Inborn Errors Of Metabolism Flashcards
What are inborn errors of metabolism (IEM)?
- IEM = Group of rare genetic disorders
- Single gene defects -> deficient or absent activity of an enzyme -> results in disruption to metabolic pathways
- Affects syntheses/catabolism of proteins, carbs, fats and complex molecules
Give some key features of IEM
- Individually rare (e.g PKU 1:10,000)
- Collectively common (1:800 to 1:2500)
- High mortality within the first year of life
- Significant contribution to children of school age with physical handicap and children with severe learning difficulties
- Important to recognise in sick neonate
How is IEM treated?
- Global newborn screening programmes
- Treatment by dietary control/restrictions and/or compound supplementation. Newer drug and enzyme replacement therapy, and organ transplantation
State what the effects of IEM arise from (4) ?
- 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
- Can vary in age of onset and clinical severity
What’s the Difference between congenital and inborn?
- Congenital = Present at birth
- Inborn = Transmitted through gametes
State 2 features of alkaponuria
- Autosomal recessive disease
- Congenital
State 2 symptoms and 2 causes of alkaponuria
- Symptoms: Urine turns black on standing, Black ochrontic pigmentation cartilage and collagenous tissue
- Causes: Homogentisic acid oxidase deficiency
State the one gene - one enzyme concept?
- All biochemical processes in all organisms are under genetic control
- Biochemical processes are resolvable into a series of stepwise reactions
- Each biochemical reaction is under the ultimate control of a different single gene
- Mutation of a single gene results in an alteration in the ability of the cell to carry out a single primary chemical reaction -> affects metabolic pathway
How does the one gene- one enzyme concept link with the molecular disease concept in IEM?
- Molecular disease concept: Direct evidence that human gene mutations produce an alteration in the primary structure of proteins.
- Inborn errors of metabolism are caused by mutations in genes which then produce abnormal proteins whose functional activities are altered
Inheritance patterns
State the different mechanisms of inheritance of IEM?
- Autosomal recessive
- Autosomal dominant
- X-linked
- Mitochondrial
Describe autosomal recessive as a mechanism of inheritance and give 3 examples of AR IEM?
- Both parents carry a mutation affecting the same gene
- 1 in 4 risk each pregnancy
- Consanguinity (same blood) increases risk of autosomal recessive conditions
- Examples: PKU (phenylketonuria), alkaponuria, MCADD
Is autosomal dominant rare in IMs and state 2 examples?
- Rare in IEM
- Examples: Marfan’s, acute intermittent porphyria
Describe how the X-linked conditions pass through each gender and state 2 examples of X-linked IEMs?
- 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 carbonyl transferase deficiency
What is mitochondrial gene mutation and describe how mitochondrial inheritance occurs?
- Mitochondrial gene DNA mutation -> Causes M to fail to produce energy to function properly
- M DNA is 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
State 2 examples of mitochondrial mutation IEM disorders with symptoms?
- MERFF -Myoclonic epilepsy and ragged red fibre disease:
- deafness, dementia, seizures
- MELAS - Mitochondrial encephalopathy with lacticacidosis and stroke-like episodes
