Inborn errors of metabolism

Question 1

What is an inborn error of metabolism?

Answer 1

Single gene defects resulting in disruption to metabolic pathways, blocking the pathway:

Synthesis/catabolism of proteins, carbohydrates, fats, complex molecules

Question 2

What 4 things cause inborn errors of metabolism?

Answer 2

• 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

Question 3

What are the 4 disorders of inborn errors of metabolism?

Answer 3

• Alkaptonuria
• Cystinuria
• Albinism
• Pentosuria

Question 4

How can IEM proposed by garrod arise

Answer 4

• Congenital (present at birth)
• Inborn (transmitted through the gametes)
• Followed Mendel’s laws of inheritance

Question 5

What is Alkaptonuria?

Answer 5

• 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

Question 6

Describe the one gene-one enzyme concept

Answer 6

• 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

Question 7

Describe the molecular disease concept

Answer 7

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

Question 8

What genetic methods can IEM follow?

Answer 8

• Autosomal recessive
• Autosomal dominant
• X-linked
• Mitochondrial

Question 9

Define autosomal recessive and dominant

Answer 9

• 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

Question 10

What is X-linked inheritance?

Answer 10

• 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

Question 11

What does a mitochondrial gene mutation result in?

Who is it inherited from?

Who is affected and who can pass it on?

Answer 11

• 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

Question 12

Define heteroplasmy

Answer 12

Heteroplasmy - Cell contains varying amounts of normal mt DNA and also mutated mt DNA

Question 13

Describe the prevalence of IEM

Answer 13

• 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

Question 14

What 3 ways can IEM be classified?

Answer 14

• 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

Question 15

How can IEM present itself?

Answer 15

• 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

Question 16

What are the signs of neonates with IEM?

Answer 16

• 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

Question 17

How can IEM present itself in neonates

Answer 17

•	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

Question 18

What lab tests can be performed, both routine and specliast

Answer 18

•	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

Question 19

How can we confirm an IEM?

Answer 19

• 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

Question 20

What is the criteria for screening?

Answer 20

• 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

Question 21

What screening process is used for newborns?

Answer 21

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.