What are inherited metabolic disorders?
-Group of genetic diseases involving metabolic defects.
-Individually rare, but collectively not uncommon
-Typically result in deficiencies of key enzymes.
-Results in abnormal synthesis or catabolism of:
Proteins
Amino acids
Carbohydrate
Lipids
- Clinical symptoms usually severe and typically present in infancy or childhood.
Effects of enzyme defects
- Decreased formation of final product.
- Accumulation of first 2 substrates
- Increased formation of other metabolites.
What are some common clinical features of inherited metabolic disorders presenting in childhood?
- Acidosis
- Failure to thrive
- Vomiting, refusal of feeds, irritability.
- Central nervous system dysfunction
- Hypoglycaemia
- Usual odour
The Urea Cycle
- Cycle is split between mitochondrial matrix and cytosol
- 5 enzymes catalyse the cycle in the liver and their concentrations increase or decrease in response to high or low protein diets.
- CPS1 is the regulatory enzyme
- N-Acetylglutamate is allosteric activator of CPS1.
Urea Cycle defects
6 inherited disorders of the urea cycle
Most common is ornithine transcarbamoylase (OTC) deficiency
- OTC has X-linked inheritance, rest are autosomal recessive.
- Characterised by hyperammonaemia (elevated blood ammonia level)-highly toxic
- Elevated blood ammonia is a medical emergency.
-Typically presents in newborn period.
Amino acid disorders
- Amino acids may be metabolised into other amino acids, hormones, pigments, neurotransmitters.
- Enzymes play a key role in these processes.
- Inherited gene defects cause decreased enzyme activity.
- Decreased product
- Increased precursors
Alternative metabolic products (potentially toxic).
Know PKU
Phenylketonuria (PKU)
- Absence/deficiency of Phenylalanine hydroxylase (PAH) - classical PKU
- Autosomal recessive disorder
- Associated with increased phenylalanine (Phe) levels (toxic)
- Untreated individuals exhibit signs of impaired brain development.
- Treatable condition - Reduced protein diet supplemented with tyrosine.
- Neonatal screening programme (carried out on day 5).
Phenylketonuria (PKU) - Clinical features
- Normal at birth with near normal blood Phe levels.
- Phe levels rise rapidly once feeding is established.
- Days 3-4 may present with irritability and feeding difficulties.
- If untreated, delayed mental development and neurological features are evident by 6 months of age.
- Musty odour
Phenylketonuria (PKU) - Treatment
-Low protein diet supplemented with “protein” substitute.
_maintain blood Phe levels between 120-360 umol/l
-Blood Tyr maintained at upper limit of reference range.
- Monitor vitamin and trace element status.
- Managed by multi-disciplinary team: Dietitians, metabolic physicians, biochemists, genetic counselling.