32. Inborn Errors of Metabolism Flashcards
Describe alkaptonuria
•Autosomal recessive condition •Urine turns black on standing (and alkalinisation) •Black ochrontic pigmentation of cartilage and collagenous tissue •Arthritis •(Homogentisic acid oxidase def.)
Describe cystinuria
- Autosomal recessive condition
- 1:7,000 people
- 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
- COLA or COAL
- Mutations of SLC3A1 aa transporter gene (Chr 2p) and SLC7A9 (Chr 19)
Describe albinism
TYROSINASE NEGATIVE
• Type 1a - complete lack of enzyme activity due to production of inactive tyrosinase
•Type 1b - reduced activity of tyrosinase
TYROSINASE POSITIVE
•Type II
- AR, biosynthesis of melanin reduced in skin hair and eyes
- most individuals do acquire a small amount of pigment with age
Describe pentosuria
- Excrete 1-4g pentose sugar L-xylulose daily (reducing sugar)
- Benign
- Almost exclusively Ashkenazi Jews of Polish-Russian extraction (1:2,500 births)
What are the features of the one gene - one gene enzyme concept?
Beadle and Tatum 1945
- 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
What are the features of the molecular disease concept?
- Brought about with the help of work on haemoglobin in sickle cell disease
- Direct evidence that human gene mutations actually 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
List some different mechanisms of inheritance
- Autosomal recessive
- Autosomal dominant
- X-linked
- Codominant
- Mitochondrial
Expand on the autosomal recessive mechanism of inheritance.
- 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
Expand on the autosomal dominant mechanism of inheritance
- Rare in IEMs
- Examples: Huntingdon disease, Marfan’s, Familial hypercholesterolaemia
Expand on the x-linked mechanism of inheritance
- Characterised by carrier females passing on condition to their affected sons
- No male to male transmission
- Female carriers may manifest condition –Lyonisation (random inactivation of one of the X chromosomes)
- X-linked dominant : fragile X
- X-linked recessive: haemophilia, Fabry’s disease
Expand on the codominant mechanism of inheritance
- 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
Expand on the mitochondrial mechanism of inheritance
•Mitochondrial DNA is 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
Affects both male and female offspring
How is mitochondrial inheritance determined?
- Distribution of affected mitochondria determine presentation
- High energy-requiring organs more frequently affected
- Current debate on three parent babies
What are some features of inborn error of metabolism?
- Inborn errors of metabolism or inherited metabolic disease (IMD)
- Individually rare (1:10,000 - 1:500,000)
- Collectively present sizeable problem but cumulatively frequent and account for approx 42% of deaths within the first year of life
- They make a significant contribution to the 1% of children of school age with physical handicap and the 0.3% with severe learning difficulties
- Screening programmes ~ for newborns
- Important to recognise in sick neonate
What are the WHO criteria for a good screening test?
- condition screened for should be an important one
- there should be an acceptable treatment for patients with the disease
- facilities for diagnosis and treatment should be available
- there should be a recognised latent or early symptomatic stage
- there should be a suitable test or examination which has few false positives -specificity - and few false negatives - sensitivity
- test or examination should be acceptable to the population
- cost, including diagnosis and subsequent treatment, should be economically balanced in relation to expenditure on medical care as a whole
In the UK, what do we look for in newborn blood spot screening?
Initial National programme
- PKU
- Congenital hypothyroidism
Extended to include
- Cystic fibrosis
- MCADD
- Haemoglobinopathies
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)
How would you take blood spots for a screen?
- You would prick the heel of a newborn and get blood samples (spots) from there
- 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
Describe the presentation of IEM
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
Describe neonates with IEM
Most are born at term with normal birthweight and no abnormal features
Symptoms frequently in the first week of life when starting full milk feeds
clues for IEMs
- Consanguinity
- FH of similar illness in sibs or unexplained deaths
- Infant who was well at birth but starts to deteriorate for no obvious reason
What would be the classical representation of an IEM?
Full term pregnancy
Symtoms: •Can be very non-specific - Poor feeding - Lethargy - Vomiting - Hypotonia - Fits •or Specific - Abnormal smell (sweet, musty, cabbage-like) - Cataracts - Hyperventilation secondary to metabolic acidosis - Hyponatraemia and ambiguous genitalia - Neurological dysfunction with respiratory alkalosis
What are some other clinical scenarios that may occur with IEMs?
•Biochemical abnormalities
- Hypoglycaemia
- Hyperammonaemia
- Unexplained metabolic
- acidosis / ketoacidosis
- Lactic acidosis
•Clinical
- Cognitive decline
- Epileptic encephalopathy
- Floppy baby
- Exercise intolerant
- Cardiomyopathy
- Dysmorphic features
- SUDI
- Fetal hydrops
List some routine laboratory investigations
- Blood gas analysis
- Blood glucose
- Plasma ammonia
List some specialist laboratory
- Plasma amino acids (PKU)
- Urinary organic acids + orotic acid (urea cycle defects)
- Blood acyl carnitines (whole range of inborn errors)
- Blood lactate and pyruvate (mitochondrial)
- Urinary glycosaminoglycans
- Plasma very long chain fatty acids (peroxisomal disorders)
List some confirmatory laboratory investigations
•Enzymology
- Red cell galactose-1-phosphate uridyl transferase
- Lysosomal enzyme screening
- Biopsy (muscle, liver)
- Fibroblast studies
- Complementation studies
- Mutation analysis – whole genome sequencing
