Charcot-Marie-Tooth disease type 4F (CMT4F) is a rare hereditary sensorimotor neuropathy, linked to the periaxin (PRX) gene. Early onset, pronounced sensory ataxia and comparatively moderate muscular weakness are characteristic hallmarks. We here report a child with corresponding features carrying a pathogenic PRX variant in trans with a very rare variant of uncertain significance in the 5’ untranslated region predicted to interfere with splicing. High-resolution ultrasound depicted an age-related pattern of nerve enlargement and muscle hyperechogenicity resembling other CMT4 subtypes with similar clinical and histopathological characteristics. Based on this differential analysis, we propose these genetic findings to be possibly causative. The online version contains supplementary material available at 10.1007/s10048-026-00891-6.

Periaxins (encoded by PRX) play an important role in the stabilization of peripheral nerve myelin. Mutations in PRX can lead to Charcot-Marie-Tooth disease type 4F (CMT4F). In this study, we screened for PRX mutations using next-generation sequencing and whole-exome sequencing in a large Chinese CMT cohort consisting of 465 unrelated index patients and 650 healthy controls. Sanger sequencing was used for the validation of all identified variants. We also reviewed all previously reported PRX-related CMT cases and summarized the clinical manifestations and genetic features of PRX-related CMTs. The hit rate for biallelic PRX variants in our cohort of Chinese CMT patients was 0.43% (2/465). One patient carried a previously unreported splice-site mutation (c.25_27 + 9del) compound heterozygous with a known nonsense variant. Compiling data on CMT4F cases and PRX variants from the medical literature confirmed that early-onset (95.2%), distal amyotrophy or weakness (94.0%), feet deformity (75.0%), sensory impairment or sensory ataxia (65.5%), delayed motor milestones (60.7%), and spinal deformity (59.5%) are typical features for CMT4F. Less frequent features were auditory impairments, respiratory symptoms, late onset, dysarthria or hoarseness, ophthalmic problems, and central nervous system involvement. The two cases with biallelic missense mutations have later onset age than those with nonsense or frameshift mutations. We did not note clear correlations between the type and site of mutations and clinical severity or distinct constellations of symptoms. Consistent with observations in other countries and ethnic groups, PRX-related CMT is rare in China. The clinical spectrum is wider than previously anticipated.

To explore the genetic etiology of a child suspected for peroneal muscular atrophy. The child and his parents were analyzed by using next generation sequencing. The child was found to harbor compound heterozygous variants of c.52G>T (p.Glu18X) and c.1390C>T (p.Arg464X) of the PRX gene, which were inherited from his father and mother, respectively. Among these, the c.52G>T variant was previously unreported. Based on the standards and guidelines of the American College of Medical Genetics and Genomics, both variants were predicted to be pathogenic (PVS1+PM2+PM3, PVS1+PM3-Strong+PM2+BS2). The compound heterozygous variants of the PRX gene probably underlay the Charcot-Marie-Tooth disease type 4F in this child. Above finding has enriched the mutational spectrum of the PRX gene.

Charcot-Marie-Tooth disease type 4F (CMT4F) is an autosomal recessive disorder with symptoms presenting in early adulthood. This clinical case series demonstrates atypical findings in cervical and ocular vestibular evoked myogenic potentials (VEMP) in siblings with CMT4F. The aim of this study was to highlight the audiovestibular test findings in CMT4F. Case series study sample: 4 siblings, 3 of whom diagnosed with CMT4F. Audiological test battery and electrophysiological tests comprising auditory brainstem response (ABR) and VEMP (both cervical and ocular) were performed in our patient population. Older siblings, in whom the hearing loss was present, manifested prolonged peak V latencies in ABR. Three out of four siblings with CMT4F showed prolongation of latencies on cervical and ocular VEMP. In many neurodegenerative conditions, prolongation of ABR peak latencies has often been reported in the literature. There have also been a few reports of prolonged VEMP peak latencies. This article reports prolongation of only VEMP peak latencies (in both cervical and ocular recordings). The youngest sibling had prolongation of VEMP latencies, with ABR peak latencies being normal. The assumption we put forth that CMT4F may affect the vestibular pathway first requires to be tested on a larger sample and by longitudinally studying the individuals with disease condition.

Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuropathy. Mutations in the periaxin gene (PRX) can cause CMT type 4F, an autosomal recessive neuropathy, which is clinically characterized by slowly progressive distal muscle atrophy and weakness, with pes cavus deformity of the foot, and the absence of deep tendon reflexes. To date, dozens of reports of PRX mutations have been published worldwide, but none have been reported in Chinese patients. Here, we describe a 14-year-old Chinese boy with neuropathy characterized by slowly progressive limb weakness and atrophy, as well as sensory ataxia, whose cerebrospinal protein levels were 1627 mg/L. Genetic analysis identified a novel homozygous mutation, c.1174C>T (p.R392X), in exon 6 of PRX, which is the first case of its kind recorded in China.