Inborn Errors of Metabolism Flashcards
What are inborn errors of Metabolism? Define them
These are single gene defects which result in disruption to metabolic pathways.
What can IEM effects be due to ?
- Toxic accumulation of substrates
- Toxic accumulation of intermediates from alternative metabolic pathways
- Defects in energy production/use due to deficiency of products
- All of these together
What are the four disorders which were studied by Garrod?
Alkaptonuria -rare genetic metabolic disorder characterized by the accumulation of homogentisic acid in the body.
Cystinuria- inherited autosomal recessive disease characterized by high concentrations of the amino acid cystine in the urine
Alibinism- congenital absence of any pigmentation or colouration
Pentosuria-condition where the sugar xylitol, a pentose, presents in the urine in unusually high concentrations
Describe Alkaptonuria and how it presents
Urine turns black on standing (alkalinisation)
Black ochronotic (accumulation of homogentisic acid in connective tissue) pigmentation of cartilage and collagenous tissue
Homogentisic acid oxidase deficiency
Autosomal recessive disease
Congenital
What is the one gene- one enzyme concept ?
- All biochemical processes in organisms are under genetic control
- Biochemical processes are resolvable into a series of stepwise reactions
- Each biochemical reaction is under the ultimate control of different single gene
- Mutation of a single gene results in alterations in the ability of the cell to carry out a single primary chemical reaction
What is the Molecular disease concept.
This was studied using haemoglobin in SCD
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 will then produce abnormal proteins which functional activities are altered.
What are the different mechanisms of inheritance ?
Autosomal recessive
Autosomal dominant
X-linked
Mitochondrial
Using a accurate family history can establish
What is the autosomal recessive mechanism of inheritance ?
Both of the parents carry a mutation which affects the same gene
1 in 4 risk -each pregnancy
Consanguinity (the fact of being descended from the same ancestor.) increases risk of autosomal recessive conditions
E.g diseases: PKU(Phenylketonuria) Alkaptonuria, MCADD
What is the autosomal dominant mechanism of inheritance ?
These are rare in IEMS.
One copy of a mutated (changed) gene from one parent can cause the genetic condition.
50% chance of getting the disease
No carrier status
E.g :Marfans, acute intermittent porphyria
What is the X-linked inheritance mechanism ?
Recessive X-linked conditions passed through the maternal line :
- Condition appears in males
- Condition carried in females
Female carriers may manifest condition
(Lyonization-Random inactivation of one of the X chromosomes)
Examples:Fabry’s disease, Ornithine carbamoyl transferase deficiency.
What is Mitochondrial inheritance ?
Mitochondrial gene mutation
Inherited exclusively from mother
- The egg will contribute mitochondria to the developing embryo
- Only females can pass on mitochondrial mutations to their children
Affects both male and female offspring
Example :
- MERFF (Myoclonic epilepsy and ragged red fibre disease: deafness, dementia, seizure)
- MELAS(Mitochondrial encephalopathy with lactic acidosis and stroke like episodes
What is Heteroplasmy?
This is when the cell contains varying amounts of normal mt DNA and also mutated mtDNA
What organs are worsely affected by Mitochondrial diseases?
High energy requiring organs are more frequently affected
How are IEM classified ?
Describe the three categories and subsections within them .
Toxic accumulation -Protein metabolism o Amino acids-PKU, tyrosinemia o Organic acids-propionyl acidaemia o urea cycle disorders -OTCD -Carbohydrate intolerance o galactosaemic
Deficiency in energy production/utilisation
- Fatty acid oxidation -MCADD
- Carbohydrate utilisation/production-GSDS
- Mitochondrial disorders -MERFF
Disorders of complex molecules involving organelles -Lysosomal storage disorders o Fabry's -Peroxisomal disorders o Zellweger's
What is the presentation of IEM?
Describe the two main categories of this.
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 is due to accumulation of toxic molecules
- Patients have residual enzyme activity allowing slower accumulation of toxins
- Symptoms appear at adulthood
- Present with organ failure, encephalopathy(Damage that affects the brain), seizures.
Describe neonates who are born with IEM.
What clues may be present to help diagnose them with IEM?
They may be born at term with normal weight and no abnormal features.
Symptoms present frequently in the first week of life when starting full milk feeds
Clues:
Consanguinity
FH of similar illness in siblings or unexplained deaths
Infant who was well at birth but deteriorates for no clear reason
What symptoms will Neonates present with ?
Clinical :
- Poor feeding, lethargy ,vomiting
- Epilitic encephalopathy
- Profound hypotonia(floppy baby )
- Organomegaly
- Dysmorphic features
- SUDI-Sudden death
Biochemical abnormalities:
- Hypoglycaemia
- Hyperammonaemia
- Unexplained metabolic acidosis /ketoacidosis
- Lactic acidosis
What laboratory investigations can becarried out to diagnose IEM ?
Routine laboratory investigations :
- Blood gas analyisis
- 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 - CSF lactate pyruvate, neurotransmitters
What are some confirmatory investigations which are carried out ?
Enzymology
- Red cell galactrose -1 -phosphate uridyl transferase for galactosaemia
- Lysosomal enzyme screening for Fabry’s
- Biopsy (Muscle ,Liver)
- Fibroblast studies
- Mutation analysis-Whole genome sequencing
What is New-born screening and what can it lead to ?
The first was for foetal ketounuria and the tests was a bacterial inhibition test.
The UK more than 770,000 babies are screened every year.
Early identification of life threatening disease in pre-symptomatic babies
Earlier initiation of medical treatment
Reduction of morbidity and mortality
What is the criteria for screening ?
Condition should be an important health problem
Must know incidence/prevalence in screening population
(This may vary in different populations)
Natural history of the condition should be understood
(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.
What are the different new born spot screening programmes?
PKU Congenital hypothyroidism SCD Cystic fibrosis Medium -chain acyl-CoA dehydrogenase deficiency (MCADD)
From 2015 expanded to include : Maple syrup urine disease Homocystinuria Isovaleric acidaemia Glutaric aciduria type 1
How are samples taken for new born screening ?
Blood spots which are taken on day 5 via a heel prick.
All four circles on ‘Guthrie’ card need to be filled with a single drop of blood which soaks through to the back of the card.
What are the possible metabolic causes for acute liver disease in neonate?
Classical galactosaemia Hereditary fructose intolerance An organic acidaemia Tyrosinaemia type 1 -Urine organic acid analysis shows an increase in succinylacetone
