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
Give clinical background of DMD and BMD
Describe the inheritance
DMD more severe than BMD - progressive and symmetrical muscle weakness, raised CK, Gower’s sign, cardiomyopathy
Often de novo or germline mosaic, het female can be asymptomatic or manifesting carriers
What is the role of dystrophin?
What types of mutation cause D/BMD?
Forms dystrophin-associated protein complex (DAPC) - forms links between actin cytoskeleton and extracellular matrix
DMD expression highest in skeletal, smooth and cardiac muscle
Inframe = BMD, out of frame = DMD but exceptions exist
What treatments are there for DMD?
Exondys51 - causing skipping of exon to restore reading frame
Translana - stop codon read through, alternative aa inserted at stop codon
What does variation in the AR gene cause?
CAG repeat = SBMA
Progressive neuromuscular disorder, muscular weakness/atrophy, gynecomastia, testicular atrophy
Degeneration of lower motor neurones, GoF, peptide fragments retained in nucleus - form inclusions
SNVs/indels = androgen insensitivity
AR allow cells to respond to androgen hormones (direct male sexual development)
Feminisation of genitalia at birth, abnormal sexual development, infertility
Other than DMD, and SBMA/androgen insensitivity, name 2 other XLR disorders
ALD/AMN/Addison’s disease (ABCD1) - defect of peroxisomes, raised VLCFAs - affects adrenal glands and white matter –> progressive loss of physical/mental skills
Fabry disease (GLA) - alpha galactosidase A active in lysosomes, breaks down globotriaosylceramide. KIdney damage, heart attack, stroke
