inborn errors of metabolism Flashcards
inborn errors of metabolism
Single gene defects resulting in disruption to metabolic pathways
Synthesis/catabolism of proteins, carbohydrates, fats, 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
Can vary in age of onset and clinical severity
croonian lectures by Garrod
Studies of 4 disorders Alkaptonuria Cystinuria Albinism Pentosuria Garrod proposed that these were: Congenital (present at birth) Inborn (transmitted through the gametes) Followed Mendel’s laws of inheritance
describe alkaptonuria
Urine turns black on standing (and
alkalinisation)
Black ochrontic pigmentation of cartilage & collagenous tissue
Homogentisic acid oxidase deficiency
Autosomal recessive disease
Congenital
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
molecular disease concept
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
mechanism of inheritance
Autosomal recessive Autosomal dominant X-linked Mitochondrial An accurate family history required to establish pattern of inheritance
mechanism of inheritance 2
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
Autosomal Dominant
Rare in IEMs
Examples: Marfan’s, acute intermittent porphyria
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
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
mitochondrial DNA replication
heteroplasmy = cell contains varying amounts of normal mt DNA and mutated mt DNA
mitochondrial inheritance
Distribution of affected mitochondria determines presentation
Mitochondrial disease can vary in symptoms, severity, age of onset
High energy-requiring organs more frequently affected
Recent debate on three parent babies
2017 – UK granted first licence to Newcastle fertility centre
inborn errors of metabolism
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
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
classification of IEM
Toxic accumulation
Protein metabolism
Amino acids e.g. PKU, tyrosinaemia
Organic acids e.g. propionylacidaemia
urea cycle disorders e.g. OTCD
Carbohydrate intolerance e.g. galactosaemia
Deficiency in energy production/utilization
Fatty acid oxidation e.g. MCADD
Carbohydrate utilization/production e.g. GSDs
Mitochondrial disorders e.g. MERFF
Disorders of complex molecules involving organelles
Lyososomal storage disorders e.g. Fabry’s
Peroxisomal disorders e.g. Zellwegers
presentation of IEM
Neonatal to adult onset depending on 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
neonates with IEM
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:
Consanguinity
FH of similar illness in siblings or unexplained deaths
Infant who was well at birth but starts to deteriorate for no obvious reason
neonatal presentation
Clinical scenarios 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 Hypoglycaemia Hyperammonaemia Unexplained metabolic acidosis / ketoacidosis Lactic acidosis
lab testing
Routine laboratory investigations Blood gas analysis Blood glucose and lactate Plasma ammonia Specialist investigations 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
confirmatory investigations
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
newborn screening
UK >770000 babies screened/year
Early identification of life-threatening disease in pre-symptomatic babies
Earlier initiation of medical treatment
Reduction of morbidity and mortality
criteria for screening
wilson and jungner
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
newborn blood spot screening
Initial National programme included: PKU Congenital hypothyroidism Extended to include Sickle cell disease Cystic fibrosis Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) From 2015, the screening in England expanded to include four additional conditions (analysis by tandem mass spectrometry) Maple syrup urine disease (MSUD) Homocystinuria (pyridoxine unresponsive) (HCU) Isovaleric acidaemia (IVA) Glutaric aciduria type 1 (GA1)
newborn blood spot screening 2
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
