Inborn Errors of Metabolism Flashcards
What are inborn errors of metabolism and what are they a product of?
Single gene defects resulting in disruption to metabolic pathways
- Synthesis/catabolism of proteins, carbohydrates, fats, complex molecules
IEM effects due to:
- 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 are the croonian lectures by Garrod and what did she propose?
Studies of 4 disorders - Alkaptonuria - Cystinuria - Albinism - Pentosuria Garrod proposed that these were: - 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
- Work on haemoglobin in sickle cell disease - 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 four mechanisms of inheritance?
- Autosomal recessive
- Autosomal dominant
- X-linked
- Mitochondrial
How are inborn errors of metabolism inherited?
Autosomal Recessive
- 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
Autosomal Dominant
- Rare in IEMs
- Examples: Marfan’s, acute intermittent porphyria
How can metabolic diseases be inherited through X-linked inheritance?
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
How can metabolic diseases be passed down through mitochondrial inheritance?
Mitochondrial gene mutation
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
Eg. MERFF -Myoclonic epilepsy and ragged red fibre disease: deafness, dementia, seizures
Eg. MELAS – Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes
Mitochondrial Disease can affect both male and female offspring but an affected male cannot pass on the mitochondrial disorder
What is heteroplasmy?
Heteroplasmy - Cell contains varying amounts of normal mt DNA and also mutated mt DNA
Mitochondrial disease can vary in symptoms, severity, age of onset
What are the classifications of IEM?
Toxic accumulation
- Protein metabolism
· Amino acids e.g. PKU, tyrosinaemia
· Organic acids e.g. propionylacidaemia
· urea cycle disorders e.g. OTCD
- Carbohydrate intolerance e.g. galactosaemia
Deficiency in energy production/utilization
- Fatty acid oxidation e.g. MCADD
- Carbohydrate utilization/production e.g. GSDs
- Mitochondrial disorders e.g. MERFF
Disorders of complex molecules involving organelles
- Lyososomal storage disorders e.g. Fabry’s
- Peroxisomal disorders e.g. Zellwegers
How does IEM present at different stages of life?
Neonatal to adult onset depending on severity of metabolic defect
- Neonatal presentation often acute
- Often caused by defects in carbohydrate intolerance and energy metabolism
Late-onset due to accumulation of toxic molecules
- Patients have residual enzyme activity allowing slower accumulation of toxins
- Symptoms appear at adulthood
- Present with organ failure, encepalopathy, seizures
What are neonatal characteristics of IEM?
May be born at term with normal birth weight and no abnormal features
Symptoms present frequently in the first week of life when starting full milk feeds
Clues for IEMs:
- Consanguinity
- FH of similar illness in siblings or unexplained deaths
- Infant who was well at birth but starts to deteriorate for no obvious reason
How do neonates with IEM clinically and biochemically present?
Clinical scenarios - Poor feeding, lethargy, vomiting - Epileptic encephalopathy - Profound hypotonia –’floppy’ baby - Organomegaly e.g. cardiomyopathy, hepatomegaly - Dysmorphic features - Sudden unexpected death in infancy (SUDI) Biochemical abnormalities - Hypoglycaemia - Hyperammonaemia - Unexplained metabolic acidosis / ketoacidosis - Lactic acidosis
What laboratory tests can you carry out to diagnose IEM?
Routine laboratory investigations - Blood gas analysis - Blood glucose and lactate - Plasma ammonia Specialist investigations - Plasma amino acids - Urinary organic acids + orotic acid - Blood acyl carnitines - Urinary glycosaminoglycans - Plasma very long chain fatty acids - CSF tests e.g. CSF lactate/pyruvate, neurotransmitters
