Abstract
BackgroundCharcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder characterized by wide clinical, genetic and pathomechanistic heterogeneity. Recently, the gene encoding peripheral myelin protein 2 (PMP2) was identified as a novel cause for CMT neuropathy with three mutations that structurally cluster together (p.Ile43Asn, p.Thr51Pro, p.Ile52Thr) reported in five families.ResultsUsing whole exome sequencing and cohort screening we identified two novel missense substitutions in PMP2 in Bulgarian (p.Met114Thr, c.341C > T) and German (p.Val115Ala, c.344 T > C) families. The mutations affect adjacent and highly conserved amino acid residues outside of the known mutation-rich region in the protein. Crystal structure analysis positions the affected residues within a cluster of highly conserved fatty acid coordinating residues implying their functional significance. The clinical, electrophysiological and imaging features in both families were consistent with a childhood onset polyneuropathy with variable patterns of demyelination, slow to very slow progression, and most severe involvement of the peroneal muscles.ConclusionsWe expand the genetic and phenotypic spectrum of PMP2-related peripheral neuropathy. Our findings reveal a second mutational cluster in the protein.
Highlights
Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder characterized by wide clinical, genetic and pathomechanistic heterogeneity
It is very sensitive to changes in its protein or lipid composition and alterations lead to inefficient compaction and insulation of the axons resulting in a significant reduction in Nerve conduction velocities (NCV) [6]
Foot deformities became apparent in the first decade of life. During her teens proximal muscle weakness in the lower limbs was noticed with difficulties in climbing stairs
Summary
Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder characterized by wide clinical, genetic and pathomechanistic heterogeneity. The gene encoding peripheral myelin protein 2 (PMP2) was identified as a novel cause for CMT neuropathy with three mutations that structurally cluster together (p.Ile43Asn, p.Thr51Pro, p.Ile52Thr) reported in five families. Charcot-Marie-Tooth disease (CMT) represents a genetically and phenotypically highly heterogeneous group of disorders of the peripheral nervous system, affecting 9.7–82.3/100,000 individuals in the European population [1]. All forms of inheritance are observed in CMT and mutations in over 80 genes with diverse functions have been described as disease-causing [2]. The disease affects the myelin sheath, a complex structure made out of layers of highly compacted Schwann cell membrane. A genomic duplication that includes PMP22 was the first identified genetic cause of Palaima et al Orphanet Journal of Rare Diseases (2019) 14:197
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