A Family with Duchenne Muscular Dystrophy: Pedigree and Prenatal Risk
A 7-year-old boy is brought with progressive proximal weakness, calf pseudohypertrophy, and Gower sign. Serum creatine kinase is 16,000 U/L. His mother's brother died at 16 of respiratory failure; two maternal uncles are unaffected. The mother has no weakness, but her CK is mildly elevated (280 U/L; normal <170). The family has one unaffected daughter aged 10. The mother is pregnant with a male fetus and asks about the chance the baby is affected. Molecular testing of the boy shows a deletion of exons 50–52 in the DMD gene. The mother's carrier testing by multiplex ligation-dependent probe amplification (MLPA) is pending. The family is from a rural area and has limited access to genetic services.
1. Deduce the mode of inheritance and explain the findings in the mother and the maternal uncles. Why is the mother not affected?
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The pattern is X-linked recessive. The boy is male with only one X chromosome; a deletion in the DMD gene (exons 50–52) removes dystrophin and causes Duchenne muscular dystrophy. His mother has an affected brother and an affected son, which is typical of a carrier female. She is not affected because she has a second X chromosome with a normal DMD gene; in carriers, random X-inactivation usually leaves enough dystrophin in muscle. Her mildly raised CK (280 U/L) is a carrier clue, but CK can be normal in carriers, so it is not decisive. The unaffected maternal uncles may have inherited the grandmother's normal X; if the grandmother is a carrier, each son has a 50% chance of inheriting the mutation. The family therefore needs MLPA confirmation in the mother, because the boy's deletion may be inherited or de novo.
2. The mother is pregnant with a male fetus. What is the probability the fetus is affected if she is a confirmed carrier? What test would you offer and when? Why is CK testing not enough?
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If the mother is a confirmed carrier, each male fetus has a 50% chance of inheriting the deleted X and being affected. The male fetus in this pregnancy therefore has a 50% risk, not 100%, because the mother also has a normal X. Prenatal diagnosis should be offered by chorionic villus sampling at about 11–14 weeks or amniocentesis at about 15–18 weeks, with MLPA or deletion-specific PCR on fetal DNA. Ultrasound cannot diagnose DMD. CK testing is not suitable for a fetus and is unreliable for carrier females; it reflects muscle damage, not genotype. If the mother's MLPA is negative, the recurrence risk is low but not zero because of possible gonadal mosaicism, so genetic counselling is still needed.
3. The unaffected 10-year-old daughter asks about her own risk. How would you counsel her, and what test is appropriate at what age?
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The 10-year-old daughter has a 50% chance of being a carrier if her mother is a carrier. If the mother is not a carrier, the daughter's risk is very low unless the boy's mutation arose as maternal gonadal mosaicism. The most informative test is MLPA or targeted deletion testing for the same exons 50–52 deletion, after genetic counselling. CK testing is not a reliable screening test in girls because carriers often have normal CK. Testing a minor should generally be deferred until she is old enough to understand the implications and consent, unless there is a medical reason. If she is a carrier, each of her sons will have a 50% risk of DMD and each daughter a 50% risk of being a carrier; reproductive options can be discussed later.