Inborn Errors of Metabolism Flashcards
what can IEM be defined as?
very rare genetic disorders involving specific genes which control proteins – if they are structurally altered it will affect their function, which will also affect their pathways in metabolism
role of Garrod and croonian lectures?
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?
- an autosomal recessive disorder
- benign disorder, but can cause arthritis later in life
- urine turns black on standing (and alkalinisation)
- bluish black ochrontic pigmentation of the pinna
- homogentisic acid oxidase deficiency
Cystinuria?
- Autosomal recessive disease
- 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
- COAL
- Mutations of SLC3A1 aa transporter gene (Chr 2p) & SLC7A9 (Chr 19)
One gene - one enzyme concept
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
concept that a mutation in 1 gene caused a defect in 1 enzyme in a specific metabolic pathway
Molecular disease concept
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 then produce abnormal proteins whose functional activities are altered
Looked at electrophoretic ability of Hb in normal patients
Mechanisms of inheritance (ways in which single gene disorders are transmitted)
Autosomal recessive Autosomal dominant X-linked Codominant Mitochondrial
Autosomal recessive
- need 2 copies of the variant gene for the disease to manifest itself
- both parents carry a mutation affecting the same gene
- 1 in 4 risk each pregnancy (If you’re a carrier, you have a 1 in 4 chance of each child being a carrier)
- consanguinity increases risk of autosomal recessive conditions
Examples: Cystic fibrosis, sickle cell disease
Autosomal dominant
- Rare in IEMs
- You only need one copy of that faulty allele to be affected, so you these are more commonly seen across the generations
Examples: Huntingdon disease, Marfan’s, Familial hypercholesterolaemia
X-Linked inheritance can be?
recessive or dominant
-No male to male transmission
X linked inheritance - recessive?
- 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)
- examples: Haemophilia A, Ornithine carbamoyl transferase deficiency, Duchenne muscular dystrophy and Fabry’s disease
X linked inheritance - dominant?
- 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
when can random x inactivation occur?
random inactivation of the x chromosome happens in Ornithine carbamoyl transferase deficiency
-some female carriers, after they give birth, get shrinking of their uterus due to random x inactivation
Codominance?
- two different versions 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
inheriting mt gene mutations
mutations affect mt genes and are inherited exclusively from the mother
- only the egg contributes mitochondria to the developing embryo
- only females can pass on mitochondrial mutations to their children
- mothers can pass onto both male and female offspring
MERFF -Myoclonic epilepsy and ragged red fibre disease: deafness, dementia, seizures
MELAS – Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes
what does the father contribute to mt dna mutations?
nothing
Heteroplasmy?
Cell contains varying amounts of normal mt DNA and also mutated mt DNA
the distribution of affected mitochondria determines what?
presentation
Mitochondrial diseases can vary in what?
symptoms, severity and age of onset
with mt diseases, which areas of the body are affected?
High energy-requiring organs more frequently affected
-brain, liver
why can severity of mt disease vary between individuals?
Because its randomly distributed in organs
are IEM’s rare?
they are individually rare but collectively common
-significant contribution to disability in early ages, hence why there are neonate screening programmes
Presentation of IEM in neonates?
-often acute
-often caused by defects in energy metabolism
for example, Maple syrup urine disease, Tyrosinaemia, OTC (urea cycle defect)
-Most are born at term with normal birthweight and no abnormal features
Presentation of IEM - adults?
Adult
- Wilson’s
- Haemochromatosis
explain why presentation is variable?
- because full blockage of an enzyme is severe, it affects an enzyme pathway (eg. in metabolism) - can be seen in the neonate
- but, sometimes it can be a partial deficiency of an enzyme, and if its not severe you might not get presentation until adulthood due to an intercurrent illness that might affect that metabolic pathway with the defect
Neonates with IEM - when do symptoms present?
Symptoms present frequently in the first week of life when starting full milk feeds
- start to see deterioration
- see if the parents are blood related, look for unexplained deaths in the family or if siblings have a disease
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
Classic presentation - non specific and specific symptoms
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
name some Biochemical abnormalities
Hypoglycaemia
Hyperammonaemia
Unexplained metabolic acidosis / ketoacidosis
Lactic acidosis
name some clinical abnormalities
Cognitive decline Epileptic encephalopathy Floppy baby Exercise intolerant Cardiomyopathy Dysmorphic features Sudden unexpected death in infancy (SUDI) Fetal hydrops
types of laboratory investigations
Routine
Specialist tests
Confirmatory
Routine laboratory investigations
Blood gas analysis
Blood glucose
Plasma ammonia
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
Enzymology
- Red cell galactose-1-phosphate uridyl transferase
- Lysosomal enzyme screening
Biopsy (muscle, liver)
Fibroblast studies
Mutation analysis – whole genome sequencing
Neonatal Screening
- UK >770000 babies screened/year
- 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)
Condition should be an important health problem
Must know incidence/prevalence 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?
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 - how does it work?
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
No double spotting or insufficient spots
