Non-Cancerous Genetic Disorders

Question 1

Describe genetic features of Huntington’s Disease

Answer 1

It is an autosomal dominant disease with a trinucleotide (CAG) repeat in the Huntington protein. This encodes for a polyglutamine tract which causes protein misfolding, aggregation and the formation of inclusion bodies (neurotoxic).

Question 2

Explain the genetic anticipation in Huntington’s disease

Answer 2

• If person has up to 35 repeats, they will be unaffected.
• 36-39 repeats there will be incomplete penetrance.
• Number of repeats is prone to expansion during meiosis especially when inherited by the father

Question 3

Explain the presentation of Huntington’s disease

Answer 3

Onset of symptoms occurs between 30-50 years old. Symptoms include progressive chorea, dementia and psychiatric symptoms

Question 4

What are the clinical aspects of myotonic dystrophy?

Answer 4

Progressive muscle weakness in early adulthood with myotonia (prolonged contraction of muscles) and cataracts.
It is an autosomal dominant condition with genetic anticipation.

Question 5

What is the genetic basis of myotonic dystrophy

Answer 5

Unstable length mutation of a CTG repeat in 3’ transcribe but untranslated region of DMPK gene (non-coding trinucleotide repeat).
Abnormal DMPK mRNA has an indirect toxic effect upon the slicing of other genes (eg chloride ion channel which causes myotonia)
- Affected if have 50 repeats or more. Higher chance of expansion if transmitted by females.

Question 6

What are the clinical aspects of cystic fibrosis

Answer 6

It is an autosomal recessive mutation which results in recurrent lung infections with exocrine pancreatic insufficiency (90% of cases)

Question 7

How is cystic fibrosis diagnosed?

Answer 7

• Screening of new-borns via immunoreactive trypsin levels
• DNA testing
• Sweat testing (looks for increased chloride concentration)

Question 8

What is the pathogenic mechanism of CF?

Answer 8

CFTR mutations (most common is F508del which results in a deletion of phenylalanine causing abnormal protein folding) results in defective chloride ion channel secretions which causes an increased thickness of secretions

Question 9

What is cascade screening?

Answer 9

This is when the identification of mutation permits prenatal diagnosis and the subsequent identification of carrier relatives

Question 10

Describe features of neurofibromatosis Type 1

Answer 10

Presents with - Cafe au lait macules and neurofibromas, short stature and macrocephaly. Lisch Nodules on slit lamp examination. Learning difficulties in 30%
Variable expressivity

Question 11

What is the implication of serum creatine kinase?

Answer 11

Creatine kinase leaks out of damage muscle fibres (damaged sarcomeres) into the blood.
Boys with DMD have massively raised SCK from birth (before physical symptoms start)

Question 12

Describe the differences between Duchenne muscular dystrophy and Becker muscular dystrophy

Answer 12

DMD - Mutation results in absence of dystrophin. Onset from 3ys and wheelchair bound by 12 ys. 65% deletions, mostly out of frame.
BMD - Genetic mutation results in misshapen dystrophin. Onset from 11ys, wheelchair bound much later in life/not at all. 85% deletions in frame.

Question 13

Describe the genetic features of Fragile X syndrome

Answer 13

X-linked recessive with genetic anticipation. Repeats in 5’ UTR region of FMR1 gene.
- Most common inherited cause of significant learning difficulties

Question 14

Describe the phenotype of fragile X syndrome

Answer 14

Occurs if there is over 500 repeats.
Present with elongated face and large ears. Some carrier females can also be affected (more mild).

Question 15

Describe features of Trisomy 21

Answer 15

• Downs syndrome. (translocation type of trisomy 21 can be high).
• Presents with learning difficulties, heart malformations (>40%) and hypothyroidism (30%)

Question 16

Describe features of Edwards syndrome

Answer 16

Trisomy 18.
- Presents with small chin, clenched hands with overlapping fingers, malformations of heart, kidneys and other organs.
- Profound intellectual disability (if survive first year)
- Potentially more severe as chromosome 18 is a larger chromosome with more genes on it

Question 17

Describe features of Patau Syndrome

Answer 17

• Trisomy 13
• Many die within 1 month
• Present with Cleft lip/palate, microphthalmia, abnormal wars, clenches fists, post-axial (on pinky side) polydactyly. Many have congenital heart defects

Question 18

What is the cause of trisomies?

Answer 18

Typically it is maternal non-disjunction (failure of normal chromosome separation) at the first meiotic division.
They become more common with increased maternal age.

Question 19

What can account for multiple miscarriages/stillbirths

Answer 19

Translocations in balanced carriers as this can produce offspring with unbalanced translocations.

Question 20

What is the function of dystrophin?

Answer 20

It stabalises the sarcolemma (cell membrane of sarcomere) without it, the cell membrane becomes weak and wilts. Eventually creatine kinase leaks out of the cell and calcium enters, resulting in cell death

Question 21

What is Gower’s Sign?

Answer 21

When a child gets up from laying on their tummy, they use their arms to help them. Due to leg weakness.

Question 22

What is the 3’ and 5’ region?

Answer 22

3’ - Area on mRNA that immediately follows the translation termination codon
5’ - Area prior to the translation start codon