Inborn Errors Of Metabolism Flashcards
What are inborn errors of metabolism (IEM)?
- IEM = Group of rare genetic disorders
- Single gene defects -> deficient or absent activity of an enzyme -> results in disruption to metabolic pathways
- Affects syntheses/catabolism of proteins, carbs, fats and complex molecules
Give some key features of IEM
- Individually rare (e.g PKU 1:10,000)
- Collectively common (1:800 to 1:2500)
- High mortality within the first year of life
- Significant contribution to children of school age with physical handicap and children with severe learning difficulties
- Important to recognise in sick neonate
How is IEM treated?
- Global newborn screening programmes
- Treatment by dietary control/restrictions and/or compound supplementation. Newer drug and enzyme replacement therapy, and organ transplantation
State what the effects of IEM arise from (4) ?
- 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’s the Difference between congenital and inborn?
- Congenital = Present at birth
- Inborn = Transmitted through gametes
State 2 features of alkaponuria
- Autosomal recessive disease
- Congenital
State 2 symptoms and 2 causes of alkaponuria
- Symptoms: Urine turns black on standing, Black ochrontic pigmentation cartilage and collagenous tissue
- Causes: Homogentisic acid oxidase deficiency
State the one gene - one enzyme concept?
- 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 -> affects metabolic pathway
How does the one gene- one enzyme concept link with the molecular disease concept in IEM?
- 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
Inheritance patterns
State the different mechanisms of inheritance of IEM?
- Autosomal recessive
- Autosomal dominant
- X-linked
- Mitochondrial
Describe autosomal recessive as a mechanism of inheritance and give 3 examples of AR IEM?
- Both parents carry a mutation affecting the same gene
- 1 in 4 risk each pregnancy
- Consanguinity (same blood) increases risk of autosomal recessive conditions
- Examples: PKU (phenylketonuria), alkaponuria, MCADD
Is autosomal dominant rare in IMs and state 2 examples?
- Rare in IEM
- Examples: Marfan’s, acute intermittent porphyria
Describe how the X-linked conditions pass through each gender and state 2 examples of X-linked IEMs?
- 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 carbonyl transferase deficiency
What is mitochondrial gene mutation and describe how mitochondrial inheritance occurs?
- Mitochondrial gene DNA mutation -> Causes M to fail to produce energy to function properly
- M DNA is 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
State 2 examples of mitochondrial mutation IEM disorders with symptoms?
- MERFF -Myoclonic epilepsy and ragged red fibre disease:
- deafness, dementia, seizures
- MELAS - Mitochondrial encephalopathy with lacticacidosis and stroke-like episodes
What can be the result when mitochondrial DNA replication occurs when a mitochondrial mutation has been inherited?
- Heteroplasmy occurs - Cells contain varying amounts of normal mtDNA and also mutated mt DNA (heteroplasmic cells)
How can the mitochondrial disease differ between individuals?
- Distribution of affected mitochondria determines presentation
- Mitochondrial disease can vary in symptoms, severity, age of onset
- High energy-requiring organs more frequently affected
State the major classifications of IEM with examples of diseases for each one?
- Toxic Accumulation
- Deficiency in energy Production/Utilization
- Disorders of complex molecules involving organelles
Describe 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
Describe Deficiency in energy production/utilization
- Fatty acid oxidation e.g. MCADD
- Carbohydrate utilization/production e.g. GSDs
- Mitochondrial disorders e.g. MERFF
Describe Disorders of complex molecules involving organelles
- Lyososomal storage disorders e.g. Fabry’s
- Peroxisomal disorders e.g. Zellwegers
How does onset of neonate and adult of IEM differ?
- Neonatal to adult onset depending on severity of metabolic defect:
- Neonatal presentation often acute
- Often caused by defects in carbohydrate intolerance and energy metabolism
How does onset of neonate and adult of IEM differ?
- 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
Neonates with IM, how are they born like and state clues for 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, Family history of similar illness in siblings or unexplained deaths, Infant who was well at birth but starts to deteriorate for no obvious reason
State clinical symptoms of neonates with IM?
- Poor feeding, lethargy, vomiting
- Epileptic encephalopathy
- Profound hypotonia -‘floppy’ baby
- Organomegaly e.g. cardiomyopathy, hepatomegaly
- Dysmorphic features - abnormality in shape of part of body
- Sudden unexpected death in infancy (SUDI)
State biochemical abnormalities found in neonates with IEM
- Hypoglycaemia
- Hyperammonaemia
- Unexplained metabolic acidosis / ketoacidosis
- Lactic acidosis
Lab testing
State 3 routine lab investigations for IEM?
- Blood gas analysis
- Blood glucose and lactate
- Plasma ammonia
Lab testing
State 6 specialist investigations for IM?
- Plasma amino acids
- Urinary organic acids + orotic acid
- Blood acvl carnitine
- Urinary glycosaminoglycans
- Plasma very long chain fatty acids
- CSF tests e.g. CS lactate/pyruvate, neurotransmitters
State 4 confirmatory tests for IEM?
- Enzymology: Red cell galactose-1-phosphate uridyl transferase for galactosaemia, Lysosomal enzyme screening for Fabry’s
- Biopsy (muscle, liver)
- Fibroblast studies
- Mutation analysis - whole genome sequencing for FH
State the criteria required for a successful screening programme?
- Condition should be an important health problem
- Must know incidence/prevelence in screening population
- Natural history of the condition should be understood:
- There should be a recognisable latent or early symptomatic stage
- Availability of a screening test that is easy to perform and interpret:
- acceptable, accurate, reliable, sensitive and specific
- Availability of an accepted treatment for the condition:
- More effective if treated earlier
- Diagnosis and treatment of the condition should be cost-effective
State the disorders tested for in the UK newborn blood spot screening programme?
- Initial National programme included: PKU! Congenital hypothyroidism
- Extended to include: Sickle cell disease, Cystic fibrosis, Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)
- From 2015, the screening in England expanded to include four additional conditions (analysis by tandem mass spectrometry): Maple syrup urine disease (MSUD), Homocystinuria (pyridoxine unresponsive) (HCU), Isovaleric acidaemia (IVA), Glutaric aciduria type 1 (GA1)
Describe how the newborn blood spot screening occurs?
- Samples taken on day 5 after birth
- Taken from heel prick
- All four circle on ‘Guthrie’ card must be completely filled with single drop of blood
- UK national screening programme centre regulates this all
Neonatal causes
What are some possible metabolic causes for acute liver disease in neonate
- Classical galactosaemia
- Hereditary fructose intolerance g An organic acidaemia
- Tyrosinaemia type 1
- Urine organic acid analysis showed increase in succinylacetone
- Confirmation by sequence analysis of gene
Describe 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)
- Treatment with Nitisinone (NTBC)
- inhibits an earlier step in the pathway to prevent accumulation of toxic metabolites
- early treatment achieves >90% survival rate with normal growth, improved liver function and prevention of cirrhosis
- NTBC side effect is accumulation of tyrosine, and requires dietary restriction of tyrosine and precursor phenylalanine
Late onset case
What types of diagnostic biopsies can be taken?
- Diagnostic test - liver biopsy
- Liver enzymology
- Ornithine transcarbamylase 1.00 (ref range 11.8 - 44.7)
- Carbamylphosphate synthase 0.98 (ref range 0.73 - 3.19)
Describe Ornithine transcarbamylase deficiency
- Urea cycle disorder, OTC incidence 1:14000
- Symptoms range from mild to profound neuropsychiatric manifestations
- Ataxia, seizures, hyperammmonaemic encephalopathy
- Factors can trigger hyperammonaemic crisis
- Increased endogenous protein catabolism e.g. infection, fasting, trauma, steroid administration
- High protein intake (too much cheese intake)
- The mother remembers that on the day of the collapse, their fridge had been full of cheese in the morning, but empty in the evening!
