Inheritance of a Metabolic Disorder in a Family
A couple, Priya and Daniel, have a son with a metabolic disorder. Neither parent is affected. Priya's brother is affected; Daniel has no family history. Testing shows the disorder is caused by deficiency of an enzyme encoded by a gene on an autosome. Enzyme activity assays show Priya has about 50% of normal activity, Daniel has 100%, and their affected son has near zero. A second, unrelated condition in the same family is caused by a mitochondrial DNA variant: an affected grandmother passed it to all her children, but severity varies widely among them, and an unaffected daughter's children are unaffected.
1. Determine the most likely mode of inheritance for the enzyme-deficiency disorder and calculate the probability that Priya and Daniel's next child is affected. Justify with the enzyme activity data.
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Mode: autosomal recessive.
Reasoning from the data:
- Both parents unaffected but have an affected child → the allele is recessive and both parents carry it.
- Priya has ~50% enzyme activity: consistent with being heterozygous (one functional allele).
- Daniel has 100% activity: this argues against him being a carrier of the same variant, which complicates the simple model.
The enzyme data force a judgement: if the disorder were autosomal recessive and Daniel were a carrier, his activity would typically be intermediate. A full-activity result suggests either that the assay cannot resolve carriers for this variant, or that the affected son inherited two different pathogenic variants (one from each parent) - compound heterozygosity - with Daniel carrying a variant that does not reduce assayed activity in his tissue.
Probability: if both parents are confirmed carriers, each child has a 1 in 4 chance of being affected, 1 in 2 of being a carrier, 1 in 4 unaffected non-carrier. The answer must be stated conditionally, because Daniel's carrier status is not established by the activity data alone and would require DNA testing.
2. Explain the mitochondrial condition's inheritance pattern and why severity varies among the grandmother's children.
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Inheritance: mitochondrial DNA is maternally inherited. An affected mother passes her mitochondrial genome to all children, which matches the observation that all the grandmother's children inherited the variant. An unaffected daughter's children are unaffected because that daughter did not inherit the variant (or inherited a load below the threshold for expression) and so cannot transmit it.
Variable severity - heteroplasmy: each egg receives a variable proportion of mutant versus normal mitochondria. Children therefore differ in the fraction of mutant mitochondrial DNA in their tissues. Because mitochondria carry out oxidative phosphorylation, cells with a high mutant fraction produce less ATP. A threshold effect means symptoms appear only when the mutant proportion exceeds a tissue-specific level, and tissues with high energy demand (muscle, nerve) are affected first. This explains why the same variant produces mild symptoms in one child and severe disease in another, and why severity can differ between tissues within one person.