inborn errors of metabolism Flashcards
What causes Inborn Error Metabolism (IEM)?
- IEM occur due to block in pathway of metabolism.
- single gene defects resulting in disruption to metabolic pathways
- can vary in age of onset and clinical severity.
What are effects due to IEM?
- 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 the history of IEM?
- Archibold R Garrod 1857-936
- Father of IEM
- Croonian lectures to the Royal College of Physicians in june 1908
- published in the Lancet July 1908
- Reprinted as a book ‘ inborn errors of metabolism’
What are 4 disorders outlined in Croonian lectures by Garrod?
- Alkaptonuria
- Cystinuria
- Albinism
- Pentosuria
What did Garrod propose the 4 disorders to be?
- congenital (present at birth)
- inborn(transmitted through the gametes)
- followed Mendel’s laws of inheritance
What are characteristics of Alkaptonuria?
- urine turns black on standing
- black ochrontic pigmentation of cartilage & collagenous tissue
- homogentisic acid oxidase deficiency
- autosomal recessive disease
- congenital
What link between gene and metabolism did Beedle and Tatum establish in 1945?
=> one gene - one enzyme concept
- all biochemical processes in all organisms are under genetic control
- biochemical processes are resolvable into 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 cell to carry out a single primary chemical reaction.
What molecular disease concept did Pauling et al 1949, Ingram 1956 discover?
- worked on hemoglobin in sickle cell disease
- direct evidence that human gene mutations produce an alteration of 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.
What are mechanisms of inheritence of IEM?
- IEM are genetic conditions (single gene disorders)
- autosomal recessive
-autosomal dominant - X-linked
- Mitochondrial
An accurate family history required to establish pattern of inheritance.
What are examples of autosomal recessive conditions?
- 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
What is autosomal dominant conditions?
- Rare in IEMs
- Examples : Marfan’s, acute intermittent porphyria
How do x-linked inheritance occur?
- 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)
What are examples of X- linked inheritance?
- Fabry’s disease
- ornithine carbamoyl transferase deficiency
What are mitochondrial diseases?
- chronic genetic disorder occur when mitochondria fails to produce enough energy for body to function properly
- most occur mtDNA mutation
- affected male cant pass on mitochondrial disorder, we get our mothers mitochondria.
define heteroplasmy
cells contains varying amounts of normal mtDNA and also mutated mtDNA