Inborn errors of metabolism Flashcards
what is inborn errors of metabolism
- single gene defects resulting in disruption to metabolic pathways
- including synthesis/catabolism of proteins, carbohydrates, fays, 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
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
Mechanisms of inheritance -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
Mechanisms of inheritance-Autosomal Dominant
— Rare in IEMs
— Examples: Marfan’s, acute intermittent porphyria
Mechanisms of inheritance- 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
Mechanisms of inheritance- Mitochondrial inheritance
• 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
meaning of heteroplasmy
cells contains varying amounts of normal mtDNA and also mutated mtDNA
what are the 3 classification of IEM
- Toxic accumulation
- Deficiency in energy production/utilization
- Disorders of complex molecules involving organelles
classification of IEM- Toxic accumulation
- protein metabolism
- –amino acid e.g. PKU, tyrosinaemia
- –organic acids e.g. propionylacidaemia
- –urea cycle disorders e.g. OTCD
- Carbohydrate intolerance e.g. galactosaemia
classification of IEM-Deficiency in energy production/utilization
— Fatty acid oxidation e.g. MCADD
— Carbohydrate utilization/production e.g. GSDs
— Mitochondrial disorders e.g. MERFF
classification of IEM- Disorders of complex molecules involving organelles
— Lyososomal storage disorders e.g. Fabry’s
— Peroxisomal disorders e.g. Zellwegers
Presentation of IEM - Neonates
-Neonatal to adult onset depending on severity of
metabolic defect
—Neonatal presentation often acute
—Often caused by defects in carbohydrate intolerance
and energy metabolism
Presentation of IEM-late onset
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
Clues of neonates with 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
Clinical scenarios- neonates
— 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- Neonates
— Hypoglycaemia
— Hyperammonaemia
— Unexplained metabolic acidosis / ketoacidosis
— Lactic acidosis
Routine lab investigation for IEM
- Blood gas analysis
- blood glucose and lactate
- plasma ammonia
Special investigation for IEM
-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
Confirmatory investigation
• 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
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
- —–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
which disorders are tested for in the UK Newborn blood spot screening programme.
- 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)
Newborn blood spot screening
samples should be taken at day 5 and taken from heel prick
all 4 circles on ‘gruthrie’ card need to completely filled
