Mutation update for myelin protein zero-related neuropathies and the increasing role of variants causing a late-onset phenotype

• Published in: Journal of neurology 2019-11, Vol.266 (11), p.2629-2645
• Main Authors: Callegari, Ilaria, Gemelli, C., Geroldi, A., Veneri, F., Mandich, P., D’Antonio, M., Pareyson, D., Shy, M. E., Schenone, A., Prada, V., Grandis, M.
• Format: Article
• Language: English
• Subjects: Age; Age of Onset; Charcot-Marie-Tooth disease; Charcot-Marie-Tooth Disease - genetics; Children; Demyelination; Genotype & phenotype; Genotypes; Humans; Medicine; Medicine & Public Health; Mutation; Myelin; Myelin P0 protein; Myelin P0 Protein - genetics; Nerve conduction; Neurology; Neuropathy; Neuroradiology; Neurosciences; Original Communication; Phenotype; Phenotypes
• ISSN: 0340-5354; 1432-1459
• DOI: 10.1007/s00415-019-09453-3

Mutations of myelin protein zero gene ( MPZ ) are found in 5% of Charcot–Marie–Tooth patients. In 2004, Shy et al. identified two main phenotypes associated with them: an early-onset subtype with mainly demyelinating features and a late-onset subgroup with prominent axonal impairment. We evaluated whether novel MPZ mutations described in literature during the last 14 years could still fit with this classification. We collected and revised reports of 69 novel MPZ mutations. Almost 90% of them could be alternatively classified as responsible for: (a) an early-onset phenotype, with first limitations starting before 3 years (2.5 ± 0.50 years), motor milestones delays, frequently severe course and upper limb MNCVs below 15 m/s; (b) late-onset neuropathy, with mean age of onset of 42.8 ± 1.5 years and mean upper limbs motor nerve conduction velocities (MNCVs) of 47.2 ± 1.4 m/s; (c) a phenotype more similar to typical CMT1A neuropathy, with onset during the 2nd decade, MNCV in the range of 15–30 m/s and slowly progressive course. The present work confirms that P0-related neuropathies may be separated into two main distinct phenotypes, while a third, relatively small, group comprehend patients carrying MPZ mutations and a childhood-onset disease, substantiating the subdivision into three groups proposed by Sanmaneechai et al. (Brain 138:3180–3192, 2015 ). Interestingly, during the last years, an increasing number of novel MPZ mutations causing a late-onset phenotype has been described, highlighting the clinical relevance of late-onset P0 neuropathies. Since the family history for neuropathy is often uncertain, due to the late disease onset, the number of patients carrying this genotype is probably underestimated.