Clinical Genetics: Inborn Errors of Metabolism Flashcards
Alkaptonuria, Cystinuria, Albinism and Pentosuria were all described as what by Archibold Garrod?
- Congenital (present at birth)
- Inborn (transmitted through the gametes)
- Had the discontinuous distribution of a Mendelian trait
What are some of the clinical features of Alkaptonuria?
- Autosmal recessive
- Urine turns black on standing (and
alkalinisation of urine) - Black ochrontic pigmentation of cartilage & collagenous tissue e.g. pinna of ear
- Can lead to Arthritis
- Caused by homogentisic acid oxidase deficiency
Why does urine as well as the cartilage & collagenous tissue turn black as a result of Alkaptonuria?
- Because due to the homogentisic acid oxidase deficiency homogenistic acid builds up within the body
What are some of the clinical features of Cystinuria?
- Autosomal recessive
- Results in defective transport of cystine and other dibasic amino acids through epithelial cells of renal tubule and intestinal tract
- Cystine has low solubility (so can’t be transported and has to be excreted) which results in formation of calculi in renal tract if it does build up
- COAL - (cystine, ornithine, arginine, lysine) is a test used for diagnosis and monitoring of cystinuria
- Caused by mutations of SLC3A1 aa transporter gene (Chr 2p) & SLC7A9 (Chr 19)
Explain the one gene - one enzyme concept
- Mutation of a single gene results in an alteration in the ability of the cell to carry out a single primary chemical reaction
Explain the molecular disease concept
- Direct evidence that human gene mutations produce an alteration in the primary structure of proteins
- Inborn errors of metabolism are therefore caused by mutations in genes which then produce abnormal proteins whose functional activities are altered
What are all the different mechanisms of inheritance?
- Autosomal recessive
- Autosomal dominant
- X-linked
- Codominant
- Mitochondrial
What is autosomal recessive inheritance and what are some of its features?
- A form of inheritance in which an individual needs to have both copies of a mutated allele in order to be affected
- Both parents carry a mutation affecting the same gene
- 1 in 4 risk each pregnancy
- Consanguinity, being descended from same ancestor, increases risk of autosomal recessive conditions
- Examples: Cystic fibrosis, sickle cell disease
What is autosomal dominant inheritance and what are some of its features?
- A form of inheritance in which an individual only needs to have one copy of the mutant allele in order to be affected
- Rare in Inborn errors of metabolism
- Examples: Huntingdon disease, Marfan’s, Familial hypercholesterolaemia
What is X-linked inheritance and what are some of its features?
- A form of inheritance in which a mutation within a gene on the X-chromosome (X-linked gene) leads to a male developing a disorder
-
Recessive X-linked conditions
- Condition passed through the maternal line
- Condition appears in males
- Condition carried in females, but not usually expressed - may be expressed if lyonisation (random inactivation of one of the X chromosomes occurs)
-
Dominant X-linked disorders
- Condition passed on from either affected parents
- Affected father will only pass the condition to his daughters
- Affected mother can pass the condition to sons and daughters
- NO MALE TO MALE TRANSMISSION
What are some examples of dominat X-linked conditions?
- Fragile X
What are some examples of recessive X-linked conditions?
- Haemophilia A
- Duchenne muscular dystrophy
- Fabry’s disease
What is codominant inheritance and what are some of its features?
- Two different versions (alleles) of a gene are equally expressed - no dominant or recessive allele
- 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-1-antitrypsin deficiency (α1AT)
What is mitochondrial inheritance and what are some of its features?
- Mitochondrial DNA is Inherited exclusively from mother
- Only the egg contributes mitochondria to the developing embryo
- This means 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
What are some examples of mitochondrial inheritance conditions?
- MERFF (Myoclonic epilepsy and ragged red fibre disease): deafness, dementia, seizures
- MELAS (Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes)
What does the term “heteroplasmy” mean in regards to mitochondrial DNA replication?
- Cell contains varying amounts of normal mtDNA and mutated mtDNA
What affects the presentation of mitochondrial inheritance conditions?
- Distribution of affected mitochondria within cells
- This means mitochondrial disease can vary in symptoms, severity, age of onset
Are inborn errors of metabolism rare or common?
- They’re Individually rare but collectively quite common
Describe the presentation of IEM’s in neonates and adults
- Neonatal presentation often acute
- Often caused by defects in energy metabolism. E.g.
- Maple syrup urine disease
- Tyrosinaemia
- OTC (urea cycle defect)
- Sometimes deficiency in particular enzyme is partial and so may not get presentation of condition until adulthood, E.g.
- Wilson’s
- Haemochromatosis
When do the symptoms of an IEM within a neonate typically present themselves?
- Most are born at term with normal birthweight and no abnormal features
- Symptoms present frequently in the first week of life when starting full milk feeds
What are some signs of an IEM within a neonate?
- Consanguinity - Parents are blood-related
- Family history of similar illness in siblings or unexplained deaths
- Infant who was well at birth but starts to deteriorate for no obvious reason
What are some non-specific symptoms of an inborn error of metabolism?
- Poor feeding
- Lethargy
- Vomiting
- Hypotonia
- Fits
What are some specific symptoms of an inborn error of metabolism?
- Abnormal smell (sweet, musty, cabbage-like)
- Cataracts
- Hyperventilation secondary to metabolic acidosis
- Hyponatraemia and ambiguous genitalia
- Neurological dysfunction with respiratory alkalosis
What are some biochemical abnormalities of an inborn error of metabolism?
- Hypoglycaemia
- Hyperammonaemia
- Unexplained metabolic acidosis / ketoacidosis
- Lactic acidosis
What are some clinical abnormalities of an inborn error of metabolism?
- Cognitive decline
- Epileptic encephalopathy
- Floppy baby
- Exercise intolerant
- Cardiomyopathy - disease of the heart muscle which affects its size, shape and structure.
- Dysmorphic features
- Sudden unexpected death in infancy (SUDI)
- Fetal hydrops - abnormal accumulation of fluid in two or more fetal compartments
What are the different types of laboratory tests used to diagnose an inborn error of metabolism?
- Routine tests
- Specialist tests
- Confirmatory tests
What are some routine tests used to confirm an IEM?
- Blood gas analysis
- Blood glucose level
- Plasma ammonia level
What are some specialist tests used to confirm an IEM?
- Plasma amino acids
- Urinary organic acids + orotic acid
- Blood acyl carnitines
- Blood lactate and pyruvate
- Urinary glycosaminoglycans
- Plasma very long chain fatty acids
What are some confirmatory tests used to confirm an IEM?
-
Enzymology
- Red cell galactose-1-phosphate uridyl transferase
- Lysosomal enzyme screening
- Biopsy (muscle, liver)
- Fibroblast studies from skin
- Mutation analysis – whole genome sequencing
What are the advantages of using 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?
- 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
What is the criteria for a good screening test?
- 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)
What conditions was the newborn bloodspot test initially used to detetct?
- PKU (Phenylketonuria)
- Congenital hypothyroidism
What conditions was the newborn bloodspot test extended to so it could diagnose them as well as PKU and congenital hypothyroidism?
- Cystic fibrosis
- Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)
- Haemoglobinopathies
What conditions was the newborn bloodspot test extended to allow diagnosis of these conditions in 2015?
- Maple syrup urine disease (MSUD)
- Homocystinuria (pyridoxine unresponsive) (HCU)
- Isovaleric acidaemia (IVA)
- Glutaric aciduria type 1 (GA1)
How are the bloodspots used for the newborn bloodspot test taken?
- 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
