Learning Objective: By the end of this lesson, the learner will be able to identify common X-linked recessive disorders, understand their inheritance pattern, and explain the role of X-inactivation (lyonization) in disease expression.
Key Features of X-Linked Recessive Inheritance
- Inheritance pattern:
- Males (XY) are hemizygous, so a single pathogenic allele → disease
- Females (XX) are usually carriers; the disease manifests rarely unless skewed X-inactivation occurs
- Transmission:
- No male-to-male transmission
- Sons of carrier mothers have a 50% chance of being affected
- Daughters of carrier mothers have a 50% chance of being carriers
- Special case: Turner syndrome (45, XO) females are more susceptible
Examples of X-Linked Recessive Disorders
| Disease | Key Feature / Notes |
|---|---|
| Bruton agammaglobulinemia | BTK mutation; absent B cells → recurrent bacterial infections |
| Duchenne muscular dystrophy | Frameshift mutation → absent dystrophin; calf pseudohypertrophy, progressive weakness, cardiomyopathy |
| Becker muscular dystrophy | In-frame mutation → partially functional dystrophin; milder than Duchenne |
| Fabry disease | α-galactosidase A deficiency; angiokeratomas, neuropathy, renal/cardiac disease |
| G6PD deficiency | Hemolytic anemia with oxidative stress triggers (fava beans, drugs, infections) |
| Hemophilia A & B | Factor VIII & IX deficiency; bleeding tendency |
| Hunter syndrome | Iduronate sulfatase deficiency; mild Hurler-like phenotype; aggressive behavior |
| Lesch-Nyhan syndrome | HPRT deficiency; hyperuricemia, gout, self-mutilation |
| Ocular albinism | Hypopigmentation of the retina, vision problems |
| Ornithine transcarbamylase (OTC) deficiency | Urea cycle defect; hyperammonemia |
| Wiskott-Aldrich syndrome | WAS gene; eczema, thrombocytopenia, immunodeficiency |
X-Inactivation (Lyonization)
- Mechanism: One X chromosome in females is randomly deactivated → Barr body
- Effect on disease:
- Skewed inactivation may lead to the manifestation of X-linked recessive disease in females (e.g., G6PD deficiency)
- It can also influence the penetrance and severity of X-linked dominant disorders
High-Yield Tips
- Remember: X-linked recessive = mostly males affected
- Carrier females are usually asymptomatic unless skewed X-inactivation diseases: Duchenne, Hemophilia, G6PD, Lesch-Nyhan, Bruton agammaglobulinemia
- Turner syndrome (45,XO) = unopposed X → more likely to express X-linked recessive disorders
