X-linked Recessive

Question 1

Duchenne Muscular Dystrophy

Answer 1

Onset around 2 yrs, lose motor function, in wheelchair by 18 yrs, median age at death is 18 yrs.
Progressive myopathy, characterized by large calves (adipose tissue overcomes muscle tissue); Gowers Maneuver; median age of death 18 yrs; abnormal gait; progressive myopathy; high creatine kinase levels (shows evidence of muscle damage)

Loss of Function: Large deletions in many exons in Xp21.2 (dystrophin gene); nonsense frameshift
High new mutation rate (alleles have 0 fitness because sons not living to reproduce)
Sometimes carrier females will demonstrate milder symptoms later in life (8%);
In-frame deletion or missense leads to milder Becker dystrophy

Question 2

Hemophilia A

Answer 2

Bleed complications (decreased clotting)

Factor VIII deficiency
Note: Hemophilia B is Factor IX

Question 3

Testicular Feminization

Answer 3

Feminine features (due to end-organ unresponsiveness to testosterone)

Absence or abnormality of cytosolic androgen receptor protein; similar to androgen insensitivity syndrome, mutations androgen receptor gene.

Question 4

Dosage Sensitive Sex Reversal (DSS)

Answer 4

Leads to development of ovaries even in the presence of expressed SRY

Duplication of a gene DAX1
DAX1 is a member of the nuclear hormone receptor superfamily

Question 5

Fabry Disease

Answer 5

Neurologic pain crises in childhood; reduced sweating, risk of heat stroke; progressive renal failure (cause of death prior to renal transplanation); risk of heart attacks and stroke; hypertrophy of cardiac tissue also seen

Due to deficiency of alpha-galactosidase (protein misfolding); Accumulation of glycosphingolipids causes widespread microvascular damage
One particular mutation (25% of disease)

Chaperone-based therapy, helps alpha-galactosidase A fold correctly
Approved in the United States􏲲annual cost $150-200,000 / patient (lifelong)
Recombinant enzyme replacement therapy appears to mitigate parts of disease