Inborn Errors of Metabolism Flashcards
What did Garrod propose
Garrod proposed that: Alkaptonuria Cystinuria Albinism Pentosuria Congenital (present at birth) Inborn (transmitted through the gametes) Had the discontinuous distribution of a Mendelian trait
Alkaptonuria - define
Black ochrontic pigmentation of cartilage & collagenous tissue
Alkaptonuria - characteristics
Autosmal recessive Urine turns black on standing (and alkalinisation) Arthritis Homogentisic acid oxidase deficiency
Cystinuria - define
Defective transport of cystine and dibasic aa’s through epithelial cells of renal tubule and intestinal tract
Cystinuria - cause
Mutations of SLC3A1 aa transporter gene (Chr 2p) & SLC7A9 (Chr 19)
AR
What 4 things did Beadle and Tatum propose
All biochemical processes in all organisms are under genetic control
These 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
Inborn errors of metabolism are caused by
Inborn errors of metabolism are caused by mutations in genes which then produce abnormal proteins whose functional activities are altered
Mechanisms of inheritance - list 5
Autosomal recessive Autosomal dominant X-linked Codominant Mitochondrial
Autosomal recessive - describe action, effect and examples
Both parents carry a mutation affecting the same gene
1 in 4 risk each pregnancy
Consanguinity increases risk of autosomal recessive conditions
Examples: Cystic fibrosis, sickle cell disease
Autosomal dominant - in IEMs and examples
Rare in IEMs
Examples: Huntingdon disease, Marfan’s, Familial hypercholesterolaemia
Describe passing of recessive X linked conditions - explain
Recessive X linked conditions passed through the maternal line
condition appears in males
condition carried in females, but not usually expressed. Female carriers may manifest condition –Lyonisation (random inactivation of one of the X chromosomes)
Describe passing of dominant X linked conditions - explain
Dominant X-linked conditions passed on from either affected parent
Affected father will only pass the condition to his daughters
Affected mother can pass the condition to sons and daughters
X-linked dominant: examples
X-linked dominant: Fragile X, Ornithine carbamoyl transferase deficiency
X-linked recessive: examples
X-linked recessive: Haemophilia A, Duchenne muscular dystrophy, Fabry’s disease
Codominant - describe w/examples
Codominant
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.
Example: ABO Blood group, α1AT
Mitochondrial inheritance - describe and explain
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
Heteroplasmy - define
Heteroplasmy - Cell contains varying amounts of normal mt DNA and also mutated mt DNA
Presentation of IEM - neonate to adult
Neonate to adult
Neonatal presentation often acute
Often caused by defects in energy metabolism:
Maple syrup urine disease
Tyrosinaemia
OTC (urea cycle defect)
Adult
Wilson’s
Haemochromatosis
Neonates with IEM - weight significance
Most are born at term with normal birthweight and no abnormal features
Neonates with IEM - symptoms
Symptoms present frequently in the first week of life when starting full milk feeds
Neonates with IEM - clues
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
IEM - presentation (specific vs unspecific)
Symptoms - can be very non-specific
Poor feeding, lethargy, vomiting, hypotonia, fits
Or specific
Abnormal smell (sweet, musty, cabbage-like)
Cataracts
Hyperventilation 2° to metabolic acidosis
Hyponatraemia and ambiguous genitalia
Neurological dysfunction with respiratory alkalosis
IEM clinical scenarios - Biochemical abnormalities list
Biochemical abnormalities:
Hypoglycaemia
Hyperammonaemia
Unexplained metabolic acidosis / ketoacidosis
Lactic acidosis
IEM clinical scenarios - clinical list = 8
Clinical:
Cognitive decline Epileptic encephalopathy Floppy baby Exercise intolerant Cardiomyopathy Dysmorphic features Sudden unexpected death in infancy (SUDI) Fetal hydrops
Routine laboratory investigations (IEM) - list 3
Blood gas analysis
Blood glucose
Plasma ammonia
Specialist investigations for IEM - list 6
Specialist investigations:
Plasma amino acids Urinary organic acids + orotic acid Blood acyl carnitines Blood lactate and pyruvate Urinary glycosaminoglycans Plasma very long chain fatty acids
Confirmatory investigations - list 4
Enzymology
- Red cell galactose-1-phosphate uridyl
transferase
- Lysosomal enzyme screening
Biopsy (muscle, liver)
Fibroblast studies
Mutation analysis – whole genome sequencing
Neonatal Screening - benefits
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) - neonatal
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
Criteria for a good screening test, neonatal
Accurate and reproducible
Cheap and produces rapid result
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)
Newborn blood spot screening - Initial National programme included:
PKU
Congenital hypothyroidism
Newborn blood spot screening - extended to include
Extended to include:
Cystic fibrosis
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)
Haemoglobinopathies
Newborn blood spot screening - From 2015, the screening in England expanded to include four additional conditions
Maple syrup urine disease (MSUD) Homocystinuria (pyridoxine unresponsive) (HCU) Isovaleric acidaemia (IVA) Glutaric aciduria type 1 (GA1)
Taking blood spots for screening (neonates) - requirements
Samples should be taken on day 5 (day of birth is 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
Acute liver failure - treatment
Treatment:
iv dextrose, bicarbonate, antibiotics and FFP
Possible metabolic causes for acute liver disease in neonate
Classical galactosaemia
Hereditary fructose intolerance
An organic acidaemia
Tyrosinemia type 1
Tyrosinaemia type1 - define + cause
Most severe form of tyrosinemia, a buildup of too much of the amino acid tyrosine in the blood and tissues due to an inability to metabolize it.
It is caused by a deficiency of the enzyme fumarylacetoacetate hydrolase.
