Examkin

Question

Difficulty: HardGenetic and Molecular Mechanisms

Match each adult patient's clinical presentation to the precise underlying genetic and molecular mechanism responsible for their condition.

  • A 42-year-old man with recurrent unprovoked deep venous thromboses. Laboratory testing reveals no prolongation of the activated partial thromboplastin time when activated protein C is added to the plasma.Missense mutation (G to A substitution) causing replacement of arginine with glutamine, resulting in resistance to proteolytic cleavage by a regulatory serine protease.
  • A 29-year-old man presenting with sudden, painless, central vision loss in his right eye, followed by the left eye two months later. His maternal uncle experienced a similar clinical course in his twenties.Point mutation in extranuclear circular DNA leading to defective oxidative phosphorylation in NADH dehydrogenase (Complex I), exhibiting a threshold effect.
  • A 31-year-old woman with sudden-onset tearing chest pain radiating to the back. Physical examination shows a high-arched palate, joint hypermobility, and a mid-systolic click.Missense mutation causing a dominant-negative effect on an extracellular matrix glycoprotein, resulting in defective microfibril assembly and excessive TGF-\beta signaling.
  • A 52-year-old man evaluated for new-onset diabetes mellitus, generalized fatigue, and hyperpigmented skin. Laboratory studies show markedly elevated serum ferritin and transferrin saturation.Missense mutation (C282Y) in a major histocompatibility complex class I-like protein, leading to decreased hepcidin synthesis and unregulated basolateral iron transport.

Answer

The presentations map to their mechanisms as follows: The hypercoagulable state matches the Factor V mutation (resistance to serine protease cleavage). The maternally inherited vision loss matches the mitochondrial DNA mutation (NADH dehydrogenase defect). The connective tissue disorder matches the fibrillin-1 mutation (excessive TGF-\beta signaling). The iron overload syndrome matches the HFE mutation (decreased hepcidin).
Each matching pair requires translating a classic clinical phenotype into its specific molecular mechanism. Factor V Leiden involves a mutated factor V that cannot be inactivated by activated protein C. LHON involves mitochondrial DNA mutations causing defective oxidative phosphorylation. Marfan syndrome is caused by fibrillin-1 defects leading to poor microfibril assembly and excessive TGF-\beta signaling. Hemochromatosis is driven by HFE mutations that decrease hepcidin, increasing iron absorption.

Step-by-Step Solution

1
Analyze the first patient's presentation of unprovoked thromboses and activated protein C (APC) resistance.
Identify Factor V Leiden as the diagnosis.
To connect the lack of PTT prolongation with the specific arginine-to-glutamine substitution that prevents Factor V degradation.
2
Evaluate the second patient's sudden sequential vision loss and maternal family history.
Identify Leber Hereditary Optic Neuropathy (LHON).
To trace the maternal inheritance pattern to the extranuclear (mitochondrial) DNA point mutation affecting oxidative phosphorylation.
3
Assess the third patient's tall stature, hypermobility, and aortic dissection.
Identify Marfan syndrome.
To link the connective tissue phenotype to the dominant-negative mutation in fibrillin-1 and the resulting overactivity of TGF-\beta.
4
Interpret the fourth patient's triad of diabetes, hyperpigmentation, and iron overload.
Identify Hereditary Hemochromatosis.
To map the systemic iron toxicity to the HFE mutation that disrupts hepcidin synthesis and increases intestinal iron absorption.

Key Concept

Integration of adult-onset clinical phenotypes with their precise underlying genetic and molecular pathophysiology.
Rate this question

Topics

Genetic and Molecular Mechanisms

More questions from this topic