Inborn Errors of Metabolism Flashcards
Define inborn errors of metabolism
A single gene defect resulting in disruption to metabolic pathways (blocked pathways)
What causes the symptoms faced in IEM
- 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
Describe the discovery of the idea of IEM
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’
What disorders did Garrod study
- Alkaptonuria
- Cystinuria
- Albinism
- Pentosuria
What did Garrod propose about the disorders
- 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
What is the one gene - one enzyme concept
Beadle and Tatum 1945 (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 is the molecular disease concept
Pauling et al 1949, Ingram 1956
- 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 the mechanisms of inheritance for IEM
- Autosomal recessive
- Autosomal dominant
- X-linked
- Mitochondrial
An accurate family history required to establish
pattern of inheritance
Describe Autosomal Recessive inheritance of IEM
- Both parents carry a mutation affecting the same gene
- 1 in 4 risks each pregnancy
- Consanguinity increases the risk of autosomal recessive
conditions - Examples: PKU, alkaptonuria, MCADD
Describe the Autosomal Dominant Inheritance of IEM
- Only one parent needs to have a dominant allele
- 2 in 4 risks each pregnancy
- Rare in IEMs
- Examples: Marfan’s, acute intermittent porphyria
Describe X-Linked Inheritance of IEM
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
Describe mitochondrial inheritance of IEM
- Mitochondrial gene mutation
- Inherited exclusively from mother
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
What does heteroplasmy mean in mitochondrial inheritance
Cell contains varying amounts of normal mt DNA and also mutated mt DNA
What are the characteristics of mitochondrial inheritance
- Distribution of affected mitochondria determines
presentation - Mitochondrial disease can vary in symptoms, severity,
age of onset - Varying penetrance - High energy-requiring organs are more frequently affected
- Recent debate on three parent babies
What is the prevalence 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
How are IEMs classified
Toxic accumulation:
- Protein metabolism
- Carbohydrate intolerance
Deficiency in energy production/utilisation:
- Fatty acid oxidation
- Carbohydrate utilisation/intolerance
- Mitochondrial disorders
Disorders of complex molecules involving organelles:
- Lysosomal storage disorders
- Peroxisomal disorders
How does IEM present in patients
Neonatal to adult-onset depending on the 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
What are the clinical scenarios faced in neonatal presentation
- Poor feeding, lethargy, vomiting
- Epileptic encephalopathy
- Profound hypotonia – ’floppy’ baby
- Organomegaly e.g. cardiomyopathy, hepatomegaly
- Dysmorphic features
- Sudden unexpected death in infancy (SUDI)
What are the biochemical abnormalities faced in neonatal IEM
- Hypoglycaemia
- Hyperammonaemia
- Unexplained metabolic acidosis / ketoacidosis
- Lactic acidosis
What could be the causes for neonatal IEM
- 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 routine laboratory investigation can we carry out to test for IEM
- Blood gas analysis
- Blood glucose and lactate
- Plasma ammonia
What specialist investigation can we carry out to test for IEM
- 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
What confirmatory investigation can we carry out to test 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
How can newborn screen help with treatment for IEM
- Carry out bacterial inhibition assay
- Early identification of life-threatening disease in pre-symptomatic babies
- Earlier initiation of medical treatment
- Reduction of morbidity and mortality
What are the criteria for screening
- Condition should be an important health problem
- Must know incidence/prevalence in screening population
The natural history of the condition should be understood - Availability of a screening test that is easy to perform and interpret
- Availability of an accepted treatment for the condition
- Diagnosis and treatment of the condition should be cost-effective
What is the newborn blood spot screening
Blood samples taken from days 0 to 5 to test for various conditions in newborns
What does the blood spot screening test for
- PKU
- Congenital hyperthyroidism
- Sickle cell disease
- Cystic fibrosis
- Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)
What does the tandem mass spectrometry test screen for after being introduced in 2015
- Maple syrup urine disease (MSUD)
- Homocystinuria (pyridoxine unresponsive) (HCU)
- Isovaleric acidaemia (IVA)
- Glutaric aciduria type 1 (GA1)
