IEM Flashcards
What are inborn errors of metabolism?
→Single gene defects resulting in disruption to metabolic pathways
What are 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
What is alkaptonuria?
→inherited disorder that prevents the body fully breaking down tyrosine and phenylalanine
What deficiency is seen in alkaptonuria?
→Homogentisic acid oxidase
What is the genotype o alkaptonuria?
→Autosomal recessive disease
→congenital
What are the symptoms of alkaptonuria?
→black urine
→Black ochrontic pigmentation of cartilage & collagenous tissue
What is the one gene-one enzyme concept?
→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?
→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?
→Autosomal recessive
→Autosomal dominant
→X-linked
→Mitochondrial
What are examples of autosomal recessive disease?
→PKU,
→alkaptonuria,
→MCADD
What are examples of autosomal dominant disease?
→Marfan’s,
→acute intermittent porphyria
Are autosomal dominant diseases common or rare for IEMs?
→rare
What is lyonisation?
→random inactivation of one of the X chromosomes
What are examples of X-linked inheritance?
→Fabry’s disease,
→Ornithine carbamoyl transferase deficiency
How are mitochondrial mutations inherited?
→Inherited exclusively from mother
→only the egg contributes mitochondria to the developing embryo
Who does mitochondrial disease affect?
→both female and male
What are some examples of mitochondrial disease?
→MERFF -Myoclonic epilepsy and ragged red fibre disease: deafness, dementia, seizures
→MELAS – Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes
What is hetroplasmy?
→Cell contains varying amounts of normal mt DNA and also mutated mt DNA
Which types of organs are most affected by mitochondrial diseases?
→high-energy
What are the classification of IEM?
→Toxic accumulation
→Deficiency in energy production/utilization
→Disorders of complex molecules involving organelles
What is toxic accumulation in IEM?
→protein metabolism
→carbohydrate intolerance
What molecules are more likely to be accumulated?
→Amino acids e.g. PKU, tyrosinaemia
→Organic acids e.g. propionylacidaemia
→urea cycle disorders e.g. OTCD
What are examples of disorders of complex molecules involving organelles?
→Lyososomal storage disorders e.g. Fabry’s
→Peroxisomal disorders e.g. Zellwegers
What are examples of disorders in deficiency in energy production?
→Fatty acid oxidation e.g. MCADD
→Carbohydrate utilization/production e.g. GSDs
→Mitochondrial disorders e.g. MERFF
What are the neonatal presentation of IEM?
→often acute
→Often caused by defects in carbohydrate intolerance and energy metabolism
What are the late onset presentation of IEM due to?
→Patients have residual enzyme activity allowing slower accumulation of toxins
→Present with organ failure, encepalopathy, seizures
What are the 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
What may bring on the onset of of IEMs in neonates?
→Change in diet, stopped night feeds- hypoglycemia and seizures
What are examples of neonatal presentation of IEM?
→Poor feeding, lethargy, vomiting
→Epileptic encephalopathy
→Profound hypotonia –’floppy’ baby
→Organomegaly e.g. cardiomyopathy, hepatomegaly
→Dysmorphic features
→Sudden unexpected death in infancy (SUDI)
What are the biochemical abnormalities of IEM in neonates?
→Hypoglycaemia
→Hyperammonaemia
→Unexplained metabolic acidosis / ketoacidosis
→Lactic acidosis
What are routine lab investigations for IEMs?
→Blood gas analysis
→Blood glucose and lactate
→Plasma ammonia
What are specialist investigations for IEMs?
→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- lumbar puncture
What are confirmatory investigations of IEMs?
→Enzymology →Biopsy (muscle, liver, skin) →Fibroblast studies →Mutation analysis – whole genome sequencing →Family history
What are the criteria for screening Wilson and Junger?
→Condition should be an important health problem
→Must know incidence/prevelence in screening population
→Natural history of the condition should be understood
→Availability of a screening test that is easy to perform and interpret
→Availability of an accepted treatment for the condition
→Diagnosis and treatment of the condition should be cost-effective
Describe newborn blood spot screening
→Samples should be taken on day 5 (day of birth is day 0).
→Taken from heel prick
→All four circles on ‘Guthrie’ card need to be completely filled with a single drop of blood which soaks through to the back of the card.
→Require good quality bloodspot for analysis.
→Demographics checked
What is one cause of raised plasma amino acids?
→Liver damage
→Gross elevations in tyrosine and methionine
What are the causes of acute liver disease in neonate?
→Classical galactosaemia
→Hereditary fructose intolerance
→An organic acidaemia
→Tyrosinaemia type 1
What is shown in tyrosinaemia type 1?
→Urine organic acid analysis showed increase in succinylacetone-
How is tyrosinaemia type 1?
→nitisinone
How does nitisinone work?
→ inhibits an earlier step in the pathway to prevent accumulation of toxic metabolites
→prevents cirrhosis
What are the side effects of nitisinone?
→accumulation of tyrosine,
→ requires dietary restriction of tyrosine
→precursor phenylalanine
→What is tyrosinaemia type 1?
→Genetic deficiency in fumarylacetoacetase (FAH)
→Catalyzes the final step in tyrosine metabolism.
→Increased byproduct succinylacetone leads to significant organ toxicity (liver, kidney)
What is ornithine transcarbamylase?
→urea cycle disorder
→converts carbamylphosphate to citrulline
→hyperammonemia
What is the mode of inheritance in OTC disorders?
→X-linked
What are the symptoms of OTC deficiency?
→Ataxia,
→seizures,
→hyperammmonaemic encephalopathy
What factors can trigger a hyperammonaemic crisis?
→Increased endogenous protein catabolism e.g. infection, fasting, trauma, steroid administration
→High protein intake
