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

Abstract

A 19-year-old woman was brought by her 46-year-old mother for evaluation of a chronic neuropathy present since childhood. The case was described by Dyck et al1Dyck P.J. Karnes J.L. Windebank A.J. Sparks M. Stevens J.C. O'Brien P.C. Minimal pathologic expression of a mutant gene for hereditary motor and sensory neuropathy.Mayo Clin Proc. 1983; 58: 419-425Google Scholar in Mayo Clinic Proceedings in 1983. The daughter had high arches and hammertoes since infancy. During childhood, she had delayed motor milestones with progressive lower- and upper-limb weakness. At the time of her initial evaluation, she had sensory loss over the distal aspect of all extremities, distal greater than proximal weakness, and diffuse areflexia with difficulty walking. Her cerebrospinal fluid protein level was elevated (168 mg/dL; <45 mg/dL is normal). Electromyography and nerve conduction studies showed markedly slowed motor nerve conduction velocities indicative of a primary demyelinating neuropathy. The mother was asymptomatic apart from reduced to absent ankle reflexes. Sural nerve biopsies revealed abnormal Schwann cell morphology with fibroblast proliferation and collagen deposition around nerve fibers (onion bulbs), mild in mother but severe in her daughter, supporting an inherited cause (Figure). The daughter's condition worsened and she developed progressive motor and neuromuscular respiratory weakness, leading to her death at age 53 years, whereas her mother at age 80 years has minimal clinical and electromyographic findings. Modern copy number genetic analysis has now revealed that the mother has a PMP22 duplication whereas her daughter had a triplication of the same region on chromosome 17p11.2 where PMP22 resides. This allowed for the diagnosis of hereditary motor and sensory neuropathy type 1A, also known as Charcot-Marie-Tooth 1A, by triplication. PMP22 duplications are the most common known cause of hereditary neuropathy (∼1:2500 persons in the population). Triplications of PMP22 from incomplete crossover during meiosis of parents with PMP22 duplication have recently been reported by Lupski et al2Liu Pengfei Gelowani V. Zhang F. et al.Mechanism, prevalence, and more severe neuropathy phenotype of the Charcot-Marie-Tooth type 1A triplication.Am J Hum Genet. 2014; 94: 462-469Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar as an explanation for why children may be much more severe by genetic anticipation in successive generations. Application of modern DNA sequencing and copy number technologies has helped to close this long-standing previously unsolved case. We acknowledge Peter J. Dyck, MD, and James Klaas, MD, for providing important clinical information related to this case, and Erik Thorland, PhD, for verifying the mutation discussed in the clinical laboratory using CytoScan technology.