Inborn Errors of Metabolism Flashcards
1
Q
Who was Archibold E Garrod?
A
- Father of Inborn Errors of Metabolism (IEM)
- Trained as a doctor with an interest in chemistry
- Croonian lectures to the Royal College of Physicians
2
Q
What are the 4 IEM?
A
- Alkaptonuria
- Cystinuria
- Albinism
- Pentosuria
3
Q
Characteristics of IEM
A
- Congenital (present at birth)
- Inborn (transmitted through the gametes)
- Had the discontinuous distribution of a Mendelian trait
4
Q
What is Alkaptonuria?
A
- It is an autosomal recessive condition.
- Patients have black urine on standing (and alkalinisation) and older patients have discolouring of the ear. This is ochronosis.
- Black ochrontic pigmentation of cartilage and collagenous tissue.
- It is linked to a single gene disorder.
- It is benign but can cause osteoarthritis as effects bone.
- (Homogentisic acid oxidase deficiency)
5
Q
What is Cystinuria?
A
- Autosomal recessive disorder
- Defective transport of cystine and dibasic aa’s (arginine and lycine) through epithelial cells of renal tubule and intestinal tract.
- Cystine has low solubility - causing the formation of calculi in the renal tract.
- COAL?
- Mutations of SLC3A1 aa transporter gene (Chr 2p) and SLC7A9 (Chr 19).
6
Q
What are the two concepts of IEM?
A
- One gene - one enzyme concept
- Molecular disease concept
7
Q
What is the one-gene and one-enzyme concept and when was it proposed?
A
It was proposed by Beadle and Tatum 1945 (won a Nobel prize 1958).
- Proposed that all biochemical processes in all organisms are under genetic control. These processes are resolvable into a series of stepwise reactions.
- Each biochemical reaction is under the ultimate control of a single gene.
- The mutation of a single gene results in an alteration in the ability of the cell to carry out a single primary chemical reaction.
8
Q
What is the molecular disease concept?
A
- Proposed by Pauling et al 1949, Ingram 1956.
- Used to look at the electrophoretic ability of HbA and HbS. It works on haemoglobin in sickle cell disease.
- They found direct evidence that human gene mutations produced 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.
9
Q
What are the mechanisms of inheritance?
A
- Autosomal recessive
- Autosomal dominant
- X-linked
- Codominant
- Mitochondrial
These are ways that single-gene disorders are transmitted.
10
Q
Define autosomal recessive inheritance
A
- Read two copies to display the disease
- Both parents carry a mutation affecting the same gene.
- 1 in 4 risks each pregnancy
- Consanguinity (sharing cousin blood) increases risk of autosomal recessive conditions.
e. g. Cystic fibrosis, sickle cell disease
11
Q
Define autosomal dominant inheritance
A
- Rare in IEMs
- One copy to cause the disease is needed
- e.g. Huntington disease, Marfan’s, Familial hypercholesterolemia
12
Q
Recessive X-linked inheritance
A
- Conditions are passed through the maternal line.
- The conditions appear in males but usually, the females are only carriers and do not express.
- Female carriers may manifest condition - Lyonisation (random inactivation of one of the X chromosomes).
13
Q
Dominant X-linked inheritance
A
- Passed on from either affected parent
- Affected father will only pass the condition to his daughters
- The affected mother can pass the condition to sons and daughters.
14
Q
X-linked inheritance both types
A
- No male to male transmission
- X-linked dominant: Fragile X
- X-linked recessive: Haemophilia A, Duchenne muscular dystrophy, Fabry’s disease and Ornithine Carboamoyl transferase deficiency
15
Q
What is codominant inheritance?
A
Where two different versions (alleles) of a gene are expressed, and each version makes a slightly different protein. Both alleles influence the genetic trait or determine the characteristics of the genetic condition. E.g. ABO blood group, alpha 1AT
16
Q
Characteristics of mitochondrial inheritance
A
- Mitochondrial gene mutation
- Inherited exclusively from the mother as only the egg contributes mitochondria to the developing embryo. As well as this, only females can pass on mitochondrial mutations to their children. Fathers do not pass on these disorders.
- Affects both male and female offspring
17
Q
Examples of mitochondrial diseases
A
- Myoclonic epilepsy and ragged red fibre disease (MERFF); deafness, dementia and seizures
- Mitochondrial encephalopathy with lactic acidosis (MELAS) and stroke-like episodes
18
Q
How does heteroplasmy affect mitochondrial DNA replication?
A
The cell contains varying amounts of normal mtDNA and also mutated mtDNA. When cell division occurs, some cells have normal copies and some have mutated because of the way it is distributed.
19
Q
What determines the distribution of mitochondrial diseases?
A
- Distribution of affected mitochondria determines the presentation
- Mitochondrial disease can vary in symptoms, severity, age of onset.
- High energy-requiring organs more frequently affected e.g. brain, liver, kidneys, etc
- The current debate on three-parent babies.
20
Q
Key information on inborn errors of metabolism
A
- Individually rare
- Collectively common
- cumulative frequency accounting for high mortality within the first year of life.
- a significant contribution to the 1% of children of school age with physical handicaps and 0.3% with severe learning difficulties.
- Important to recognize in the sick neonate
- Newborn screening programs
21
Q
What is the presentation of IEM in neonates?
A
- Often acute
- Often caused by defects in energy metabolism: maple syrup urine defects; Tyrosinaemia; OTC (urea cycle defect)
22
Q
What is the presentation of IEM in an adult?
A
- Wilson’s
- Haemochromatosis
23
Q
Neonates with IEM
A
- Most are 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 IEM: consanguinity; FH of similar illness in siblings or unexplained deaths; an infant who was well at birth but starts to deteriorate for no obvious reason.
24
Q
The classical presentation of IEM
A
Symptoms can be very non-specific: poor feeding, lethargy, vomiting, hypotonia, fit - can be mistaken for sepsis when they’re actually an IEM.
Symptoms can also be specific: abnormal smell (sweet, musty, cabbage-like), cataracts, hyperventilation 2o to metabolic acidosis; Hyponatraemia and ambiguous genitalia; neurological dysfunction with respiratory alkalosis.
25
What are some biochemical abnormalities that IEM has?
- Hypoglycemia
- Hyperammonaemia
- Unexplained metabolic acidosis/ketoacidosis
- Lactic acidosis
26
What are some clinical presentations in IEM?
- Cognitive decline
- Epileptic encephalopathy
- Floppy baby
- Exercise intolerant
- Cardiomyopathy
- Dysmorphic features
- Sudden unexpected death in infancy (SUDI)
- Fetal hydrops
27
What are the routine lab investigations done for people with IEM?
- Blood gas analysis
- Blood glucose
- Plasma ammonia
28
Specialist investigations and when are they used?
- Plasma amino acids
- Urinary organic acids + orotic acid
- Blood acylcarnitines
- Blood lactate and pyruvate
- Urinary glycosaminoglycans
- Plasma very-long-chain fatty acids
- Done after to see the further cause of the disease
29
What are the confirmatory investigations for IEM?
- Enzymology
- Red cell galactose-1-phosphate uridyl transferase: Blood is sent to do enzyme activity assays to see if there is a particular deficiency
- Lysosomal enzyme screening
- Biopsy (muscle, liver)
- Fibroblast studies
- Mutation analysis - whole-genome sequencing: as it is a genetic disease; important to do a full family history.
30
What is neonatal screening?
- Early identification of life-threatening disease in pre-symptomatic babies.
- Earlier initiation of medical treatment; PKU causes mental retardation because of the buildup of phenylalanine
- The first cause of IEM that is being spotted earlier.
- Reduction of morbidity and mortality
31
What is the Wilson and Jungner screening criteria?
- The criteria is made as not every disease can be screened for e.g. with PKU
- The condition being screened must be an important health problem.
- Must be known as incidence/prevalence in the screening population
- The natural history of the condition needs to be understood. There should be a recognizable 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 accepted treatment for the condition - more effective if treated earlier.
- Diagnosis and treatment of the condition should be cost-effective
32
How to test if a screening test is good or not?
- Accurate and reproducible
- Cheap and produces rapid results
- Ethical
- Good statistical performance: how well the diagnosis influences the test result (sensitivity and specificity); how well the test result predicts the diagnosis (positive and negative predictive values)
33
What does the newborn blood spot screening program include?
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Initial National Screening programme:
1. PKU - started in the 1970s
2. Congenital hypothyroidism
Extended to include:
3. Cystic fibrosis
4. Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)
5. Haemoglobinopathies e.g. SCA
In 2015, extended to include:
6. Maple syrup urine disease (MSUD)
7. Homocystinuria (pyridoxine unresponsive) (HCU)
8. Isovaleric acidaemia (IVA)
9. Glutaric aciduria type 1 (GA1)
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34
How is the medium-chain acyl-CoA dehydrogenase deficiency tested?
Using a tandem mass spec which improved the screening programme for IEM
35
What are the standards for blood spotting?
- No double spots
- The technique needs to be right first time
- Samples should be taken on day 5 (birth = day 0)
- All four circles on card need to be completely filled with a single drop of blood which soaks through to the back of the Guthrie card.
