Inborn errors of metabolism Flashcards
what is inborn errors of metabolism
- single gene defects resulting in disruption to metabolic pathways
- including synthesis/catabolism of proteins, carbohydrates, fays, complex molecules
IEM effects due to
- Toxic accumulation of substrates
- Toxic accumulation of intermediates from
alternative metabolic pathways
-Defects in energy production/use due to
deficiency of products
-Combination of above
what is alkaptonuria
•Urine turns black on standing (and alkalinisation) •Black ochrontic pigmentation of cartilage & collagenous tissue •Homogentisic acid oxidase deficiency •Autosomal recessive disease •Congenital
Mechanisms of inheritance -Autosomal Recessive
— Both parents carry a mutation affecting the same gene
— 1 in 4 risk each pregnancy
— Consanguinity increases risk of autosomal recessive
conditions
— Examples: PKU, alkaptonuria, MCADD
Mechanisms of inheritance-Autosomal Dominant
— Rare in IEMs
— Examples: Marfan’s, acute intermittent porphyria
Mechanisms of inheritance- X-Linked inheritance
—Recessive X linked conditions passed through the
maternal line
• condition appears in males
• condition carried in females
• Female carriers may manifest condition —
Lyonisation (random inactivation of one of the X
chromosomes)
• Examples: Fabry’s disease, Ornithine carbamoyl
transferase deficiency
Mechanisms of inheritance- Mitochondrial inheritance
• Mitochondrial gene mutation
• Inherited exclusively from mother
— only the egg contributes mitochondria to the developing embryo
— only females can pass on mitochondrial mutations to their children
Fathers do not pass these disorders to their daughters or sons
• Affects both male and female offspring
Eg. MERFF -Myoclonic epilepsy and ragged red fibre disease:
deafness, dementia, seizures
Eg. MELAS — Mitochondrial encephalopathy with lactic
acidosis and stroke-like episodes
meaning of heteroplasmy
cells contains varying amounts of normal mtDNA and also mutated mtDNA
what are the 3 classification of IEM
- Toxic accumulation
- Deficiency in energy production/utilization
- Disorders of complex molecules involving organelles
classification of IEM- Toxic accumulation
- protein metabolism
- –amino acid e.g. PKU, tyrosinaemia
- –organic acids e.g. propionylacidaemia
- –urea cycle disorders e.g. OTCD
- Carbohydrate intolerance e.g. galactosaemia
classification of IEM-Deficiency in energy production/utilization
— Fatty acid oxidation e.g. MCADD
— Carbohydrate utilization/production e.g. GSDs
— Mitochondrial disorders e.g. MERFF
classification of IEM- Disorders of complex molecules involving organelles
— Lyososomal storage disorders e.g. Fabry’s
— Peroxisomal disorders e.g. Zellwegers
Presentation of IEM - Neonates
-Neonatal to adult onset depending on severity of
metabolic defect
—Neonatal presentation often acute
—Often caused by defects in carbohydrate intolerance
and energy metabolism
Presentation of IEM-late onset
Late-onset due to accumulation of toxic molecules
— Patients have residual enzyme activity allowing slower
accumulation of toxins
— Symptoms appear at adulthood
— Present with organ failure, encepalopathy, seizures
Clues of neonates with IEM
— Consanguinity
— FH of similar illness In siblings or unexplained deaths
— Infant who was well at birth but starts to deteriorate for
no obvious reason