Inborn errors of metabolism

Question 1

what is inborn errors of metabolism

Answer 1

• single gene defects resulting in disruption to metabolic pathways
• including synthesis/catabolism of proteins, carbohydrates, fays, complex molecules

Question 2

IEM effects due to

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 is alkaptonuria

Answer 3

•Urine turns black on standing (and 
alkalinisation) 
•Black ochrontic pigmentation of 
cartilage & collagenous tissue 
•Homogentisic acid oxidase deficiency 
•Autosomal recessive disease 
•Congenital

Question 4

Mechanisms of inheritance -Autosomal Recessive

Answer 4

— 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

Question 5

Mechanisms of inheritance-Autosomal Dominant

Answer 5

— Rare in IEMs

— Examples: Marfan’s, acute intermittent porphyria

Question 6

Mechanisms of inheritance- X-Linked inheritance

Answer 6

—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 7

Mechanisms of inheritance- Mitochondrial inheritance

Answer 7

• 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

Question 8

meaning of heteroplasmy

Answer 8

cells contains varying amounts of normal mtDNA and also mutated mtDNA

Question 9

what are the 3 classification of IEM

Answer 9

• Toxic accumulation
• Deficiency in energy production/utilization
• Disorders of complex molecules involving organelles

Question 10

classification of IEM- Toxic accumulation

Answer 10

• protein metabolism
• –amino acid e.g. PKU, tyrosinaemia
• –organic acids e.g. propionylacidaemia
• –urea cycle disorders e.g. OTCD
• Carbohydrate intolerance e.g. galactosaemia

Question 11

classification of IEM-Deficiency in energy production/utilization

Answer 11

— Fatty acid oxidation e.g. MCADD
— Carbohydrate utilization/production e.g. GSDs
— Mitochondrial disorders e.g. MERFF

Question 12

classification of IEM- Disorders of complex molecules involving organelles

Answer 12

— Lyososomal storage disorders e.g. Fabry’s

— Peroxisomal disorders e.g. Zellwegers

Question 13

Presentation of IEM - Neonates

Answer 13

-Neonatal to adult onset depending on severity of
metabolic defect
—Neonatal presentation often acute
—Often caused by defects in carbohydrate intolerance
and energy metabolism

Question 14

Presentation of IEM-late onset

Answer 14

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

Question 15

Clues of neonates with IEM

Answer 15

— Consanguinity
— FH of similar illness In siblings or unexplained deaths
— Infant who was well at birth but starts to deteriorate for
no obvious reason

Question 16

Clinical scenarios- neonates

Answer 16

— Poor feeding, lethargy, vomiting
— Epileptic encephalopathy
— Profound hypotonia —’floppy’ baby
— Organomegaly e.g. cardiomyopathy, hepatomegaly
— Dysmorphic features
— Sudden unexpected death in infancy (SUDI)

Question 17

Biochemical abnormalities- Neonates

Answer 17

— Hypoglycaemia
— Hyperammonaemia
— Unexplained metabolic acidosis / ketoacidosis
— Lactic acidosis

Question 18

Routine lab investigation for IEM

Answer 18

• Blood gas analysis
• blood glucose and lactate
• plasma ammonia

Question 19

Special investigation for IEM

Answer 19

-plasma amino acids
-urinary organic acids+ orotic acid
-blood acyl carnities
-Urinary glycosaminoglycans
-plasma very long chain fatty acids
CSF tests e.g. CSF lactate/pyruvate, neurotransmitters

Question 20

Confirmatory investigation

Answer 20

• Enzymology 
— Red cell galactose-l-phosphate uridyl transferase for 
galactosaemia 
— Lysosomal enzyme screening for Fabry's 
• Biopsy (muscle, liver) 
• Fibroblast studies 
• Mutation analysis— whole genome 
sequencing

Question 21

Criteria for screening

Answer 21

• -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

Question 22

which disorders are tested for in the UK Newborn blood spot screening programme.

Answer 22

• PKU
• Congenital hypothyroidism
• Sickle cell disease
• Cystic fibrosis
• Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)
• Maple syrup urine disease (MSUD) -Homocystinuria (pyridoxine unresponsive) (HCIJ)
• Isovaleric acidaemia (IVA)
• Glutaric aciduria type 1 (GAI)

Question 23

Newborn blood spot screening

Answer 23

samples should be taken at day 5 and taken from heel prick

all 4 circles on ‘gruthrie’ card need to completely filled