A 4-month-old male infant presents with progressive developmental delay, axial hypotonia with emerging limb spasticity, and pendular nystagmus noted by the parents over the past 6 weeks. Brain MRI shows diffuse lack of myelination with a "tigroid" appearance on T2-weighted sequences. The structure marked **A** in the diagram represents the genetic abnormality responsible for this presentation. Which of the following best describes the molecular consequence of this duplication?
A. Duplication of MECP2 causing abnormal methyl-CpG binding and progressive neurodegeneration in males
B. Deficiency of ARSE enzyme resulting in abnormal cartilage matrix formation and skeletal dysplasia
C. Overexpression of PLP1 leading to oligodendrocyte death and failure of myelin formation (hypomyelination)
D. Loss of ABCD1 function causing accumulation of very-long-chain fatty acids in white matter
Explanation
Why "Overexpression of PLP1 leading to oligodendrocyte death and failure of myelin formation (hypomyelination)" is right
The structure marked A (Xq22 PLP1 duplication) is the genetic basis of Pelizaeus-Merzbacher disease (PMD) in 60–70% of cases. PLP1 encodes the most abundant myelin protein in the CNS (~50% of CNS myelin protein). Duplication of this gene causes toxic overexpression, leading to oligodendrocyte death and failure of myelin formation—a hypomyelinating leukodystrophy distinct from demyelination. The clinical presentation (male infant, pendular nystagmus as first sign, hypotonia progressing to spasticity, MRI hypomyelination) is pathognomonic for classic PMD. The anchor fact is that PLP1 duplication (not deletion or point mutation) causes disease through overexpression, not loss of function (Nelson Textbook of Pediatrics 22e; GeneReviews—Pelizaeus-Merzbacher Disease).
Why each distractor is wrong
Loss of ABCD1 function causing accumulation of very-long-chain fatty acids in white matter: This describes X-linked adrenoleukodystrophy (X-ALD), which is caused by mutation at Xq28 (marked B), not Xq22. X-ALD is a peroxisomal disorder with a different pathophysiology (VLCFA accumulation, demyelination) and different clinical features (adrenal insufficiency, cerebral demyelination in childhood form).
Deficiency of ARSE enzyme resulting in abnormal cartilage matrix formation and skeletal dysplasia: This describes X-linked chondrodysplasia punctata (marked C at Xp22), a skeletal dysplasia with ichthyosis and cataracts—not a leukodystrophy. ARSE deficiency does not cause hypomyelination or nystagmus.
Duplication of MECP2 causing abnormal methyl-CpG binding and progressive neurodegeneration in males: This describes the Rett-like phenotype in males with MECP2 duplication (marked D at Xq28), which presents with severe encephalopathy and seizures but is distinct from PMD. MECP2 duplication causes a different pattern of neurodegeneration and does not produce the characteristic pendular nystagmus and hypomyelination pattern of PMD.
High-YieldNEET PG
Male infant + pendular nystagmus + hypotonia→spasticity + MRI hypomyelination = PLP1 duplication (Xq22); use MLPA first to detect duplication.
Nelson Textbook of Pediatrics 22e (Leukodystrophies); GeneReviews — Pelizaeus-Merzbacher Disease
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