Inborn errors of metabolism Flashcards
What is an inborn error of metabolism?
Single gene defects resulting in disruption to metabolic pathways, blocking the pathway:
Synthesis/catabolism of proteins, carbohydrates, fats, complex molecules
What 4 things cause inborn errors of metabolism?
- 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 are the 4 disorders of inborn errors of metabolism?
- Alkaptonuria
- Cystinuria
- Albinism
- Pentosuria
How can IEM proposed by garrod arise
- 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 as a mother gave birth to an affected child
Describe 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
Describe 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 genetic methods can IEM follow?
- Autosomal recessive
- Autosomal dominant
- X-linked
- Mitochondrial
Define autosomal recessive and dominant
• Autosomal Recessive
o Both parents carry a mutation affecting the same gene
o 1 in 4 risk each pregnancy
o Consanguinity increases risk of autosomal recessive conditions
o Examples: PKU, alkaptonuria, MCADD
• Autosomal Dominant
o Rare in IEMs
o Examples: Marfan’s, acute intermittent porphyria
What is 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
What does a mitochondrial gene mutation result in?
Who is it inherited from?
Who is affected and who can pass it on?
• Mitochondrial gene mutation – the mitochondria do not produce enough energy.
• Inherited exclusively from mother
o only the egg contributes mitochondria to the developing embryo
o 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. Affected males cannot pass on disorder
- Eg. MERFF -Myoclonic epilepsy and ragged red fibre disease: deafness, dementia, seizures
- Eg. MELAS – Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes
Define heteroplasmy
Heteroplasmy - Cell contains varying amounts of normal mt DNA and also mutated mt DNA
Describe the prevalence of IEM
• Individually rare (e.g PKU 1:10,000)
• Collectively common (1:800 to 1:2500)
o High mortality within the first year of life
o Significant contribution to children of school age with physical handicap and children with severe learning difficulties
• Important to recognise in sick neonate
• Global newborn screening programmes
• Treatment by dietary control/restrictions and/or compound supplementation. Newer drug and enzyme replacement therapy, and organ transplantation
What 3 ways can IEM be classified?
• Toxic accumulation
o Protein metabolism
Amino acids e.g. PKU, tyrosinaemia
Organic acids e.g. propionylacidaemia
urea cycle disorders e.g. OTCD
o Carbohydrate intolerance e.g. galactosaemia
• Deficiency in energy production/utilization
o Fatty acid oxidation e.g. MCADD
o Carbohydrate utilization/production e.g. GSDs
o Mitochondrial disorders e.g. MERFF
• Disorders of complex molecules involving organelles
o Lyososomal storage disorders e.g. Fabry’s
o Peroxisomal disorders e.g. Zellwegers
How can IEM present itself?
• Neonatal to adult onset depending on severity of metabolic defect
o Neonatal presentation often acute
o Often caused by defects in carbohydrate intolerance and energy metabolism
o Late-onset due to accumulation of toxic molecules
o Patients have residual enzyme activity allowing slower accumulation of toxins
o Symptoms appear at adulthood
o Present with organ failure, encepalopathy, seizures
What are the signs of neonates with 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:
o Consanguinity
o FH of similar illness in siblings or unexplained deaths
o Infant who was well at birth but starts to deteriorate for no obvious reason
How can IEM present itself in neonates
• Clinical scenarios o Poor feeding, lethargy, vomiting o Epileptic encephalopathy o Profound hypotonia –’floppy’ baby o Organomegaly e.g. cardiomyopathy, hepatomegaly o Dysmorphic features o Sudden unexpected death in infancy (SUDI) • Biochemical abnormalities o Hypoglycaemia o Hyperammonaemia o Unexplained metabolic acidosis / ketoacidosis o Lactic acidosis
What lab tests can be performed, both routine and specliast
• Routine laboratory investigations o Blood gas analysis o Blood glucose and lactate o Plasma ammonia • Specialist investigations o Plasma amino acids o Urinary organic acids + orotic acid o Blood acyl carnitines o Urinary glycosaminoglycans o Plasma very long chain fatty acids o CSF tests e.g. CSF lactate/pyruvate, neurotransmitters
How can we confirm an IEM?
• Enzymology
o Red cell galactose-1-phosphate uridyl transferase for galactosaemia
o Lysosomal enzyme screening for Fabry’s
• Biopsy (muscle, liver)
• Fibroblast studies
• Mutation analysis – whole genome sequencing
What is the criteria for screening?
• Condition should be an important health problem
• Must know incidence/prevelence in screening population
• Natural history of the condition should be understood
o there should be a recognisable latent or early symptomatic stage
• Availability of a screening test that is easy to perform and interpret
o 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
What screening process is used for newborns?
Newborn blood spot screening • Initial National programme included: o PKU o Congenital hypothyroidism • Extended to include o Sickle cell disease o Cystic fibrosis o Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) • From 2015, the screening in England expanded to include four additional conditions (analysis by tandem mass spectrometry) o Maple syrup urine disease (MSUD) o Homocystinuria (pyridoxine unresponsive) (HCU) o Isovaleric acidaemia (IVA) o Glutaric aciduria type 1 (GA1)
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.
• UK National Screening Programme Centre established to develop standards and guidelines, provide information and coordinate screening labs. Screening performance monitored e.g. timeliness of results and completeness of coverage.
