De novo mutation (Arg⁹⁸→Cys) of the myelin P₀ gene and uncompaction of the major dense line of the myelin sheath in a severe variant of Charcot–Marie–Tooth disease type 1B

Abstract

A point mutation (Arg⁹⁸→Cys) of exon 3 coding for the extracellular domain of the myelin protein zero (P₀) gene was found in a sporadic case of an eighteen year old Japanese man with a severe variant of Charcot–Marie–Tooth disease type 1B (CMT1B). A de novo mutation was established by parentage testing and analyses of the P₀ gene in the family. This patient showed delayed motor development, nonprogressive limb weakness and kyphoscoliosis. In addition to the nerve biopsy findings typical of CMT1B, such as segmental demyelination, marked decrease in the density of myelinated fibers, and frequent onion-bulb formation, ultrastructural examination disclosed uncompaction of the major dense lines with slight widening of the intraperiod distance in the inner layers of the myelin sheath. Although mutations in the extracellular domain of P₀ should affect homophilic adhesion between external surfaces of Schwann cell processes, resulting in the separation at the intraperiod lines, our study shows uncompacted major dense lines as a main myelin abnormality where the cytoplasmic domain of P₀ resides.

Introduction

The most common subtype of Charcot–Marie–Tooth disease (CMT) type 1 is CMT1A, which cosegregates with a 1.5 Mb duplication on 17p11.2 (Lupski et al., 1991, Raeymaekers et al., 1991), including the gene encoding the peripheral myelin protein 22 (PMP22) (Patel et al., 1992) or exceptionally with a point mutation of PMP22 gene (Valentijn et al., 1992). CMT1B is a rare form of CMT1 associated with mutations of the myelin protein zero (P₀) gene, which is mapped to 1q22–q23. To date, sixteen point mutations and one deletion of the P₀ gene have been described in CMT1B (Table 1). We found a second case of Arg⁹⁸→Cys substitution of P₀ in a sporadic Japanese patient with severe CMT1. A de novo mutation was confirmed by parentage testing and analyses of the P₀ gene in the family. One recent study described two types of nerve pathology, i.e., uncompacted myelin and focally folded myelin, suggesting that different amino acid substitutions in the same codon resulted in the similar pathology (Gabreëls-Festen et al., 1996). However, ultrastructural findings of the sural nerve in our case differed from those in two cases of Arg⁹⁸→His substitution (Ohnishi et al., 1994, Ohnishi et al., 1996). Because correlation of clinical severity and myelin abnormalities with different P₀ mutations remained unclear (Ionasescu et al., 1992, Hayasaka et al., 1993c, Himoro et al., 1993, Thomas et al., 1994, Latour et al., 1995), we report a clinicopathological study of this case and review the literature. The patient and his parents gave informed consent to the present study.