Metabolic disorders of proteins

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What is a metabolic disease?
Inborn errors of metabolism”
inborn error : an inherited (i.e. genetic) disorder
metabolism : chemical or physical changes in a biological system

Metabolic disorders of proteins

  1. 1. Clinical Biochemistry Metabolic Disorders of Proteins By: Amir Nader Emami Razavi
  2. 2. Clinical Biochemistry Metabolic Disorders of Proteins What is a metabolic disease? “Inborn errors of metabolism” inborn error : an inherited (i.e. genetic) disorder metabolism : chemical or physical changes in a biological system June 26, 2012 Total slide. 132 2
  3. 3. Clinical Biochemistry Metabolic Disorders of Proteins What is a metabolic disease? Garrod’s hypothesis A B Cproduct deficiency substrate excess D toxic metabolite June 26, 2012 Total slide. 132 3
  4. 4. Clinical Biochemistry Metabolic Disorders of Proteins What is a metabolic disease? Small molecule disease Organelle disease Carbohydrate Lysosomes Protein Mitochondria Lipid Peroxisomes Nucleic Acids Cytoplasm June 26, 2012 Total slide. 132 4
  5. 5. Clinical Biochemistry Metabolic Disorders of Proteins How do metabolic diseases present in the neonate ?? Acute life threatening illness encephalopathy - lethargy, irritability, coma vomiting respiratory distress Seizures, Hypertonia Hepatomegaly (enlarged liver) Hepatic dysfunction / jaundice Odour, Dysmorphism, FTT (failure to thrive), Hiccoughs June 26, 2012 Total slide. 132 5
  6. 6. Clinical Biochemistry Metabolic Disorders of Proteins How do you recognize a metabolic disorder ?? Index of suspicion eg “with any full-term infant who has no antecedent maternal fever or PROM (premature rupture of the membranes) and who is sick enough to warrant a blood culture, one should proceed with a few simple lab tests. Simple laboratory tests Glucose, Electrolytes, Gas, Ketones, BUN (blood urea nitrogen), Creatinine Lactate, Ammonia, Bilirubin Amino acids, Organic acids June 26, 2012 Total slide. 132 6
  7. 7. Clinical Biochemistry Metabolic Disorders of Proteins Inborn Errors of Metabolism An inherited enzyme deficiency leading to the disruption of normal bodily metabolism Accumulation of a toxic substrate (compound acted upon by an enzyme in a chemical reaction) Impaired formation of a product normally produced by the deficient enzyme June 26, 2012 Total slide. 132 7
  8. 8. Clinical Biochemistry Metabolic Disorders of Proteins Three Types Type 1: Silent Disorders Type 2: Acute Metabolic Crises Type 3: Neurological Deterioration June 26, 2012 Total slide. 132 8
  9. 9. Clinical Biochemistry Metabolic Disorders of Proteins Type 1: Silent Disorders Do not manifest life-threatening crises Untreated could lead to brain damage and developmental disabilities Example: PKU (Phenylketonuria) June 26, 2012 Total slide. 132 9
  10. 10. Clinical Biochemistry Metabolic Disorders of Proteins Type 2: Acute Metabolic Crisis Life threatening in infancy Children are protected in utero by maternal circulation which provide missing product or remove toxic substance Example OTC (Urea Cycle Disorders) June 26, 2012 Total slide. 132 10
  11. 11. Clinical Biochemistry Metabolic Disorders of Proteins Type 3: Progressive Neurological Deterioration Examples: Tay Sachs disease Gaucher disease Metachromatic leukodystrophy DNA analysis show: mutations June 26, 2012 Total slide. 132 11
  12. 12. Clinical Biochemistry Metabolic Disorders of Proteins Genetic Basis of Inherited Disorders Point mutations, Insertions, Deletions, Missense Mutations and Rearrangements June 26, 2012 Total slide. 132 12
  13. 13. Clinical Biochemistry Metabolic Disorders of Proteins Generalities of Inherited Disorders Although each individual IEM is rare, cumulatively they occur ~ 1:5000 live births Majority of IEM follow an autosomal recessive mode of inheritance June 26, 2012 Total slide. 132 13
  14. 14. Clinical Biochemistry Metabolic Disorders of Proteins Inborn Errors of Metabolism Uneventful delivery Normal birth weight Non-dysmorphic (no physical findings) Uneventful days /weeks June 26, 2012 Total slide. 132 14
  15. 15. Clinical Biochemistry Metabolic Disorders of ProteinsDefective Proteins and Disease Defects in Carbohydrate Metabolism Defects in Cholesterol and LipoproteinMetabolism Mucopolysaccharide and Glycolipid Disorders Defects in Amino and Organic Acid Metabolism Porphyrias and Bilirubinemias Errors in Fatty Acid Metabolism Defects in Nucleotide Metabolism Disorders in Metal Metabolism and Transport Defects in Peroxisomes Diseases Associated with Defective DNA Repair
  16. 16. Clinical Biochemistry Metabolic Disorders of Proteins Defective Proteins and Disease Oxygen carrying proteins Connective tisue proteins Clotting factors June 26, 2012 Total slide. 132 16
  17. 17. Clinical Biochemistry Metabolic Disorders of Proteins Diseases Associated with Oxygen Carrying Proteins Sikle-Cell Anemia B-Talassemia A-Talassemia June 26, 2012 Total slide. 132 17
  18. 18. Clinical Biochemistry Metabolic Disorders of Proteins Diseases Associated with Connective Tissue Proteins Ehlers-Danlos Type I- Type VIII Ehlers-Danlos with Platelet Dysfunction Marfans Syndrome Cutis Laxa Occipital Horn Syndrome Cutis Laxa, X-linked Osteogenesis Imperfecta Type I Osteogenesis Imperfecta Type I-C Osteogenesis Imperfecta Silent Type II/III Osteogenesis Imperfecta Type IV Osteogenesis Imperfecta Neonatal Lethal form Osteogenesis ImperfectaTotal slide. 132 June 26, 2012 progressively deforming 18
  19. 19. Clinical Biochemistry Metabolic Disorders of Proteins Diseases Associated with Clotting Factor Dysfunction Afibrinogenemia complete loss of fibrinogen, Factor I Dysfibrinogenemia dysfunctional fibrinogen, Factor I Factor II Disorders Factor III (tissue factor) is the only coagulation factor for which a congenital defect has not been identified Factor V Deficiency Labile Factor deficiency Factor VII Deficiency Hemophilia A Factor VIII deficiency Hemophilia B Factor IX deficiency Factor X Deficiency Factor XI Deficiency Rosenthal Syndrome, Plasma Thromboplastin Antecedent (PTA) deficiency Factor XII Deficiency Hageman factor deficiency Factor XIII Deficiency Factor V & VIII Combined Deficiency Factor VIII & IX combined Deficiency Factor IX & XI Combined Deficiency Protein C Deficiency Protein S Deficiency Thrombophilia Antithrombin III deficiency Giant Platelet Syndrome platelet glycoprotein Ib deficiency von Willebrand Disease June 26, 2012 Total slide. 132 19 Fletcher Factor Deficiency Prekallikrein deficiency
  20. 20. Clinical Biochemistry Metabolic Disorders of Proteins Defects in Amino Acid Metabolism Phenylketonuria Type I Tyrosinemia - Tyrosinosis Type II Tyrosinnemia - Richner-Hanhart Syndrome Type III Tyrosinemia Alcaptonuria Homocystinuria Histidinemia Maple Syrup Urine Disease, MSUD MSUD Type Ib MSUD Type II Methylmalonic Aciduria Non-ketonic Hyperglycinemia Type I (NKHI) Hyperlysinemia June 26, 2012 Total slide. 132 20
  21. 21. Clinical Biochemistry Metabolic Disorders of Proteins Syndrome 1 June 26, 2012 Total slide. 132 21
  22. 22. Clinical Biochemistry Metabolic Disorders of Proteins Case 1 Patrick Birth History: Full Term, 3,620 gm Uncomplicated Pregnancy, Labor & Delivery Mother 24 yr old, healthy No Prenatal exposure to alcohol, drugs, infection, known teratogens Discharged home on day of life 2 June 26, 2012 Total slide. 132 22
  23. 23. Clinical Biochemistry Metabolic Disorders of Proteins Case 1 (CONTINUED) Developmental Hx Seizure History Rolled over – 3 months First – 11 m Social smile - 4 m Generalized, tonic/clonic Stand alone – 14 m Total – 4 seizures First word – 18 m MRI – decreased grey/white differentiation Phrases – not yet and cortical atrophy Walk alone – 2 yr June 26, 2012 Total slide. 132 23
  24. 24. Clinical Biochemistry Metabolic Disorders of Proteins Case 1 (Cont) Physical Exam Growth Blond hair, blue eyes Non-dysmorphic child Neurological exam: Decreased tone, brisk reflexes June 26, 2012 Total slide. 132 24
  25. 25. Clinical Biochemistry Metabolic Disorders of Proteins Normal Patrick• Abnormal high intensity signal in deep white matter• Leucodystrophy and Cortical atrophy June 26, 2012 Total slide. 132 25
  26. 26. Clinical Biochemistry Metabolic Disorders of Proteins Case 2 Jeremy newborn male Mother - 19 yr old Full Term: 3,100 gm First Pregnancy Uncomplicated P,L & D Father -18 yr old No perinatal infection, Healthy no alcohol, no drugs, no known teratogens June 26, 2012 Total slide. 132 26
  27. 27. Clinical Biochemistry Metabolic Disorders of Proteins Case 2 Physical Exam and Labs Ht & Wt = 70% General exam normal HC< 5% Neurological exam - normal Urine Ferric Chloride (FeCl3) is positive June 26, 2012 Total slide. 132 27
  28. 28. Clinical Biochemistry Metabolic Disorders of Proteins Case 2 Jeremy is now 13 years old and exhibits Persistent microcephaly Spasticity Mental retardation Coarctation of Aorta June 26, 2012 Total slide. 132 28
  29. 29. Clinical Biochemistry Metabolic Disorders of Proteins Case 3 Luis (8yo) referred to Developmental Pediatrics clinic Chief Complaint: Hyperactivity and Learning Disabilities Patient and his Brother •Self selects diet •low in meat, eggs, cheese •enriched in fruits / vegetables June 26, 2012 •Similar Total slide. 132 pigmentation to his brother 29
  30. 30. Clinical Biochemistry Metabolic Disorders of Proteins Case 4 Hannah: 6 month old female Diagnosed with metabolic disorder on abnormal newborn metabolic screen Normal growth / development Normal physical exam On treatment with metabolic formula June 26, 2012 Total slide. 132 30
  31. 31. Clinical Biochemistry Metabolic Disorders of Proteins All four cases Examples of hyperphenylalanemia Defects in metabolism of phenylalanine Prototype – PKU Elevation of PHE > 20 mg/dl Normal < 2 mg/dl June 26, 2012 Total slide. 132 31
  32. 32. Clinical Biochemistry Metabolic Disorders of Proteins PKU Clinical Findings Mousy or musty odor Exzema Fair coloring (decreased hair and skin pigmentation) Behavior Problems Mental Retardation Lose ~ 1 IQ point per week of non-treatment June 26, 2012 Total slide. 132 32
  33. 33. Clinical Biochemistry Metabolic Disorders of Proteins Phenylalanine Metabolism Food Catabolism Phenylalanine PHE Essential AA 50% Body Protein Major TYR interconversions Melanin through tyrosine DOPA NE / EPI June 26, 2012 Total slide. 132 33
  34. 34. Clinical Biochemistry Metabolic Disorders of Proteins June 26, 2012 Total slide. 132 34
  35. 35. Clinical Biochemistry Metabolic Disorders of Proteins Conditionally Essential AA June 26, 2012 Total slide. 132 35
  36. 36. Clinical Biochemistry Metabolic Disorders of Proteins Essential Amino Acids Histidine Isoleucine Leucine Lysine Methionine (and/or cysteine) Phenylalanine (and/or tyrosine) Threonine Tryptophan Valine June 26, 2012 Total slide. 132 36
  37. 37. Clinical Biochemistry Metabolic Disorders of Proteins Urine Alternate Disposal Phenyl lactate Phenylacetate Phenylethylamine Phenylacetyl glutamine Mousy or musty odor June 26, 2012 Total slide. 132 37
  38. 38. Clinical Biochemistry Metabolic Disorders of Proteins PKU Autosomal Recessive disorder caused by mutation in PAH gene Newborn screening started in 1963 Incidence: 1 in 15,000 Subtypes and heterogeneity Classic Moderate and mild Non-classical or non-PKU hyperphenylalaninemia June 26, 2012 Total slide. 132 38
  39. 39. Clinical Biochemistry Metabolic Disorders of Proteins PKU Autosomal Recessive disorder caused by mutation in PAH gene Newborn screening started in 1963 Incidence: 1 in 15,000 Subtypes and heterogeneity Classic Moderate and mild Non-classical or non-PKU hyperphenylalaninemia  % enzyme activity determines clinical severity June 26, 2012 Total slide. 132 39
  40. 40. Clinical Biochemistry Metabolic Disorders of Proteins PKU Autosomal Recessive disorder caused by mutation in PAH gene Newborn screening started in 1963 Incidence: 1 in 15,000 Subtypes and heterogeneity Classic (tolerate < 250mg phe/day) Mild (tolerate 400-600mg phe/day) Hyperphenylalaninemia (normal diet)  % enzyme activity determines clinical severity June 26, 2012 Total slide. 132 40
  41. 41. Clinical Biochemistry Metabolic Disorders of Proteins PKU Autosomal Recessive disorder caused by mutation in PAH gene Newborn screening started in 1963 Incidence: 1 in 15,000 Subtypes and heterogeneity Classic Moderate Tetrahydrobiopterin (BH4) responsive Mild Hyperphenylalaninemia Hyperphe • Urine pterins June 26, 2012 • blood dihydropteridine reductase 41 Total slide. 132
  42. 42. Clinical Biochemistry Metabolic Disorders of Proteins June 26, 2012 Total slide. 132 42
  43. 43. Clinical Biochemistry Metabolic Disorders of Proteins June 26, 2012 Total slide. 132 43
  44. 44. Clinical Biochemistry Metabolic Disorders of Proteins June 26, 2012 Total slide. 132 44
  45. 45. Clinical Biochemistry Metabolic Disorders of Proteins BH4 Responders PAH mutation 62% catalytic 21% regulatory Allelic pattern 1 mild + 1 severe 2 mild 2 severe (rare) Diet – BH4 without protein restriction June 26, 2012 Total slide. 132 45
  46. 46. Clinical Biochemistry Metabolic Disorders of Proteins Biological Effects HyperPhe inhibits transport of large, neutral AA into the brain (as does Leucine) Inhibition of protein and neurotransmitters  Deficiencies of dopamine, serotonin June 26, 2012 Total slide. 132 46
  47. 47. Clinical Biochemistry Metabolic Disorders of Proteins Major Neuropathologic changes Hypomyelination (Phe-sensitive oligodendrocytes) White matter degeneration (leucodystrophy) Developmental delay/arrest cerebral cortex Microcephaly Mental retardation Seizures June 26, 2012 Total slide. 132 47
  48. 48. Clinical Biochemistry Metabolic Disorders of Proteins Non-Neuro pathology Hypomelanosis – Why ? June 26, 2012 Total slide. 132 48
  49. 49. Clinical Biochemistry Metabolic Disorders of Proteins Non-Neuro pathology Hypomelanosis Blond hair, blue eyes, pale Deficient Tyrosine production (precursor of Melanin) Cardiac Coarctation of the Aorta June 26, 2012 Total slide. 132 49
  50. 50. Clinical Biochemistry Metabolic Disorders of Proteins Maternal PKU syndrome First mentioned in literature in 1937 First mentioned as a complication of PKU in 1956 Women with MR and PKU has 3 children, all retarded despite not having PKU Microcephaly and cardiac defects reported in 1960’s 1983 – MPKUCS begun June 26, 2012 Total slide. 132 50
  51. 51. Clinical Biochemistry Metabolic Disorders of Proteins Maternal PKU Collaborative Study Untreated women 92% risk of mental retardation 73% risk of microcephaly 40% risk of low birth weight 12% risk of congenital heart disease Reduced risk if maternal plasma phe levels are normalized pre-conceptually June 26, 2012 Total slide. 132 51
  52. 52. Clinical Biochemistry Metabolic Disorders of Proteins Maternal PKU syndrome Dose-Response Relationship Goal: Phe level between 2-6 mg/dl by 8 weeks June 26, 2012 Total slide. 132 52
  53. 53. Clinical Biochemistry Metabolic Disorders of Proteins The longer it takes to get Phe level < 8 mg/dl the lower the IQ of the baby June 26, 2012 Total slide. 132 53
  54. 54. Clinical Biochemistry Metabolic Disorders of Proteins Balancing Metabolic Control Exposure to Elimination normal of PHE PHE intake from the diet June 26, 2012 Total slide. 132 54
  55. 55. Clinical Biochemistry Metabolic Disorders of Proteins Balancing Metabolic Control Exposure to normal PHE intake: Elevations of PHE Elevations of PHE-ketones Deficient TYR, DOPA, NE, EPI Mental retardation / seizures June 26, 2012 Total slide. 132 55
  56. 56. Clinical Biochemistry Metabolic Disorders of Proteins Balancing Metabolic Control Exposure to normal PHE intake: Elevations of PHE Elevations of PHE-ketones Deficient TYR, DOPA, = Bad NE, EPI Mental retardation / seizures June 26, 2012 Total slide. 132 56
  57. 57. Clinical Biochemistry Metabolic Disorders of Proteins Balancing Metabolic Control Elimination of PHE from the diet: Decreases PHE Decreases PHE-ketones Deficient TYR, DOPA, NE, EPI DEATH from essential AA deficiency June 26, 2012 Total slide. 132 57
  58. 58. Clinical Biochemistry Metabolic Disorders of Proteins Balancing Metabolic Control Elimination of PHE from the diet: Decreases PHE Decreases PHE-ketones Bad = Deficient TYR, DOPA, NE, EPI DEATH from essential AA deficiency June 26, 2012 Total slide. 132 58
  59. 59. Clinical Biochemistry Metabolic Disorders of Proteins Optimal Therapy of PKU Initiate treatment by 7 days of life Phenylalanine levels Age Level Freq of Testing 0-12 months 2-6 mg/dl 1x/week 1-12 years Same 2x/month > 12 years 2-15 mg/dl 1x/month Pregnancy 2-6 mg/dl* 2x/week June 26, 2012 * 3m before conception Total slide. 132 59
  60. 60. Clinical Biochemistry Metabolic Disorders of Proteins summery Hyperphenylalanemia Treatment is An abnormal lab Effective if begun finding early and continued Several defects may for life result in hyperphe Aggressive Specific Dx is critical management PHE restriction in during growth and BH4 deficiency is lethal during illness June 26, 2012 Total slide. 132 60
  61. 61. Clinical Biochemistry Metabolic Disorders of Proteins What about our cases?? Patrick – case 1 Jeremy – case 2  Dx ?  Dx ? 3 yr old with Newborn with developmental delay microcephaly and + FeCl3 and seizures….. Now mentally retarded Choices 2. Classic PKU – treated or untreated 3. Maternal PKU 4. Hyperphe June 26, 2012 Total slide. 132 61
  62. 62. Clinical Biochemistry Metabolic Disorders of Proteins What about our cases?? Patrick – case 1 Jeremy – case 2  Classic PKU (mod)  Maternal PKU syndrome Newborn with 3 yr old with microcephaly and + FeCl3 developmental delay Now mentally retarded and seizures….. He is metabolically Patrick has permanent normal… but his mother disabilities had PKU His mother wants more children but is not on diet June 26, 2012 Total slide. 132 62
  63. 63. Clinical Biochemistry Metabolic Disorders of Proteins Our Cases Luis - Case 3 Hannah - Case 4 Dx ?  Dx ? 8yo with learning 6 month old disability and Normal growth and hyperactivity development Choices 2. Classic PKU – treated or untreated 3. Maternal PKU 4. Hyperphe June 26, 2012 Total slide. 132 63
  64. 64. Clinical Biochemistry Metabolic Disorders of Proteins Our Cases Luis - Case 3 Hannah - Case 4  Classic PKU (Mexico)  Classic PKU, treated On treatment Continues to do well His hyperactivity has on therapy improved Growth, development He will not regain and intellectual normal intellect situation are normal June 26, 2012 Total slide. 132 64
  65. 65. Clinical Biochemistry Metabolic Disorders of Proteins Syndrome 2 June 26, 2012 Total slide. 132 65
  66. 66. Clinical Biochemistry Metabolic Disorders of Proteins Jakob Jakob was the product of a full term pregnancy Appeared healthy until day of life nine Hospitalized in ICU At 9 months Jakob is developmentally normal and growing well However, some times his amino acid levels are dramatically elevated. June 26, 2012 Total slide. 132 66
  67. 67. Clinical Biochemistry Metabolic Disorders of Proteins MSUD What is MSUD ? What odor was the physician asking mom about ? Where else can you smell it ? Is odor a reliable physical finding ? What causes neurotoxicity ? What is the long-term treatment and outcome ? June 26, 2012 Total slide. 132 67
  68. 68. Clinical Biochemistry Metabolic Disorders of Proteins MSUD Autosomal Recessive Mutations in branched chain α-ketoacid dehydrogenase (BCKDH) Mitochondrial enzyme complex 3 subunits (E1, E2, and E3) encoded by 4 unlinked genes E1 decarboxylase – heterotetramer (α and β subunits) E2 transacylase E3 dehydrogenase  E1 is thiamine dependent June 26, 2012 Total slide. 132 68
  69. 69. Clinical Biochemistry Metabolic Disorders of Proteins June 26, 2012 Total slide. 132 69
  70. 70. Clinical Biochemistry Metabolic Disorders of Proteins Maple Syrup Urine Disease Classical Normal newborn, hours to days Poor feeding and drowsiness metabolic acidosis, hypoglycemia, cerebral edema, respiratory distress, hiccups, apnea, bradycardia, hypothermia, coma June 26, 2012 Total slide. 132 70
  71. 71. Clinical Biochemistry Metabolic Disorders of Proteins Clinical Manifestations Time Symptom/Sign 12-24 hours Maple syrup odor to cerumen Elevated BCAA 2-3 days Irritability, poor feeding Ketonuria 4-5 days Encephalopathy (lethargy, apnea, atypical movements 7-10 days Coma and respiratory failure June 26, 2012 Total slide. 132 71
  72. 72. Clinical Biochemistry Metabolic Disorders of Proteins Metabolic Defect BCAA amino- transferases BCKDH - Rate limiting June 26, 2012 Total slide. 132 72
  73. 73. Clinical Biochemistry Metabolic Disorders of Proteins Branch Chain Amino Acids Leucine, Isoleucine and Valine Comprise ~40% of essential AA During fasting, ~ 80% of AA released is recycled back into protein synthesis June 26, 2012 Total slide. 132 73
  74. 74. Clinical Biochemistry Metabolic Disorders of Proteins Branch Chain Amino Acids Transamination and oxidative disposal of leucine occurs in skeletal muscle (50%), kidney (25%) and gut/liver (25%) Nitrogen released is used to form glutamate -> alanine - > glucose (alanine aminotransferase reaction) Leucine + α-Ketoglutarate -> α-Ketoisocaproate and Glutamate Glutamate and Pyruvate -> α-Ketoglutarate and Alanine Alanine -> -> -> Glucose June 26, 2012 Total slide. 132 74
  75. 75. Clinical Biochemistry Metabolic Disorders of Proteins Branch Chain Amino Acids Increase in supply from diet or proteolysis must be met with appropriate increase in anabolic pathway (blocked in disorder) Most severe biochemical intoxication caused by catabolism of endogenous protein June 26, 2012 Total slide. 132 75
  76. 76. Clinical Biochemistry Metabolic Disorders of Proteins Branch Chain Amino Acids Defect leads to elevated levels, more pronounced in infants and children due to enhanced rates of growth Leucine accumulation is most toxic June 26, 2012 Total slide. 132 76
  77. 77. Clinical Biochemistry Metabolic Disorders of Proteins Signs/Symptoms of Acute Toxicity Ataxia (unsteady, clumsy movements) Acute dystonia (involuntary muscle contractions) Mood swings Nausea, Vomiting, and Anorexia Hallucinations Altered level of consciousness Stroke, coma, and death June 26, 2012 Total slide. 132 77
  78. 78. Clinical Biochemistry Metabolic Disorders of Proteins Signs/Symptoms of Chronic Toxicity Mood Disorders – anxiety and depression Mental retardation Neurologic deficits (stroke) June 26, 2012 Total slide. 132 78
  79. 79. Clinical Biochemistry Metabolic Disorders of Proteins Neurotoxicity of Leucine • Leucine and KIC intracellular accumulation results in cellular edema June 26, 2012 Total slide. 132 79
  80. 80. Clinical Biochemistry Metabolic Disorders of Proteins Neurotoxicity of Leucine Leucine and KIC intracellular accumulation results in cellular edema Leucine accumulation inhibits entry of other large neutral amino acids June 26, 2012 Total slide. 132 80
  81. 81. Clinical Biochemistry Metabolic Disorders of Proteins Neurotoxicity of Leucine • Leucine and KIC intracellular accumulation results in cellular edema • Leucine accumulation inhibits entry of other large neutral amino acids Disrupted monoamine transmitter production  Decreased ‘fast’ neurotransmitter pools – glutamate, GABA, aspartate June 26, 2012 Total slide. 132 81
  82. 82. Clinical Biochemistry Metabolic Disorders of Proteins Neurotoxicity of Leucine Leucine and KIC intracellular accumulation results in cellular edema Leucine accumulation inhibits entry of other large neutral amino acids Metabolites (KIC) induce oxidative injury  Melatonin, Vitamins C and E may be protective June 26, 2012 Total slide. 132 82
  83. 83. Clinical Biochemistry Metabolic Disorders of Proteins Neurotoxicity of Leucine 1. Excess KIC results in consumption of substrates needed for malate-aspartate shuttle resulting in increased brain lactate and energy failure June 26, 2012 Total slide. 132 83
  84. 84. Clinical Biochemistry Metabolic Disorders of Proteins Neurotoxicity of Leucine KIC + glutamate Leucine + α-Ketoglutarate Increased Aspartate utilization Decreased functioning of malate-aspartate shuttle Decreased transfer of reducing equivalent Energy failure And lactic acidosis June 26, 2012 Total slide. 132 84
  85. 85. Clinical Biochemistry Metabolic Disorders of Proteins Neurotoxicity of Leucine Glutamic Acid is a critical excitatory neurotransmitter Leucine is trafficked to the brain as a source of –NH2 groups (Leucine-Glutamate cycle) June 26, 2012 Total slide. 132 85
  86. 86. Clinical Biochemistry Metabolic Disorders of Proteins Neurotoxicity of Leucine Elevated Leucine Accumulation of KIC drives leucine-glutamate cycle in reverse direction LEU decreased brain glutamate2-ketoisocaproate Isovaleryl-CoA June 26, 2012 Total slide. 132 86
  87. 87. Clinical Biochemistry Metabolic Disorders of Proteins Neurotoxicity of Leucine Elevated Leucine Altered brain water homeostasis cell edema June 26, 2012 Total slide. 132 87
  88. 88. Clinical Biochemistry Metabolic Disorders of Proteins Neurotoxicity of Leucine Elevated Leucine Inhibits entry into the brain of other large, neutral AA (as in PKU) phenylalanine, tryptophane, methionine, tyrosine,histidine, threonine, and BCAA (L1-NAA-t) Dystonia and ataxia may arise from acute deficiency of tyrosine and dopamine Decreased dendritic branching, hypomyelination June 26, 2012 Total slide. 132 88
  89. 89. Clinical Biochemistry Metabolic Disorders of Proteins MSUD Goals of Treatment Restriction of Leucine, Isoleucine, and Valine to maintain post-prandial plasma BCAA near normal level Supplement free valine and isoleucine Give glutamine and alanine Hemodialysis June 26, 2012 Total slide. 132 89
  90. 90. Clinical Biochemistry Metabolic Disorders of Proteins MSUD Goals of Treatment Excessive restriction Growth failure Anemia Breakdown of mucosa Immunodeficiency Dysmyelination, abnormal dendritic branching, microcephaly and mental retardation June 26, 2012 Total slide. 132 90
  91. 91. Clinical Biochemistry Metabolic Disorders of Proteins Follow-Up Jacob – Age 4 yr Family unwilling to tolerate Continual stress of life threatening disorder dietary management, forcing feeds by G-tube when not interested in eating) Severe limitations on their lives June 26, 2012 Total slide. 132 91
  92. 92. Clinical Biochemistry Metabolic Disorders of Proteins Liver Transplantation Liver transplantation results in increase in whole body BCKD activity Muscle = 50% Kidney = 25% Liver and gut = 25% Placed on liver transplant list at Pittsburgh and underwent successful liver transplant 3 years ago Now on unrestricted diet June 26, 2012 Total slide. 132 92
  93. 93. Clinical Biochemistry Metabolic Disorders of Proteins Jacop after liver transplantation June 26, 2012 Total slide. 132 93
  94. 94. Clinical Biochemistry Metabolic Disorders of Proteins Liver Transplant: Outcomes Normalization of BCAA within 6-12 hours Sustained normalization of BCAA on unrestricted diet (4-18 months f/u) June 26, 2012 Total slide. 132 94 Strauss KA. Am J Transpl; 2006
  95. 95. Clinical Biochemistry Metabolic Disorders of Proteins Alkaptonuria Alkaptonuria: a.k.a. Black Urine Disease First recognized “Inborn Error of Metabolism” by Archibald Garrod in 1902 Symptoms: Homogentisate in the urine oxidizes to a black color Also, black deposits in the sclera In adults, accumulation of deposits in connective tissue leads to arthritis No effective treatment June 26, 2012 Total slide. 132 95
  96. 96. Clinical Biochemistry Metabolic Disorders of Proteins Symptoms of alkaptonuria Urine from patients Normal urine with alkaptonuria June 26, 2012 Total slide. 132 96
  97. 97. Clinical Biochemistry Metabolic Disorders of Proteins Patients may display painless bluish darkening of the outer ears, nose and whites of the eyes. Longer term arthritis often occurs. June 26, 2012 Total slide. 132 97
  98. 98. Clinical Biochemistry Metabolic Disorders of ProteinsHomogentisic acid is an intermediate in the degradation pathway ofphenylalanine. The reaction is catalysed by homogentisate dioxygenase(HGO). homogentisic acid OH O O HOOC C C CH CH CH2 CH2 COOH OH HGO maleylacetoacetic acid CH2 COOH A deficiency of HGO causes alkaptonuria. June 26, 2012 Total slide. 132 98
  99. 99. Clinical Biochemistry Metabolic Disorders of Proteins Catabolic pathway for phenylalanine and tyrosine Defect here causes Homogentisate dioxygenase alkaptonuria Defect here causes Fumarylacetoacetate Type I Tyrosinemia hydrolase June 26, 2012 Total slide. 132 99
  100. 100. Clinical Biochemistry Metabolic Disorders of Proteins Tyrosinemia Tyrosinemia is diagnosed by a blood and urine test. Tyrosinemia is treated by a low protein diet (low in phenylalanine, methionine and tyrosine) and a drug called NTCB. June 26, 2012 Total slide. 132 100
  101. 101. Clinical Biochemistry Metabolic Disorders of Proteins homogentisic acid FAAH catalyses the last step in the degradation path of phenylalanine and tyrosine. O O Tyrosinemia HOOC C C O O = = CH CH CH2 CH2 COOH HOOC - CH2 - CH2 - C - CH2 - C - CH2 - COOH maleylacetoacetic acid succinylacetoacetic acid spontaneous HOOC CH CH CH2 CH2 COOH COOH C C O O O O = = fumarylacetoacetate HOOC - CH2 - CH2 - C - CH2 - C - CH3 Succinylacetone FAAH toxic and mutagenic Fumarate + acetoacetateDeficiency of the enzyme FAAH results in Type I tyrosinemia June 26, 2012 Total slide. 132 101
  102. 102. Clinical Biochemistry Metabolic Disorders of Proteins WHAT ARE THE SYMPTOMS OF TYROSINEMIA? The clinical features of the disease fall into two categories: Acute Chronic June 26, 2012 Total slide. 132 102
  103. 103. Clinical Biochemistry Metabolic Disorders of Proteins Acute tyrosinemia • abnormalities appear in the first month of life • poor weight gain • enlarged liver and spleen • distended abdomen • swelling of the legs • increased tendency to bleeding, particularly nose bleeds • Jaundice • death from hepatic failure frequently occurs between three and nine months of age unless a liver transplantation is performed. June 26, 2012 Total slide. 132 103
  104. 104. Clinical Biochemistry Metabolic Disorders of Proteins Homocystinuria Defective activity of cystathionine synthase June 26, 2012 Total slide. 132 104
  105. 105. Clinical Biochemistry Metabolic Disorders of Proteins Major phenotypic expression Ectopia lentis Vascular occlusive disease Malar flash Osteoporosis Accumulation of homocysteine and methionine June 26, 2012 Total slide. 132 105
  106. 106. Clinical Biochemistry Metabolic Disorders of Proteins June 26, 2012 Total slide. 132 106
  107. 107. Clinical Biochemistry Metabolic Disorders of Proteins June 26, 2012 Total slide. 132 107
  108. 108. Clinical Biochemistry Metabolic Disorders of Proteins A family of homocystinuria June 26, 2012 Total slide. 132 108
  109. 109. Clinical Biochemistry Metabolic Disorders of Proteins Albinism
  110. 110. Clinical Biochemistry Metabolic Disorders of Proteins What is Albinism? A lack of pigment in skin, hair, and eyes. Albinism is an inherited condition that results from a gene mutation. Altered genes are unable to exhibit natural pigments that normally occur. Albinism can occur in nearly all species: animals, plants, or humans. June 26, 2012 Total slide. 132 110
  111. 111. Clinical Biochemistry Metabolic Disorders of Proteins Albinism in all forms… June 26, 2012 Total slide. 132 111
  112. 112. Clinical Biochemistry Metabolic Disorders of Proteins Lets take a closer look… What causes Albinism? Albinism is genetic and is passed on through heredity via the genes. Genes involved are supposed to communicate the pigmentation (Retina of albino) of eyes, skin, and hair. Albino Individuals have received a recessive gene (aa) from both parents resulting in an incorrect genetic blueprint for pigment. June 26, 2012 Total slide. 132 112
  113. 113. Clinical Biochemistry Metabolic Disorders of Proteins Albinism June 26, 2012 Total slide. 132 113
  114. 114. Clinical Biochemistry Metabolic Disorders of Proteins Albinism June 26, 2012 Total slide. 132 114
  115. 115. Clinical Biochemistry Metabolic Disorders of Proteins Characteristics of albinism: Low Vision (20/50 to 20/800) Sensitivity to bright light and glare Rhythmic, involuntary eye movements Absent or decreased pigment in the skin and eye and sensitivity to sunburn that could lead to skin cancers or cataracts in later life "Slowness to see" in infancy June 26, 2012 Total slide. 132 115
  116. 116. Clinical Biochemistry Metabolic Disorders of Proteins Characteristics of albinism: Farsighted, nearsighted, often with astigmatism Underdevelopment of the central retina Decreased pigment in the retina Inability of the eyes to work together Light colored eyes ranging from lavender to hazel, with the majority being blue June 26, 2012 Total slide. 132 116
  117. 117. Clinical Biochemistry Metabolic Disorders of Proteins Problems associated with Albinism… Impaired vision due to the lack of melanin pigment Skin damage due to Sun Mild problems with blood clotting Hearing impairment June 26, 2012 Total slide. 132 117
  118. 118. Clinical Biochemistry Metabolic Disorders of Proteins Classification & Types of Albinism Oculocutaneous albinism (OCA): melanin pigment is missing in skin, hair, and eyes. Ocular albinism (OA): melanin pigment is primarily missing in the eyes and the skin and the hair appear normal. OCA is more common than OA. June 26, 2012 Total slide. 132 118
  119. 119. Clinical Biochemistry Metabolic Disorders of Proteins Oculocutaneous Albinism June 26, 2012 Total slide. 132 119
  120. 120. Clinical Biochemistry Metabolic Disorders of Proteins Genes Associated with Albinism & Pigmentation: Tyrosinase: major enzyme involved in melanin formation Location: Chromosome 11 DHICA-oxidase: loose of function of this enzyme leads to albinism Location: Chromosome 9 Ocular Albinism Gene: role unknown Location: Chromosome X (primarily Sammy’s fault not Jeff’s) June 26, 2012 Total slide. 132 120
  121. 121. Clinical Biochemistry Metabolic Disorders of Proteins Tyrosin hydroxylase dopa Tyrosin hydroxylase dopaquinone Eumelanins Indole 5,6 quinone Quinoleimine intermediate Mixed-type melanins Pheomelanins trichochroms June 26, 2012 Total slide. 132 121
  122. 122. Clinical Biochemistry Metabolic Disorders of Proteins Facts you may not know… 1 in 70 humans carries a Hey want to know recessive gene linked to something… albinism. If both parents carry an albino gene the chances are 1 in 4 (½ x ½) that offspring will display albinism. Not really, but I If one parent displays albinism, suppose and one does not but carries a you are recessive gene, the chances of going to tell me the offspring displaying anyway… albinism is 1 in 2 (1 x ½). 132 June 26, 2012 Total slide. 122
  123. 123. Clinical Biochemistry Metabolic Disorders of Proteins Common Myths & Misconceptions Persons with albinism always have red eyes. Persons with albinism are totally blind. Albinism is contagious. Persons with albinism are the result of evil spirits or wrongdoing. Persons with albinism are retarded or deaf. Albinism results from inbreeding or the mixture of two races. Persons with albinism have magical powers. June 26, 2012 Total slide. 132 123
  124. 124. Clinical Biochemistry Metabolic Disorders of Proteins In summary… Albinism is a rather rare recessive mutation that can be witnessed in many multiple species; plant, animal, and human, all with phenotypic similarities. June 26, 2012 Total slide. 132 124
  125. 125. Clinical Biochemistry Metabolic Disorders of Proteins Albinism in animals June 26, 2012 Total slide. 132 125
  126. 126. Clinical Biochemistry Metabolic Disorders of Proteins Albinism in films June 26, 2012 Total slide. 132 126
  127. 127. Clinical Biochemistry Metabolic Disorders of Proteins A family of albinism June 26, 2012 Total slide. 132 127
  128. 128. Clinical Biochemistry Metabolic Disorders of Proteins Newborn screening June 26, 2012 Total slide. 132 128
  129. 129. Clinical Biochemistry Metabolic Disorders of Proteins Newborn screening The goal of newborn screening is to eliminate, through early identification and treatment, and improve the quality of life for affected individuals. June 26, 2012 Total slide. 132 129
  130. 130. Clinical Biochemistry Metabolic Disorders of Proteins Newborn screening Newborn screening is not just a laboratory service; it is a system of care including, not only testing, but also follow up, definitive diagnosis, treatment, long term management, education and evaluation---- June 26, 2012 Total slide. 132 130
  131. 131. Clinical Biochemistry Metabolic Disorders of Proteins Newborn screening The goal of newborn screening follow up is to ensure that each affected infant receives the full benefit of early detection and optimal long term treatment and management. June 26, 2012 Total slide. 132 131
  132. 132. Clinical Biochemistry Metabolic Disorders of Proteins Follow Up short term follow up- assure that a definitive diagnostic work-up is done, that the infant really has the disorder and that the infant is started on appropriate treatment long term follow up- assure that the infant continues to receive appropriate treatment and monitors the long term outcome June 26, 2012 Total slide. 132 132
  133. 133. Clinical Biochemistry Metabolic Disorders of Proteins THE END June 26, 2012 Total slide. 132 133

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