Inborn errors of metabolism

Question 1

What is inborn errors of metabolism?

Answer 1

= single gene defects resulting in disruption to metabolic pathways

Due to:

• Toxic accumulation of substrates
• Toxic accumulation of intermediates from alternative metabolic pathways
• Defects in energy production

Question 2

How are inborn errors of metabolism caused?

Answer 2

By mutations in genes which then produce abnormal proteins whose functional activities are altered

Question 3

What is alkaptonuria?

Answer 3

• Autosomal recessive disease
• Congenital
• Homogentisic acid oxidase deficiency
• Urine turns black on standing
• Black ochronotic pigmentation of cartilage and collagenous tissue

Question 4

What is autosomal recessive mechanism of inheritance?

Answer 4

• Both parents carry a mutation affecting the same gene
• Consanguinity increases risk of autosomal recessive conditions
• Eg. PKU, alkaptonuria

Question 5

What is autosomal dominant mechanism of inheritance?

Answer 5

• Rare in IEMs
• Eg. Marfan’s, acute intermittent porphyria

Question 6

What is X-linked mechanism of inheritance?

Answer 6

• Recessive X linked conditions passed through the maternal line
• Condition appears in males
• Condition carried in females

Question 7

What is mitochondrial mechanism of inheritance?

Answer 7

• Mitochondrial gene mutation - fail to produce enough energy for the body
• Maternally inherited as only the egg contributes mitochondria to the developing embryo
• Affects both male and female but affected male cannot pass on the disorder

Question 8

What is heteroplasmy?

Answer 8

= each cell contains varying amounts of normal mtDNA and mutated mtDNA (people with mitochondrial disease)

• Distribution of affected mitochondria determines presentation
• Mitochondrial disease can vary in symptoms
• High energy-requiring organs are more frequently affected

Question 9

How can you classify to inborn errors of metabolism?

Answer 9

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

Question 10

What is the presentation of inborn error of metabolism?

Answer 10

Neonatal to adult onset depending on severity of metabolic defect

Late- onset due to accumulation of toxic molecules - organ failure, seizures

Question 11

What is the symptoms of inborn errors of metabolism in neonates?

Answer 11

Can be born with normal birth weight and no abnormal features

Symptoms present frequently in the first week of life when starting milk feeding

Neonates presentation

• Poor feeding, vomiting
• Profound hypotonia
• Organomegaly
• Dysmorphic features
• Sudden death
• Hypoglycaemia
• Unexplained ketoacidosis
• Lactic acidosis

Confirmatory investigations:

• Enzymology
• Biopsy
• Fibroblast studies
• Whole genome sequencing