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Mutation update for myelin protein zero-related neuropathies and the increasing role of variants causing a late-onset
Ilaria Callegari1,2,3, C Gemelli4, A Geroldi4
1Neuroscience Consortium Monza Policlinico and Pavia Mondino, University of Pavia, Pavia, Italy. ilaria.callegari01@universitadipavia.it.
Abstract:
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.
Insights
Mutations in the myelin protein zero gene (MPZ) cause Charcot-Marie-Tooth disease. Recent findings confirm two main phenotypes and suggest a third, with increasing evidence for late-onset P0 neuropathies.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Mutations in the myelin protein zero gene (MPZ) account for 5% of Charcot-Marie-Tooth (CMT) cases.
- Previous classification identified early-onset (demyelinating) and late-onset (axonal impairment) MPZ-related phenotypes.
- The clinical spectrum and classification of MPZ mutations require ongoing evaluation with new genetic discoveries.
Purpose of the Study:
- To reassess the classification of MPZ mutations based on newly identified variants over the past 14 years.
- To determine if recent MPZ mutations align with the established early-onset and late-onset phenotypes.
- To investigate the potential for a third distinct phenotype in MPZ-related neuropathies.
Main Methods:
- Systematic literature review of novel MPZ mutations reported in the last 14 years.
- Analysis and classification of 69 novel MPZ mutations based on clinical presentation, age of onset, and nerve conduction velocities (NCVs).
- Comparison of newly identified mutations with existing phenotypic classifications.
Main Results:
- Approximately 90% of the 69 novel MPZ mutations fit into three distinct phenotypic groups.
- Group 1: Early-onset phenotype (onset before 3 years, severe course, low MNCVs < 15 m/s).
- Group 2: Late-onset neuropathy (onset ~43 years, high MNCVs ~47 m/s).
- Group 3: Phenotype resembling CMT1A (onset in 2nd decade, MNCVs 15-30 m/s).
Conclusions:
- P0-related neuropathies can be classified into two main phenotypes, with a third group exhibiting childhood-onset disease.
- The findings support a three-group subdivision for MPZ mutations, including a distinct early-onset group.
- There is a notable increase in reported late-onset MPZ mutations, underscoring their clinical significance and potential underdiagnosis.
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