Inborn Errors of Metabolism Flashcards
Define inborn errors of metabolism
A single gene defect resulting in disruption to metabolic pathways (blocked pathways)
What causes the symptoms faced in 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
Can vary in age of onset and clinical severity
Describe the discovery of the idea of IEM
Archibold E Garrod 1857 - 1936
- 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 disorders did Garrod study
- Alkaptonuria
- Cystinuria
- Albinism
- Pentosuria
What did Garrod propose about the disorders
- Congenital (present at birth)
- Inborn (transmitted through the gametes)
- Followed Mendel’s laws of inheritance
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
What is the one gene - one enzyme concept
Beadle and Tatum 1945 (Nobel prize 1958)
- 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
What is the molecular disease concept
Pauling et al 1949, Ingram 1956
- 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
What are the mechanisms of inheritance for IEM
- Autosomal recessive
- Autosomal dominant
- X-linked
- Mitochondrial
An accurate family history required to establish
pattern of inheritance
Describe Autosomal Recessive inheritance of IEM
- Both parents carry a mutation affecting the same gene
- 1 in 4 risks each pregnancy
- Consanguinity increases the risk of autosomal recessive
conditions - Examples: PKU, alkaptonuria, MCADD
Describe the Autosomal Dominant Inheritance of IEM
- Only one parent needs to have a dominant allele
- 2 in 4 risks each pregnancy
- Rare in IEMs
- Examples: Marfan’s, acute intermittent porphyria
Describe X-Linked Inheritance of IEM
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
Describe mitochondrial inheritance of IEM
- Mitochondrial gene mutation
- Inherited exclusively from mother
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
What does heteroplasmy mean in mitochondrial inheritance
Cell contains varying amounts of normal mt DNA and also mutated mt DNA
What are the characteristics of mitochondrial inheritance
- Distribution of affected mitochondria determines
presentation - Mitochondrial disease can vary in symptoms, severity,
age of onset - Varying penetrance - High energy-requiring organs are more frequently affected
- Recent debate on three parent babies
