2026-08-17 | Neuronal Prps is required for synaptic development and motor function in Drosophila melanogaster.
Phosphoribosyl pyrophosphate synthetase (PRPS) produces phosphoribosyl pyrophosphate, which is a key precursor for nucleotide biosynthesis. Mutations in the human PRPS1 gene cause Charcot-Marie-Tooth disease and other neuropathies. However, how PRPS1 dysfunction impairs neuronal and synaptic function remains unclear. In this study, we used Drosophila melanogaster to determine the effects of reduced Prps expression on neurons in vivo. Neuronal knockdown of Prps caused severe locomotor impairment in third instar larvae and in adults, which indicated a critical requirement for Prps in motor output. At the neuromuscular junction, Prpsdepletion led to a reduced number of synaptic boutons accompanied by enlargement of boutons, disrupted presynaptic active zone organization indicated by decreased Bruchpilot puncta, and loss of Futsch-positive microtubule loops. These findings suggested destabilization of cytoskeletal architecture. These phenotypes were consistently observed using independent RNAi lines. Importantly, neuronal expression of Drosophila Prps or human PRPS1 significantly rescued locomotor activity, synaptic growth, active zone organization, and microtubule structure, which are caused by the expression of the Prps short hairpin RNA. The rescue by Drosophila Prps and human PRPS1 highlights evolutionary conservation of PRPS1 function and suggests Drosophila as a model for analyzing PRPS1-associated neuropathies.
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2026-07-29 | A Phase 1 clinical trial to evaluate the safety and tolerability of CLZ-2002 for the treatment of patients with Charcot-Marie-Tooth disease type 1.
Charcot-Marie-Tooth disease type 1 (CMT1) is a rare, genetically diverse condition and represents the most prevalent form of inherited peripheral neuropathy, characterized by Schwann cell dysfunction resulting in progressive demyelination and muscle wasting. CLZ-2002, an allogeneic Schwann cell-like product derived from human tonsillar mesenchymal stem cells, has been developed as a regenerative therapy and investigated in CMT1 patients. A Phase 1, open-label, dose-escalation clinical trial was performed in nine patients with genetically diagnosed CMT1 (five with CMT1A, four with CMT1B). Participants were allocated to three dosing cohorts: 6 million (G1), 12 million (G2), or 24 million cells (G3). CLZ-2002 was delivered as a single intramuscular injection into the lower limbs. The primary objective was to assess safety and tolerability. Exploratory endpoints included Charcot-Marie-Tooth Neuropathy Score version 2 (CMTNSv2), Overall Neuropathy Limitation Score-leg (ONLS-leg), Functional Disability Score (FDS), electrophysiology, MRI, and circulating biomarkers. No drug-related adverse reactions, serious adverse events, or dose-limiting toxicities occurred. Four participants experienced a total of five grade 1-2 treatment-emergent adverse events. By Week 24, improvements relative to baseline were noted in CMTNSv2 and ONLS-leg. Biomarker levels of NCAM1 and GDF15 declined at Week 4 but returned toward baseline by Week 24, reflecting the observed clinical trends. A single intramuscular dose of CLZ-2002 of up to 24 million cells was safe and well-tolerated in CMT1 patients. Exploratory efficacy assessments suggested possible clinical benefit, warranting continued investigation of CLZ-2002 in larger, controlled study populations.
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2026-07-15 | PXT3003 in CMT1A Phase III Multicenter Clinical Trial Dataset
This dataset contains the raw data and analysis materials related to the phase III multicenter clinical trial of PXT3003 in CMT1A patients. It includes de - identified individual patient data, statistical analysis files, etc., which can support the conclusions of the relevant paper
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2026-07-12 | High-Resolution Ultrasound Evaluation of Nerves and Muscles at Multiple Sites in Charcot-Marie-Tooth Disease.
To characterize nerve cross-sectional area (CSA) and muscle thickness at multiple sites in Charcot-Marie-Tooth disease (CMT) using high-resolution ultrasound (HRUS), with emphasis on CMT1A and comparisons with healthy controls. Fifty-nine genetically confirmed CMT patients (including CMT1A, CMT1B, CMTX1, and CMT2A) and 42 healthy controls underwent HRUS evaluation of 7 nerves (median, ulnar, radial, sciatic, tibial, common peroneal, and vagus) at 20 predefined anatomical sites, along with measurements of peroneus longus and tibialis anterior thickness. In CMT1A, we assessed correlations between CSA and clinical severity (Charcot-Marie-Tooth Examination Score [CMTES]), ankle strength, and 15-month longitudinal changes in CSA. Median thicknesses of peroneus longus and tibialis anterior were reduced across CMT subtypes compared with controls (0.99-1.52 versus 1.70 cm and 0.94-1.95 versus 2.64 cm, respectively; all p < .05). CMT1A showed significantly larger CSA at all 20 sites compared with controls (all p < .001), whereas no significant CSA differences were observed in CMT1B, CMTX1, or CMT2A. In CMT1A, no site-specific CSA correlated significantly with CMTES, muscle thickness, or ankle strength. Over 15 months, small but significant CSA increases were observed at selected nerve sites in CMT1A, with the largest increase (0.07 cm2) at the upper-arm segment of the median nerve (p = .04). Short-axis HRUS at superficial nerve segments revealed a beaded "fusion-separation-refusion" fascicular appearance in 16 of 42 CMT1A patients (38.1%). HRUS demonstrates a diffuse nerve enlargement pattern in CMT1A and muscle atrophy across CMT subtypes. Short-term CSA changes were minimal, suggesting HRUS CSA is more informative for subtype characterization than for short-interval progression monitoring.
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2026-06-20 | Autonomic Nervous System Phenotyping Across Chronic Demyelinating Peripheral Neuropathies: A Comparative Study.
This study aimed to systematically phenotype autonomic nervous system (ANS) involvement in patients with chronic inflammatory demyelinating polyneuropathy (CIDP), monoclonal gammopathy of undetermined significance-associated neuropathy (MGUS-PNP), Charcot-Marie-Tooth disease Type 1A (CMT1A), and hereditary neuropathy with liability to pressure palsies (HNPP). Autonomic symptoms were assessed using the SCales for Outcomes in Parkinson's Disease-Autonomic Dysfunction (SCOPA-AUT). Muscle strength and functional disability were evaluated using the Medical Research Council (MRC) scale, the Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale, and the Overall Neuropathy Limitation Scale (ONLS). A total of 343 participants were included: 98 with CIDP (mean age: 59.2 ± 13.2 years), 51 with MGUS-PNP (66.0 ± 11.3 years), 51 with CMT1A (51.2 ± 13.1 years), 18 with HNPP (40.6 ± 15.1 years), and 125 healthy controls (58.2 ± 13.3 years). Compared with healthy controls, patients with CIDP, MGUS-PNP, and CMT1A showed significantly higher total SCOPA-AUT scores (p < 0.01). Distinct, disease-specific ANS symptom patterns were observed across neuropathy subtypes. Overall disability was independently associated with overall autonomic symptom burden in MGUS-PNP (β = 0.42, p < 0.05) and CMT1A (β = 0.68, p < 0.05). In CIDP, patients with active disease showed higher autonomic symptom burden than those with inactive disease (12.7 ± 11.7 vs. 8.6 ± 7.9, p = 0.042). Patients with CIDP, MGUS-PNP, and CMT1A exhibit a substantial autonomic symptom burden with distinct disease-specific ANS patterns. These findings highlight the relevance of autonomic dysfunction in immune-mediated and hereditary neuropathies and warrant further studies to clarify their clinical and prognostic significance.
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