L45. Genetic Disorders

Question 1

What did Archibald Garrod Contribute to the study of genetic disorders?

Answer 1

Described the disease Alkaptonuria
Formulated the One Gene, One Enzyme hypothesis which led to the understanding that some diseases are due to inherited mutations in genes

Question 2

What is alkaptonuria?

Answer 2

A defect in the carbolic pathway of tyrosine caused by a deficiency in the enzyme homogenistic dioxygenase (HGD) which leads to a dysfunctional breakdown of toxic HGA from tyrosine instead.
It leads to an accumulation of the toxin in the urine (dark urine) with later development of arthritis, heart issues

Question 3

What is monosomy?

Answer 3

When an X is passed on but no other X or Y due to a failure of the separating process in meosis.
= half female phenotype

Question 4

What is trisomes?

Answer 4

When there are three copies of chromosomes
Most are lethal

3x Chromosome 21: Down’s Syndrome
3x Chromosome 18, 13 also relatively common
3x Chromosome 23 XXY: Klinefelter’s syndrome that are phenotypically male

Question 5

What is incomplete dominance/penetrance?

Answer 5

A cross between two different phenotypes produces an offspring with a THIRD phenotype often a BLEND of the parental phenotypes

Question 6

What is X-linked recessive?

Answer 6

Where the trait is recessive on the X chromosome. This means that only the disease mainly affects the males

Question 7

What is an autosomal dominant disease?

Answer 7

One that is independent of sex (on a different chromosome than 23) and is dominant so only need expression of one of the alleles to cause the phenotype.

Question 8

What is Mendel’s First law of Genetics?

Answer 8

Parents have 2 copies of a gene for a character and pass only one of them to their offspring.

Question 9

What is Mendel’s Second law of Genetics?

Answer 9

Different characteristics are inherited independently except for linked characters (on the same chromosome - which undergo cross-over events)

Question 10

What are congenital diseases?

Answer 10

Developmental errors that are apparent at birth which may or may not have genetic basis.
Eg. the Thalidomide drug for morning sickness caused Pacomelia of babies (not genetic)

Question 11

What is Phenylketonuria (PKU)?

Answer 11

The first disease to be routinely tested for at birth
An AUTOSOMAL RECESSIVE disease that affects 1/14000 in Australia (1 in 60 carriers)
Causes lack of pigments and brain damage

Question 12

What is the biochemistry and pathogenesis of Phenylketonuria?

Answer 12

A lack of the phenylalanine hydroxylase enzyme
Normally converts phenylalanine into tyrosine. Without it there is a build up of pheylalanine causing damage to the brain and instead a transaminase converts it into a phenylketone which builds up and inhibits tyrosinase (melanin making)

Question 13

What is the treatment of PKU?

Answer 13

Low phenylalanine diets

Question 14

What is the Guthrie Test?

Answer 14

A dried blood spot from a heel prick for mass screening of newborns

Question 15

What is Cystic Fibrosis?

Answer 15

A relatively common autosomal recessive disorder (1 in 2500 births with 1/25 carriers)
A mutation on chromosome 7 which encodes the Cystic Fibrosis Transmembrane Conductance (CTFR) chloride channel - the pore domain meaning to channel opening

Question 16

What are the symptoms and consequences of cystic fibrosis?

Answer 16

Mainly affects the Respiratory System but also the digestive system (pancreas) and the reproductive system
By a build up of mucous in the lungs

Question 17

How is CF detected?

Answer 17

Heel prick and elevated immune reactive trypsinogen (IRT) secreted be pancreas
Genetic testing (PCR gene amplification)
Diagnosis confirmed by salty sweat

Question 18

Why are mutations in collagen encoding genes important?

Answer 18

Because collagen is the most abundant protein and is an important family of structural proteins that gives toughness, inextensibality and protection to organs and in providing a scaffold for mineralisation

Question 19

What is the biochemical structure of collagen?

Answer 19

Multiple repeats of the sequence Gly-Pro-Ala
Hydrogen bonds between the Prolines and chemical cross linking between lysin = strength and bundling
Triple helix structure with the glycines in the centre of it

Question 20

What are some examples of genetic collagen diseases?

Answer 20

1. Osteogenesis imperfect: glycine mutated to cystein = disrupted helx causing kink and brittle bones and wak tissues: PENETRANCE
2. Ehlers Danlos Syndrome: autosomal dominant hypermobility mutation in fibrous proteins or enzymes
3. Marfan’s Syndrome: Mutation in Fibrillin 1 Gene leading to lack of fibrillin and elasticity (decreased flexibility, bone overgrowth, joint laxity)

Question 21

What is sickle cell anaemia?

Answer 21

Many variants of the disease
Single Base mutation from glutamic acid to a hydrophobic valine which binds to a hydrophobic pocket in deoxyHb (stabilsed as this) and formation of insoluble crystalline structures. RBCs don’t have elasticity to pass through small capillaries

Question 22

What happens in porphyria?

Answer 22

A rare inherited disorder of enzymes that normally produce the porphyrin ring and haem. These mutations lead to elevated haem (feedback to attempt to make functional haem) and a build up leading to neurotoxicity from high levels of haem.