In born errors of metabolism

Question 1

Define IEM

Answer 1

Single gene defects resulting in disruption to metabolic pathways

• Synthesis/catabolism of proteins, carbohydrates, fats, complex molecules

Question 2

What causes IEM?

Answer 2

• 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

Question 3

In the Croonian lectures what four disorders did Garrod describe his studies on?

Answer 3

• Alkaptonuria - black urine, alkalinisation
• Cystinuria - stones made of cysteine
• Albinism - no melanin
• Pentosuria - pentose sugar in urine

Proposed these were

• congenital
• inborn (transmitted through gametes)
• followed Mendel’s law of inheritance

Question 4

Describe the disorder Alkaptonruia

Answer 4

Urine turns black on standing (and alkalinisation)

Black ochronotic pigmentation of cartilage and collagenous tissue

Homogentisic acid oxidase deficiency

Autosomal recessive disease

Congenital because he monitored pregnancy of mother who gave birth to an affected child

Question 5

What is the one gene-one enzyme concept?

By Beadle and Tatum, 1945

Answer 5

X-rays used to create mutations in strains of mould, saw mutations affected single gene and enzymes in specific metabolic pathway

All biochemical processes in all organisms are under genetic control

Biochemical processes are resolvable into a series of stepwise reactions

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

Question 6

Describe the molecule disease concept

By Pauling et al 1949, Ingram 1956

Answer 6

Work on haemoglobin in sickle cell disease

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

Question 7

What are the four mechanisms of interitance?

Answer 7

Autosomal recessive

Autosomal dominant

X-linked

Mitochondrial

Question 8

What is the most common mechanism of IEM inheritance?

Answer 8

Autosomal recessive

• Both parents carry a mutation affecting the same gene
• 1 in 4 risk in each pregnancy
• Consaguinity increases the risk of autosomal recessive conditions
• E.g PKU (phenylketonuria), alkaptonuria, MCADD

Question 9

What are examples of autosomal dominant IEMs?

Answer 9

Rare in IEMs

Marfan’s syndrome , acute intermitten porphyria

Question 10

Give examples of recessive linked conditions passed through the maternal line

Answer 10

Condition appears in males – so more frequently affected and often present in each generation

Condition carried in females

Female carriers may manifest condition – lyonisation (Random inactivation of one of the X chromosomes)

Examples: Fabry’s disease, Ornithine carbamoyltransferase deficiency (ammonia accumulation in blood)

Question 11

Describe mitochondrial inhertiance and give examples

Answer 11

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

MERFF – myoclonic epilepsy and ragged red fibre disease: deafness, dementia, seizures

MELAS – mitochondrial encephalopathy with lactic acidosis and stroke-like episodes

Question 12

What is homoplasmic and heteroplasmic cells?

Answer 12

Homoplasmic = cells contain normal mtDNA

Heteroplasmy = cell contians varying amounts of normal mtDNA and mutated mtDNA

People with maternally inherited mitochondrial disease have heteroplasmic cells.

Question 13

What three subgroups can IEM disorders be classified into?

Answer 13

Toxic accumulation - accumulation of toxic compounds

Deficiency in energy production/utilisation

Disorders of complex molecules involving organelles

Question 14

Examples of IEM disorders due to toxic accumulation

Answer 14

Protein metabolism

• Amino acids disorders e.g PKU, tyrosinemia
• Organic acids e.g propionylacidaemia
• Urea cycle disorders e.g OTCD

Carbohydrate intolerance e.g galactosaemia

Question 15

Examples of IEM disorders due to deficiency in energy production/utilisation

Answer 15

Fatty acid oxidation disorders e.g MCADD

Carbohydrate utilisation/production e.g GSDs

Mitochondrial disorders e.g MERFF

Question 16

Examples of IEM disorders due to disorders of complex molecules involving organelles

Answer 16

Lysosomal storage disorders e.g Fabry’s

Peroxisomal disorders e.g Zellwegers

Question 17

How can IEM present?

Answer 17

Neonatal to adult onset depending on severity of metabolic defect

• Neonatal presentation often acute
• Often caused by defects in carbohydrate intolerance and energy metabolism
• Can be rapidly progressive and sometimes fatal

Late-onset due to accumulation of toxic molecules

• Patients have residual enzyme activity allowing slower accumulation of toxins
• Symptoms appear at adulthood when pathway can’t perform any longer
• Present with organ failure, encephalopathy, seizures

Question 18

What are the clinical features of IEM in neonates?

Answer 18

Poor feeding, lethargy, vomiting

Epileptic encephalopathy

Profound hypotonia - “floppy” baby

Organomegaly e.g cardiomyopathy, hepatomegaly

Dysmorphic features

Sudden unexpected death in infancy (SUDI)

Question 19

What are some biochemical abnormalities seen in neonates with IEM?

Answer 19

Hypoglycaemia - low blood sugar

Hyperammonaemia - excess ammonia

Unexplained metabolic acidosis/ketoacidosis

Lactic acidosis - too much lactic acid

Question 20

What laboratory testing is done to diagnose IEM?

Answer 20

Routine laboratory investigations

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

Specialist investigations

• Plasma amino acids
• Urinary organic acids and orotic acid
• Blood acyl carnitines
• Urinary glycosaminoglycans
• Plasma very long chain fatty acids
• CSF tests e.g CSF lactate/pyruvate, neurotransmitters

Question 21

What confirmatory investigations are done for IEM?

Answer 21

Enzymology

• Red cell galactose-1-phosphate uridyl transferase for galactosaemia
• Lysosomal enzyme screening for Fabry’s

Biopsy (muscle, liver) where enzyme activities are higher

Fibroblast studies

Mutation analysis – whole genome sequencing

Question 22

What is newborn screening?

Answer 22

One of the largest screening programmes in the UK for over 770,000 babies a year

Early identification of life-threatening disease in pre-symptomatic babies

Earlier initiation of medical treatment

Reduction of morbidity and mortality

Question 23

What is the criteria for screening, Wilson and jungner 1968?

Answer 23

Condition should be an important health problem where impact of disease on individual and family is known

Must know incidence/prevalence 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

Question 24

What does the newborn blood spot screening screen for?

Answer 24

PKU

Congenital hypothyroidism

Sickle cell disease

Cystic fibrosis

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)

expanded to include:

Maple syrup urine disease (MSUD)

homocystinuria (pyridoxine unresponsive) (HCU)

Isovaleric acidaemia (IVA)

Glutaric aciduria type 1 (GA1)

Question 25

How is a blood sample for newborn blood spot screening taken?

Answer 25

• Sample taken on day 5, day 0 is day of birth
• Taken from heel prick
• Use of Guthrie card