X-linked Charcot-Marie-Tooth disease type 1 (CMTX1) is a rare inherited neuropathy caused by mutations in the GJB1 gene, leading to progressive distal muscle weakness and atrophy. In this case study, a 37-year-old man presented with recurrent episodes of numbness involving the lips, right hand, and foot, followed by right-sided limb weakness and dysarthria four times over the past 20 years. Notably, the last three episodes were consistently triggered within 3 days after descent to sea level following exposure to high-altitude environments (8,500-10,000 feet, with transit above 13,000 feet). Based on the neurologic examination, brain magnetic resonance imaging (MRI), and genetic testing, the patient was diagnosed with X-linked Charcot-Marie-Tooth disease. This case underscores the importance of considering high-altitude exposure as a potential trigger and highlights the value of GJB1 testing in young patients presenting with acute stroke-like episodes and signs of peripheral neuropathy.

Neurofilament light chain (NfL) is a sensitive biomarker of axonal damage, but its clinical relevance in chronic autoimmune neuropathies remains incompletely defined. This study evaluated plasma NfL levels in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN), compared with hereditary neuropathy (Charcot–Marie–Tooth disease type 1 A, CMT1A) and healthy controls, focusing on disease activity rather than diagnostic discrimination. Plasma NfL concentrations were measured using single molecule array (Simoa) technology in 41 patients (CIDP n = 16, MMN n = 7, CMT1A n = 18) and 25 age- and sex-matched controls. Disease severity was assessed using the Inflammatory Rasch-built Overall Disability Scale for autoimmune neuropathies and the Charcot–Marie–Tooth Neuropathy Score version 2 for CMT. Plasma NfL levels were significantly higher in patients with autoimmune neuropathies and CMT compared with controls. No significant differences were observed between inflammatory and hereditary neuropathies, and NfL levels did not correlate with disability scores. However, patients with autoimmune neuropathies and an unstable disease course, defined by more than two relapses, exhibited significantly higher plasma NfL levels. Across all groups, NfL concentrations showed a strong correlation with age. These findings suggest that while plasma NfL lacks diagnostic specificity among chronic neuropathies, it may be associated with disease instability in autoimmune neuropathies.

The Peripheral Myelin Protein 22 (PMP22) gene plays a central role in peripheral nerve myelination, and dosage alterations (deletion, duplication, or point mutation) are established causes of hereditary neuropathies such as Charcot-Marie-Tooth disease type 1 A (CMT1A), CMT1E, and Hereditary Neuropathy with Liability to Pressure Palsies (HNPP). However, its potential contribution to atypical developmental motor phenotypes such as persistent toe-walking (PTW) has not been systematically explored. To characterize the phenotypic spectrum of pediatric PMP22 variant carriers presenting with PTW and to compare their clinical features with those of established PMP22-related neuropathies. This retrospective study analyzed 22 children with PMP22 variants (pathogenic, likely pathogenic, or of uncertain significance) identified through a targeted 49-gene next-generation sequencing panel. Detailed phenotypic data were collected across five clinical domains-genetic, developmental, gait and musculoskeletal, neurological, and associated comorbidities-and compared to standardized phenotype frequencies for CMT1A, CMT1E, and HNPP derived from Orphanet and the Human Phenotype Ontology (HPO) databases. Persistent tip-toe gait was universal, accompanied by pes cavus, lumbar hyperlordosis, tremor, and hyporeflexia. Speech and language difficulties were reported in 45 % of cases, and a family history of toe-walking in 40 %. Additional muscle symptoms and neurological findings were reported, developmental disorders were also reported. Children carrying PMP22 variants with PTW exhibit a distinct phenotype differing from classic demyelinating neuropathies. The findings suggest that a subset of idiopathic toe-walking cases may represent a developmental manifestation within the PMP22-related disease spectrum, highlighting the value of genetic testing in reevaluating gait disorders of uncertain etiology.

Charcot-Marie-Tooth Type 1 A (CMT1A) is a hereditary neuropathy caused by a duplication of the peripheral myelin protein 22 (PMP22) gene. Emerging evidence suggests that lipid metabolism plays a central role in CMT1A pathology. This study investigated metabolic profiles in sciatic nerve tissue and plasma of PMP22 transgenic (TG) and wild-type (WT) rats at 2, 4, and 6 months of age. Utilizing targeted metabolomics, more than 600 metabolites covering central metabolic pathways and major lipid classes were analyzed, revealing distinct age-dependent changes in metabolic pathways. Alterations that emerged early and became increasingly pronounced with age were observed in sphingolipids and glycerophospholipids, while changes in other metabolic pathways, such as amino acids, storage lipids, bile acids, and nucleotide metabolism, were age-specific. Notably, in contrast to these age-dependent adaptive changes, three lipid signatures were identified that remained stable from the earliest age examined. These include: (1) an elevated ratio of hydroxylated to non-hydroxylated sphingolipids, (2) a reduced ratio of monounsaturated-containing to saturated fatty acid containing phosphatidylcholines, and (3) a decreased ratio of hexosylceramides to ceramides. Imaging mass spectrometry analyses confirmed disruptions in sphingolipid metabolism. These findings suggest a key regulatory role of PMP22 in lipid metabolism, as demonstrated by the early stabilization of specific lipid signatures compared to other metabolic changes that occurred in an age-dependent and adaptive manner. These observations provide valuable insights into the pathogenic mechanisms underlying CMT1A.

Autoimmune nodopathy (AN), as patients positive for IgG4 autoantibodies against NF155, NF186, CNTN1, or CASPR1, is a distinct form of chronic inflammatory demyelinating polyneuropathy (CIDP) that shares similar clinical and electrophysiological characteristics with Charcot-Marie-Tooth disease type 1 (CMT1). This study aimed to determine the clinical presentation and electrophysiological features of AN and compare them with antibody-negative CIDP and CMT1. We collected clinical data from 29 patients who met the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) electrophysiological diagnostic criteria for definite CIDP. Autoimmune antibodies (anti-NF155, NF186, CNTN1, and CASPR1) were tested using cell-based assays. Additionally, 17 CMT1 patients, diagnosed with hereditary motor sensory neuropathy type 1, were included. We compared the clinical and electrophysiological characteristics of AN, antibody-negative CIDP, and CMT1 patients. Among the 29 CIDP patients, 10 tested positive for autoantibodies (8 for NF155, 1 for CASPR1, and 1 for CNTN1). AN patients had a younger age of onset compared to antibody-negative CIDP and were similar in age to CMT1 patients. Hand tremor was more common in AN patients (60%) compared to antibody-negative CIDP (21%) and CMT1 (5.8%). Conversely, 76.4% of CMT1 patients exhibited cavus foot, significantly higher than the 20% in AN patients. Cerebrospinal fluid (CSF) analysis revealed higher cell count and protein levels in AN patients compared to antibody-negative CIDP and CMT1. AN patients showed poor response to corticosteroids and intravenous immunoglobulin (IVIG), but rituximab was more effective. Electrophysiological findings revealed significantly prolonged distal motor latencies (DML) in the tibial posterior and peroneal nerves, as well as prolonged F-wave latencies in the ulnar and posterior tibial nerves in AN patients than antibody-negative CIDP. In contrast, compared with AN, CMT1 patients showed prolonged DML and significantly reduced motor conduction velocities (MCV) in the median and ulnar nerves. AN patients exhibited sparing of the sural nerve, whereas this phenomenon was not observed in CMT1 patients. In young male patients with hand tremors, demyelinating electrophysiological features (especially prolonged DML and F-wave latencies), elevated CSF protein levels, and poor response to corticosteroids, autoimmune nodopathy, AN antibody testing is recommended. Compared to AN, CMT1 patients tend to have a slower disease course, less frequent tremors, and normal CSF protein levels. A median nerve DML greater than 10 ms and MCV less than 25 m/s supports a diagnosis of CMT1.