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Clinical genetics > Inborn Errors of Metabolism > Flashcards

Inborn Errors of Metabolism Flashcards

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Biology 101 flashcards
1
Q

What mode of inheritance does Alkaptonuria have?

A

➝ Autosomal recessive

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2
Q

What happens during alkaptonuria?

A

➝ urine turns black on standing and alkalinisation
➝ black ochronotic pigementation of cartilage and collagenous tissue
➝ arthritis

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3
Q

What is alkaptonuria caused by?

A

➝ homogentisic acid oxidase deficiency

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4
Q

What is the mode of inheritance of cystinuria and how common is it?

A

➝ autosomal recessive

➝ 1 : 7000

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5
Q

What is the cause of cystinuria?

A

➝ mutations of SLC3A1 amino acid transporter gene (on chromosome 2p) and SLCA9 (chromosome 19)

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6
Q

What happens during cystinuria?

A

➝ defective transport of cystine and dibasic amino acids through epithelial cells of the renal tubule and intestinal tract

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7
Q

Why does cystine form calculi in the renal tract?

A

➝ low solubility

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8
Q

Who came up with the one gene one enzyme concept?

A

➝ Beadle and tatum 1945

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9
Q

What is the principle of the ‘one gene, one enzyme’ concept?

A

➝ 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

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10
Q

Who came up with the molecular disease concept?

A

➝ Pauling et al

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11
Q

What is 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 caused by mutations in genes which then produce abnormal proteins whose functional activities are altered

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12
Q

What is autosomal recessive?

A

➝ when both parents carry a mutation affecting the same gene

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13
Q

What is the risk of a child with a disorder if the inheritance is autosomal recessive?

A

➝ 1 in 4 risk

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14
Q

What increases the risk of an autosomal recessive disorder?

A

➝ consanguinity

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15
Q

What are two examples of autosomal recessive diseases?

A

➝ sickle cell

➝ cystic fibrosis

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16
Q

What are 3 examples of autosomal dominant disorders?

A

➝ Huntingtons
➝ Marfans
➝ familial hypercholesterolemia

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17
Q

How are X linked conditions passed?

A

➝ through the maternal line

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18
Q

Who has the condition in X linked inheritance?

A

➝ condition appears in males

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19
Q

How can female carriers manifest an X linked condition?

A

➝ Random inactivation of one X chromosome (Lyonization)

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20
Q

How are dominant X linked conditions passed on?

A

➝ from either parents

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21
Q

Who will an affected father of an X linked condition pass it on to?

A

➝ only to daughters

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22
Q

Who will an affected mother of an X linked condition pass it on to?

A

➝ sons and daughters

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23
Q

What are 2 examples of X linked dominant conditions?

A

➝ Fragile X

➝ Ornithine carbamoyltransferase deficiency

24
Q

What are 3 examples of X linked recessive conditions?

A

➝ Haemophilia A
➝ Duchenne muscular dystrophy
➝ Fabry’s disease

25
Q

What is a co-dominant condition?

A

➝ two different alleles are expressed and each version makes a slightly different protein
➝ both alleles influence the genetic trait or determine the characteristics of the genetic condition

26
Q

What are two examples of co dominance?

A

➝ ABO blood group

➝ α1AT

27
Q

How are mitochondrial gene mutations inherited?

A

➝ exclusively from the mother

28
Q

What contributes mitochondria to the embryo?

A

➝ the egg

29
Q

Who do mitochondrial gene mutations affect?

A

➝ male and female

30
Q

What are two examples of mitochondrial disease?

A

➝ MERFF - myoclonic epilepsy and ragged red fibre disease : deafness, dementia and seizures
➝ MELAS - mitochondrial encephalopathy with lactic acidosis and stroke like episodes

31
Q

What is heteroplasmy?

A

➝ a cell containing varying amounts of normal mtDNA and also mutated mtDNA

32
Q

What is the relationship between mtDNA and affected tissue?

A

➝ the more mutated mtDNA the more affected the tissue

33
Q

What is more frequently affected in mitochondrial disease?

A

➝ high energy requiring organs

34
Q

How do you recognise inborn errors of metabolism?

A

➝ newborn screening programmes

35
Q

What are three energy metabolism defects?

A

➝ Maple syrup urine disease
➝ tyrosinemia
➝ OTC (urea cycle defect)

36
Q

What is neonatal presentation of inborn errors of metabolism like?

A

➝ acute

37
Q

What are two adult forms of inborn errors of metabolism?

A

➝ Wilsons- build up of copper

➝ Haemochromatosis - excess iron

38
Q

Why do men present with haemochromatosis sooner than women?

A

➝ women menstruate so they get rid of excess iron

39
Q

When do neonates present with IEM?

A

➝ first week of life when starting full milk feeds

40
Q

What are three clues to IEM?

A

➝ consanguinity
➝ family history of similar illness in siblings or unexplained deaths
➝ infant who was well at birth but starts to deteriorate for no obvious reasons

41
Q

What are the 5 non-specific symptoms of babies with IEM?

A 
➝ poor feeding
➝ lethargy 
➝ vomiting
➝hypotonia 
➝ fits
42
Q

What are the 5 specific symptoms of babies with IEM?

A

➝ Abnormal smell (sweet, musty, cabbage-like)
➝ cataracts
➝ hyperventilation secondary to metabolic acidosis
➝ hyponatremia and ambiguous genitalia
➝ neurological dysfunction with respiratory alkalosis

43
Q

What are 4 biochemical abnormalities with IEM?

A

➝ Hypoglycaemia
➝ Hyperammonemia
➝ unexplained metabolic acidosis/ketoacidosis
➝ lactic acidosis

44
Q

What are 8 clinical signs of babies with IEM?

A 
➝ Cognitive decline
➝ epileptic encephalopathy
➝ floppy baby
➝ exercise intolerant
➝ cardiomyopathy
➝ dysmorphic features
➝ sudden unexpected death in infancy
➝ fetal hydrops
45
Q

What are the 3 routine tests for IEM?

A

➝ blood gas analysis
➝ blood glucose
➝ plasma ammonia

46
Q

What are the 6 specialist investigations with 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
47
Q

What are the 4 confirmatory investigations for IEM?

A

➝ enzymology
➝ biopsy (muscle and liver)
➝ fibroblast studies
➝ mutation analysis - WGS

48
Q

What are the 2 enzyme confirmatory tests for IEM?

A

➝ red cell galactose-1-phosphate uridyl transferase

➝ lysosomal enzyme screening

49
Q

Why do you screen neonates for IEM?

A

➝ early identification of life threatening disease in pre-symptomatic babies
➝ earlier initiation of medical treatment
➝ reduction of morbidity and mortality

50
Q

What are the 6 Wilson and Junger criteria for screening?

A

➝ Condition should be an important health problem
➝ must know the incidence/prevalence in screening population
➝ natural history of the condition should be understood
➝ availability of a screening test that is easy to perform and interpret
➝ availability of an accepted treatment for the condition
➝ diagnosis and treatment of the condition should be cost-effective

51
Q

What are the 6 criteria for a good screening test?

A

➝ accurate and reproducible
➝ cheap and produces a 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 ( +ve and -ve values)

52
Q

What are the 9 newborn blood spot screening tests?

A 
➝ PKU
➝ congenital hypothryoidism
➝ cystic fibrosis 
➝ medium chain acyl CoA dehydrogenase deficiency 
➝ haemoglobinopathies
➝ maple syrup urine disease
➝ homocystinuria
➝ isovaleric acidaemia
➝ glutaric aciduria
53
Q

When should samples be taken for a newborn blood spot screening test?

A

➝ day 5

54
Q

What do you perform newborn blood spot screening tests on?

A

➝ A guthrie card

55
Q

What are 4 possible causes for acute liver disease in neonate?

A

➝ classic galatosemia
➝ hereditary fructose intolerance
➝ organic acidaemia
➝ tyrosinaemia type 1

56
Q

How does tyrosinaemia type 1 occur?

A

➝ Block in the metabolism of tyrosine at the fumarylacetoacetase stage
➝ build up of metabolites and it forms succinyl acetoacetate and succinyl acetetate which are indicative of tyrosinaemia

Clinical genetics (5 decks)

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