inborn errors of metabolism

Question 1

describe what inborn errors of metabolism means

Answer 1

rare genetic disorders

single gene defects can lead to disruption in metabolic pathway

Question 2

why do IEM occur

Answer 2

toxic accumulation of substrates
toxic accumulation of intermediates from other metabolic pathways
defects in energy production

varies in age of onset and severity

Question 3

describe alkaptonuria

Answer 3

urine turns black on standing 
black ochrontic pigmentation of cartilage and collagenous tissue 
homogenetic acid oxidase deficiency 
autosomal recessive 
congenital

Question 4

mechanism of inheritance

Answer 4

autosomal recessive
autosomal dominant
X-linked
mitochondrial

Question 5

what is autosomal recessive

Answer 5

both patients carry mutation, affecting the same gene
1/4 risk each pregnancy
consanguinity = increased risk

Question 6

what is autosomal dominant

Answer 6

more rare

e.g. Marfan’s

Question 7

describe mitochondrial inheritance

Answer 7

mitochondrial gene mutation
inherited from the mother
only the egg contributes to developing embryo, only females can pass mitochondrial mutations
affects female and male offspring
distribution of affected mitochondria determines presentation
vary in symptoms, severity and age of onset
high energy organs more frequently affected

Question 8

define heteroplasmy

Answer 8

cell contains varying amounts of normal mt DNA and mutated mt DNA

Question 9

treatment options for IEM

Answer 9

dietary control/restrictions
compound supplementation
newer drug and enzyme replacement therapy
organ transplantation

Question 10

classification of IEM

Answer 10

1. toxic accumulation = protein metabolism
   - amino acids, organic acids, urea cycle disorders, carbohydrate inheritance
2. deficiency in energy production/utilisation
   - fatty acid oxidation
   - carbohydrate utilisation/production
3. disorders of complex molecules involving organelles
   - lysosomal storage disorders
   - peroxisomal disorders

Question 11

describe presentation of IEM

Answer 11

neonatal to adult onset depending on severity of metabolic defect
late onset due to accumulation of toxic molecules

Question 12

describe neonates with IEM

Answer 12

may be born normal at birth

symptoms present in 1st week of life when starting full milk feeds

Question 13

what are the clues for IEM

Answer 13

consanguinity
FH of similar illness in siblings/unexplained death
random deterioration in infant

Question 14

describe neonatal presentation

Answer 14

poor feeding/lethargy/vomiting
profound encephalopathy
profound hypotonia
organomegaly

Question 15

describe biochemical abnormalities

Answer 15

hypoglycaemia
hyperammonaemia
unexpected metabolic acidosis/ketoacidosis
lactic acidosis

Question 16

list lab testings

Answer 16

blood gas analysis
blood glucose and lactate
plasma ammonia

Question 17

list specialist investigations

Answer 17

plasma amino acids
urinary organic acids/orotic acid
blood acyl carnotines 
urinary glycosaminoglycans 
plasma v long chain fatty acids

Question 18

describe confirmatory investigations

Answer 18

enzymology = red cell galactose leading to phosphatase

• biopsy
• fibroblast studies
• mutation analysis = whole genome sequencing

Question 19

describe newborn blood spot screening

Answer 19

mainly for congenital hypothyroidism

extended to include: sickle cell and cystic fibrosis