overview of inherited metabolic disorders pediatric resident academic half day
TRANSCRIPT
Overview of Inherited Metabolic Disorders
Pediatric Resident Academic Half Day
Outline
1. Overview of genetic / metabolic diseases2. Overview of cell metabolism
Amino acids Glucose homeostasis Fatty acids Complex molecule biosynthesis & degradation Energy metabolism
3. Approaches to treatment4. Example case histories for discussion
What Are Genetic Metabolic Disorders?
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?
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
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
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 symptoms due 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)
Sandhoff Disease
Hurler-Scheie Syndrome
Untreated Phenylketonuria
Overview of Intermediary Metabolism as It Relates to
Inherited Metabolic Diseases
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
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)
The Cellular Basis of Metabolism
Overview of Metabolism
Amino Acid Metabolism
Dietary BodyProtein Protein
Free amino acid
“Overflow” “Biosynthesis”
NH3Gluconeogenesis OtherKetogenesis Bioactive
metabolites
Branched Chain Amino Acid Metabolism:Leucine & Isovaleric Acidemia
Isovaleryl-CoA Dehydrogenase
Deficiency
“Isovaleric Acidemia”
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
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
Homeostatic Processes Maintaining Euglycemia(insulin & glucagon in response to glucose levels)
FED STATE High GI absorption High Glycogen
biosynthesis High triglyceride
biosynthesis Low gluconeogenesis Low lipolysis
FASTING STATE Low GI absorption High Glycogenolysis High Lipolysis with
mobilization of fatty acids & ketones
High Gluconeogenesis
Phases of Glucose Homeostasis
1.Glucose absorptive phase: 3 - 4 hrs after glucose ingestion (high insulin)
2.Post absorptive/early starvation: 3-12 hrsglucose (from hepatic glycogen) to brain, RBC, renal medulla
3. Early / Intermediate Starvation: 14+ hrsgluconeogenesis & (later) lipolysis
GSD-0
GSD-IV
GSD-1a&b
GSD-V, GSD-VI, GSD-IX
GSD-II ( lysosomal)
GSD-III
GSD-VII
GSD-X, GSD-XII, GSD-XIII
GSD-XI (LDH)
LIVER
MUSCLE
Trifunctional protein
VLCAD,MCAD, SCAD
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
Endoplasmic Reticulum: Synthesis of Glycoproteins
N-Glycosylation & the Mannose Pathway
Abnormal glycopeptide Biosynthesis Disorders of N-Glycosylation
Abnormal Glycopeptide BiosynthesisO-Glycosylation and its Disorders
Lysosomes: Degradation ofMacromolecules
Metabolic Role of Lysosomes
Degradation of endogenous and exogenous macromolecules
Acidic hydrolysis: Molecules include:mucopolysaccharides sphingolipids
peptidesoligosaccharides glycopeptides lipids
S-acetylated proteins monosaccharides/aminoacids/monomers
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)
40+ Lysosomal Storage Diseases Identified
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
GlycogenosesPompe disease
Lipid Storage diseasesWolman, cholesterol ester, NP”C”
Oligosaccharide/glycopeptidoses
Mannosidoses, fucosidosis, Schindlers, sialidoses,
aspartylglycosaminuria
Multiple enzyme deficiencies
I-cell & MLIII, multiple sulfatase deficiency, galactosialidosis
Transport deficienciesCystinosis, Salla disease, ISS
Peptide Storage DiseasesPycnodysostoses, infantile NClF
Salla Disease FibroblastsDistended Lysosomes
Mitochondria: Abnormal Energy Production
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
Metabolic Jobs of Mitochondria
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
Mitochondria: Electron Transport Chain Enzyme Complexes ATP produced in using the respiratory chain
TCA Cycle & Respiratory Chain
Energy Production in Mitochondria
Cplx I
Cplx II
Cplx III
Cplx IV
Cplx V
FAD-H2
NAD-H2
NAD
FAD
Glycolysis, pyruvate, aconitate, Malate + other dehydrogen’n
Rx’s
Succinate, Isol, Val, Met, Thr, SCFA’s
ETF / ETF-QO
Fatty .Acid B-oxid’n, dimethylglycine, sarcosine
(CoQ10)
(CoQ10)
(Cyt-C)
H+
O2
H20
H+
H+
H+ADP
ATPInner Mitoch. Membrane
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)
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.
Approaches to treatment
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
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:
End Organ Protection in PKUCNS
High plasma phenylalanine
BBB
High plasma phenylalanine
CNS
BBB
Isol
Leu
Val
Tyr
Trypt
Met
Low PHE Diet PreKunil
High PHE Lower PHE
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”
Indirect Therapy: Replacement of Essential Metabolites
Urea Cycle DisordersMay need increased leucine, isoleucine & valine to compensate for loss of “N” as phenylacetyl-glutamine
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
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
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
LYSOSOME
Glucosylceramide
Glucosylceramide
BiosynthesisDegradation
ERT
Biosynthesis
Inhibitor
Cellular Damage
Enzyme Replacement Therapy vrs.
Substate Biosynthesis Inhibition
Endoplasmic
Endoplasmic protein modification & folding
Misfolded Properly folded
“Chaperone” Therapy
Protein Biosynthesis in RER
Degradation via Ubiquitin plus proteosome
system
Transport from trans-GOLGI to lysosme with activation at acidic pH
Case Histories
1. Case 1 – Positive Newborn Metabolic Screen2. Case 2 – Hepatomegaly with abnormal liver
pathology3. Case 3 – 18 month boy with hepatomegaly
and obtundation4. Case 4 – 5 year girl with hearing loss &
macrocephaly5. Case 5 – 10 month boy with developmental
delay & dysmorphic facies