Disorders of carbohydrate metabolism

1. Disorders of carbohydrate metabolism

2. Carbohydrates are sugars. Some sugars are simple, and others are more complex. Sucrose (table sugar) is made of two simpler sugars called glucose and fructose. Lactose (milk sugar) is made of glucose and galactose. Both sucrose and lactose must be broken down into their component sugars by enzymes before the body can absorb and use them. The carbohydrates in bread, pasta, rice, and other carbohydrate-containing foods are long chains of simple sugar molecules. These longer molecules must also be broken down by the body. If an enzyme needed to process a certain sugar is missing, the sugar can accumulate in the body, causing problems. Carbohydrate metabolic disorders result due to the defect in one or more enzymes involved in carbohydrate metabolism.

3. Glycogen storage diseases (GSD)

4. Glycogen Storage Diseases Glycogen storage diseases occur when there is a defect in the enzymes that are involved in the metabolism of glycogen, resulting in growth abnormalities, weakness, and confusion. A genetic defect in catabolic pathway of glycogen leading to develop glycogen storage diseases. Glycogen consists of branched-chain polymers of glucose residues (up to 50,000) and the residues link together within chain by glycosidic bonds (α-1 → 4 and α-1 →6). Glycogen is a storage form of glucose stored mainly in the liver and muscles. When blood sugar level goes down, glycogen is broken down into glucosewhich furthers transports into the blood. Deficiency of enzymes involved in the glycogen metabolism result in progressive accumulation of glycogen in the liver and muscles. The most affected organ is the liver

5. Glycogen storage diseases are caused by lack of an enzyme needed to change glucose into glycogen and break down glycogen into glucose. Typical symptoms include weakness, sweating, confusion, kidney stones, and stunted growth. The diagnosis is made by examining a piece of tissue under a microscope (biopsy). Treatment depends on the type of glycogen storage disease and usually involves regulating the intake of carbohydrates.

6. Glycogen is made of many glucose molecules linked together. The sugar glucose is the body’s main source of energy for the muscles (including the heart) and brain. Any glucose that is not used immediately for energy is held in reserve in the liver, muscles, and kidneys in the form of glycogen and is released when needed by the body. There are many different glycogen storage diseases (also called glycogenoses), each identified by a roman numeral. These diseases are caused by a hereditary lack of one of the enzymes that is essential to the process of forming glucose into glycogen and breaking down glycogen into glucose. About 1 in 20,000 infants has some form of glycogen storage disease.

7. Glycogen storage disease type I (GSD-I) or Von-Gierke disease Cause An inherited defect in the glucose-6-phosphatase enzyme causes metabolic abnormalities in glycogen metabolism. This enzyme catalyzes glucose-6-phosphate to glucose in liver and muscles. This enzymatic defect leads to developing Von Gierke disease in which glycogen cannot convert finally into glucose molecules. This disease is characterized by low blood sugar level and excessive accumulation of glycogen in liver and muscle. Due to absence of this enzyme,

9. Clinical symptoms The primary symptom in untreated infants is hypoglycemia, hepatomegaly, lactic acidosis, hyperuricemia, hyperlipidemia, hypoglycemic seizures. Progressive complications are fatty liver, doll-like faces, short stature and protuberant abdomen are observed in affected people and children. Diagnosis Histological examination of liver tissues can be used to visualize abnormal glycogen content in affected people with type I disease. The detection of GSD-I gene in patients can allow for early diagnosis of this disease. Treatment Nutritional therapy may help to maintain blood glucose levels, to control hypoglycemia, and to provide optimal nutrition for growth and development. The nutritional interventions include frequent daytime feedings, nighttime intragastric continuous glucose infusion and oral uncooked cornstarch may necessary for the management of this disease. Liver function test must be monitored for the efficacy of dietary treatments.

10. Symptoms Some of these diseases cause few symptoms. Others are fatal. The specific symptoms, age at which symptoms start, and their severity vary considerably among these diseases. For types II, V, and VII, the main symptom is usually weakness. For types I, III, and VI, symptoms are low levels of sugar in the blood and protrusion of the abdomen (because excess or abnormal glycogen may enlarge the liver). Low levels of sugar in the blood cause weakness, sweating, confusion, and sometimes seizures and coma. Other consequences for children may include stunted growth, frequent infections, and sores in the mouth and intestines. Glycogen storage diseases tend to cause uric acid (a waste product) to accumulate in the joints, which can cause gout, and in the kidneys, which can cause kidney stones. Intype I glycogen storage disease, kidney failure is common in the second decade of life or later.

11. Diagnosis and Treatment The specific type of glycogen storage disease is diagnosed by examining a piece of muscle or liver tissue under a microscope (biopsy). Treatment depends on the type of glycogen storage disease. For most types, eating many small carbohydrate-rich meals every day helps prevent blood sugar levels from dropping. For people who have glycogen storage diseases that cause low blood sugar levels, levels are maintained by giving uncooked cornstarch every 4 to 6 hours around the clock. For others, it is sometimes necessary to give carbohydrate solutions through a stomach tube all night to prevent low blood sugar levels from occurring at night.

12. glycogen storage disease Type II or Pompe disease It is an autosomal recessive inheritance disorder caused by mutation in the gene coding, acid-α-glucosidase enzyme. It is also commonly shortened to GAA that stands for glucosidase acid alpha, which is the name given to the gene. This GAA gene active in lysosomes of liver, heart and muscle tissues. This disease occurs in infant, children and people who inherit a defective gene from their parents. This disease is also referred to as lysosomal storage disease. Cause People with the pompe disease have a deficiency of acid-α-glucosidase enzyme .With this genetic disorder, the body cannot breakdown glycogen into the simple sugar (glucose) leading to accumulation of lysosomal glycogen in the heart, skeletal and smooth muscle, and the nervous system

14. Clinical symptoms Classical infantile-onset pompe disease symptoms can appear in infants with muscle weakness, breathing problems, feeding problems leading to failure of respiratory system and hearing loss. Without treatment or delay diagnosis, this disease can be harmful to health of the infants or children. Diagnosis Enzymatic assay of GAA activity in blood is the common way to confirm the Pompe disease in patient. GAA mutation analysis is confirmatory test for diagnosis of this diseases. Treatment Nutritional therapy may provide temporary improvement in patient with Pompe disease but early diagnosis is better option for the treatment. Enzyme replacement therapy (ERT) can become new treatment options for affected people with the Pompe disease.

15. Glycogen storage disease Type III or Cori disease It is an inherited, an autosomal recessive genetic disorder caused by a mutation in the gene coding debranching enzyme “amylo (α-1→6) glucosidase” which is a key enzyme to split branched-glucose molecules from glycogen in glycogen degradation. The conversion of glucose to lactate in the muscles and lactate to glucose in the liver is called the Cori cycle Cause People who lack the debranching enzyme leading to develop the Cori disease. This diseases causes progressive accumulation of glycogen which impaired the physiological functions of organ and tissues particularly, in liver and muscle

17. Clinical symptoms The dominant clinical features of this disease are hepatomegaly, hypoglycemia with fasting and its clinical significance ranges from asymptomatic in the majority to severe cardiac dysfunction, congestive heart failure, and (rarely) sudden death. Diagnosis Elevated serum concentrations of transaminases and CK are the hallmarks of GSD III. The debranching enzyme activity test and histopathology examination are useful for the definitive diagnosis of Cori diseases. Treatment GSD III’s patients treated with high protein diet to control the clinical symptoms.Currently, there is no effective treatment for progressive hepatomegaly

19. Galactosemia

20. Galactosemia The term “Galactosemia” means high galactose level in the blood. It is a rare inherited genetic disorder of carbohydrate metabolism in which the body unable to metabolize the galactose leading to metabolic abnormalities. Although, galactose is natural component found in milk and milk products. The incidence of this disease is about 1 in 18,000 live births. Galactosemia (a high blood level of galactose) is caused by lack of one of the enzymes necessary for metabolizing galactose, a sugar present in lactose (milk sugar). A metabolite that is toxic to the liver and kidneys builds up. The metabolite also damages the lens of the eye, causing cataracts.

21. Cause People with galactosemia have an inherited defective gene that code galactose-1-phosphate uridyltransferase enzyme. This enzyme converts galactose-1-phosphate to glucose-1-phosphate.Some other inherited defective enzymes such as galactokinase and epimeraseinvolved in the galactose metabolism can cause galactosemia disease. Hence, galactose accumulates in the cells which further transport into blood leading to galactosemia

24. Clinical symptoms Convulsions, irritability, lethargy, poor feeding, poor weight gain, yellow skin and whites of the eyes (jaundice) and vomiting are common symptoms. Diagnosis Enzymatic essay of galactose-1-phosphate uridylyl-transferase in the blood is used to detect of affected people with galactosemia. Newborn screening can be done on total galactose levels in blood sample.

25. Treatment The clinical symptoms of galactosemia can be controlled with nutritional therapy mainly both galactose and lactose free diet. Infants should be fed a formula (e.g., soy formula) that contains trace levels of galactose or lactose. Continued dietary restriction of dairy products in older children is recommended for galactosemia.

26. Galactosemia is caused by lack of one of the enzymes needed to metabolize the sugar in milk. Symptoms include vomiting, jaundice, diarrhea, and abnormal growth. The diagnosis is based on a blood test. Even with adequate treatment, affected children still develop mental and physical problems. Treatment involves completely eliminating milk and milk products from the diet.

27. Galactose is a sugar that is present in milk and in some fruits and vegetables. A deficient enzyme or liver dysfunction can alter the metabolism, which can lead to high levels of galactose in the blood (galactosemia). There are different forms of galactosemia, but the most common and the most severe form is referred to as classic galactosemia. Symptoms Newborns with galactosemia seem normal at first but, within a few days or weeks, lose their appetite, vomit, become jaundiced, have diarrhea, and stop growing normally. White blood cell function is affected, and serious infections can develop. If treatment is delayed, affected children remain short and become intellectually disabled or may die.

28. Diagnosis Galactosemia is detectable with a blood test. This test is done as a routine screening test for newborns in all states in the United States. Before conception, adults with a sibling or child known to have the disorder can be tested to find out whether they carry the gene that causes the disease. If two carriers conceive a child, that child has a 1 in 4 chance of being born with the disease.

29. Prognosis If galactosemia is recognized at birth and adequately treated, liver and kidney problems do not develop, and initial mental development is normal. However, even with adequate treatment, children with galactosemia may have a lower intelligence quotient (IQ) than their siblings, and they often have speech problems. Girls often have ovaries that do not function, and only a few are able to conceive naturally. Boys, however, have normal testicular function.

30. Treatment Galactosemia is treated by completely eliminating milk and milk products-the source of galactose-from an affected child’s diet. Galactose is also present in some fruits, vegetables, and sea products, such as seaweed. Doctors are not sure whether the small amounts in these foods cause problems in the long term. People who have the disorder must restrict galactose intake throughout life.

31. Hereditary Fructose Intolerance

32. Hereditary Fructose Intolerance Hereditary fructose intolerance is caused by lack of the enzyme needed to metabolize fructose. Very small amounts of fructose cause low blood sugar levels and can lead to kidney and liver damage.

34. Clinical symptoms Affected people with this disease have symptoms like abdominal pain, vomiting and weakness. Diagnosis The direct detection of catalytic activity of Aldolase B enzyme in liver and kidney tissue is useful for diagnosis of HFI. Recently, the diagnosis of HFI has made simpler by the PCR-based method for detection of mutated aldolase-B gene in patients Treatment Nutritional treatment along with fructose-free diet may help to manage biochemical symptoms of HFI.

35. Cause The Acatalytic deficiency of an aldolase-B enzyme (fructose-1,6-bisphosphate aldolase) causes the HFI disease. This enzyme normally converts fructose-1-phosphate to dihydroxyacetone phosphate and glyceraldehyde in glycolysis pathway .Deficiency of this enzyme allows accumulation of fructose-1-phosphate in the liver, kidney and small intestine resulting in metabolic inhibition of glycogen and glucose, thereby causing severe hypoglycemic condition (low sugar in the blood) in the human body.

36. In this disorder, the body is missing an enzyme that allows it to use fructose, a sugar present in table sugar (sucrose) and many fruits. As a result, a by-product of fructose accumulates in the body, blocking the formation of glycogen and its conversion to glucose for use as energy. Ingesting more than tiny amounts of fructose or sucrose causes low blood sugar levels (hypoglycemia), with sweating, confusion, and sometimes seizures and coma. Children who continue to eat foods containing fructose develop kidney and liver damage, resulting in jaundice, vomiting, mental deterioration, seizures, and death. Chronic symptoms include poor eating, failure to thrive, digestive symptoms, liver failure, and kidney damage. For most types of this disorder, early diagnosis and dietary restrictions started early in infancy can help prevent these more serious problems.

37. The diagnosis is made when a chemical examination of a sample of liver tissue determines that the enzyme is missing. Treatment involves excluding fructose (generally present in sweet fruits), sucrose, and sorbitol (a sugar substitute) from the diet. Severe attacks of hypoglycemia respond to glucose given by vein. Milder attacks are treated with glucose tablets, which should be carried by anyone who has hereditary fructose intolerance

38. Hereditary lactose intolerance (HLI)

39. Lactose intolerance is a common inherited disease in childhood. Lactose, a milk sugar is metabolized by the lactase enzyme in the body. It is an intestinal enzyme which splits dietary lactose into glucose and galactose during the process of digestion . Lactose intolerance can exhibit in children at age three Cause Individuals with lactose intoleranceis unable to digest milk and milk product due to lack or insufficient amounts of the lactase enzyme in the body. Normally, lactase breaks down lactose into glucose and galactose. With this insufficiency, lactose accumulates in the intestine wherein intestinal bacteria fermented the lactose by converting it into short-chain acids and gases like hydrogen (H2) and carbon dioxide (CO2) which leads to flatulence or stomach pain.

41. Clinical symptoms Abdominal cramps, diarrhea, flatulence. production of gases like hydrogen (H2) and carbon-dioxide (CO2) are common symptoms of lactose-intolerance which leads to intestinal irritants. Diagnosis The direct biochemical assay of lactase activity from a jejunal sample is the most common method for the diagnosis of lactose intolerance. Molecular technique is used to identify the defective lactase gene for early diagnosis . Treatment Treatment requires both fructose and lactose-free diet and limited intake of dairy products recommended for patients.

42. Mucopolysaccharidoses Mucopolysaccharidoses are a group of hereditary disorders in which complex sugar molecules are not broken down normally and accumulate in harmful amounts in the body tissues. The result is a characteristic facial appearance and abnormalities of the bones, eyes, liver, and spleen, sometimes accompanied by intellectual disability.

43. Mucopolysaccharidoses occur when the body lacks enzymes needed to break down and store complex sugar molecules (mucopolysaccharides). Typically, symptoms include short stature, hairiness, stiff finger joints, and coarseness of the face. The diagnosis is based on symptoms and a physical examination. Although a normal life span is possible, some types cause premature death. A bone marrow transplant may help.

44. Complex sugar molecules called mucopolysaccharides are essential parts of many body tissues. In mucopolysaccharidoses, the body lacks enzymes needed to break down and store mucopolysaccharides. As a result, excess mucopolysaccharides enter the blood and are deposited in abnormal locations throughout the body. During infancy and childhood, short stature, hairiness, and abnormal development become noticeable. The face may appear coarse. Some types of mucopolysaccharidoses cause intellectual disability to develop over several years. In some types, vision or hearing may become impaired. The arteries or heart valves can be affected. Finger joints are often stiff.

45. A doctor usually bases the diagnosis on the symptoms and a physical examination. The presence of a mucopolysaccharidosis in other family members also suggests the diagnosis. Urine tests may help but are sometimes inaccurate. X-rays may show characteristic bone abnormalities. Mucopolysaccharidoses can be diagnosed before birth by using amniocentesis or chorionic villus sampling.

46. Prognosis and Treatment The prognosis depends on the type of mucopolysaccharidosis. A normal life span is possible. Some types, usually those that affect the heart, cause premature death. In one type of mucopolysaccharidosis, attempts at replacing the abnormal enzyme have had limited, temporary success. Bone marrow transplantation may help some people. However, death or disability often results, and this treatment remains controversial.

47. Metabolic Disorders of Carbohydrate Metabolism.

48. Disorders of Pyruvate Metabolism

49. Disorders of Pyruvate Metabolism Pyruvate metabolism disorders are caused by a lack of the ability to metabolize a substance called pyruvate. These disorders cause a buildup of lactic acid and a variety of neurologic abnormalities.

50. A deficiency in any one of the enzymes involved in pyruvate metabolism leads to one of many disorders. Symptoms Include seizures, intellectual disability, muscle weakness, and coordination problems. Some of these disorders are fatal. Some children are helped by diets that are either high in fat and low in carbohydrates or high in carbohydrates and low in protein.