Inborn errors of metabolism Flashcards

1
Q

what is inborn errors of metabolism

A
  • single gene defects resulting in disruption to metabolic pathways
  • including synthesis/catabolism of proteins, carbohydrates, fays, complex molecules
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2
Q

IEM effects due to

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

what is alkaptonuria

A
•Urine turns black on standing (and 
alkalinisation) 
•Black ochrontic pigmentation of 
cartilage & collagenous tissue 
•Homogentisic acid oxidase deficiency 
•Autosomal recessive disease 
•Congenital
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4
Q

Mechanisms of inheritance -Autosomal Recessive

A

— Both parents carry a mutation affecting the same gene
— 1 in 4 risk each pregnancy
— Consanguinity increases risk of autosomal recessive
conditions
— Examples: PKU, alkaptonuria, MCADD

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5
Q

Mechanisms of inheritance-Autosomal Dominant

A

— Rare in IEMs

— Examples: Marfan’s, acute intermittent porphyria

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6
Q

Mechanisms of inheritance- X-Linked inheritance

A

—Recessive X linked conditions passed through the
maternal line
• condition appears in males
• condition carried in females
• Female carriers may manifest condition —
Lyonisation (random inactivation of one of the X
chromosomes)
• Examples: Fabry’s disease, Ornithine carbamoyl
transferase deficiency

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7
Q

Mechanisms of inheritance- Mitochondrial inheritance

A

• Mitochondrial gene mutation
• 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
Eg. MERFF -Myoclonic epilepsy and ragged red fibre disease:
deafness, dementia, seizures
Eg. MELAS — Mitochondrial encephalopathy with lactic
acidosis and stroke-like episodes

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8
Q

meaning of heteroplasmy

A

cells contains varying amounts of normal mtDNA and also mutated mtDNA

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9
Q

what are the 3 classification of IEM

A
  • Toxic accumulation
  • Deficiency in energy production/utilization
  • Disorders of complex molecules involving organelles
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10
Q

classification of IEM- Toxic accumulation

A
  • protein metabolism
  • –amino acid e.g. PKU, tyrosinaemia
  • –organic acids e.g. propionylacidaemia
  • –urea cycle disorders e.g. OTCD
  • Carbohydrate intolerance e.g. galactosaemia
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11
Q

classification of IEM-Deficiency in energy production/utilization

A

— Fatty acid oxidation e.g. MCADD
— Carbohydrate utilization/production e.g. GSDs
— Mitochondrial disorders e.g. MERFF

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12
Q

classification of IEM- Disorders of complex molecules involving organelles

A

— Lyososomal storage disorders e.g. Fabry’s

— Peroxisomal disorders e.g. Zellwegers

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13
Q

Presentation of IEM - Neonates

A

-Neonatal to adult onset depending on severity of
metabolic defect
—Neonatal presentation often acute
—Often caused by defects in carbohydrate intolerance
and energy metabolism

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14
Q

Presentation of IEM-late onset

A

Late-onset due to accumulation of toxic molecules
— Patients have residual enzyme activity allowing slower
accumulation of toxins
— Symptoms appear at adulthood
— Present with organ failure, encepalopathy, seizures

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15
Q

Clues of neonates with IEM

A

— Consanguinity
— FH of similar illness In siblings or unexplained deaths
— Infant who was well at birth but starts to deteriorate for
no obvious reason

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16
Q

Clinical scenarios- neonates

A

— Poor feeding, lethargy, vomiting
— Epileptic encephalopathy
— Profound hypotonia —’floppy’ baby
— Organomegaly e.g. cardiomyopathy, hepatomegaly
— Dysmorphic features
— Sudden unexpected death in infancy (SUDI)

17
Q

Biochemical abnormalities- Neonates

A

— Hypoglycaemia
— Hyperammonaemia
— Unexplained metabolic acidosis / ketoacidosis
— Lactic acidosis

18
Q

Routine lab investigation for IEM

A
  • Blood gas analysis
  • blood glucose and lactate
  • plasma ammonia
19
Q

Special investigation for IEM

A

-plasma amino acids
-urinary organic acids+ orotic acid
-blood acyl carnities
-Urinary glycosaminoglycans
-plasma very long chain fatty acids
CSF tests e.g. CSF lactate/pyruvate, neurotransmitters

20
Q

Confirmatory investigation

A
• Enzymology 
— Red cell galactose-l-phosphate uridyl transferase for 
galactosaemia 
— Lysosomal enzyme screening for Fabry's 
• Biopsy (muscle, liver) 
• Fibroblast studies 
• Mutation analysis— whole genome 
sequencing
21
Q

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
22
Q

which disorders are tested for in the UK Newborn blood spot screening programme.

A
  • PKU
  • Congenital hypothyroidism
  • Sickle cell disease
  • Cystic fibrosis
  • Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)
  • Maple syrup urine disease (MSUD) -Homocystinuria (pyridoxine unresponsive) (HCIJ)
  • Isovaleric acidaemia (IVA)
  • Glutaric aciduria type 1 (GAI)
23
Q

Newborn blood spot screening

A

samples should be taken at day 5 and taken from heel prick

all 4 circles on ‘gruthrie’ card need to completely filled