Inborn Errors Of Metabolism Flashcards
How do inborn errors of metabolism (IEM) affect the organism?
Toxic accumulation of substrates
Defects in energy production/ use due to deficiency of products
Or a combination of the two
What things can accumulate toxically in inborn errors of metabolism?
Substrates
Intermediates from alternative metabolic pathways
What can inborn errors of metabolism vary in?
Age of onset and clinical severity
What are the four disorders studied in the croonian lectures?
Alkaptonuria
Cystinuria
Albinism
Pentosuria
What did Archibold Garrod propose the disorders were?
Congenital
Inborn
Followed mendels laws of inheritance
Who came up with the one gene - one enzyme concept?
Beadle and tatum
What does the one gene-one enzyme concept mean?
One mutated gene causes a non functional enzyme
What is an example of molecular disease concept?
Gene mutations produce an alteration in the primary structure of proteins by hamoglobin in sickle cell diesase
What are the four mechanisms of inheritance?
Autosomal recessive
Autosomal dominant
X-linked
Mitochondrial
Who transfers autosomal recessive inheritance?
Both parents carry a mutation affecting the same gene
What is the risk size in each autosomal recessive pregnancy?
1 in 4
What increases the risk of autosomal recessive conditions?
Cosanguinity
What are some examples of autosomal recessive diseases?
PKu, alkaptonuria, McADD
Are autosomal dominant conditions rare or common in IEMs?
Rare
What are some examples of autosomal dominant diseases?
Marfans, acute intermittent porphyria
How are X-linked mutations passed down?
Maternal line
Where do X-linked diseases appear and where are they carried?
Appear in men, carried in women
What are some examples of X-linked conditions?
Fabrys disease, ornithine carbamoyl transferase deficiency
Where are mitochondrial diseases inherited from?
Mother
Which gender do mitochondrial diseases affect?
Male and female offspring
Why are mitochondrial diseases exclusively inherited from the mother?
Only the egg contributes mitochondria to the developing embryo
What are some examples of mitochondrial IEM diseases?
MERFF and MELAS
What does MERFF stand for?
Myoclonic epilepsy and red ragged fibre disease
What does MERFF cause?
Deafness, dementia, seizures
What does MELAS stand for?
Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes
How do you establish the pattern of inheritance?
Accurate family history
What determines the presentation of mitochondrial inheritance?
Distribution of affected mitochondria
What are more frequently affected in mitochondrial inheritance?
High-energy requiring organs
What are IEM treated by?
Dietary control restriction and/or compound supplementation
What are the classifications of IEM?
Toxic accumulation
Deficiency in energy production/utilisation
Disorders of complex molecules involving organelles
What are the types of toxic accumulation?
Protein metabolism
Carbohydate intolerance
What are the categories of deficiency in energy production/utilisation IEMs?
Fatty acid oxidation
Carbohydrate utilisation/production
Mitochondrial disorders
What is an example of a fatty acid oxidation deficiency IEM?
MCADD
What is an example of a deficiency of carbohydrate utilisation/production?
GSD
What are the deficiencies of mitochondria?
MERFF
What is an example of a lysosomal storage disorder?
Fabrys
What is an example of a peroxisomal disorder?
Zellwegers
How do IEM present?
Depends on the severity of the metabolic defect
What are neonatal IEMs often caused by?
Defects in carb intolerance and energy metabolism
What are late onset IEMs caused by?
Accumulation of toxic molecules
What do late onset IEMS present with?
Organ failure, encephalopathy and seizures
When do IEM symptoms start to present in neonates?
First week of life when starting full milk feeds
What are the clues for IEM?
Cosanguinity
Family history of similar illness and siblings or unexplained deaths
Infants who was well at birth and starts to deteriorate for no obvious reason
What are the clinical scenarios of neonate IEM presentation?
Poor feeding, lethargy, vomiting Epileptic encephalopathy Profound hypotonia Organomegaly Dysmorphic features Sudden unexpected death in infancy
What are the biochemical abnormalities in neonate IEM presentation?
Hypoglycaemia
Hyperammonia
Unexplained metabolic acidosis/ketoacidosis
Lactic acidosis
What are the routine blood tests for IEMs?
Blood gas
Blood glucose and lactate
Plasma ammonia
What are the specialist lab investigations for IEMs?
Plasma amino acids Urinary organic and orotic acid Blood acyl carnitines Urinary glycosaminoglycans Plasma very long chain fatty acids CSF tests
What are the confirmatory investigations that you can do for IEM?
Enzymology
Biopsy
Fibroblasts studies
Mutation analysis (WGS)
What are the wilson and junger criteria for screening?
Condition should be an important health problem
Must know prevelence in screening population
History of condition understood
Easy and reliable screening test
Availibility of an accepted treatment
Diagnosis and treatment should be cost effective
What conditions are tested for in newborn blood spot screening?
PKU congenital hypothyroidism Sickle cell disease Cystic fibrosis MCADD
When are newborn blood spot screening samples taken?
Day 5 (day of birth is day 0)
What are the guidlines for a good quality bloodspot of newborn blood spot screening?
All four circles on ‘guthrie’ card need to be completely filled with a single drip of blood which soaks through to the back of the card
What is Tyrosinaemia type 1?
Genetic deficiency in fumarylacetoacetase
What is the function of fumarylacetoacetase?
Catalyses the final step in tyrosine metabolism
What is the treatment for tyrosinaemia type 1 and how does it work?
Nitisinone inhibits an earlier step in the pathway to prevent accumulation of toxic metabolites
What are the symptoms of ornithine transcarbamylase deficiency?
Ataxia,
seizures,
Hyperammonaemic encephalopathy
What can trigger a hyperammonaemic crisis?
Increased endogenous protein catabolism (infection, fasting, trauma, steroid administration)
High protein intake
