A Family with Duchenne-Like Weakness: Reading a Pedigree Before DNA Testing
Six-year-old Ġorġ is referred with progressive difficulty climbing stairs and a waddling gait. His serum creatine kinase is 12,400 U/L (normal < 200), and he has calf pseudohypertrophy and a positive Gowers sign. There is no known family history, but his mother's brother died at 17 from respiratory failure after years of weakness, and another maternal uncle is unaffected. Ġorġ's mother has a serum CK of 230 U/L. Her sister, Maria, is 28 and 10 weeks pregnant with a male fetus; she has a CK of 90 U/L. The maternal grandmother is healthy and has two unaffected sons and one affected son. No genetic test has yet been done. The family asks whether the baby is at risk and whether Maria should have invasive testing. The clinic has a validated next-generation sequencing panel for dystrophin (DMD) variants but no prenatal testing without a familial variant.
1. Identify the most likely mode of inheritance and explain which pedigree features and CK results support it.
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Most likely X-linked recessive (Duchenne muscular dystrophy). Only males are affected; the affected boy's maternal uncle is affected, and the unaffected maternal uncle shows the pattern can pass through females. There is no male-to-male transmission. The boy's mother has a raised CK (230 U/L), a recognised feature of DMD carriers, while the affected males have very high CK.
Autosomal recessive is less likely because two affected males in different sibships occur through females, and the carrier mother's CK is elevated; an autosomal recessive condition would not explain the CK elevation in a heterozygote. The grandmother is an obligate carrier because she has an affected son, and the mother is an obligate carrier because she has an affected son. The normal CK in Maria does not exclude carriership.
2. Calculate the probability that Maria's male fetus is affected, stating your assumptions.
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The grandmother is an obligate carrier. Maria and Ġorġ's mother are sisters; the mother is an obligate carrier because she has an affected son. Maria's probability of being a carrier is 1/2, assuming the mother inherited the variant from the grandmother and no new mutation occurred. If Maria is a carrier, a male fetus has a 1/2 chance of inheriting the variant and being affected.
Therefore P(affected male fetus) = 1/2 × 1/2 = 1/4 (25%). This assumes no germline mosaicism, full penetrance in males, and that the affected boy's variant is the familial one. A normal CK in Maria does not exclude carriership; CK is not a reliable carrier test. The risk is a prior probability until DMD sequencing confirms the family variant.
3. Discuss the limitations of using CK and the ethical issues raised by prenatal testing in this family.
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CK is raised in many carriers but can be normal, and it rises after exercise or muscle damage, so it cannot be used alone for carrier diagnosis or prenatal prediction. DMD sequencing is needed; prenatal testing (chorionic villus sampling or amniocentesis) can only be offered if the familial variant is known.
Counselling should be non-directive, explain the 25% risk to a male fetus and the 50% chance that a female fetus is a carrier, and discuss the option of testing. Results can cause anxiety and family disclosure issues; confidentiality and the child's future autonomy must be considered. If no variant is found, risk remains empirical and should not be reported as zero. Maria should also be told that invasive testing carries a small miscarriage risk and that a normal CK is not reassurance.