Inborn Errors of Inheritance (Lec 10)

Question 1

Inborn Errors of Metabolism

Answer 1

Any rare disorder caused by an inherited genetic defect in metabolism. Usually autosomal recessive and represent as reduced activity/complete absense of enzymes in metabolic pathways

Question 2

Encephalopathy

Answer 2

Accumulation of an otherwise normal metabolite to levels that become toxic in the brain

Question 3

Inborn Errors of Metabolism: Amino Acid Metabolism

Answer 3

E.g. Phenylketonuria (PKU)

• Autosomal recessive, Chromosome 12
• Liver enzyme Phenylalanine hydroxylase missing
• Conversion of Phenylalanine to Tyrosine impeded and accumulation of Phenylalanine occurs, harms CNS

Question 4

Inborn Errors of Metabolism: Carbohydrate Metabolism

Answer 4

E.g. Galactosemia Type I

• Autosomal recessive
• Mutations in GALT gene impedes ability to metabolise Galactose (unable to use Galactose for energy)

E.g. Diabetes Mellitus

• Type I: loss of insulin-producing Beta cells
• Type II: cells become insensitive to Insulin, do not respond
• Both can cause hyperglycaemia

Question 5

Inborn Errors of Metabolism: Lipid Metabolism

Answer 5

E.g. Tay Sachs

• Autosomal recessive mutation of HEXA gene on Chromosome 15 causes decreased production of enzyme Hexoaminidase A
• Lipid storage disorder causes hearing loss, seizures, physical and mental retardation, dementia

Question 6

Inborn Errors of Metabolism: Protein Metabolism

Answer 6

E.g. Haemophilia

- X-linked recessive causes absense of clotting factors

Question 7

Inborn Errors of Metabolism: Pigment Metabolism

Answer 7

E.g. Albinism

- Autosomal recessive causes defection of enzyme Tyrosinase and complete absense of Melanin synthesis

Question 8

Mutant Genes: Achondroplasia

Answer 8

Autosomal dominant gene that causes a form of short-limbed dwarfism. 2 specific mutations in the FGFR3 gene responsible for almost all cases

Question 9

Mutant Genes: Polydactyly

Answer 9

100 genes identified to cause Polydactyly (person born with extra fingers or toes). Small finger duplication is usually hereditary

Question 10

Autosomal Dominant Disorders

Answer 10

Autosomal: both sexes effected equally
Dominant: allele cannot skip generations

Question 11

Autosomal Dominant Disorders: Huntington’s Disease

Answer 11

Affects 1:20,000, Chromosome 4

• Expansion of a Cytosine, Adenine, Guanine (CAG) triplet with Huntingtin gene, alters expression of Huntingtin protein
• Mutated protein increases decay of specific neurons

Question 12

Autosomal Recessive Disorders

Answer 12

Autosomal: both sexes effected equally
Recessive: allele can skip generations

Question 13

Autosomal Recessive Disorders: Cystic Fibrosis

Answer 13

Affects 1:2,500 in AUS
- CFTR: membrane channel in cells produces mucus which accumulates and progressively destroys respiratory system and causes chronic digestive system problems

Question 14

X-Linked Dominant Disorders

Answer 14

X-Linked: allele carried on the X chromosome

• If father is affected, he will pass allele down to daughter and she will become affected, not to son as X not Y.
• If mother is affected, offspring have 50% chance of inheriting defective allele (both sexes)

Question 15

X-Linked Dominant Disorders: Rhett Syndrome

Answer 15

Affects 1:10,000 live female births

• Mutation in the Methyl CpG binding protein 2 (MECP2) on the X chromosome
• Causes neurodevelopmental disorder as protein is required for brain development

Question 16

X-Linked Recessive Disorders

Answer 16

X-Linked: Males more affected than females
- Women require 2 defective alleles for phenotypic expression
- Men require only 1 to express defect
Recessive: can skip generations
- Differences in X-inactivation can lead to varying degrees of clinical expression in women

Question 17

X-Linked Recessive Disorders: Colour Blindness

Answer 17

Affects 1:12 males, 1:200 females

• No actual blindness but deficiency in colour vision
• Caused by fault in the development of retinal cones that percieve colour