Inborn Errors of Metabolism Flashcards
What did Garrod propose in the Croonian lectures?
The following disorders were Congenital, Inborn (transmitted through the gametes) and had discontinuous distribution of a Mendelian trait
- Alkaptonuria
- Cystinuria
- Albinism
- Pentosuria
What is alkaptonuria?
Alkaptonuria is a rare autosomal recessive metabolic disorder characterized by the accumulation of homogentisic acid in the body due to Homogentisic acid oxidase deficiency
What are the effects of alkaptonuria?
Urine turns black on standing (and alkalinisation)
Black ochronotic pigmentation of cartilage & collagenous tissue
Arthritis in knee joints
What is cystinuria?
Inherited autosomal recessive disease characterized by high concentrations of a.a. cystine in urine, leading to formation of cystine stones in the kidneys, ureter, and bladder
What is the key mechanism of cystinuria?
Mutations of SLC3A1 aa transporter gene (Chr 2p) & SLC7A9 (Chr 19)
Defective transport of cystine and dibasic aa’s through epithelial cells of renal tubule and intestinal tract
Cystine has low solubility - formation of calculi in renal tract
Describe the molecular disease concept
Direct evidence that human gene mutations produce an alteration in the primary structure of proteins
What are inborn errors of metabolism caused by?
Inborn errors of metabolism are caused by mutations in genes which then produce abnormal proteins whose functional activities are altered
What are the 5 mechanisms of inheritance?
- Autosomal recessive
- Autosomal dominant
- X-linked
- Codominant
- Mitochondrial
Describe autosomal recessive inheritance
Both parents carry a mutation affecting same gene
- 1 in 4 risk each pregnancy
Consanguinity increases risk of autosomal recessive conditions
Examples: Cystic fibrosis, sickle cell disease
Give examples of autosomal dominant inborn errors of metabolism
Rare in IEMs
e.g.
Huntingdon disease, Marfan’s, Familial hypercholesterolaemia
Outline X linked recessive inheritance
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)
How are dominant X linked conditions inherited?
Dominant X-linked conditions passed on from either affected parent
No male to male transmission
Affected father will only pass condition to his daughters
Affected mother can pass condition to sons and daughters
Give examples of an X linked dominant inborn error of metabolism
Fragile X, Ornithine carbamoyl transferase deficiency
Name some X linked recessive disorders of metabolism
Haemophilia A, Duchenne muscular dystrophy, Fabry’s disease
What is codominance?
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.
Give examples of codominant inheritance
ABO Blood group, α1AT
Explain how mitochondrial inheritance works
Mitochondrial gene mutation
Inherited exclusively from mother
- only egg contributes mitochondria to developing
embryo
- only females pass on mitochondrial mutations to their
children
- Fathers do not pass these disorders to their daughters
or sons
Affects both male and female offspring
Give examples of mitochondrial inborn errors of metabolism
MERFF -Myoclonic epilepsy and ragged red fibre disease: deafness, dementia, seizures
MELAS – Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes
What is heteroplasmy?
Cell contains varying amounts of normal mtDNA and also mutated mtDNA
What factor affects the presentation of mitochondrial disease?
Distribution of affected mitochondria determine presentation
Mitochondrial disease can vary in symptoms, severity, age of onset
Which organs are more affected by mitochondrial disease?
High energy-requiring organs more frequently affected
Current debate on three parent babies
How common are inborn errors of metabolism?
Individually rare (1:10,000 - 1:500,000)
Collectively common
cumulative frequency accounting for high mortality within first year of life
Significant contribution to 1% school age children with physical handicap and 0.3% with severe learning difficulties
When are inborn metabolism disorders preferably diagnosed?
Important to recognise in sick neonate via newborn screening programmes
Describe the neonatal presentation of inborn errors of metabolism
Neonatal presentation often acute Often caused by defects in energy metabolism - Maple syrup urine disease - Tyrosinaemia - OTC (urea cycle defect)
How do inborn errors of metabolism present in adults?
- Wilson’s
- Haemochromatosis
Describe how IEM affects neonates birth
Most are born at term with normal birthweight and no abnormal features
When do neonatal IEM symptoms begin to present?
Symptoms present frequently in the first week of life when starting full milk feeds
What are the clues for IEM in neonates?
- Consanguinity
- FH of similar illness in siblings or unexplained deaths
- Infant well at birth but deteriorates for no obvious
reason
What are the non-specific symptoms of IEM?
Symptoms - can be very non-specific
Poor feeding, lethargy, vomiting, hypotonia, fits
What are the specific IEM symptoms?
- Abnormal smell (sweet, musty, cabbage-like)
- Cataracts
- Hyperventilation 2° to metabolic acidosis
- Hyponatraemia and ambiguous genitalia
- Neurological dysfunction with respiratory alkalosis
What other clinical scenarios present in IEMs?
- Biochemical abnormalities
- Hypoglycaemia
- Hyperammonaemia
- Unexplained metabolic acidosis / ketoacidosis
- Lactic acidosis
What are the clinical signs of IEMs in neonates?
- Cognitive decline
- Epileptic encephalopathy
- Floppy baby
- Exercise intolerant
- Cardiomyopathy
- Dysmorphic features
- Sudden unexpected death in infancy (SUDI)
- Fetal hydrops
What types of lab investigations are used to diagnose?
- Routine
- Specialist tests
- Confirmatory
Outline the routine lab investigations carried out for IEMs
- Blood gas analysis
- Blood glucose
- Plasma ammonia
What soecialist investigations are done when investigating IEMs?
- Plasma amino acids
- Urinary organic acids + orotic acid
- Blood acyl carnitines
- Blood lactate and pyruvate
- Urinary glycosaminoglycans
- Plasma v. long chain fatty acids
What are the confirmatory IEM lab investigations?
Enzymology
- Red cell galactose-1-phosphate uridyl transferase
- Lysosomal enzyme screening
Biopsy (muscle, liver)
Fibroblast studies
Mutation analysis – whole genome sequencing
What is the significance of neonatal screening?
- 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?
- Should be an important health problem
- Known incidence/prevalence in screening population
- Natural history of condition understood
- Availability of an easy to perform and interpret screening test
- Availability of an accepted treatment for condition
- Diagnosis and treatment of condition should be cost-effective
How do we know if a disease is well understood?
There should be a recognisable latent or early symptomatic stage
Why is it important to have an acceptable available test?
We know it’s acceptable, accurate, reliable, sensitive and specific
Why should a treatment be available before screening?
More effective if treated earlier
What makes a good screening test?
- Accurate and reproducible
- Cheap and produces rapid result
- Ethical
- Good statistical performance
Describe what is meant by ‘good statistical performance’
How well diagnosis influences test result (sensitivity and specificity)
How well test result predicts diagnosis (positive and negative predictive values)
Which conditions qualify for a newborn blood spot screening?
- PKU
- Congenital hypothyroidism
- Cystic fibrosis
- Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)
- Haemoglobinopathies
- Maple syrup urine disease (MSUD)
- Homocystinuria (pyridoxine unresponsive) (HCU)
- Isovaleric acidaemia (IVA)
- Glutaric aciduria type 1 (GA1)
How is a blood spot taken for screening?
- Samples should be taken on day 5 (day of birth is day 0)
- All four circles on card are completely filled with a single drop of blood which soaks through to back of the Guthrie card
What are the possible metabolic causes for liver disease in neonates?
- Classical galactosaemia
- Hereditary fructose intolerance
- An organic acidaemia
- Tyrosinaemia type 1
What is tyrosinaemia?
Tyrosinaemia type 1 is a blockage of fumarylacetoacetase enzyme causing build up of toxic metabolites
What toxins build up in tyrosinaemia?
e.g. succinyl acetoacetate into succinyl acetates and acetone
What are the consequences of toxin build up in tyrosinaemia?
Those metabollites are toxic to your liver and kidneys, also produces neurological damage
What is orthinine transcarbamylase deficiency?
OTC deficiency is inherited in an X-linked recessive urea cycle disorder which causes toxic levels of ammonia to build up in the blood
What are common markers of OTC?
raised ammonia and glutamine
Why is glutamine raised in OTC?
Glutamine is raised as it acts as a buffer to the increased ammonia
What is the consequence of increased ammonia levels?
Ammonia is v. toxic to the brian and needs to be detoxified in the urea cycle
How is OTC treated?
Treated using ammonia scavengers e.g. sodium benzoate or sodium phenylbutyrate
How is tyrosinaemia type 1 treated?
Treatment : iv dextrose, bicarbonate, antibiotics and FFP
