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What is Inborn errors of metabolism
LJ Mienie
Genetic defectsNumeric defects Structural defects Point mutations
Die at an early age
Structure abnormal
Mental retardation
Infections
Die at an early age
Structure abnormal
Mental retardation
Infections
Die at an early age
Structure abnormal
Mental retardation
Infections
Point mutations50 %
50 % Enzymes 100% active
50 %
50 %
Structural proteins
100% functional
0
50 %
Enzymes 50% active
0
50 %
Structural proteins
Not functional
Recessive diseases
No symptoms at birth
Symptoms at birth
Dominant diseases
Point mutations
Inborn errors of metabolism
Enzyme 0% activity
Father Mother
Child
MetabolismFood
Amino acids
Carbohydrates
Lipids
Nucleic acids
Energy
Biomolecules
Enzyme A
Enzyme B
Enzyme C
Inborn errors of metabolismFood
Amino acids
Carbohydrates
Lipids
Nucleic acids
Energy
Biomolecules
Enzyme A
Enzyme B
Enzyme C
Accumulation in cells
Spills into blood
Toxic effects
Clinical effect
0% activity (homozygotes)
50 % activity (heterozygotes)
100% activity
Toxic substance reaches toxic levels
(25% activity) Toxic substance reaches toxic levels
Toxic substance does not reach toxic levels
Toxic substance does not reach toxic levels
(50% activity) Toxic substance: reaches not toxic levels
Environment
Phenotype
0-15 yearsDieNeurological diseasesLiver diseasesHeart diseasesMuscle problemsCancerEar and Eye problemsAbnormal behavior
20-60- yearsDieNeurological diseasesLiver diseasesHeart diseasesMuscle problemsEar and Eye problemsAbnormal behaviorCancer
EnvironmentNo symptoms
1/1000 births 5 mutations/person 1/5 serious
Classification of IEM• Organic acid metabolic defects • Carbohydrate metabolic defects• Amino acid metabolic defects• Membrane transport defects• Lipid metabolic defects• Mitochondrial defects• Purine & Pyrimidine metabolic defects• Vitamin defects• Lysosomal defects• Peroxisomal defects• Porphyrin metabolic defects• Metal metabolic defects• Hormonal defects
Other Defects• Blood• Immune and defense systems• Connective tissue• Cardiovascular system• Kidney• Muscle• Lung• Skin• Neurogenetics• Eye• Multisystem inborn errors of development• DNA repair defects
Diagnosis : HomozygotesFood
Amino acids
Carbohydrates
Lipids
Nucleic acids
Energy
Biomolecules
Enzyme A
Enzyme B
Enzyme C
Accumulation in cells
Spills into blood
And urine
Toxic effects
GCGC-MSHPLCMSMSCETLC
Enzyme Analysis
RFLP-analysis
Methods: Chemical analysisOrganic analysis – GC-MS
Amino acid analysis- GC-MS
Acylcarnitine analysis-ES-MSMS
Carbohydrate analysis-TLC GC-MS
Oligosaccharide analysis-TLC
Mucopolisaccharide analysis-Electrophoresis
Glycoprotein analysis-Isoelectrophoresis
Purine and Pyrimidine analysis-CE
Very long chain fatty acid analysis/phytanic acid-GC-MS
Bile acid analysis-ES-MSMS
DNA Repair analysis-Comet single cell eletrophoreses
Treatment and prevention : HomozygotesFood
Amino acids
Carbohydrates
Lipids
Nucleic acids
Energy
Biomolecules
Enzyme A
Enzyme B
Enzyme C
Accumulation in cells
Spills into blood
Toxic effects
Reduce Intake
Detoxify
Supplementation
Inhibitors
Prenatal diagnosis