Inborn Errors of Metabolism Flashcards
what can IEM be defined as?
very rare genetic disorders involving specific genes which control proteins – if they are structurally altered it will affect their function, which will also affect their pathways in metabolism
role of Garrod and croonian lectures?
Garrod proposed that: Alkaptonuria Cystinuria Albinism Pentosuria
- Congenital (present at birth)
- Inborn (transmitted through the gametes)
- Had the discontinuous distribution of a Mendelian trait
Alkaptonuria?
- an autosomal recessive disorder
- benign disorder, but can cause arthritis later in life
- urine turns black on standing (and alkalinisation)
- bluish black ochrontic pigmentation of the pinna
- homogentisic acid oxidase deficiency
Cystinuria?
- Autosomal recessive disease
- Defective transport of cystine and dibasic aa’s through epithelial cells of renal tubule and intestinal tract
- Cystine has low solubility - formation of calculi in renal tract
- COAL
- Mutations of SLC3A1 aa transporter gene (Chr 2p) & SLC7A9 (Chr 19)
One gene - one enzyme concept
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
concept that a mutation in 1 gene caused a defect in 1 enzyme in a specific metabolic pathway
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
Looked at electrophoretic ability of Hb in normal patients
Mechanisms of inheritance (ways in which single gene disorders are transmitted)
Autosomal recessive Autosomal dominant X-linked Codominant Mitochondrial
Autosomal recessive
- need 2 copies of the variant gene for the disease to manifest itself
- both parents carry a mutation affecting the same gene
- 1 in 4 risk each pregnancy (If you’re a carrier, you have a 1 in 4 chance of each child being a carrier)
- consanguinity increases risk of autosomal recessive conditions
Examples: Cystic fibrosis, sickle cell disease
Autosomal dominant
- Rare in IEMs
- You only need one copy of that faulty allele to be affected, so you these are more commonly seen across the generations
Examples: Huntingdon disease, Marfan’s, Familial hypercholesterolaemia
X-Linked inheritance can be?
recessive or dominant
-No male to male transmission
X linked inheritance - recessive?
- passed through the maternal line
- condition appears in males
- condition carried in females, but not usually expressed
- female carriers may manifest condition –Lyonisation (random inactivation of one of the X chromosomes)
- examples: Haemophilia A, Ornithine carbamoyl transferase deficiency, Duchenne muscular dystrophy and Fabry’s disease
X linked inheritance - dominant?
- passed on from either affected parent
- Affected father will only pass the condition to his daughters
- Affected mother can pass the condition to sons and daughters
when can random x inactivation occur?
random inactivation of the x chromosome happens in Ornithine carbamoyl transferase deficiency
-some female carriers, after they give birth, get shrinking of their uterus due to random x inactivation
Codominance?
- two different versions of a gene are expressed, and each version makes a slightly different protein
- both alleles influence the genetic trait or determine the characteristics of the genetic condition
Example: ABO Blood group, α1AT
inheriting mt gene mutations
mutations affect mt genes and are inherited exclusively from the mother
- only the egg contributes mitochondria to the developing embryo
- only females can pass on mitochondrial mutations to their children
- mothers can pass onto both male and female offspring
MERFF -Myoclonic epilepsy and ragged red fibre disease: deafness, dementia, seizures
MELAS – Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes
