Carbohydrate Metabolism: Inherited Disorders CHO 2

• Inherited disorders affect carbohydrate metabolism

Objectives

• Discussing and understanding metabolic pathways of some carbohydrates
• Understanding inherent metabolic disorders of carbohydrate metabolism

Galactose Metabolism

• Galactose metabolizes through the Leloir pathway
• Galactose is converted into glucose-1-phosphate in a series of enzymatic reactions
• The enzymes involved are galactokinase (GALK1), galactose-1-phosphate uridylyltransferase (GALT), and UDP-galactose-4'-epimerase (GALE)
• Glucose-1-phosphate is then isomerized to glucose-6-phosphate, which can enter glycolysis or be used in glycogenesis

Classic Galactosemia

• Galactose 1-phosphate uridyltransferase (GALT) deficiency
• Accumulation of galactose 1-phosphate and galactitol in nerve, lens, liver, and kidney tissue causes liver damage, severe mental retardation, and cataracts
• Toxic levels of galactose-1-phosphate are reached, and galactose is alternatively reduced to galactitol
• Galactitol leads to direct tissue damage, resulting in hepatomegaly, tremors, and primary ovarian insufficiency
• Galactosemia and galactosuria, vomiting, diarrhea, and jaundice can occur
• There can be developmental delay and premature ovarian failure
• Treatment involves removing lactose (i.e., galactose) from diet

Non-classic Galactosemia

• A deficiency of galactokinase
• Elevation of galactose in blood (galactosemia) and urine (galactosuria)
• Galactitol accumulates if galactose is present in the diet
• Elevated galactitol can cause cataracts
• Treatment is dietary restriction
• Rare autosomal recessive disorder

Aldose Reductase Deficiency

• The enzyme is present in liver, kidney, retina, lens, nerve tissue, seminal vesicles, and ovaries
• It is physiologically unimportant in galactose metabolism unless galactose levels are high (in galactosemia)
• Elevated galactitol can cause cataracts

Fructose Metabolism

• Fructose is metabolized mainly in the liver
• Fructose is phosphorylated to fructose-1-phosphate by fructokinase
• Fructose-1-phosphate is cleaved to glyceraldehyde and dihydroxyacetone phosphate by aldolase B
• Glyceraldehyde is phosphorylated to glyceraldehyde-3-phosphate by triose kinase
• Glyceraldehyde-3-phosphate and dihydroxyacetone phosphate enter glycolysis

Hereditary Fructose Intolerance

• It is an autosomal recessive disorder
• Deficiency of aldolase B leads to intracellular trapping of fructose 1-phosphate
• Accumulation of fructose-1,6-bisphosphate inhibits both hepatic glycogenolysis and gluconeogenesis, hence inducing hypoglycemia and resulting in ATP depletion
• Severe hypoglycemia, vomiting, jaundice, hemorrhage, hepatomegaly, renal dysfunction, hyperuricemia, and lacticacidemia
• Fructose, sucrose, and sorbitol can cause hepatic failure and death

Glycogen Metabolism

• Glycogen synthesis (glycogenesis) and degradation (glycogenolysis) are reciprocal processes
• Glycogenesis involves glycogen synthase and branching enzyme
• Glycogenolysis involves phosphorylase and debranching enzyme
• Glucose-1-phosphate, a product of glycogenolysis, is converted to glucose-6-phosphate
• Glucose-6-phosphate can enter glycolysis or be dephosphorylated to glucose in the liver

Glycogen Storage Diseases (GSD)

• Inherent glycogen metabolism disorder
• Associated with abnormal concentration and/or structure of glycogen in different tissues
• Twelve different types of GSD are classified based on the deficient enzymes and affected tissue
• Liver and muscles
• Most common types with hepatic involvement are GSD I, III, and IX

GSD I (von Gierke)

• Glucose-6-phosphatase (G6Pase) deficiency
• Defects affects glycogenolysis and gluconeogenesis
• There are two forms, GSDIa and GSDIb
• GSD Ia → mutations in the gene encoding for G6Pase
• GSD Ib → mutations in the glucose-6-phosphate translocase (G6PT) gene, which transports glucose-6-phosphate from cytoplasm to microsomes
• G6Pase is expressed in liver, kidney, and intestine
• Enzyme deficiency results in excessive accumulation of glycogen and lipids in affected organs
• Endogenous glucose production by G6PT pathway is essential for normal neutrophil function
• Is an autosomal recessive trait

GSD 1 Features

• Normal glycogen structure but increased glycogen stored
• Impaired glucose release from glycogen
• Impaired lactate metabolism
• Metabolic acidosis and elevated transaminases
• Hyperlipidaemia, hypothyroidism and anaemia
• Fatty liver, hepato- and renomegaly
• Hyperuricaemia due to increased metabolism of glucose-6-P via the PPP
• Forms ribose-5-P and purines
• Catabolism of purines occurs, causing uric acid formation
• Display Symptoms in infancy, such as, severe fasting hypoglycaemia and hepatomegaly
• Growth retardation and delayed puberty
• Recurrent infections
• Can be treated with nocturnal gastric infusions of glucose

GSD II (Pompe)

• Alpha-1,4-glucosidase deficiency
• Alpha-1,4-glucosidase degrades smaller fragments of glycogen
• Deficiency leads to glycogen accumulation in cells, mostly in lysosomes, which transform into large vacuoles
• Abundant deposits in cardiac and skeletal muscles
• Deficiency in precursor protein synthesis OR mature enzyme is insufficient OR enzyme lacks catalytic activity
• Recessive autosomal trait

GSD II Features

• Manifests in infantile, juvenile, or adult forms
• Heavy glycogen deposits in the heart, liver, and tongue (infantile form) → tissue enlargement
• Hypotonia (muscle weakness) - skeletal and respiratory muscles and progressive respiratory insufficiency
• Disease primarily affects nuclei of brainstem and cells of ventral horn of the spinal cord in CNS
• Mental functions are preserved

GSD III (Cori)

• Deficiency of cytosolic glycogen debrancher enzyme
• A monomer consisting of two catalytic units: amylo-1,6-glucosidase and oligo-1,4-1,4-glucanotransferase
• The accumulated glycogen resembles dextrin, which is a product of glycogen degradation by phosphorylase
• Clinical presentation may be similar to type I GSD, with hypoglycaemia, hepatomegaly, and hyperlipidaemia
• Two forms of the disease exist: GSD type IIIa (the liver, skeletal muscles and cardiac muscle are involved) and GSD type IIIb (only the liver is involved)

GSD IV

• Accumulation of abnormally structured glycogen in the liver, heart, and neuromuscular system
• The abnormal glycogen has long external branches that resemble amylopectin
• This form of glycogen is less soluble; liver cirrhosis probably arises due to this insoluble material
• Associated with polyglucosan inclusions in myofibrils
• Inclusions are characteristic of brancher enzyme deficiency
• Is an autosomal recessive disorder

GSD V (McArdle)

• Muscle Glycogen Phosphorylase deficiency
• Muscle glycogen concentrations increase
• Affects skeletal muscles - principal sources of energy are glycogen and anaerobic glycolysis
• Exercise intolerance with early fatigue, muscle stiffness, and cramping, which are all relieved by rest
• Through fatty acid oxidation, resting phase can acquire energy
• During intense physical exertion, skeletal muscles use energy from endogenous glycogen (glycogenolysis by way of muscle phosphorylase), and signs of muscle fatigue occur after glycogen depletion
• Patients tolerate moderate physical activity well, while intense physical exertion leads to disturbances and symptoms of the disease

GSD VI (Hers)

• Deficiency of liver glycogen phosphorylase
• Rate-limiting enzyme that is necessary for glycogenolysis
• Liver phosphorylase is activated in a series of reactions that requires adenylate cyclase, protein kinase A, and phosphorylase kinase
• Glucagon stimulates the chain of reactions involved in the activation of phosphorylase

GSD VII

• Deficiency of PFK → irreversible conversion of fructose-6-P to fructose-1,6-bisP
• PFK subunits: muscle (M), liver (L) and platelets (P)
• Each subunit is coded by a gene located in different chromosomes: (1) PFKM gene (chromosome 1); (2) PFKL gene (chromosome 21); (3) PFKP gene (chromosome 10)
• PFKL subunit is expressed in the liver and kidneys, whereas muscles contain only the M subunit

Insufficient G-6-Pase Activity

• G-6-P cannot be converted into free glucose
• G-6-P is metabolized to lactic acid or into glycogen
• Large quantities of glycogen are formed and stored in the cytoplasm of hepatocytes
• Metabolic effects: hypoglycaemia
• Secondary abnormalities: hyperlactataemia, metabolic acidosis, hyperlipidaemia, and hyperuricaemia

Hypoglycaemia

• Glucose levels lower than normal in blood
• G-6-Pase deficiency blocks the process of glycogen degradation and gluconeogenesis in the liver, preventing the production of free glucose molecules
• Individuals with GSD Type I have fasting hypoglycaemia
• Hypoglycaemia inhibits insulin secretion and stimulates glucagon (enhance glu formation) and cortisol (enhance glu presence in blood) release

Hyperlactatemia

• Occurs when lactic acid production exceeds lactic acid clearance.
• Undegraded G-6-P, galactose, fructose, and glycerol are metabolized via the G-6-P pathway to lactate.
• Elevated blood lactate levels cause metabolic acidosis

Hyperuricaemia

• Blood uric acid levels are raised
• Due to the increased endogenous production of uric acid.
• Uric acid clearance exceeds production

Glycogen Synthase Deficiency

• In glycogen synthase deficiency (rare)
• Very little glucose is converted to glycogen
• Although conversion to lactate does occur
• Results in hyperglycaemia and hyperlactataemia