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Myelin uncompaction in Charcot-Marie-Tooth neuropathy type 1A with a point mutation of peripheral myelin protein-22

From the Department of Neurological and Visual Sciences (Drs. Fabrizi, Cavallaro, Taioli, Simonati, and Rizzuto), Section of Clinical Neurology, University of Verona; Department of Neurology (Dr. Orrico), "Santa Chiara" Hospital, Trento; and "Carlo Besta" Neurological Institute (Dr. Morbin), Milan, Italy.

Address correspondence and reprint requests to Dr. Gian Maria Fabrizi, Department of Neurological and Visual Sciences, Section of Clinical Neurology, University of Verona, Ospedale Policlinico, via delle Menegone 10, 37134 Verona, Italy.

BACKGROUND: The peripheral myelin protein-22 (PMP22) gene has four transmembrane domains, two extracellular loops, and a short cytoplasmic tail. Its roles in the peripheral nervous system remain unclear. The most common cause of Charcot-Marie-Tooth neuropathy type 1A (CMT1A) is a PMP22 gene duplication. Missense point mutations in the transmembrane domains are rare alternative causes that have undetermined pathogenetic mechanisms.

OBJECTIVE: To investigate the phenotype-to-genotype correlations in a pedigree with unusual CMT1A.

METHODS: We identified a pedigree with an autosomal dominant motor-sensory neuropathy and severely reduced nerve conduction velocities who did not have the PMP22 duplication. Specimens from sural nerve biopsies from two patients of different ages were evaluated morphometrically. By automated direct nucleotide sequencing we analyzed PMP22 and the gene of the major structural myelin protein zero (P₀).

RESULTS: Nucleotide 159 of PMP22 showed an A-to-T heterozygous mutation, predicted to cause an aspartate-to-valine substitution at codon 37 in the first extracellular loop of the protein. The mutation co-segregated with the disease in the pedigree and was absent in 80 healthy controls. The histopathologic phenotype was a de-remyelinating neuropathy with onion bulb formations, characterized by prominent uncompaction of the myelin sheath in the majority of fibers and by frequent tomacula.

CONCLUSION: We have described a novel mutation in the first extracellular loop of PMP22 associated with an atypical CMT1A that overlaps pathologically with CMT1B caused by point mutations in the extracellular domain of P₀.

Key words: Peripheral myelin protein-22—Charcot-Marie-Tooth neuropathy type 1A.

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