3. X-linked recessive Flashcards
Describe the inheritance observed in XLR disorders
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
For what reasons can females be affected by XLR disorders?
Skewed X-inactivation
X chr deletion
Turner syndrome
UPD for X chr
Compound het
Give clinical background of DMD and BMD
DMD more severe than BMD - progressive and symmetrical muscle weakness, raised CK, Gower’s sign, cardiomyopathy
DMD onset before 6, BMD in 20s, neck flexor muscle strength preserved in BMD
Describe the inheritance in D/BMD
Often de novo or germline mosaic, het female can be asymptomatic or manifesting carriers
What types of mutation cause DMD/BMD?
Inframe = BMD, out of frame = DMD but exceptions exist
Apply reading frame rule with caution for duplications - often exceptions to rule
What is the role of dystrophin?
Forms dystrophin-associated protein complex (DAPC) - forms links between actin cytoskeleton and extracellular matrix
DMD expression highest in skeletal, smooth and cardiac muscle
What treatments are there for DMD?
Exondys51 - causing skipping of exon to restore reading frame
Translana/Ataluren - stop codon read through, alternative aa inserted at stop codon
What does variation in the AR gene cause?
Exon 1 CAG repeat = SBMA
Muscle weakness/atrophy, gynecomastia, testicular atrophy
SNVs/indels = androgen insensitivity
Feminisation of genitalia at birth, abnormal sexual development, infertility
What is the clinical presentation of ALD?
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, adrenocortical insufficiency
Addison disease = adrenocortical insufficiency only
What is the clinical presentation of Fabry disease?
Pain in hands & feet, small, dark red spots on skin, decreased ability to sweat, corneal opacity, tinnitus
Kidney damage, heart attack, stroke
What causes ALD?
ALD/AMN/Addison’s disease (ABCD1) - defect of peroxisomes which break down fatty acids - affects adrenal glands and white matter
What causes Fabry disease?
Fabry disease (GLA) - alpha galactosidase A active in lysosomes, breaks down glycosphingolipid - these build up in skin, kidneys, heart, CNS
How is Fabry disease treated?
ERT with Fabrazyme & Replagol
