Inborn Errors of Metabolism Flashcards
Define Inborn Errors of Metabolism
Inborn Errors of Metabolism = Monogenic defects which disrupt metabolic pathways. A group of rare genetic disorders
IEMs can cause:
- Toxic accumulation of substrate
- Toxic accumulation of intermediates from other metabolic pathways
- Insufficient products = defects in energy production/use
-All of these together
What are the 4 IEM disorders which were studied by Garrod?
Alkaptonuria - homogentisic acid accumulates, autosomal recessive
Cystinuria - ↑ cysteine(aa) conc. in urine, autosomal recessive
Alibinism - Congenital absence of any pigmentation
Pentosuria - High xylitol(a pentose sugar) conc. in urine
These are all:
- Congenital(present at birth)
- Inborn (transmitted through gametes)
- Inherited
Describe Alkaptonuria and how it presents
Homogentisic acid oxidase deficiency
Autosomal recessive disorder
Urine turns black on standing/alkalinisation
Black ochronotic (accumulation of homogentisic acid in connective tissue) pigmentation of cartilage and collagenous tissue
Black material in articular cartilage + ligaments
What is the One-Gene, One-Enzyme concept ?
1-Gene, 1-Enzyme Concept: Mutation in 1 gene alters 1 enzyme, and therefore affects 1 biochemical reaction
Molecular disease concept: Gene mutn->Abnormal protein->Abnormal protein (causes IEMs)
- Genes control all biochemical processes (stepwise reactions)
- Each biochemical reaction is under the ultimate control of a different single gene
- Mutation of a single gene alters the cell’s ability to carry out a single primary chemical reaction
What is the Molecular Disease Concept?
Inborn errors of metabolism are caused by: Gene mutn->abnormal protein->abnormal protein function/activity
Diff. electrophoretic ability b/w healthy Hb + sickle cell anaemia Hb. Diff. number of ionisable aa residues in globin protein = diff molecular structure = sickling process.
Abnormal protein causes disease. Gene determines protein structure + functional activity
What are the different inheritance patterns?
Single gene disorders (IEM) inheritance patterns:
- Autosomal recessive
- Autosomal dominant
- X-linked
- Mitochondrial
Using a accurate family history can establish
What is the autosomal recessive mechanism of inheritance?
Autosomal Recessive = Most common IEM mode of inheritance
Both parents carry a mutation which affects the same gene
Homozygotes have the disease
Heterozygotes = carriers
1 in 4 risk per pregnancy. Both parents are carriers
Consanguinity (the fact of being descended from the same ancestor, cousin-cousin marriage) increases risk of autosomal recessive conditions
E.g diseases: PKU(Phenylketonuria) Alkaptonuria, MCADD
What is the autosomal dominant mechanism of inheritance ?
These are rare in IEMS.
1 copy of a mutated gene from one parent causes the genetic condition.
50% chance of having an affected child
No carrier status
E.g: Marfans, Acute Intermittent Porphyria
What is the X-linked inheritance mechanism ?
Copy of gene on X-chr has the genetic mutation.
Recessive X-linked conditions always pass through the maternal line :
- Condition appears in males = more frequently affected
- Condition carried in females
Female carriers usually don’t express the disease but may manifest condition
(Lyonization - Random inactivation of one of the X chromosomes)
E.g: Fabry’s disease, Ornithine carbamoyl transferase deficiency.
X-chr of male comes from mother as mother has no Y chr. + there is no male-male transmission
What is Mitochondrial inheritance ?
Mitochondrial gene mutation = Mitochondria fail to produce enough energy for body to function
Mitochondria are Inherited exclusively from mother
- The egg will contribute mitochondria to the developing embryo
- Only females can pass on mitochondrial mutations to their children
Affects both male and female offspring. but affected male cannot pass on mitochondrial disorder
Example :
- MERFF (Myoclonic epilepsy and ragged red fibre disease: deafness, dementia, seizure)
- MELAS(Mitochondrial encephalopathy with lactic acidosis and stroke like episodes
most mit. diseases are caused by mutations in mit DNA which is maternally inherited
What is Heteroplasmy?
Heteroplasmy = Each cell contains varying amounts of normal mt DNA and also mutated mtDNA
each cell contains 2 copies of every gene
most normal ppl have homoplasmic cells = their cells contain only normal mitochondrial DNA.
Ppl w maternally-inherited mit disease usually have heteroplasmic cells = cell contains some normal mit DNA + some mutated mit DNA
Heteroplasmy = symptoms, severity, age of onset of mit disorder vary greatly within family. symptoms appear when mutation affects much of the mitochondrial DNA
=mother w mit mutation will pass the mut onto her children but not all her children will become symptomatic. if children are symptomatic, disease that each child has varies depending on % of mutant mit DNA in each part of body
there is a threshold proportion of mutant mit DNA after which the cell can’t cope = disease. diff. threshold in diff tissues = some more sensitive to energy deficiency.
=infinite num of manifestations of mit disease = hard to diagnose accurately
Which types of organs are severely affected by Mitochondrial diseases?
High-energy-requiring organs are more frequently affected
Treatment of IEMs
- Dietary control/Compound supplementation
- Enzyme replacement therapy
- Drug therapy
- Organ transplant for damaged organs
How are IEM classified ?
Describe the 3 categories and subsections within them.
Toxic accumulation - toxic compounds accumulate: -Protein metabolism o Amino acids-PKU, tyrosinemia o Organic acids-propionyl acidaemia o urea cycle disorders -OTCD -Carbohydrate intolerance o galactosaemic
Deficiency in energy production/utilisation:
- Fatty acid oxidation -MCADD
- Carbohydrate utilisation/production-GSDS
- Mitochondrial disorders -MERFF
Disorders of complex molecules involving organelles:
- Lysosomal storage disorders e.g. Fabry’s
- Peroxisomal disorders e.g. Zellweger’s
