Journal of the Peripheral Nervous System最新文献

Background and aims: CMT1H is a rare, autosomal dominant, demyelinating subtype of CMT caused by variants in FBLN5. Symptomatic cranial nerve involvement has never been reported in patients with CMT1H.

Case report: We report a 45-year-old woman with a history of long-standing diplopia. On examination, she had bilateral limitation of eye abduction, with double vision in all directions of gaze, particularly horizontally. She was unable to heel-walk, had mild lower limb distal weakness, decreased tendon reflexes with absent Achilles reflexes, reduced distal vibration sense, pes cavus, and hammertoes. A dominant family history was noted. Brain MRI revealed bilateral contrast enhancement and thickening of cranial nerves III through XII. Genetic testing with whole exome sequencing revealed a known, recurring, heterozygous, likely pathogenic missense variant in FBLN5 [c.1117C>T; p. (Arg373Cys)], consistent with a diagnosis of CMT1H.

Interpretation: This is the first reported case of FBLN5-related CMT1H with symptomatic cranial nerve involvement, expanding the known phenotypic spectrum of the disease.

Background and aims: Monoclonal gammopathy of undetermined significance (MGUS) occurs in some patients with chronic inflammatory demyelinating polyneuropathy (CIDP), but its impact on clinical phenotype and treatment response remains unclear. We assessed the prevalence of paraproteinemia in CIDP and compared disease features between CIDP patients with and without MGUS.

Methods: We used data from the International CIDP Outcome Study (ICOS), a prospective cohort study. We compared the prevalence and causes of paraproteinemia in CIDP to matched disease controls (axonal polyneuropathy or motor neuron disease) and compared disease features and treatment responses between CIDP patients with and without MGUS. Treatment response, defined as a ≥ 1-point improvement on the modified Rankin scale, was retrospectively assessed.

Results: IgG paraproteinemia was more common in CIDP than in controls (9%, 17/193 vs. 3%, 6/192; p = 0.03). IgM and IgA paraprotein prevalences did not differ. One CIDP patient had Waldenström macroglobulinemia; others had MGUS. Patients with IgG MGUS less often had an acute clinical presentation (6% vs. 33%; p = 0.02), more often had sensory deficits (94% vs. 67%; p = 0.02), and prolonged distal CMAP duration (64% vs. 31%; p = 0.02), compared to patients without MGUS. First-line treatment response rates were comparable (80% [IgG MGUS] vs. 67% [no MGUS]; p = 0.39).

Interpretation: IgG MGUS is more prevalent in CIDP than in controls. Presence of IgG MGUS is weakly associated with some CIDP disease features, but not treatment response. These findings indicate that, although IgG MGUS is associated with CIDP, the presence of IgG MGUS does not constitute a distinct subgroup with unique clinical features or treatment implications.

Background: Diabetic painful neuropathy is a cause of significant disability and sleep disturbance but may be undiagnosed in up to 80% of patients with diabetes. Various neuropathic pain (NP) questionnaires have good diagnostic utility but are impractical in resource-constrained and busy clinical settings. A simple sCreening Tool (ACT) was developed as a concise, patient-led tool to rapidly detect NP. This study evaluates the screening validity and psychometric properties of ACT compared with the DN4 questionnaire (reference standard).

Methods: We conducted an observational study employing clinic-based recruitment of patients with diabetes at a tertiary outpatient clinic in Guayaquil, Ecuador. All enrolled participants completed the ACT, DN4, and MNSI questionnaires during the study visit. MNSI was administered as part of the study to confirm the diagnosis of DPN using predefined cut-offs (MNSI-q ≥ 4 and MNSI-e ≥ 2.5). Time to completion, inter-item consistency, sensitivity, specificity, Youden's index, and the area under the receiver operating characteristic (ROC) curve were calculated for ACT using DN4 ≥ 4 as the criterion for NP.

Results: Of the 300 participants (median age 63 years, diabetes duration 10 years), 65 (21.7%) had NP per DN4. Total ACTq+e (questionnaire+examination) yielded a cut-off score of ≥ 6 items as optimal, with area under the ROC curve 0.836, sensitivity 80.0% and specificity 75.7% for painful DPN. ACT demonstrated moderate internal consistency (Cronbach's alpha = 0.65) and was well received by patients and clinicians on face validity. The completion time for ACT was comparable to that of DN4.

Conclusion: The ACT tool is a rapid screening tool for identifying neuropathic pain in the busy clinic, with acceptable sensitivity and specificity compared to DN4. The brevity and ease of patient self-administration of ACT make it promising for integration into busy outpatient workflows to improve the diagnosis of painful DPN.

Background: Thermoceptive dysfunction is a frequent but understudied feature of peripheral neuropathies and aging. Patients often report abnormal heat perception, yet the underlying sensory mechanisms remain unclear. This study evaluated thermoceptive behavior and corresponding structural changes in mouse models of inherited dysmyelinating neuropathy and natural aging to identify shared and divergent mechanisms.

Methods: Thermal preference was assessed using a user-independent gradient apparatus spanning physiological to noxious temperatures, with automated quantification of time in zone, distance traveled, and velocity. Nocifensive responses were evaluated by hot plate latency. Intraepidermal nerve fiber density (IENFD) was measured in paw pads, and TRPV1-positive dorsal root ganglion (DRG) neurons were analyzed by immunofluorescence and confocal imaging.

Results: Thermal gradient testing revealed preserved temperature preference in CMT1A and HNPP mice but significantly altered behavior in aged animals, which spent less time in warmer zones. Hot plate testing showed prolonged times to nocifensive behavior in aged and CMT1A mice, whereas HNPP mice exhibited variable responses. IENFD was markedly reduced in aged mice but preserved in CMT1A and HNPP. DRG analysis revealed smaller soma diameters and reduced proportions of TRPV1-positive Aδ neurons in aged mice, while CMT1A animals maintained normal morphology.

Interpretation: Aging produces thermoceptive deficits through axonal degeneration and selective Aδ-fiber vulnerability, whereas CMT1A mice display conduction-related impairment due to dysmyelination. Both models reproduce key human sensory phenotypes and provide translational platforms for studying small-fiber dysfunction and therapeutic interventions in peripheral neuropathies.

Background and aims: Severe peripheral nerve injury (PNI) remains a major clinical challenge, and functional recovery after conventional neurorrhaphy is often unsatisfactory due to fascicular mismatch, suture tension, and limited Schwann cell viability. To address these limitations, we previously developed a small-gap chitosan-based conduit that provides a controlled microenvironment for regenerative interventions. This study aimed to investigate whether SOX5 overexpression enhances Schwann cell regenerative potential and, when combined with this conduit, synergistically promotes peripheral nerve regeneration.

Methods: Schwann cells were transduced with SOX5 lentivirus and assessed for proliferation, migration, and neurotrophic factor secretion in vitro. In a rat sciatic nerve transection model (2-mm gap), animals received a chitosan conduit with intraluminal injection of SOX5 lentivirus. Histological, electrophysiological, and behavioral assessments were conducted at 12 weeks post-surgery.

Results: SOX5 overexpression significantly enhanced Schwann cell proliferation, migration, and secretion of BDNF, NGF, CNTF, and VEGF, while maintaining the dedifferentiated repair phenotype. In vivo, the combination of SOX5 lentivirus and chitosan conduit improved axonal regeneration, reduced muscle atrophy, and increased conduction velocity and locomotor recovery relative to the empty conduit group.

Interpretation: Lentivirus-mediated SOX5 overexpression drives Schwann cells toward a repair phenotype and, when integrated with a small-gap chitosan-based conduit, effectively promotes structural and functional nerve regeneration.

Background: The American Diabetes Association recommends three rather than one physical examination test for diabetic peripheral neuropathy (DPN) screening, although supporting evidence for the more complex screening strategy remains limited.

Aims: We aimed to determine if a three-test strategy was superior to a single-test in sensitively identifying early stages of neuropathy risk.

Methods: Using longitudinal data from 170 adults without DPN, we compared the overall accuracy, represented by the area under the receiver operating characteristic curve (AUC), for the three-test versus one-test strategies. These were conducted for monofilament, pinprick, and vibration sensation compared to the Sum of Abnormal Tests (primary analysis) or a model-based probability from quantitative scores for each test in the prediction of nerve conduction study-defined incident DPN.

Results: Incident DPN occurred in 53 (31%) participants over a mean 4-year follow-up. Predictive AUC for both the Sum of Abnormal Tests or the model-based probability did not differ from the AUC for monofilament (0.66 vs. 0.71, p = 0.05 and 0.71 vs. 0.71, p = 0.79, respectively).

Interpretation: A complex three-test strategy did not outperform the best-performing single-test strategy, implying that practice guidelines that recommend simplified approaches to neuropathy screening are valid.

Background: Biallelic pathogenic variants in MCM3AP, encoding the germinal center-associated nuclear protein (GANP), have been linked to autosomal recessive peripheral neuropathies variably accompanied by cognitive impairment and multisystem involvement. To date, anterior horn cell involvement has not been documented in association with MCM3AP-related disorders.

Objective: To describe a patient with biallelic MCM3AP variants presenting with a motor neuronopathy phenotype and to provide the first whole-body muscle MRI characterization associated with this gene.

Methods and results: A 53-year-old woman born to non-consanguineous parents presented with early-onset motor neuronopathy and lifelong learning difficulties. Neurological examination revealed generalized areflexia and widespread fasciculations without sensory abnormalities. Electroneuromyography demonstrated diffuse mixed acute-on-chronic denervation process. Whole-body muscle MRI showed a selective non-length-dependent pattern of fatty infiltration. Whole-exome sequencing identified two likely pathogenic heterozygous variants in the MCM3AP gene.

Standard protocol approvals, registrations, and patient consents: According to the policies of our institution, single-patient case reports do not require review or approval by the institutional ethics committee. Written informed consent for participation and for publication of clinical information, photographs, electrophysiological data, and muscle MRI images was obtained from the patient. No clinical trial registration was applicable.

Conclusion: This case extends the phenotypic spectrum of MCM3AP-related disorders to include a slowly progressive, non-syndromic motor neuronopathy with electrophysiological evidence of active denervation and distinctive MRI findings. These observations highlight the hidden boundaries between hereditary motor neuropathies and anterior horn cell diseases, emphasizing the need for integrated clinical, neurophysiological, and genetic evaluation.