How to Study for NBME Shelf Exams

Answer: A. Hereditary spherocytosis is caused by defects in RBC cytoskeletal proteins such as spectrin, leading to membrane instability and spherocyte formation. This results in increased osmotic fragility and extravascular hemolysis. Hemoglobin S causes sickling rather than spherocytes. G6PD deficiency causes oxidative hemolysis. Iron deficiency causes microcytic anemia.

Answer: C. Fabry disease is an X-linked lysosomal storage disorder caused by deficient alpha-galactosidase A activity, which normally degrades globotriaosylceramide (Gb3) and related glycosphingolipids; progressive lysosomal accumulation of these glycosphingolipids within vascular endothelium and other tissues produces the characteristic acroparesthesias, angiokeratomas, corneal opacities, and progressive renal and cardiac disease, and the X-linked inheritance pattern explains why affected males (like the uncle) transmit disease risk through unaffected or mildly symptomatic carrier female relatives (like the mother), rather than the recessive pattern that would require two mutant alleles in females. Option A incorrectly proposes autosomal recessive inheritance, which does not match the pedigree pattern described. Option B incorrectly substitutes the glucocerebroside/Gaucher disease mechanism. Option D incorrectly proposes autosomal dominant inheritance with full penetrance in all carriers, which does not reflect the X-linked pattern with typically milder or absent symptoms in heterozygous females. Option E incorrectly dismisses the well-established, defining renal and cardiac manifestations of this disease.

Answer: D. Huntington disease is caused by an expanded CAG trinucleotide repeat in the huntingtin gene, and this repeat is unstable during meiosis, particularly spermatogenesis, tending to expand further with each generation; longer repeat lengths correlate with earlier age of onset and greater disease severity, a phenomenon known as genetic anticipation, which explains why this patient's disease began a decade earlier than his father's. This repeat instability is distinct from genomic imprinting, which involves parent-of-origin-specific gene silencing rather than repeat expansion, and from somatic mosaicism or loss of heterozygosity, neither of which explains the intergenerational pattern described. Huntington disease follows autosomal dominant, not X-linked, inheritance, ruling out the final distractor.