Inherited Disorders: Single-Gene, Multigenic, and Mitochondrial
Core concepts
Know the major inheritance patterns and representative disorders: autosomal dominant (Huntington disease, Marfan syndrome, familial hypercholesterolemia), autosomal recessive (cystic fibrosis, sickle cell disease, phenylketonuria), X-linked (Duchenne muscular dystrophy, hemophilia, Fragile X), imprinting (Prader-Willi/Angelman), and mitochondrial (MELAS, MERRF, Leber hereditary optic neuropathy). Understand trinucleotide repeat disorders and anticipation, and the concept of penetrance and variable expressivity.
For mitochondrial disease, know maternal inheritance, heteroplasmy, threshold effect, and the tissues most affected (high-energy: brain, muscle, heart, retina, cochlea). Recognize that mitochondrial DNA mutations may be detectable in blood only at low levels, so urine or muscle may be more informative.
Traps
Questions test imprinting (parent of origin matters), anticipation (earlier onset and more severe with successive generations in repeat expansions), and the fact that mitochondrial inheritance is maternal but not all offspring are equally affected because of heteroplasmy. Another trap is assuming a negative blood test excludes mitochondrial disease.
Rule of thumb
For repeat expansions, think anticipation and parent-of-origin effects (e.g., paternal expansion in Huntington disease; maternal in Fragile X for full mutation risk). For mitochondrial disease, think heteroplasmy and threshold, and test the most affected tissue.
Worked example
A child with developmental regression, lactic acidosis, and stroke-like episodes: consider MELAS (m.3243A>G). Because heteroplasmy varies by tissue, a blood test may show a low mutant load; urine sediment or muscle may reveal a higher fraction.