A 28-year-old man presents with recurrent episodes of foot drop and wrist weakness following minor compression (squatting, leaning on elbows). Nerve conduction studies show diffuse slowing of conduction velocities and conduction block at common entrapment sites. Genetic testing confirms the chromosomal abnormality marked as **A** in the diagram. Which of the following best describes the molecular basis of this condition?
A. 1.5 Mb deletion at 17p11.2 encompassing PMP22, resulting in PMP22 haploinsufficiency and demyelination
B. Deletion at 17p13.3 affecting the LIS1 gene, resulting in lissencephaly and severe developmental abnormalities
C. Point mutations or small intragenic deletions in the RAI1 gene at 17p11.2, causing developmental delay and behavioral features
D. 1.5 Mb duplication at 17p11.2 encompassing PMP22, resulting in PMP22 overexpression and severe polyneuropathy
Explanation
Why option 1 is correct
The structure marked A represents the 17p11.2 PMP22 deletion responsible for Hereditary Neuropathy with Liability to Pressure Palsies (HNPP). This condition is caused in 80% of cases by a 1.5 Mb deletion at chromosome 17p11.2 encompassing the PMP22 gene, leading to PMP22 haploinsufficiency. The clinical presentation of recurrent, painless focal deficits triggered by minor compression, combined with diffuse conduction slowing and conduction block at entrapment sites, is pathognomonic for HNPP. The deletion is the reciprocal of the CMT1A duplication—a classic example of genomic disorders arising from non-allelic homologous recombination between flanking CMT1A-REP repeats.
Why each distractor is wrong
Option 2: This describes the 1.5 Mb duplication at 17p11.2 (marked B in the diagram), which causes CMT1A—a severe demyelinating polyneuropathy with early onset and progressive course. This is the mirror-image entity to HNPP, not the condition presented here. The patient's episodic, pressure-sensitive presentation is characteristic of deletion (HNPP), not duplication (CMT1A).
Option 3: RAI1 gene mutations at 17p11.2 (marked C) cause Smith-Magenis syndrome, characterized by developmental delay, intellectual disability, behavioral problems, and distinctive facial features. This does not match the clinical presentation of recurrent pressure palsies and focal nerve deficits in an otherwise cognitively normal adult.
Option 4: LIS1 deletion at 17p13.3 (marked D) causes Miller-Dieker lissencephaly, a severe neuronal migration disorder presenting with profound developmental delay, seizures, and lissencephalic brain malformation. This is incompatible with the patient's normal development and focal neuropathic presentation.
High-YieldNEET PG
HNPP (deletion, haploinsufficiency) = recurrent pressure palsies; CMT1A (duplication, overexpression) = severe progressive polyneuropathy—reciprocal genomic disorders from non-allelic homologous recombination at 17p11.2.
Harrison's Principles of Internal Medicine 21e (Peripheral Neuropathies); GeneReviews — HNPP
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