Charcot-Marie-Tooth disease 1 A (CMT1A) is caused by an intrachromosomal duplication of the gene encoding for PMP22 leading to peripheral nerve dysmyelination, axonal loss, and progressive muscle weakness. No therapy is available. PXT3003 is a low-dose combination of baclofen, naltrexone, and sorbitol which has been shown to improve disease symptoms in Pmp22 transgenic rats, a bona fide model of CMT1A disease. However, the superiority of PXT3003 over its single components or dual combinations have not been tested. Here, we show that in a dorsal root ganglion (DRG) co-culture system derived from transgenic rats, PXT3003 induced myelination when compared to its single and dual components. Applying a clinically relevant ("translational") study design in adult male CMT1A rats for 3 months, PXT3003, but not its dual components, resulted in improved performance in behavioral motor and sensory endpoints when compared to placebo. Unexpectedly, we observed only a marginally increased number of myelinated axons in nerves from PXT3003-treated CMT1A rats. However, in electrophysiology, motor latencies correlated with increased grip strength indicating a possible effect of PXT3003 on neuromuscular junctions (NMJs) and muscle fiber pathology. Indeed, PXT3003-treated CMT1A rats displayed an increased perimeter of individual NMJs and a larger number of functional NMJs. Moreover, muscles of PXT3003 CMT1A rats displayed less neurogenic atrophy and a shift toward fast contracting muscle fibers. We suggest that ameliorated motor function in PXT3003-treated CMT1A rats result from restored NMJ function and muscle innervation, independent from myelination.
Baclofen/administration & dosage , Charcot-Marie-Tooth Disease/drug therapy , Demyelinating Diseases/drug therapy , Naltrexone/administration & dosage , Neuromuscular Junction/drug effects , Sorbitol/administration & dosage , Animals , Charcot-Marie-Tooth Disease/genetics , Charcot-Marie-Tooth Disease/physiopathology , Coculture Techniques , Demyelinating Diseases/genetics , Demyelinating Diseases/physiopathology , Drug Synergism , Drug Therapy, Combination , Female , Male , Myelin Proteins/genetics , Neural Conduction/drug effects , Neural Conduction/physiology , Neuromuscular Junction/physiology , Rats , Rats, Sprague-Dawley , Rats, Transgenic
BACKGROUND: Kleefstra syndrome is characterized by intellectual disability, muscular hypotonia in childhood and typical facial features. It results from either a microdeletion of or a deleterious sequence variant in the gene euchromatic histone-lysine N-methyltransferase 1 (EHMT1) on chromosome 9q34. RESULTS: We report on a 3-year-old girl with characteristic symptoms of Kleefstra syndrome. Array comparative genomic hybridization analysis revealed a 145 kilobases duplication spanning exons 2 to 10 of EHMT1. Sequence analysis characterized it as an intragenic tandem duplication leading to a frame shift with a premature stop codon in EHMT1. CONCLUSIONS: This is the first description of an intragenic duplication of EHMT1 resulting in Kleefstra syndrome.
