Metabolic disorders

1. Metabolic disorders

2. A metabolic disorder is a medical disorder which affects the production of energy within individual human (or animal) cells. Most metabolic disorders are genetic, though a few are "acquired" as a result of diet, toxins, infections, etc. Genetic metabolic disorders are also known as inborn errors of metabolism.

3. The largest classes of metabolic disorders are: - Disorders of carbohydrate metabolism - Disorders of amino acid metabolism - Disorders of fatty acid oxidation and mitochondrial metabolism - Disorders of porphyrin metabolism - Disorders of purine or pyrimidine metabolism - Disorders of steroid metabolism - Disorders of mitochondrial function - Disorders of peroxisomal function - Lysosomal storage disorders

4. Disorders of carbohydrate metabolism

5. Pyruvate metabolism and gluconeogenesis • Glucose-P-isomerase deficiency • Anaemia, neurologic symptoms (musc. spasticity) • -Pyruvate kinase deficiency • hemolytic anaemia • Pyruvate Dehydrogenase Deficiency(PDHA) • It affects a gene which codes for a critical enzyme complex, the Pyruvate dehydrogenase complex (PDC) • PDHA causes Lactic acidosis; large amounts of lactic acid in the blood but with a normal pyruvate/lactate ratio. Symptoms are varied, and include developmental defects (especially of the brain and nervous system), muscular spasticity and early death.

6. Pyruvate carboxylase deficiency is an inherited disorder that causes lactic acid and other potentially toxic compounds to accumulate in the blood. High levels of these substances can damage the body's organs and tissues, particularly in the nervous system. Type A:Characteristic features include developmental delay and a buildup of lactic acid in the blood (lactic acidosis). Increased acidity in the blood can lead to vomiting, abdominal pain, extreme tiredness (fatigue), muscle weakness, and difficulty breathing. Children with pyruvate carboxylase deficiency type A typically survive only into early childhood. Type BPyruvate carboxylase deficiency type B has life-threatening signs and symptoms that become apparent shortly after birth. This form of the condition has been reported mostly in Europe, particularly France. Affected infants have severe lactic acidosis, a buildup of ammonia in the blood (hyperammonemia), and liver failure. They experience neurological problems including weak muscle tone (hypotonia), abnormal movements, seizures, and coma. Infants with this form of the condition usually survive for less than 3 months after birth.

7. Drug induced hemolytic anemia

8. Glucose 6-phosphate dehydrogenase deficiency -inherited disease characterized by hemolytic anemia due to inability to detoxify oxidizing agents -most common disease-producing enzyme abnormality in humans (>200 million people worldwide, ~7%; ~2% of U.S. population) -X-linked deficiency caused by >300 different mutations in the G6PD gene -only some mutations cause clinical disease -life span of individuals with G6PD deficiency shortened somewhat due to complications of chronic hemolysis -G6PD deficiency has been maintained in the human gene pool by the evolutionary advantage of increased resistance to falciparum malaria in female carriers of the mutations in the tropics -geographic distribution (highest in tropical Africa, Asia, Middle East, Mediterranean and Papua New Guinea) follows sickle cell trait (also confers relative resistance to malaria)

9. Formation of Heinz Bodies in Red Blood Cells - RBCs generate superoxide and other ROS during non-enzymatic oxidation of hemoglobin (Hb) to metHb by spontaneous transfer of an electron from the Fe2+ in Hb to bound O2 - RBCs depend on G6PD for generating NADPH to re-reduce glutathione to protect against this oxidative stress - G6PD deficiency results in disulfide linked aggregates of Hb forming on the red cell membrane - mechanical stress from lack of deformability in small capillaries and ROS peroxidation of membrane lipids

10. Precipitating factors for G6PD deficiency disease Oxidant Drugs (A3): AAA= Antibiotics (e.g. sulfamethoxazole) , Antimalarials (e.g. primaquine), Antipyretics (acetanilid, not aspirin or acetominophen) Favism: Mediterranean variant is susceptible to hemolytic affects of ingesting fava bean purine glycosides (vicine and isouramil) which react with reduced glutathione, decreasing GSH levels Infection: inflammatory response to infection results in the generation of free radicals (ROS) by macrophages and neutrophils; ROS can diffuse into RBCs and induce oxidative damage Neonatal jaundice: results from impaired hepatic catabolism or increased production of bilirubin (heme degradation product from hemoglobin, myoglobin, cytochromes)

11. Classification of Glucose-6-phosphate dehydrogenase deficiency

12. Common Hexoses • Sucrose (table sugar): glucose + fructose and • Lactose: (dairy products) glucose + galactose

13. Sucrose(Table Sugar) α-D-glucopyranosyl-(1→2)-β-D-fructofuranoside

14. Cleavage of Sucrose(α-glucosidase or invertase)

15. Muscle Metabolism of Fructose(Anaerobic Glycolysis)Muscle Hexokinase can accept fructose as a substrate

16. Liver Metabolism of Fructose IGlucokinase, the liver isoform ofhexokinasecannot transform fructose

17. Liver Metabolism of Fructose II

18. Fructose Intolerance • Too Much Fructose • Fructose-1-P Aldolase( Aldolase B) is rate-limiting • Depletion of Pi • Reduction in [ATP] • Increase in glycolysis • Accumulation of lactate (acid) in blood • Fructose-1-P Aldolase Deficiency (Genetic Disease) + Liver damage

19. Galactose Metabolism

20. Lactose Metabolism(Dairy Products) Glycolytic Enzymes are specific and do not recognize galactose!

21. Need Epimerization

22. A T P A D P C H O H C H O H 2 2 O O O H H O H H H H O H H O H H G a l a c t o k i n a s e = H O H H O P O 3 H O H H O H G a l a c t o s e G a l a c t o s e - 1 - P Phosphorylation of Galactose

23. Activation of Galactose

24. Epimerization of UDP-Galactose

25. Lactose intolerance (or hypolactasia) is the term used to describe a decline in the level of lactase, an enzyme needed for proper metabolization of lactose (a sugar that is a constituent of milk and other dairy products), in human beings. Lactose intolerance in varying degrees is physiologically normal in adult mammals, including many human beings. However, certain ethnic groups - particularly those of European descent - continue to produce lactase throughout their lives. Without lactase, the lactose in milk and dairy remains uncleaved and unabsorbed. Lactose cannot pass easily through the intestinal wall into the bloodstream, so it remains in the intestines. Soon, enteral bacteria adapt to the relative abundance of lactose (relative to other usable sugars like glucose) and their operons quickly switch over to lactose metabolism. Along the way they produce copious amounts of gas by fermentation. The gas causes a range of unpleasant abdominal symptoms, including stomach cramps, bloating, flatulence and diarrhea. Like other unabsorbed sugars, e.g. mannitol, the lactose raises the osmotic pressure of the colon contents, preventing the colon from reabsorbing water and hence causing a laxative effect to add to the excessive gas production.

26. Galactosemia(Mental Retardation and Death) Treatment Galactose-free diet (reversal of all symptoms except mental retardation)

28. Cataracts

29. Glycogen storage disease (synonyms: glycogenosis, dextrinosis) is any one of several inborn errors of metabolism that result from enzyme defects that affect the processing of glycogen synthesis or breakdown within muscles, liver, and other cell types. Types There are nine diseases that are commonly considered to be glycogen storage diseases. (Although glycogen synthase deficiency does not result in storage of extra glycogen in the liver, it is often classified with the GSDs as type 0 because it is another defect of glycogen storage and can cause similar problems.)

30. Glycogen Storage Diseases Type 0 Type IV Type I Type VII Type II

32. Glycogen Storage 1: von Gierke disease Accumulation of glycogen in liver and kidney => hepatomegaly Hypoglycemia Enzyme deficiency: Glucose 6 phosphatase Accumulation: Glycogen

33. Pompe Disease Signs &Symptoms Infantile onset < 12 months Late onset > 12 months Daytime somnolence Morning headache Head lag Shortness of breath/sleep apnea Respiratoryinsufficiency Enlarged tongue Cardiomegaly/cardiomyopathy Scapular winging Respiratoryinsufficiency Scoliosis Low back pain Delayed motordevelopment Gait abnormality Organomegaly Muscle weakness Muscle weakness Hirschhorn R, Reuser AJJ. In: The Metabolic and Molecular Bases of Inherited Disease. 2001:3389-3420.

34. Glycogen storage 2: Pompe disease Muscle hypotonia Splenomegaly cardiomegaly Death before age 3 of cardiorespiratory failure Intractable Hypoglycemia Enzyme deficiency: alpha-1,4 glucosidase Accumulation: Glycogen

35. Pompe Disease Signs &Symptoms Data on file, Genzyme Corporation. Courtesy of R. R. Howell, MD. Enlarged tongue/ lax facial features Hypotonia/head lag/ floppy baby Cardiomegaly

36. Pompe Disease Signs &Symptoms Lordosis / Scoliosis Weak pelvic girdle muscles

37. Inheritance Pompe Disease is autosomal recessive: Father Carrier Mother Carrier 1 2 3 4 Affected Individual (25%) Unaffected Carriers (50%) Unaffected Noncarrier (25%) Unaffected (75%)

38. Glycogen Storage 3: Cori Disease Glycogen accum in heart Glycogen in liver -> Hepatomegaly hypoglycemia Glycogen in skeletal muscle Stunted growth Enzyme deficiency: Amylo-1,6-glucosidase Accumulation: Glycogen

39. Case Description A female baby was delivered normally after an uncomplicated pregnancy. At the time of the infant’s second immunization, she became fussy and was seen by a pediatrician, where examination revealed an enlarged liver. The baby was referred to a gastroenterologist and later diagnosed to have Glycogen Storage Disease Type IIIB

40. Glycogen Storage DiseaseType IIIb • Deficiency of debranching enzyme in the liver needed to completely break down glycogen to glucose • Hepatomegaly and hepatic symptoms • Usually subside with age • Hypoglycemia, hyperlipidemia, and elevated liver transaminases occur in children

41. Glycogen Storage 4: McArdle Syndrome Enzyme deficiency: Muscle phosphorylase Accumulation: Glycogen Muscle cramps and weakness after exercise

42. Disorders of amino acid metabolism

43. Phenylketonuria (PKU) Phenylalanin hydroxylase (PAH) defected 12. chromosome, >400 diff. mutations (autosomal recessive disorder) Symptoms: Without treatment severe mental retardation (very low IQ) epilepsy hypopoigmentation: blond, blue eyes Eczema

44. Types of PKU 1./ Classical PKU : Phe level in the blood > 10mg%- life-long treatment 2./ Non PKU hyperfenylalaninaemia: Blood Phe 2-10mg %: not so strict diet 3./ Atypical PKU, PAH-cofactor tetrahydrobiopterin, (BH4) def: retardation during pregnancy, early symptoms, fever, spasticity, mental and developmental retardation. Th: BH4 , diet not enough, serotonin, dopamin supplementation

45. Without phenylalanine hydroxylasePHE→Tyr not occur Tyr deficiency may lead to hypopigmentation High Phe can cause neurologic damage

48. Newborn screening Important- early diagnosis and treatment of affected infants resuling in normal growth and development! Since 1965! At 5. day or after feeding Method: GUTHRIE test: Bacillus Subtilis grows only Phe containing broth.

49. Guthrie test