cells canextract energy or build other substances (e.g.riboses).

G-6-P (which is also produced from glucose) acts as aninput substance for:

• Glycolysis (see above)
• ThePentose phosphate pathway (PPP)

(See alsobioenergetic systems.)

An alternative to glycolysis is thePentose phosphate pathway (PPP): Depending on cellular conditions the PPP can produceNADPH (another energy transport formin the cell) or synthesizeriboses (important for substances based on ribose like e.g.RNA) - the PPP is for example important inred blood cells.

If glycogenolysis is taking place in the liver, G-6-P can beconverted to glucose by the enzymeglucose 6-phosphatase (G6Pase); 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 enzymeacid alpha-glucosidase inlysosomes 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 (muscle glycogen phosphorylase) comes in two forms: form 'a' is phosphorylated byphosphorylase kinase, form 'b' is not phosphorylated. Form 'a' is de-phosphorylated into form 'b' by the enzymephosphoprotein phosphatase, which is activated by elevated insulin.

Both forms 'a' and 'b' of myophosphorylase have twoconformational states: active (R or relaxed) and inactive (T or tense). When either form 'a' or 'b' are in the active state, then the enzyme converts glycogen into glucose-1-phosphate.

Myophosphorylase-b isallosterically 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. (SeeGlycogen phosphorylase§Regulation).

Mutations in the PRKAG2 gene have been traced to fatal congenital nonlysosomal cardiac glycogenosis; PRKAG2 is a noncatalytic gamma subunit ofAMP-activated protein kinase (AMPK), which affects the release of G-1-P by phosphorylase kinase during nonlysosomal glycogenolysis.^[24]

• Glycogen Storage Disease
• Metabolic Myopathies
• Exercise intolerance § low ATP reservoir
• Myogenic hyperuricemia
• Purine nucleotide cycle § pathology (low ATP reservoir, ADP>ATP, ↑AMP)
• Tachycardia § sinus (inappropriate rapid heart rate response to exercise)
• IST § differential diagnoses
• Second Wind (exercise phenomenon)

• Media related toDisorders of carbohydrate metabolism at Wikimedia Commons

• Inborn errors of carbohydrate metabolism
• Types of diabetes

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