3. X-linked recessive

Question 1

Describe the inheritance observed in XLR disorders

Answer 1

All daughters of an affected male are obligate carriers

Female carriers have 50% chance of having an affected son, 50% chance of daughter being a carrier

Affected males usually born to unaffected parents (mother asymptomatic carrier)

Absence of male-to-male transmission

Question 2

For what reasons can females be affected by XLR disorders?

Answer 2

Skewed X-inactivation

X chr deletion

Turner syndrome

UPD for X chr

Compound het

Question 3

Give clinical background of DMD and BMD

Describe the inheritance

Answer 3

DMD more severe than BMD - progressive and symmetrical muscle weakness, raised CK, Gower’s sign, cardiomyopathy

DMD earlier onset, neck flexor muscle strength preserved in BMD

Question 4

Describe the inheritance in D/BMD

Answer 4

Often de novo or germline mosaic, het female can be asymptomatic or manifesting carriers

Question 5

What types of mutation cause DMD?

Answer 5

Inframe = BMD, out of frame = DMD but exceptions exist

Apply reading frame rule with caution for duplications - often exceptions to rule

Question 6

What is the role of dystrophin?

What types of mutation cause D/BMD?

Answer 6

Forms dystrophin-associated protein complex (DAPC) - forms links between actin cytoskeleton and extracellular matrix

DMD expression highest in skeletal, smooth and cardiac muscle

Question 7

What treatments are there for DMD?

Answer 7

Exondys51 - causing skipping of exon to restore reading frame

Translana - stop codon read through, alternative aa inserted at stop codon

Question 8

What does variation in the AR gene cause?

Answer 8

Exon 1 CAG repeat = SBMA

Progressive neuromuscular disorder, muscular weakness/atrophy, gynecomastia, testicular atrophy

SNVs/indels = androgen insensitivity

Feminisation of genitalia at birth, abnormal sexual development, infertility

Question 9

What is the clinical presentation of ALD?

Answer 9

ALD = Childhood onset. Raised VLCFAs, progressive impairment of cognition, behaviour, vision, hearing, and motor function

AMN = later onset. Progressive stiffness and weakness of the legs, impaired adrenocortical function.

Addison disease = adrenocortical insufficiency only

Question 10

What is the clinical presentation of Fabry disease?

Answer 10

Pain in hands & feet, small, dark red spots on skin, decreased ability to sweat, corneal opacity, tinnitus

Kidney damage, heart attack, stroke

Question 11

What causes ALD?

Answer 11

ALD/AMN/Addison’s disease (ABCD1) - defect of peroxisomes which break down fatty acids - affects adrenal glands and white matter

Question 12

What causes Fabry disease?

Answer 12

Fabry disease (GLA) - alpha galactosidase A active in lysosomes, breaks down globotriaosylceramide which builds up in skin, kidneys, heart, CNS