Download Overview of Inherited Metabolic Disorders

Overview of Inherited
Metabolic Disorders
Pediatric Resident
Academic Half Day
Outline
1. Overview of genetic / metabolic diseases
2. Overview of cell metabolism
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Amino acids
Glucose homeostasis
Fatty acids
Complex molecule biosynthesis & degradation
Energy metabolism
3. Approaches to treatment
4. 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:
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Enzymes
Transport proteins
Receptor proteins
Sub-cellular organelles:
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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)
Untreated
Phenylketonuria
Sandhoff
Disease
Hurler-Scheie
Syndrome
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:
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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
Protein
Body
Protein
Free amino acid
“Overflow”
“Biosynthesis”
NH3
Gluconeogenesis
Ketogenesis
Other
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)
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FED STATE
High GI absorption
High Glycogen
biosynthesis
High triglyceride
biosynthesis
Low gluconeogenesis
Low lipolysis
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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 hrs
glucose (from hepatic glycogen) to brain,
RBC, renal medulla
3. Early / Intermediate Starvation: 14+ hrs
gluconeogenesis & (later) lipolysis
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
VLCAD,MCAD, SCAD
Trifunctional
protein
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 Biosynthesis
O-Glycosylation and its Disorders
Lysosomes: Degradation ofMacromolecules
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
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
Glycogenoses
Pompe disease
Lipid Storage diseases
Wolman, cholesterol ester, NP”C”
Oligosaccharide/glycopep
tidoses
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
Salla Disease Fibroblasts
Distended Lysosomes
Mitochondria: Abnormal Energy Production
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
Mitochondria:
Electron Transport Chain Enzyme Complexes
ATP 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
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TCA Cycle & Respiratory Chain
Energy Production in Mitochondria
H+
H+
Cplx I
(CoQ10)
Cplx II
(CoQ10)
H+
Cplx III
(Cyt-C)
Cplx IV
NAD-H2
NAD
FAD-H2
FAD
H20
ADP
Cplx V
Inner Mitoch. Membrane
Succinate, Isol,
Val, Met, Thr,
SCFA’s
ETF /
ETF-QO
O2
H+
Glycolysis, pyruvate,
aconitate, Malate +
other dehydrogen’n
Rx’s
ATP
Fatty .Acid B-oxid’n,
dimethylglycine,
sarcosine
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
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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 PKU
CNS
CNS
High PHE
Lower PHE
BBB
BBB
Isol
Leu
High plasma
phenylalanine
Val
Tyr
Trypt
High plasma
phenylalanine
Met
Low PHE Diet
PreKunil
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
Organ Transplantation
(to provide metabolic capability)
Liver
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Familial Hypercholesterolemia (LDL-cholesterol receptor deficiency)
Tyrosinemia
Glycogen Storage Disease (Type I)
Primary hyperoxaluria *
Kidney
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Fabry Disease
Cystinosis
Primary hyperoxaluria *
Bone Marrow
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Various lysosomal storage diseases ie. Hurler syndrome (MPSI)
Cornea
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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
Enzyme Replacement Therapy
vrs.
Substate Biosynthesis Inhibition
LYSOSOME
Glucosylceramide
Biosynthesis
Inhibitor
Glucosylceramide
Cellular Damage
ERT
“Chaperone” Therapy
Protein Biosynthesis in RER
Endoplasmic protein modification & folding
Misfolded
Degradation via
Ubiquitin plus
proteosome
system
Properly folded
Transport from transGOLGI to lysosme with
activation at acidic pH
Case Histories
1. Case 1 – Positive Newborn Metabolic Screen
2. Case 2 – Hepatomegaly with abnormal liver
pathology
3. Case 3 – 18 month boy with hepatomegaly
and obtundation
4. Case 4 – 5 year girl with hearing loss &
macrocephaly
5. Case 5 – 10 month boy with developmental
delay & dysmorphic facies