1 / 49

Overview of Inherited Metabolic Disorders

Overview of Inherited Metabolic Disorders. Pediatric Resident Academic Half Day. Outline. Overview of genetic / metabolic diseases Overview of cell metabolism Amino acids Glucose homeostasis Fatty acids Complex molecule biosynthesis & degradation Energy metabolism

fawzi
Download Presentation

Overview of Inherited Metabolic Disorders

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Overview of Inherited Metabolic Disorders Pediatric Resident Academic Half Day

  2. Outline • Overview of genetic / metabolic diseases • Overview of cell metabolism • Amino acids • Glucose homeostasis • Fatty acids • Complex molecule biosynthesis & degradation • Energy metabolism • Approaches to treatment • Example case histories for discussion

  3. Genetic disorders of the body’s biochemistry that can cause: Death disability Our goal is: prevention of these outcomes by early diagnoses and treatment Primary, secondary & tertiary prevention How expensive is this? What Are Genetic Metabolic Disorders?

  4. Inborn Errors of Metabolism(Genetic / Metabolic Disorders) Genetic deficiencies in production of proteins: • Enzymes • Transport proteins • Receptor proteins • Sub-cellular organelles: • structural, assembly & chaperone proteins

  5. Overview of Inherited Metabolic Disease • over 700 separate IEM described • most present early: in utero 8 % birth - 1 yr 55 % 1 yr-puberty 32 % adulthood 5 % • for many, early detection prior to irreversible pathology may permit intervention with diet or medical therapy to prevent long-term death or disability • approaches to early detection: • symptomatic presentation • screening • IEM affect about about 1/1000 to 1/2000 persons

  6. Classification by Pathogenic Mechanism • IEM that lead to an acute or progressive intoxication from accumulation of toxic compounds proximal to the metabolic block ( PKU,UCD,MMA,IVA,galactosemia etc.) • IEM with symptomsdue to partial deficiency in energy production ( GSD’s, B-oxidation defects, mitochondrial disorders, congenital lactic acidosis etc.) • IEM that have: • disturbed biosynthesis of complex molecules( CDGS) • disturbed degradation of complex molecules (MPS, GM1 gangliosidosis, Tay-Sach’s/Sandhoff)

  7. UntreatedPhenylketonuria Hurler-Scheie Syndrome Sandhoff Disease

  8. Overview of Intermediary Metabolism as It Relates to Inherited Metabolic Diseases

  9. Key Metabolic Functions That Our Bodies Must Do: • Accept dietary nutrients and supply them to appropriate body tissues in sufficient but non-toxic amounts • maintain appropriate biosynthetic mechanisms to convert dietary nutrients into required metabolites • maintain metabolic homeostatic mechanisms to ensure that critical nutrients are available as necessary • ensure optimum levels of nutrients by controlling absorption, degradative metabolism and elimination (renal, GI, biliary etc.) • provide mechanisms to support tissue turnover / growth

  10. Genetic Metabolic Disorders Can Cause Disruption of any of these Essential Processes The particular process disrupted determines the clinical outcome in a particular patient Mechanisms of Disruption Include: • toxicity due to excessive metabolite levels (PKU) • inadequate essential precursors (SLOS) • inadequate energy production (mitochondrial disorders) • abnormal biosynthesis of macromolecules (CDGS) • abnormal macromolecule degradation (LSD / peroxisomes) • abnormal transport (cystinuria, cystinosis)

  11. The Cellular Basis of Metabolism

  12. Overview of Metabolism

  13. Amino Acid Metabolism

  14. Branched Chain Amino Acid Metabolism:Leucine & Isovaleric Acidemia Isovaleryl-CoA Dehydrogenase Deficiency “Isovaleric Acidemia”

  15. Maintainence of Euglycemia during Fed & Fasting States Maintenance of blood and tissue glucose levels is critical for function • CNS function (except in the infant, CNS is almost completely dependent on glucose from the blood for energy • other tissues also require glucose but can utilize other energy sources as well ie fatty acids and amino acids, glycerol and lactate

  16. Requirements to Maintain Euglycemia Under “Fasting” Conditions • Functioning hepatic gluconeogenic & glycogenolytic enzyme systems • adequate endogenous gluconeogenic substrates (amino acids, glycerol, lactate) • adequate B-oxidation of fatty acids to synthesize glucose & ketones • functional endocrine system to modulate & integrate the above system components

  17. FED STATE High GI absorption High Glycogen biosynthesis High triglyceride biosynthesis Low gluconeogenesis Low lipolysis FASTING STATE Low GI absorption High Glycogenolysis High Lipolysiswith mobilization of fatty acids & ketones High Gluconeogenesis Homeostatic Processes Maintaining Euglycemia(insulin & glucagon in response to glucose levels)

  18. Phases of Glucose Homeostasis 1.Glucose absorptive phase: 3 - 4 hrs after glucose ingestion (high insulin) 2.Post absorptive/early starvation: 3-12 hrs glucose (from hepatic glycogen) to brain, RBC, renal medulla 3. Early / Intermediate Starvation: 14+ hrs gluconeogenesis & (later) lipolysis

  19. GSD-II ( lysosomal) GSD-IV GSD-V,GSD-VI,GSD-IX GSD-0 GSD-III GSD-1a&b GSD-VII GSD-X,GSD-XII,GSD-XIII GSD-XI (LDH) LIVER MUSCLE

  20. VLCAD,MCAD, SCAD Trifunctional protein

  21. Biosynthesis & Degradation of Complex Molecules Considerable energy and substrates are used in cells for the synthesis and degradation of macromolecules that: • Perform biological functions • Become components of sub-cellular structures

  22. Endoplasmic Reticulum: Synthesis of GlycoproteinsN-Glycosylation & the Mannose Pathway

  23. Abnormal glycopeptide BiosynthesisDisorders of N-Glycosylation

  24. Abnormal Glycopeptide BiosynthesisO-Glycosylation and its Disorders

  25. Lysosomes: Degradation ofMacromolecules

  26. Metabolic Role of Lysosomes • Degradation of endogenous and exogenous macromolecules • Acidic hydrolysis: • Molecules include: mucopolysaccharides sphingolipids peptides oligosaccharides glycopeptides lipids S-acetylated proteins monosaccharides/aminoacids/monomers

  27. Typical Lysosomal Storage Disease History • Initially “clinically normal” • Slow onset of symptoms usually involving multiple organs / systems • Progressive deterioration • Usually premature death • Typical features often include: neurodegeneration, organ enlargement, connective tissue involvement, cardiac & pulmonary involvement, other organs (vascular endothelium, muscle, kidney)

  28. Sphingolipidoses: Tay-Sach’s, Sandhoff, GM1 gangliosidosis, MLD,Krabbes, Fabry, Gaucher, Farber, Niemann-Pick Mucopolysaccharidoses: Hurler/ Hurler-Scheie/Scheie, Hunter, San Filippo, Morquio, Maroteau-Lamy, Sly Glycogenoses Pompe disease Lipid Storage diseases Wolman, cholesterol ester, NP”C” Oligosaccharide/glycopeptidoses Mannosidoses, fucosidosis, Schindlers, sialidoses, aspartylglycosaminuria Multiple enzyme deficiencies I-cell & MLIII, multiple sulfatase deficiency, galactosialidosis Transport deficiencies Cystinosis, Salla disease, ISS Peptide Storage Diseases Pycnodysostoses, infantile NClF 40+ Lysosomal Storage Diseases Identified

  29. Salla Disease FibroblastsDistended Lysosomes

  30. Mitochondria: Abnormal Energy Production

  31. Metabolic Jobs of Mitochondria • Amino acid metabolism • Urea cycle ( removal of ammonia) • Steroid biosynthesis • Fatty acid oxidation ( carnitine, B-oxidation) • Ketone body metabolism • Carbohydrate metabolism (PDH) • Aerobic energy product’n

  32. Mitochondria: Electron Transport Chain Enzyme ComplexesATP produced in using the respiratory chain Respiratory chain (inner compartment) (Five multimeric complexes + two electron carriers) • Complex I: 46 subunits ( 7 mDNA + 39 nDNA) • Complex II: 4 subunits ( 4 nDNA) • Coenzyme Q10 (ubiquinone) - carrier to complex III) • Complex III: ( 11 subunits (1 mDNA – 10nDNA) • Cytochrome C - mobile carrier to complex IV • Complex IV: 13 subunits (3 mDNA – 10 nDNA) Protons extruded by Cplx’s I,II, III, & IV • Complex V: ATP synthase – “Couples” proton reintake which is coupled to ATP synthesis

  33. TCA Cycle & Respiratory Chain Glucose TCA Cycle Electron Transport Chain

  34. Energy Production in Mitochondria Glycolysis, pyruvate, aconitate, Malate + other dehydrogen’n Rx’s NAD-H2 Cplx I H+ NAD (CoQ10) FAD-H2 H+ Cplx II Succinate, Isol, Val, Met, Thr, SCFA’s (CoQ10) FAD Cplx III ETF / ETF-QO (Cyt-C) H+ Cplx IV Fatty .Acid B-oxid’n, dimethylglycine, sarcosine O2 H20 ADP H+ Cplx V ATP Inner Mitoch. Membrane

  35. Mitochondria • Only organelle other then nucleus that has: • DNA (circular / double stranded) - 16,569 bases • Can synthesize own RNA & proteins • mDNA– 37 genes • 24 for translation (2 rRNA / 22 tRNA) • 13 for proteins of Respiratory Chain subunits • nDNA – many genes • code for 1000+ mitochondrial proteins (structural, transport, chaparone & enzyme)

  36. Any significant defect can lead to deficient function and result in clinical abnormality • Based on physiological function(s) affected • Based on organ(s) affected • Based on severity of mutation and resulting deficiency of protein-mediated biochemical function • Recognition often difficult clinically and usually requires laboratory support for screeening, diagnosis and treament.

  37. Approaches to treatment

  38. Common Treatment Examples • Restriction / supplements / medications • PKU& other aminoacidopathies • Urea cycle disorders • Organic acidopathies (MMA,PA, IVA etc.) • Ensure nutrient availability • Glycogen storage disorders • B-oxidation disorders • Enhancement of organelle function • mitochondrial disorders • Cell / organ replacement • lysosomal storage disorders

  39. More Recent Approaches to Therapy • End organ protection: large chain neutal amino acids in PKU • Stabilization of “mis-folded” proteins: otherwise that would be recognized as having defective “folding” and removed via proteosome mechanism • Improved correction of biochemical milieu in cells of patient with the metabolic defect:

  40. End Organ Protection in PKU CNS CNS High PHE Lower PHE BBB BBB Isol Leu Val Tyr Trypt Met High plasma phenylalanine High plasma phenylalanine PreKunil Low PHE Diet

  41. Indirect Therapy: Replacement of Essential Metabolites PKU: Extra tyrosine for protein synthesis, neurotransmitter biosynthesis, pigment biosynthesis Urea Cycle Disorders: Extra arginine to maintain adequate levels of urea cycle intermediates “ Many IEM Diets require Further Modification” Urea Cycle Disorders May need increased leucine, isoleucine & valine to compensate for loss of “N” as phenylacetyl-glutamine

  42. Organ Transplantation(to provide metabolic capability) Liver • Familial Hypercholesterolemia (LDL-cholesterol receptor deficiency) • Tyrosinemia • Glycogen Storage Disease (Type I) • Primary hyperoxaluria * Kidney • Fabry Disease • Cystinosis • Primary hyperoxaluria * Bone Marrow • Various lysosomal storage diseases ie. Hurler syndrome (MPSI) Cornea • Cystinosis, Fabry disease

  43. Biopterin-responsive PKU(PAH Deficiency) • Not due to a biopterin biosynthesis disorder • Up to 1/3 of PKU patients (usually milder variants) • Will have higher tolerance for PHE in diet when on BH4 OR • Be able to avoid low-PHE diet • Clinical trials now in process

  44. Lysosomal Storage Disorders:Treatment options • Supportive care • Enzyme replacement therapy • Substrate depletion (biosynthesis inhibitors) • Hematopoeitic stem cell transplant • Chaperone Therapy (research only) • End organ protection therapy (research only) • Gene therapy

  45. Enzyme Replacement Therapy vrs. Substate Biosynthesis Inhibition Biosynthesis Degradation LYSOSOME Glucosylceramide Glucosylceramide Biosynthesis Inhibitor ERT Cellular Damage

  46. “Chaperone” Therapy Protein Biosynthesis in RER Endoplasmic Endoplasmic protein modification & folding Misfolded Properly folded Degradation via Ubiquitin plus proteosome system Transport from trans-GOLGI to lysosme with activation at acidic pH

  47. Case Histories • Case 1 – Positive Newborn Metabolic Screen • Case 2 – Hepatomegaly with abnormal liver pathology • Case 3 – 18 month boy with hepatomegaly and obtundation • Case 4 – 5 year girl with hearing loss & macrocephaly • Case 5 – 10 month boy with developmental delay & dysmorphic facies

More Related