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Small-Fiber Neuropathy (SFN) is a disorder of the peripheral nervous system, characterised by neuropathic pain; approximately 11% of cases are linked to variants in Voltage-Gated Sodium Channels (VGSCs). This study aims to broaden the genetic knowledge on painful SFN by applying Whole-Exome Sequencing (WES) in Early-Onset (EO) cases. A total of 88 patients from Italy (n = 52) and the Netherlands (n = 36), with a disease onset at age ≤ 45 years old and a Pain Numerical Rating Score ≥ 4, were recruited. After variant filtering and classification, WES analysis identified 142 potentially causative variants in 93 genes; 8 are Pathogenic, 15 are Likely Pathogenic, and 119 are Variants of Uncertain Significance. Notably, an enrichment of variants in transient receptor potential genes was observed, suggesting their role in pain modulation alongside VGSCs. A pathway analysis performed by comparing EO cases with 40 Italian healthy controls found enriched mutated genes in the "Nicotinic acetylcholine receptor signaling pathway". Targeting this pathway with non-opioid drugs could offer novel therapeutic avenues for painful SFN. Additionally, with this study we demonstrated that employing a gene panel of reported mutated genes could serve as an initial screening tool for SFN in genetic studies, enhancing clinical diagnostics. [ABSTRACT FROM AUTHOR]

Background and purpose: Mutations in DNAJB2 are associated with autosomal recessive hereditary motor neuropathies/ Charcot‐Marie‐Tooth disease type 2 (CMT2). We describe an Italian family with CMT2 due to a homozygous DNAJB2 mutation and provide insight into the pathomechanisms. Methods: Patients with DNAJB2 mutations were characterized clinically, electrophysiologically and by means of skin biopsy. mRNA and protein levels were studied in lymphoblastoid cells (LCLs) from patients and controls. Results: Three affected siblings were found to carry a homozygous DNAJB2 null mutation segregating with the disease. The disease manifested in the second to third decade of life. Clinical examination showed severe weakness of the thigh muscles and complete loss of movement in the foot and leg muscles. Sensation was reduced in the lower limbs. All patients had severe hearing loss and the proband also had Parkinson's disease (PD). Nerve conduction studies showed an axonal motor and sensory length‐dependent polyneuropathy. DNAJB2 expression studies revealed reduced mRNA levels and the absence of the protein in the homozygous subject in both LCLs and skin biopsy. Interestingly, we detected phospho‐alpha‐synuclein deposits in the proband, as already seen in PD patients, and demonstrated TDP‐43 accumulation in patients' skin. Conclusions: Our results broaden the clinical spectrum of DNAJB2‐related neuropathies and provide evidence that DNAJB2 mutations should be taken into account as another causative gene of CMT2 with hearing loss and parkinsonism. The mutation likely acts through a loss‐of‐function mechanism, leading to toxic protein aggregation such as TDP‐43. The associated parkinsonism resembles the classic PD form with the addition of abnormal accumulation of phospho‐alpha‐synuclein. [ABSTRACT FROM AUTHOR]

The article discusses the collaboration in headache research which is evident in international clinical trials and organizations like the International Headache Society which provide opportunities through various fellowship and scholarship programs for individuals to build connections. It states that clinical collaboration could be improved through discussions with patients and colleagues.