Inborn errors of carbohydrate metabolism
- 1. INBORN ERRORS OF CARBOHYDRATE METABOLISM DR. UMOH, OFONMBUK
- 2. OUTLINE • INTRODUCTION • BRIEF OVERVIEW • GLYCOGEN STORAGE DISEASES • LACTOSE INTOLERANCE • DISORDERS OF GALACTOSE • DISORDERS OF FRUCTOSE • ESSENTIAL PENTOSURIA • SUMMARY & CONCLUSION • REFERENCES 2
- 3. INTRODUCTION • Inborn errors of metabolism are single gene disorders resulting in enzymatic defects in the biochemical pathways of the body. • Although IEMs are individually rare, their collective incidence is approximately 1 in 10,000. • Most of them are inherited as autosomal recessive disorders. 3
- 4. BRIEF OVERVIEW • Sometimes, inborn errors may occur in the metabolism of biomolecules, usually due to a defective enzyme. The affected enzyme may either be absent or deficient. 4
- 5. • When such abnormalities occurs in metabolic pathways involving the catabolism and anabolism of carbohydrates, the resulting diseases are termed Inborn Errors of Carbohydrate Metabolism. • Glycogen Storage Disease (GSD), lactose intolerance, galactosemia and hereditary disorders of fructose metabolism are the common representatives of inborn errors of carbohydrate metabolism. 5
- 6. GLYCOGEN STORAGE DISEASES • Glycogen, although present in most tissue, is stored principally in the liver and skeletal muscle to a larger degree. During fasting, these muscle or liver glycogen is converted to glucose to provide energy for the whole body. • Glycogen storage disease are a group of diseases in which enzyme deficiencies impair glycogen synthesis, glycogen degradation and its resulting glycolysis. 6
- 7. • Glycogen storage diseases that affect the liver typically cause hepatomegaly and hypoglycemia; those that affect skeletal muscle cause exercise intolerance, progressive weakness and cramping. • Glycogen Storage Disease (GSD) is usually inherited as an autosomal recessive disorder. 7
- 8. 8 GLYCOGEN STORAGE DISEASES CAN BE CLASSIFIED INTO: • Type I (Von Gierke’s disease) • Type II (Pompe’s disease) • Type III (Cori’s disease) • Type IV (Andersen’s disease) • Type V (McArdle’s disease) • Type VI (Her’s disease) • Type VII (Tarui’s disease) • Type IX (Phosphorylase kinase deficiency)
- 10. GLYCOGEN STORAGE DISEASE TYPE I (GSD-I) • Also known as von Gierke’s disease. • This is the most common type of glycogen storage disease, and accounts for 90% of all glycogen storage disease cases. • It is due to absence or severe deficiency of glucose-6- phosphatase in liver and kidneys. • Conversion of glucose-6-phosphate into glucose does not occur. 10
- 11. …GSD-1 Clinical features in GSD-1 includes: • Fasting Hypoglycemia • Massive hepatomegaly • Growth retardation • Lactic acidosis • Hyperlipidemia • Failure of blood glucose to increase in response to oral or intravenous galactose administration is diagnostic. • Also, low Gluc-6-phosphatase activities can be assayed in liver biopsy. 11
- 12. GLYCOGEN STORAGE DISEASE TYPE II • Also known as Pompe’s disease • There is lysosomal alpha-1,4-glucosidase deficiency • Glycogen accumulates in lysosomes of skeletal and cardiac muscles • There is progressive muscle weakness and hypotonia, cardiomegaly and CCF. • Involvement of respiratory muscles my cause difficulty in breathing • Serum CK and LDH will be elevated. 12
- 13. GLYCOGEN STORAGE DISEASE TYPE III • Also known as Cori’s disease. • There is deficiency of the debranching enzyme amylo-1,6- glucosidase • Glycogenolysis stops at the branch point, producing Limit Dextrins, of which excess gets deposited in tissues. • Therefore, this disease is also known as limit dextrinosis. • Clinical features include: hypoglycemia, hepatomegaly, muscle weakness/atrophy, growth retardation. 13
- 14. GLYCOGEN STORAGE DISEASE TYPE IV • Also known as Andersen’s disease • There is deficiency of the branching enzyme: amylo-1,4 1,6 -transglucosidase • Therefore, glycogen having very few branches, resembling amylopectins, accumulates in the liver and muscles tissues. • There is growth retardation, hepatomegaly, liver cirrhosis and liver failure, as well as hypotonia, muscle weakness and atrophy. 14
- 15. GLYCOGEN STORAGE DISEASE TYPE V • This is also known as McArdle’s disease. • There is deficiency of muscle phosphorylase enzyme. Hence, glycogen accumulates in the muscles. • It manifests in adulthood as exercise intolerance and cramps on exercise. Avoiding strenuous exercise helps to prevent the symptoms. • Serum CK is highly elevated with physical activity. 15
- 16. GLYCOGEN STORAGE DISEASE TYPE VI • Also known as Her’s disease. • There is deficiency of liver phosphorylase enzyme, causing glycogen accumulation in the liver. • Hypoglycemia and hepatomegaly are the usual clinical abnormalities. Though mild ketosis also occurs. • The condition improves with age. 16
- 17. GLYCOGEN STORAGE DISEASE TYPE VII • This is also known as Tarui’s disease. • There is deficiency of the enzyme phosphofructokinase (PFK) in the muscles. • PFK is a glycolytic enzyme with 4 isoforms M, B and L. • The muscles have the M form only, which is defective in this disease. • The clinical features include cramps on exercise and easy fatigability, and severe exercise may cause myoglobinuria. • Some degree of hemolysis is present, from PFK deficiency in RBCs 17
- 18. GLYCOGEN STORAGE DISEASE TYPE IX • This is due to phosphorylase kinase deficiency in the liver. • Therefore, hypoglycemia occurs due to decreased glycogenolysis in the liver. 18
- 19. DIAGNOSIS OF GLYCOGEN STORAGE DISEASES • The presenting symptom of GSD with liver involvement is usually a marked hepatomegaly. • A careful history, clinical findings with a tendency for hypoglycemia (fasting/stressor) can help to differentiate these GSDs from other types of GSD. • Today, definite diagnosis is usually established by measurement of enzyme activity in blood cells or mutational analysis, if possible. If these investigations are not conclusive, a biopsy is done to measure enzyme activity in liver/muscle tissue, as well as assay for glycogen 19
- 20. • Biotinidase activity has been proposed for use, as a useful screening parameter with a sensitivity of about 100% for patients with GSD I, III, IV, VI & IX. However, conformational diagnostic investigations for the specific type are always necessary. 20
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- 23. LACTOSE INTOLERANCE • This is due to the congenital absence or deficiency of lactase. • The enzyme lactase is located in the brush border (microvilli) of the small intestine. It hydrolyzes dietary lactose into the monosaccharides: glucose and galactose, for transport across epithelial cell membranes. • When lactase is absent or deficient, unhydrolyzed lactose remains in the intestinal lumen. Fluid is osmotically driven into the intestine, increasing the volume and fluidity of the gastrointestinal contents, allowing undigested lactose to enter the colon. 23
- 24. • The fermentation of lactose by colonic microflora produces lactic acid and hydrogen. In the presence of methanogenic bacteria, hydrogen and carbon dioxide combine together to form methane gas in the colon. • Bloating, abdominal distension, flatulence and non-specific abdominal pains as well as diarrhea may occur. • The most accurate test for the diagnosis of lactose intolerance is an intestinal biopsy to measure the mucosal lactase activity. 24 …Lactose intolerance
- 25. • The lactose hydrogen breath test, which is non-invasive and cost effective, is currently considered to be the best diagnostic test for identifying lactose intolerance. After fasting for at least 12hrs, lactose, at a concentration of 1 gm/kg body weight dissolved into a 20% solution with water, and given to the patient. • Breath samples are collected at 20-minute intervals for 2 hours. An increase in breath hydrogen or methane in three consecutive samples confirms the diagnosis of lactose intolerance. A meta-analysis found that the overall sensitivity for the breath test to be 0.88 and the specificity 0.85. 25 …Lactose intolerance
- 26. • The mainstay of treatment for lactose intolerance is avoidance of all lactose containing food especially milk products, but that is typically not necessary. • Yogurt is an option for patients diagnosed with lactose intolerance, because lactose is digested by yoghurt bacteria, improving absorption compared with other dairy products. 26 Treatment
- 27. DISORDERS OF GALACTOSE • Deficiency of galactose-1-phosphate uridyl transferase (GALT) in the liver…most common form. • Deficiency of Galactokinase (GALK), which catalyzes the conversion of galactose to galactose-1- phosphate. • Deficiency of galactose-6-phosphate epimerase (GALE). 27 There are 3 forms of the Congenital galactosemia Diagnosis is clinical, and by assessment of these deficient enzymes in blood.
- 28. • NOTE: Galactosemia and galactosuria occurs after ingestion of milk. • Here, galactose ingested as this milk sugar cannot be metabolized. Hence accumulates. • Galactose is excreted in urine, even soon after birth. Also, there is hypoglycemia, hepatomegaly jaundice, growth retardation, convulsion, premature cataract, mental retardation. 28 Congenital galactosemia …contd
- 29. DISORDERS OF FRUCTOSE 1. Essential Fructosuria – a rare, benign elevation of fructose level in blood and eventually urine, due to deficiency of fructokinase. •Usually asymptomatic, and diagnosed accidentally when a non-glucose reducing substrate is detected by routine screening for reducing sugars in urine. 29
- 30. 2. Fructose-1,6-bisphosphatase 1 deficiency. (FBPase, or FBP1) is a key enzyme of the gluconeogenic pathway. Its deficiency impairs glucose production from all gluconeogenic precursors, including dietary fructose, leading to fasting hypoglycemia, ketosis and acidosis. • Diagnosis can be made by DNA analysis of enzyme activity from EDTA-anticoagulated blood, or in a liver biopsy. 30
- 31. 3. Hereditary fructose intolerance (HFI) – caused by deficiency of the enzyme aldolase B which splits fructose-1- phosphate into dihydroxyacetone phosphate and glyceraldehyde. 31
- 32. •Accumulation of fructose-1-phosphate inhibits both hepatic glycogenolysis and gluconeogenesis, hence inducing hypoglycemia, and results in depletion of ATP. •The best non invasive approach for confirmation of diagnosis is carried out by DNA analysis for Aldolase from EDTA-anticoagulated blood. 32
- 33. ESSENTIAL PENTOSURIA • This is a benign condition common in the Jews. • It is due to the absence of L-Xylulose reductase. L-Xylulose is excreted in urine, and identified by serendipity. 33
- 34. MANAGEMENT OF INBORN ERRORS OF CARBOHYDRATE METABOLISM • Clinically, the diagnosis of inborn errors of carbohydrates requires a careful nutritional history. Specific enzyme assay can be done for definitive diagnosis of the disorder. 34 The management of inborn errors of metabolism has traditionally been dietary and supportive therapy, but recently other treatment options have become available, including enzyme and coenzyme replacement, removal of harmful substances, cell and organ transplantation, and gene therapy.
- 35. SUMMARY •Inborn errors of carbohydrate metabolisms are usually autosomal recessive disorders resulting from the deficiency or absence of an enzyme involved in an intermediary metabolic pathway. •While clinical diagnosis is often used, routine biochemistry tests for reducing substances can sometimes elicit the presence of disorders of carbohydrate metabolism. •However, definitive diagnosis is usually achieved by measurement of the activity of the affected enzyme in tissues. 35
- 36. CONCLUSION • Newborn screening does not identify all metabolic disorders, and some patients can be missed during this screening. Therefore a symptomatic patient, at any age, should be investigated despite normal newborn screening results. • Treatment approaches such as special diets have been widely used for IEMs, while long term approaches includes enzyme replacement therapy, substrate inhibition, and organ transplantation. 36
- 37. REFERENCES • Tietz Clinical Chemistry and Molecular Diagnostics, 5th Ed • Bishops Clinical Chemistry – Principles, Techniques, Correlations, 7th Ed. • Rake JP, Visser G, Labrune P, Leonard JV, Ullrich K, Smit GP. Glycogen storage disease type I: diagnosis, management, clinical course and outcome. Eur J Pediatr 2000;159:322–30 • Results of the European Study on Glycogen Storage Disease Type I (ESGSD I). Eur J Pediatr 2002;161(Suppl. 1):S20–34. 37
- 38. THANK YOU 38
Editor's Notes
- #11: 4 - There is inability to maintain interprandial glucose homeostasis
- #12: Lactic acidosis…from excessive anaerobic glycolysis …increased lipolysis, as insufficient glucose Galactose…converts to glucose in a series of enzymatic processes which Gluc-6-Phosphatase is one of those. But in these patients, …previously used ephinephrine test (i.m 0.1% epinephrine increases bld gluc by up to 45mg within 60mins)
- #14: Glycogen is a multibranched polysaccharide of glucose that serves as the storage form of energy in animals, fungi, and bacteria.
- #18: PFK catalyzes the phosphorylation of G6P to G1,6Biphosphate …Liver LBM, Muscle M only, Erythrocytes B & M.
- #21: Biotinidase is an enzyme that helps recycle biotin to be reused by the body. Biotin Vitamin B7 aka Vit H help convert certain nutrients into energy.
- #25: The excessive production of hydrogen and methane in the intestine leads to bloating, distention of the abdomen, excessive flatulence, and non-specific abdominal pain. In some patients diarrhea & vomiting can occur. …note: these symptoms overlap with those of IBS and IBD (Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder characterized by abdominal pain and altered bowel habit in the absence of a specific and unique organic pathology)
- #28: …marking the entry of galactose into the glycolytic pathway …the first reaction step in the metabolism of galactose. …epimerase enzyme, a racemase enzyme that catalyzes the reversible conversion of UDP Gluc to UDP Galact
- #32: … Aldolase A-muscle, B-Liver, C-Brain …these triphosphates don’t get converted into pyruvate and lactate.