Inborn Errors of Metabolism Flashcards
What are inborn errors of metabolism? (IEM)
They are a group of rare genetic disorders that result from a block to an essential pathway in the body’s metabolism
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
Who is viewed as the ‘father of Inborn errors of metabolism?
Archibold E Garrod 1857 - 1936:
Father of IEM
Croonian lectures to the Royal College of Physicians in June 1908
Published in the Lancet July 1908
Reprinted as a book ‘Inborn errors of metabolism’
He studied 4 disorders: Alkaptonuria Cystinuria Albinism Pentosuria
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 discovered (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 was the molecular disease concept?
Pauling et al 1949, Ingram 1956
Worked on haemoglobin in sickle cell disease
found 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 some mechanisms of inheritance of IEM?
(Inborn errors of metabolism are usually single-gene disorders)
Mechanisms of Inheritance include: Autosomal recessive Autosomal dominant X-linked Mitochondrial An accurate family history required to establish pattern of inheritance
More detail on them:
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
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
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
However, this can be complicated by the concept of Heteroplasmy - Cell contains varying amounts of normal mt DNA and also mutated mt DNA
(most cells show homoplasy)
What can treatment of Inborn errors of metabolism include?
Treatment by dietary control/restrictions and/or compound supplementation. Newer drug and enzyme replacement therapy, and organ transplantation
How can IEMs be classified?
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
When can IEMs present?
Can babies present with any clues for IEMs?
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
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:
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 is consanguinity?
the fact of being descended from the same ancestor.
How can neonates present (with IEM)?
Neonatal Presentation:
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 investigations can be done to identify 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
Confirmatory Investigations
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
What is the criteria for screening for IEM?
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
What happens in a new-born 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.
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)
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
What is Ornithine transcarbamylase deficiency?
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.
