Clinical Genetics: Inborn Errors of Metabolism Flashcards

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1
Q

Alkaptonuria, Cystinuria, Albinism and Pentosuria were all described as what by Archibold Garrod?

A
  • Congenital (present at birth)
  • Inborn (transmitted through the gametes)
  • Had the discontinuous distribution of a Mendelian trait
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2
Q

What are some of the clinical features of Alkaptonuria?

A
  • 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
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3
Q

Why does urine as well as the cartilage & collagenous tissue turn black as a result of Alkaptonuria?

A
  • Because due to the homogentisic acid oxidase deficiency homogenistic acid builds up within the body
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4
Q

What are some of the clinical features of Cystinuria?

A
  • 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)
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5
Q

Explain the one gene - one enzyme concept

A
  • Mutation of a single gene results in an alteration in the ability of the cell to carry out a single primary chemical reaction
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6
Q

Explain the molecular disease concept

A
  • 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
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7
Q

What are all the different mechanisms of inheritance?

A
  • Autosomal recessive
  • Autosomal dominant
  • X-linked
  • Codominant
  • Mitochondrial
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8
Q

What is autosomal recessive inheritance and what are some of its features?

A
  • 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
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9
Q

What is autosomal dominant inheritance and what are some of its features?

A
  • 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
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10
Q

What is X-linked inheritance and what are some of its features?

A
  • 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
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11
Q

What are some examples of dominat X-linked conditions?

A
  • Fragile X
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12
Q

What are some examples of recessive X-linked conditions?

A
  • Haemophilia A
  • Duchenne muscular dystrophy
  • Fabry’s disease
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13
Q

What is codominant inheritance and what are some of its features?

A
  • 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)
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14
Q

What is mitochondrial inheritance and what are some of its features?

A
  • 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
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15
Q

What are some examples of mitochondrial inheritance conditions?

A
  • MERFF (Myoclonic epilepsy and ragged red fibre disease): deafness, dementia, seizures
  • MELAS (Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes)
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16
Q

What does the term “heteroplasmy” mean in regards to mitochondrial DNA replication?

A
  • Cell contains varying amounts of normal mtDNA and mutated mtDNA
17
Q

What affects the presentation of mitochondrial inheritance conditions?

A
  • Distribution of affected mitochondria within cells
  • This means mitochondrial disease can vary in symptoms, severity, age of onset
18
Q

Are inborn errors of metabolism rare or common?

A
  • They’re Individually rare but collectively quite common
19
Q

Describe the presentation of IEM’s in neonates and adults

A
  • 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
20
Q

When do the symptoms of an IEM within a neonate typically present themselves?

A
  • 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
21
Q

What are some signs of an IEM within a neonate?

A
  • 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
22
Q

What are some non-specific symptoms of an inborn error of metabolism?

A
  • Poor feeding
  • Lethargy
  • Vomiting
  • Hypotonia
  • Fits
23
Q

What are some specific symptoms of an inborn error of metabolism?

A
  • Abnormal smell (sweet, musty, cabbage-like)
  • Cataracts
  • Hyperventilation secondary to metabolic acidosis
  • Hyponatraemia and ambiguous genitalia
  • Neurological dysfunction with respiratory alkalosis
24
Q

What are some biochemical abnormalities of an inborn error of metabolism?

A
  • Hypoglycaemia
  • Hyperammonaemia
  • Unexplained metabolic acidosis / ketoacidosis
  • Lactic acidosis
25
Q

What are some clinical abnormalities of an inborn error of metabolism?

A
  • 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
26
Q

What are the different types of laboratory tests used to diagnose an inborn error of metabolism?

A
  • Routine tests
  • Specialist tests
  • Confirmatory tests
27
Q

What are some routine tests used to confirm an IEM?

A
  • Blood gas analysis
  • Blood glucose level
  • Plasma ammonia level
28
Q

What are some specialist tests used to confirm an IEM?

A
  • Plasma amino acids
  • Urinary organic acids + orotic acid
  • Blood acyl carnitines
  • Blood lactate and pyruvate
  • Urinary glycosaminoglycans
  • Plasma very long chain fatty acids
29
Q

What are some confirmatory tests used to confirm an IEM?

A
  • Enzymology
    • Red cell galactose-1-phosphate uridyl transferase
    • Lysosomal enzyme screening
  • Biopsy (muscle, liver)
  • Fibroblast studies from skin
  • Mutation analysis – whole genome sequencing
30
Q

What are the advantages of using neonatal screening?

A
  • Early identification of life-threatening disease in pre-symptomatic babies
  • Earlier initiation of medical treatment
  • Reduction of morbidity and mortality
31
Q

What is the criteria for screening?

A
  • 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
32
Q

What is the criteria for a good screening test?

A
  • 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)
33
Q

What conditions was the newborn bloodspot test initially used to detetct?

A
  • PKU (Phenylketonuria)
  • Congenital hypothyroidism
34
Q

What conditions was the newborn bloodspot test extended to so it could diagnose them as well as PKU and congenital hypothyroidism?

A
  • Cystic fibrosis
  • Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)
  • Haemoglobinopathies
35
Q

What conditions was the newborn bloodspot test extended to allow diagnosis of these conditions in 2015?

A
  • Maple syrup urine disease (MSUD)
  • Homocystinuria (pyridoxine unresponsive) (HCU)
  • Isovaleric acidaemia (IVA)
  • Glutaric aciduria type 1 (GA1)
36
Q

How are the bloodspots used for the newborn bloodspot test taken?

A
  • 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