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Mutations in the small heat-shock protein 27 kDa protein 1 (HSPB1) and 22 kDa protein 8 (HSPB8) genes were associated with distal hereditary motor neuropathy (dHMN) and with the axonal form of Charcot-Marie-Tooth disease type 2 (CMT2). Here we report the clinical and molecular evaluation of an Italian dHMN and CMT2 cohort to establish HSPB1 and HSPB8 mutation occurrence and associated clinical features. One hundred and sixty-seven patients with dHMN or CMT2 were studied. HSPB1 and HSPB8 exons 1 and 3 molecular analysis was carried out through DHPLC and direct sequencing of each variant chromatogram. HSPB8 exon 2 was analyzed by direct sequencing. Four mutations in five unrelated dHMN patients and four mutations in four unrelated CMT2 cases were found in HSPB1. The p.Arg136Leu mutation was found in two patients with different phenotypes. Electroneurographical follow-up study in a dHMN patient revealed that sensory impairment occurred with disease progression. The HSPB1 mutation frequency was 8% in dHMN and 4% in CMT2 patients. The significant HSPB1 mutation frequency in both phenotypes indicates its relevance in the pathogenesis of these neuropathies. Recent literature data suggest a continuum between dHMN and CMT2. We confirm this finding in our cohort, proposing a definite relationship between these disorders.

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The tumor necrosis factor-α (TNF-α) gene has been proposed as a major candidate gene in psoriatic arthritis (PsA). TNF-α is a therapeutic target for patients responding poorly to conventional treatments. We investigated the role of single-nucleotide polymorphisms (SNPs) at positions -238, -308, and +489 of the TNF-α gene in the genetic susceptibility to PsA, in the severity of the disease, and, finally, in the response to TNF-α inhibitors (adalimumab, etanercept, or infliximab). Fifty-seven Caucasian PsA patients and 155 healthy matched controls were studied. The SNP +489 variant allele A was significantly associated with PsA susceptibility (P=0.0136) and severity of clinical (Psoriasis Area and Severity Index score, American College of Rheumatology criteria, Disease Activity Score 28, and Disability Index Health Assessment Questionnaire) and laboratory (C-reactive protein and erythrocyte sedimentation rate) parameters (P-values ranging from 0.016 to 2.908 × 10(-12)). The difference in severity was accounted for by the differences between the AA and GA genotypes with respect to the GG genotype. The SNP +489A allele shows a trend of association with the response to PsA treatment with etanercept. These findings suggest a role of the SNP +489A allele in the susceptibility and severity of PsA.

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