Thirty Years Later, Case Closed: A Case of PMP22 Triplication From Anticipation

Copy-number variations cause genomic disorders. Triplications, unlike deletions and duplications, are poorly understood because of challenges in molecular identification, the choice of a proper model system for study, and awareness of their phenotypic consequences. We investigated the genomic disorder Charcot-Marie-Tooth disease type 1A (CMT1A), a dominant peripheral neuropathy caused by a 1.4 Mb recurrent duplication occurring by nonallelic homologous recombination. We identified CMT1A triplications in families in which the duplication segregates. The triplications arose de novo from maternally transmitted duplications and caused a more severe distal symmetric polyneuropathy phenotype. The recombination that generated the triplication occurred between sister chromatids on the duplication-bearing chromosome and could accompany gene conversions with the homologous chromosome. Diagnostic testing for CMT1A (n = 20,661 individuals) identified 13% (n = 2,752 individuals) with duplication and 0.024% (n = 5 individuals) with segmental tetrasomy, suggesting that triplications emerge from duplications at a rate as high as ∼1:550, which is more frequent than the rate of de novo duplication. We propose that individuals with duplications are predisposed to acquiring triplications and that the population prevalence of triplication is underascertained.

Mechanism, Prevalence, and More Severe Neuropathy Phenotype of the Charcot-Marie-Tooth Type 1A Triplication

Transverse sections of the sural nerve of a 46-year-old woman without neuropathic symptoms or abnormalities on nerve conduction, electromyography, or computer-assisted sensory examination contained minute regions with large onion bulbs intermingled with normal-appearing myelinated fibers and surrounded by fields of normal myelinated fibers. This woman's 19-year-old daughter had long-standing hypertrophic neuropathy with diffusely distributed large onion bulbs. Computer-imaging reconstruction of myelinated fibers and teased myelinated fiber studies of fascicles containing focal regions with onion bulbs of the mother's nerve provided evidence that onion bulbs surrounded atrophic axons with short internodes and demyelination. This is the least expression for inherited neuropathy which has been reported. These findings therefore suggest that an inherited neuropathy may be minimally expressed by a pathologic alteration of only selected neurons (axons).

Thirty Years Later, Case Closed: A Case of PMP22 Triplication From Anticipation

References

Mechanism, Prevalence, and More Severe Neuropathy Phenotype of the Charcot-Marie-Tooth Type 1A Triplication

Minimal pathologic expression of a mutant gene for hereditary motor and sensory neuropathy.