inborn errors of metabolism Flashcards
1
Q
What causes Inborn Error Metabolism (IEM)?
A
- IEM occur due to block in pathway of metabolism.
- single gene defects resulting in disruption to metabolic pathways
- can vary in age of onset and clinical severity.
2
Q
What are effects due to IEM?
A
- 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
3
Q
What is the history of IEM?
A
- Archibold R Garrod 1857-936
- 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’
4
Q
What are 4 disorders outlined in Croonian lectures by Garrod?
A
- Alkaptonuria
- Cystinuria
- Albinism
- Pentosuria
5
Q
What did Garrod propose the 4 disorders to be?
A
- congenital (present at birth)
- inborn(transmitted through the gametes)
- followed Mendel’s laws of inheritance
6
Q
What are characteristics of Alkaptonuria?
A
- urine turns black on standing
- black ochrontic pigmentation of cartilage & collagenous tissue
- homogentisic acid oxidase deficiency
- autosomal recessive disease
- congenital
7
Q
What link between gene and metabolism did Beedle and Tatum establish in 1945?
A
=> one gene - one enzyme concept
- all biochemical processes in all organisms are under genetic control
- biochemical processes are resolvable into 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 cell to carry out a single primary chemical reaction.
8
Q
What molecular disease concept did Pauling et al 1949, Ingram 1956 discover?
A
- worked on hemoglobin in sickle cell disease
- direct evidence that human gene mutations produce an alteration of 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.
9
Q
What are mechanisms of inheritence of IEM?
A
- IEM are genetic conditions (single gene disorders)
- autosomal recessive
-autosomal dominant - X-linked
- Mitochondrial
An accurate family history required to establish pattern of inheritance.
10
Q
What are examples of autosomal recessive conditions?
A
- 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
11
Q
What is autosomal dominant conditions?
A
- Rare in IEMs
- Examples : Marfan’s, acute intermittent porphyria
12
Q
How do x-linked inheritance occur?
A
- 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)
13
Q
What are examples of X- linked inheritance?
A
- Fabry’s disease
- ornithine carbamoyl transferase deficiency
14
Q
What are mitochondrial diseases?
A
- chronic genetic disorder occur when mitochondria fails to produce enough energy for body to function properly
- most occur mtDNA mutation
- affected male cant pass on mitochondrial disorder, we get our mothers mitochondria.
15
Q
define heteroplasmy
A
cells contains varying amounts of normal mtDNA and also mutated mtDNA
16
Q
define homoplasmay
A
DNA contains only normal mtDNA.
17
Q
What are classification of IEM?
A
- toxic accumulation
=>protein metabolism
- AA, eg: PKU,tryosinaemia
-oganic acids, eg: propionylacidaemia
-urea cycle disorder eg: OTCD
=>carbohydrate intolerance eg: galactosaemia - deficiency in energy production/utilisation
- Fatty acid oxidation , eg: MCADD
-carbohydrate utilsation/production eg, GSDs
-mitochondrial disorders eg: MERFF - disorders of complex molecule involving organelle
- lysosomal storage disorders eg: Fabry’s
-peroxisomal disorders, eg: Zellwegers
18
Q
When does IEM present?
A
- neonatal to adult onset depending on severity of metabolic defect
- neonatal presentation often acute
- often caused by defects in carbohydrate intolerance and energy metabolism
19
Q
Why do we get late-onset of IEM?
A
- due to accumulation of toxic molecules
- patients have residual enzyme activity allowing slower accumulation of toxins
- symptoms appear at adulthood
- present with organ failure, endocepalopathy, seizures
20
Q
What are clues for IEMs in neonates?
A
- consanguinity
- FH of similar illness in siblings or unexplained deaths
- infants who was well at birth but starts to deteriorate for no obvious reason.
21
Q
What are clinical scenarios presented in neonatal with IEM?
A
- poor feeding, lethargy,vomiting
- eplieptic encepalopathy
- prfound hypotonia - ‘floopy’ baby
- organomegaly eg. cardiomyopathy, hepatomegaly
- dysmorphic features
- sudden unexpected death in infancy (SUDI)
22
Q
What are biochemical abnormalities presented in neonatals?
A
- hypoglycemia
- hyperammonaemia
- unexplained metabolic acidosis/ketoacidosis
- lactic acidosis
23
Q
What routine lab investigations are done to test for IEM?
A
- blood gas analysis
- blood glucose and lactate
- plasma ammonia
24
Q
What further specialist investigations can be done in the lab?
A
- plasma amino acids
- urinary organic acids +oroctic acid
- blood acyl carnitines
- urinary glycosaminoglycans
- plasma very long chain fatty acids
- CSF tests , eg: CSF lactate/pyruvate, neurotransmitters
25
What are confirmatory investigations for IEM?
1. enzymology
- red cell galactose -1- phosphate uridyl transferase for galactosaemia
- lysosomal enzyme screening for Fabry's
2. biopsy (muscle and live)
3. Fibroblast studies
4. mutations analysis - whole genome sequencing.
26
What is the aim of newborn screening?
- detect IEM before symptoms occur so medical treatment and intervention can be given to reduce morbidity and mortality.
- bacterial inhibition assay was first ever newborn screening.
- >770000 babies screened/year
27
What are criteria for screening by wilson and junger?
- condition should be an important health problem
- must know incidence/prevelence in screening population
- 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 condition
- more effective if treated earlier
- diagnosis and treatment of condition should be cost effective
28
What is the newborn blood screening programme?
1. initial national programme included:
-PKU
-congenital hypothyroidism
2. Extended to include:
- sickle cell disease
-cystic fibrosis
- medium chain acyl CoA dehydrogenase deficiency (MCADD)
=> from 2015 England expanded to include 4 additional conditions(analysis by tandem mass spectrometry)
1. maple syrup urine disease (MSUD)
2. homocystinuria (pyridoxine unresponsive)(HCU)
3. isovaleric academia (IVA)
4. glutaric aciduria type 1 (GA1)
29
How should newborn blood spot screening be carried out?
1. samples should be taken on day 5 (day birth is day 0) by heel prick.
2. all 4 circles on 'Guthrie' card need to be completely filled with single drop of blood which soaks through to the back of card.
3. screening performance monitored eg. timeliness of results and completeness of coverage.
30
case 1: What is the possible metabolic causes for acute liver disease in neonate?
1. classical galactosemia
2. hereditary fructose intolerance (baby too small to have honey or fruit in diet)
3. organic acidemia
4. tyrosinaemia type 1:
- urine organic acid analysis showed increase in succinylacetone
- confirmation by sequence analysis of gene
31
What is tyrosinaemia type 1?
- genetic deficiency in fumarylacetoacetase (FAH)
- catalyses the final step in tyrosine metabolism
- increased byproduct succinylacetone leads to significant organ toxicity (liver, kidney)
32
How can you treat tyrosinaemia type 1?
=>NITISINONE (NTBC)
- inhibits an earlier step in the pathway to prevent accumulation of toxic metabolites
- early treatment achieves >90% survival rate with normal growth, improved liver function and prevention of cirrhosis
33
What are side effects of NTBC?
accumulation of tyrosine
| - requires dietary restriction of tyrosine and precursor phenylalanine.
34
What are diagnostic test of liver biopsy?
- liver enzymology
- ornithine trancarbamylase 1.0 (ref range 11. 8 -44.7)
- carbamylphosphate synthase 0.98(ref range 0.73 - 3.19)
35
Liver biopsy shows ornithine transcarbamylase deficiency what is this common in?
- urea cycle disorder, OTC incidence 1: 14000
- symptoms range from mild to profound neuropyschiatric manifestations
- ataxia, seizures, hyperammoneamic encephalopathy
- factors can trigger hypera
36
What factors can trigger hyperammonaemic crisis?
- increased endogenous protein catabolism, eg: infection, fasting, trauma, steroid administration
- high protein intake
37
What is the metabolic pathway for?
Synthesis / catabolism of proteins, carbohydrates, fats, complex molecules
