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Molecular Basis of Disease > Inborn Errors Of Metabolism > Flashcards

Inborn Errors Of Metabolism Flashcards

1
Q

What are inborn errors of metabolism?

A

Single gene defects resulting in disruption to metabolic pathways e.g. causing blockage of enzyme in pathways such as synthesis/catabolism of proteins, carbs etc..

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2
Q

What are the effects of IEM causes by?

A
  • Toxic accumulation of substrates
  • Toxic accumulation of intermediates from alternative metabolic pathways
  • Defects in energy production due to deficiency of products
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3
Q

Name 4 IEM disorders?

A

Alkaptonuria
Cystinuria
Albinism
Pentosuria

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4
Q

How do IEM’s form? !!

A

CONGENITAL (present from birth)

INBORN (transmitted through gametes)

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5
Q

What type of disease is alkaptonuria?

A

Autosomal recessive disease

- congenital

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6
Q

What symptoms show in alkaptonuria?

A

Urine turns black when standing (+ alkanisation)

Black ochrotic pigmentation of cartilage and collagenous tissue

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7
Q

Which molecule is deficient in alkaptonuria?

A

Homogentisic acid oxidase deficiency

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8
Q

What is the one gene one enzyme concept?

A

Each biochemical reaction is under ultimate control of different single gene. Mutation of a single gene to a single enzyme in a metabolic pathway results in alteration of ability of cell to carry out single primary chemical reaction.

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9
Q

What is the molecular disease concept?

A

Evidence that human gene mutations result in altered primary structure in proteins. Inborn errors of metabolism are caused by mutations in genes that produce abnormal proteins

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10
Q

What are the 4 mechanisms of inheritance?

A 
Autosomal recessive
Autosomal dominant
X-linked
Mitochondrial
- other environmental factors can also affect onset of disease
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11
Q

Which of the 4 mechanisms of inheritance is the most common?

A

Autosomal recessive

- autosomal dominant is rare

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12
Q

Give examples of autosomal recessive IEM diseases?

A

PKU (Phenylketonuria), alkaptonuria and MCADD

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13
Q

How does autosomal recessive disease arise?

A

Both parents carry a mutation affecting the same gene

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14
Q

What increases the risk of autosomal recessive disease?

A

1 in 4 risk each pregnancy is both parents carry mutation affecting same gene
- consanguinity increases risk

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15
Q

Give examples of autosomal dominant IEMs?

A

Marfan’s, acute intermittent porphyria

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16
Q

What are the chance of inheriting autosomal recessive vs autosomal dominant?

A

25% since both parents have to carry (50% chance of child being carrier instead)
50% chance for autosomal dominant (only one parent needs to carry)

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17
Q

How are X linked conditions passed on?

A

Maternal line - no male to male transmission (females carry by pass it one, males manifest but don’t pass on)

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18
Q

Who does X linked conditions appear in?

A

Males

Females carry unless lyonisation (random inactivation of one of X chromosome)

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19
Q

Give examples of X linked conditions?

A

Fabry’s disease

Ornithine carbomoyl transferase deficiency

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20
Q

What are mitochondrial disease caused by?

A

Mutations in mitochondrial gene (in the mtDNA not in normal DNA)

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21
Q

How is mitochondrial disease passed on?

A

Only eggs contribute mitochondria so only females pass on mitochondrial mutaition, males cannot pass it on but BOTH male and female offspring affected (no one carries)

22
Q

What type of disease are mitochondrial disease - why is it not good?

A

Chronic genetic disorder

- cannot produce enough energy for body to function properly

23
Q

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

24
Q

What is heteroplasmy?

A

Cell contains varying amounts of normal mt DNA and also mutated mt DNA during mt DNA replication and cell division

25
Q

How does heteroplasmy affect mitochondrial diseases?

A

Distribution of affected mitochondria determine presentation, symptoms vary, severity and age of onset also varies

  • severity varies between children with same mother (who passed on the mutated mt DNA) due to difference in distrubution - NOT ALL CHILDREN WILL BE SYMPTOMATIC - only after threshold of mt DNA
26
Q

What does mitochondrial disease usually affect?

A

High energy requiring organs

27
Q

What is the concept of 3 parent babies?

A

Genetically alter mothers DNA to not pass on mitochondrial mutations

28
Q

When must IEM be diagnosed?

A

In sick neonates so screen newborns (high mortality in first year of life)

29
Q

What is the treatment for IEMs?

A

Dietary control/restrictions and/or compound supplementation
Drug and enzyme replacement therapy (for specific disease)
Organ transplantation

30
Q

What are the 3 classified groups of IEMs?

A

Toxic accumulation
Deficiency in energy production/utilisation
Disorders of complex molecules involving organelles

31
Q

Give examples of toxic accumulation IEMs?

A 
Protein metabolism 
- amino acids e.g PKU and tyrosinaemia 
- Organic acids e.g Propionylacidaemia
- Urea cycle disorders e.g. OTCD
Carbohydrate intolerance e.g. galactosamia
32
Q

Give examples of deficiency in energy production/utilisation IEMs?

A

Fatty acid oxidation (MCADD)
Carbohydrate utilisation/production e.g. Glycogen storage disorders (GSDs)
Mitochondrial disorders e.g MERFF

33
Q

Give examples of disorders of complex molecules involving organelles IEMs?

A

Lysosomal storage disorders e.g. Fabry’s

Peroxisomal disorders e.g. Zellwegers

34
Q

Are IEMs common?

A

Each disorder is rare but together, IEMs in general is common so must be screened for in sick neonates

35
Q

How does IEM present?

A

Severity of metabolic defect varies for neonate to adult onset varies

36
Q

What is the difference between causes of early (neonate) onset compared to late (adult) onset?

A

Acute in neonates due to defects in carbohydrate intolerance and energy metabolism

LATER ONSET DUE TO ACCUMULATION OF TOXIC MOLECULES

37
Q

What is the reason of late onset due to accumulation of toxic molecules?

A

Patient still have some residual enzyme activity so accumulation of toxins is slower = late onset

38
Q

What are the consequences of accumulation of toxic molecules in late onset?

A

Organ failure, encepalopathy, seizures

  • symptoms may not even appear
39
Q

When do symptoms present in neonates? and why

A

May be normal birth weight with no abnormalities. Symptoms present in first week of life when starting full milk feeds since metabolic pathway begins to fails

40
Q

What are clues to suspect IEM in neonates?

A

Consanguinity
Family History of similar illness / unexplained deaths
Infant was well at birth (no abnormalities) and health suddenly deteriorates with no apparent reason

41
Q

What are the clinical (physically can see) symptoms of IEMs in neonates?

A 
Poor feeding, lethargy and vomiting 
Epileptic encephalopathy
Hypotonia (floppy)
Organomegaly e.g. cardiomyopathy and hepatomegaly
Dysmorphic features

SUDDEN EXPECTED DEATH IN INFANCY (SUDI)

42
Q

What are the biochemical presentations of IEMs in neonates?

A

Hypoglycaemia
Hyperammonaemia
Metabolic acidosis / ketoacidosis
Lactic acidosis

43
Q

What routine lab tests are carried out to investigate IEMs

A

Blood gas analysis
Blood glucose and lactate
Plasma ammonia

44
Q

What special tests are done to investigate IEMs?

A

Plasma amino acids
Urinary organic acid + orotic acid
Blood acyl carnitines
Urinary glycosaminoglycans
Plasma - for very long chains of fatty acids
CSF tests e.g. for CSF lactate/pyruvate, neurotransmitters

45
Q

What tests are done to confirm an IEMs?

A

Enzymology (screen for direct enzyme defect) e.g. Lysosomal enzyme screening for Fabry’s
Biopsy (liver, muscle)
Fibroblast studies
Mutation analysis - whole genome sequencing (WGS)

46
Q

Why is newborn screening important?

A

Reduction of morbidity and mortality by earlier medical treatment by early identification in pre-symptomatic babies

47
Q

What is the criteria for screening neonates for IEMs?

A

Incidence / prevalence of screening population
Recognisable latent/ early symptomatic stage
A test that is easy to perform and interpret and still accurate
Availability of treatment for the condition (is there treatment for this condition)
Cost-effective

48
Q

What conditions are screened for in newborn using blood spot screening currently?

A 
PKU
Congenital hypothyroidism
Sickle cell disease
Cystic fibrosis
MCADD
49
Q

When is newborn blood spot screening done?

A

Day 5 (day 0 is day of birth)

50
Q

Where is blood taken from for newborn blood spot screening and what must be done carefully?

A

Heel prick

Good quality blood spot for analysis needs (single drop of blood soaks through the back of card, no multispotting or too small of a sample)

Molecular Basis of Disease (29 decks)

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