Inborn Errors of Metabolism

Question 1

What are inborn errors of Metabolism? Define them

Answer 1

These are single gene defects which result in disruption to metabolic pathways.

Question 2

What can IEM effects be due to ?

Answer 2

• Toxic accumulation of substrates
• Toxic accumulation of intermediates from alternative metabolic pathways
• Defects in energy production/use due to deficiency of products
• All of these together

Question 3

What are the four disorders which were studied by Garrod?

Answer 3

Alkaptonuria -rare genetic metabolic disorder characterized by the accumulation of homogentisic acid in the body.

Cystinuria- inherited autosomal recessive disease characterized by high concentrations of the amino acid cystine in the urine

Alibinism- congenital absence of any pigmentation or colouration

Pentosuria-condition where the sugar xylitol, a pentose, presents in the urine in unusually high concentrations

Question 4

Describe Alkaptonuria and how it presents

Answer 4

Urine turns black on standing (alkalinisation)

Black ochronotic (accumulation of homogentisic acid in connective tissue) pigmentation of cartilage and collagenous tissue

Homogentisic acid oxidase deficiency

Autosomal recessive disease

Congenital

Question 5

What is the one gene- one enzyme concept ?

Answer 5

• All biochemical processes in organisms are under genetic control
• Biochemical processes are resolvable into a series of stepwise reactions
• Each biochemical reaction is under the ultimate control of different single gene
• Mutation of a single gene results in alterations in the ability of the cell to carry out a single primary chemical reaction

Question 6

What is the Molecular disease concept.

Answer 6

This was studied using haemoglobin in SCD

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 will then produce abnormal proteins which functional activities are altered.

Question 7

What are the different mechanisms of inheritance ?

Answer 7

Autosomal recessive
Autosomal dominant
X-linked
Mitochondrial

Using a accurate family history can establish

Question 8

What is the autosomal recessive mechanism of inheritance ?

Answer 8

Both of the parents carry a mutation which affects the same gene

1 in 4 risk -each pregnancy

Consanguinity (the fact of being descended from the same ancestor.) increases risk of autosomal recessive conditions

E.g diseases: PKU(Phenylketonuria) Alkaptonuria, MCADD

Question 9

What is the autosomal dominant mechanism of inheritance ?

Answer 9

These are rare in IEMS.
One copy of a mutated (changed) gene from one parent can cause the genetic condition.

50% chance of getting the disease
No carrier status

E.g :Marfans, acute intermittent porphyria

Question 10

What is the X-linked inheritance mechanism ?

Answer 10

Recessive X-linked conditions passed through the maternal line :

• Condition appears in males
• Condition carried in females

Female carriers may manifest condition
(Lyonization-Random inactivation of one of the X chromosomes)

Examples:Fabry’s disease, Ornithine carbamoyl transferase deficiency.

Question 11

What is Mitochondrial inheritance ?

Answer 11

Mitochondrial gene mutation

Inherited exclusively from mother

• The egg will contribute mitochondria to the developing embryo
• Only females can pass on mitochondrial mutations to their children

Affects both male and female offspring

Example :

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

Question 12

What is Heteroplasmy?

Answer 12

This is when the cell contains varying amounts of normal mt DNA and also mutated mtDNA

Question 13

What organs are worsely affected by Mitochondrial diseases?

Answer 13

High energy requiring organs are more frequently affected

Question 14

How are IEM classified ?

Describe the three categories and subsections within them .

Answer 14

Toxic accumulation
-Protein metabolism
o Amino acids-PKU, tyrosinemia
o Organic acids-propionyl acidaemia
o urea cycle disorders -OTCD
-Carbohydrate intolerance 
o galactosaemic 

Deficiency in energy production/utilisation

• Fatty acid oxidation -MCADD
• Carbohydrate utilisation/production-GSDS
• Mitochondrial disorders -MERFF

Disorders of complex molecules involving organelles
-Lysosomal storage disorders 
o Fabry's
-Peroxisomal disorders
o Zellweger's

Question 15

What is the presentation of IEM?

Describe the two main categories of this.

Answer 15

Neonatal to adult onset depending on severity of metabolic defect

• Neonatal presentation often acute
• Often caused by defects in carbohydrate intolerance and energy metabolism

Late onset is due to accumulation of toxic molecules

• Patients have residual enzyme activity allowing slower accumulation of toxins
• Symptoms appear at adulthood
• Present with organ failure, encephalopathy(Damage that affects the brain), seizures.

Question 16

Describe neonates who are born with IEM.

What clues may be present to help diagnose them with IEM?

Answer 16

They may be born at term with normal weight and no abnormal features.
Symptoms present frequently in the first week of life when starting full milk feeds

Clues:
Consanguinity
FH of similar illness in siblings or unexplained deaths
Infant who was well at birth but deteriorates for no clear reason

Question 17

What symptoms will Neonates present with ?

Answer 17

Clinical :

• Poor feeding, lethargy ,vomiting
• Epilitic encephalopathy
• Profound hypotonia(floppy baby )
• Organomegaly
• Dysmorphic features
• SUDI-Sudden death

Biochemical abnormalities:

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

Question 18

What laboratory investigations can becarried out to diagnose IEM ?

Answer 18

Routine laboratory investigations :

• Blood gas analyisis
• Blood glucose and lactate
• Plasma ammonia

Specialist investigations:
Plasma amino acids
-Urinary organic acids +orotic acid
-Blood acyl carnitines
-Urinary glycosaminoglycans 
-Plasma very long chain fatty acids
-CSF tests - CSF lactate pyruvate, neurotransmitters

Question 19

What are some confirmatory investigations which are carried out ?

Answer 19

Enzymology

• Red cell galactrose -1 -phosphate uridyl transferase for galactosaemia
• Lysosomal enzyme screening for Fabry’s
• Biopsy (Muscle ,Liver)
• Fibroblast studies
• Mutation analysis-Whole genome sequencing

Question 20

What is New-born screening and what can it lead to ?

Answer 20

The first was for foetal ketounuria and the tests was a bacterial inhibition test.

The UK more than 770,000 babies are screened every year.

Early identification of life threatening disease in pre-symptomatic babies

Earlier initiation of medical treatment

Reduction of morbidity and mortality

Question 21

What is the criteria for screening ?

Answer 21

Condition should be an important health problem

Must know incidence/prevalence in screening population
(This may vary in different populations)

Natural history of the condition should be understood
(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.

Question 22

What are the different new born spot screening programmes?

Answer 22

PKU
Congenital hypothyroidism
SCD
Cystic fibrosis
Medium -chain acyl-CoA dehydrogenase deficiency (MCADD)

From 2015 expanded to include :
Maple syrup urine disease
Homocystinuria
Isovaleric acidaemia
Glutaric aciduria type 1

Question 23

How are samples taken for new born screening ?

Answer 23

Blood spots which are taken on day 5 via a heel prick.

All four circles on ‘Guthrie’ card need to be filled with a single drop of blood which soaks through to the back of the card.

Question 24

What are the possible metabolic causes for acute liver disease in neonate?

Answer 24

Classical galactosaemia
Hereditary fructose intolerance 
An organic acidaemia
Tyrosinaemia type 1
-Urine organic acid analysis shows an increase in succinylacetone

Question 25

What is Tyrosinaemia Type 1 ?

Answer 25

Genetic deficiency in fumarylacetoacetase (FAH)

Catalyses the final step in tyrosine metabolism

Increased byproduct succinylacetone leads to significant organ toxicity
(liver,kidney)

Question 26

How can Tyrosinemia TYpe 1 be treated and what are the side effects of the treatment ?

Answer 26

Treatment -Nitisinone (NTBC)

• Inhibits an earlier step in the pathway to prevent accumulation of toxic metabolites
• Early treatment achieves >90% survival rate with normal growth, improved liver function and prevention of cirrhosis(severe liver scarring)

NTBC side effect is accumulation of tyrosine and requires dietary restriction of tyrosine and precursor phenylalanine.

Question 27

Outline the metabolism of Tyrosine pathway

Answer 27

Check slide on Panopto

Question 28

What is Ornithine Transcarbamylase deficiency ?

Answer 28

Urea cycle disorder
Symptoms range from mild to profound neuropsychiatric manifestations:
Ataxia, seizure, hyperammonaemic encephalopathy

Factors can trigger hyperammonaemic crisis:
Increased endogenous protein catabolism, infection ,fasting,trauma,steroid administration
High protein intake

Question 29

Outline the Urea Cycle

Answer 29

Check slide on Panopto