Mortality and risk of progression to adult T cell leukemia/lymphoma in HTLV-1-associated myelopathy/tropical spastic paraparesis.
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ABSTRACT:
SUBMITTER: Nagasaka M
PROVIDER: S-EPMC7260950 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectivesHuman T cell leukemia virus-1 (HTLV-1) infection may lead to one or both diseases including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) or adult T cell leukemia lymphoma (ATLL). The complete interactions of the virus with host cells in both diseases is yet to be determined. This study aims to construct an interaction network for distinct signaling pathways in these diseases based on finding differentially expressed genes (DEGs) between HAM/TSP and ATLL.ResultsWe identified 57 hub genes with higher criteria scores in the primary protein-protein interaction network (PPIN). The ontology-based enrichment analysis revealed following important terms: positive regulation of transcription from RNA polymerase II promoter, positive regulation of transcription from RNA polymerase II promoter involved in meiotic cell cycle and positive regulation of transcription from RNA polymerase II promoter by histone modification. The upregulated genes TNF, PIK3R1, HGF, NFKBIA, CTNNB1, ESR1, SMAD2, PPARG and downregulated genes VEGFA, TLR2, STAT3, TLR4, TP53, CHUK, SERPINE1, CREB1 and BRCA1 were commonly observed in all the three enriched terms in HAM/TSP vs. ATLL. The constructed interaction network was then visualized inside a mirrored map of signaling pathways for ATLL and HAM/TSP, so that the functions of hub genes were specified in both diseases.
| S-EPMC7989087 | biostudies-literature
Project description:BackgroundHuman T lymphotropic virus Type 1 (HTLV-1) causes a chronic inflammatory disease of the central nervous system known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM) which resembles chronic spinal forms of multiple sclerosis (MS). The pathogenesis of HAM remains uncertain. To aid in the differential diagnosis of HAM and to identify pathogenetic mechanisms, we analysed the plasma proteome in asymptomatic HTLV-1 carriers (ACs), patients with HAM, uninfected controls, and patients with MS. We used surface-enhanced laser desorption-ionization (SELDI) mass spectrometry to analyse the plasma proteome in 68 HTLV-1-infected individuals (in two non-overlapping sets, each comprising 17 patients with HAM and 17 ACs), 16 uninfected controls, and 11 patients with secondary progressive MS. Candidate biomarkers were identified by tandem Q-TOF mass spectrometry.ResultsThe concentrations of three plasma proteins--high [β2-microglobulin], high [Calgranulin B], and low [apolipoprotein A2]--were specifically associated with HAM, independently of proviral load. The plasma [β2-microglobulin] was positively correlated with disease severity.ConclusionsThe results indicate that monocytes are activated by contact with activated endothelium in HAM. Using β2-microglobulin and Calgranulin B alone we derive a diagnostic algorithm that correctly classified the disease status (presence or absence of HAM) in 81% of HTLV-1-infected subjects in the cohort.
| S-EPMC3210102 | biostudies-literature
Project description:INTRODUCTION:In patients with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) gait disturbance is a predominant feature that leads to falls and fractures, which can further aggravate disability. We sought to evaluate the impact of fractures and orthopedic surgeries in patients with HAM/TSP. METHODS:We retrieved the medical records of HAM/TSP patients enrolled in our study center's HTLV-1 clinical cohort between 1989-2018. The selection criteria included: (1) diagnosis of HTLV-1 infection using two enzyme-linked immunosorbent assays and/or a confirmatory test, (2) clinical diagnosis of HAM/TSP by neurological assessment, and (3) fractures associated with HAM/TSP. RESULTS:We identified 24 cases of fractures, 70% of which were females. The median age at the time of fracture was 60 years (IQR=24). Six cases reported fractures in patients under 45 years old. Ten patients (42%) had hip/coccyx fractures, seven (29%) were in the lower extremities, and four (17%) in the upper extremities. Half of these patients reported the use of wheelchairs. Five patients who had previously used canes required the use of wheelchairs after the reported fracture. Eight patients underwent corrective orthopedic surgery as a result of the fracture. CONCLUSIONS:For HAM/TSP patients, fractures are a complication that can exacerbate their severe impairment.
| S-EPMC7491556 | biostudies-literature
Project description:HTLV-1-associated myelopathy (HAM/TSP) is a chronic and progressive inflammatory disease of the central nervous system. The aim of our study was to identify genetic determinants related to the onset of HAM/TSP in the Japanese population. We conducted a genome-wide association study comprising 753 HAM/TSP patients and 899 asymptomatic HTLV-1 carriers. We also performed comprehensive genotyping of HLA-A, -B, -C, -DPB1, -DQB1, and -DRB1 genes using next-generation sequencing technology for 651 HAM/TSP patients and 804 carriers. A strong association was observed in HLA class I (P = 1.54 × 10-9) and class II (P = 1.21 × 10-8) loci with HAM/TSP. Association analysis using HLA genotyping results showed that HLA-C*07:02 (P = 2.61 × 10-5), HLA-B*07:02 (P = 4.97 × 10-10), HLA-DRB1*01:01 (P = 1.15 × 10-9) and HLA-DQB1*05:01 (P = 2.30 × 10-9) were associated with disease risk, while HLA-B*40:06 (P = 3.03 × 10-5), HLA-DRB1*15:01 (P = 1.06 × 10-5) and HLA-DQB1*06:02 (P = 1.78 × 10-6) worked protectively. Logistic regression analysis identified amino acid position 7 in the G-BETA domain of HLA-DRB1 as strongly associated with HAM/TSP (P = 9.52 × 10-10); individuals homozygous for leucine had an associated increased risk of HAM/TSP (odds ratio, 9.57), and proline was protective (odds ratio, 0.65). Both associations were independent of the known risk associated with proviral load. DRB1-GB-7-Leu was not significantly associated with proviral load. We have identified DRB1-GB-7-Leu as a genetic risk factor for HAM/TSP development independent of proviral load. This suggests that the amino acid residue may serve as a specific marker to identify the risk of HAM/TSP even without knowledge of proviral load. In light of its allele frequency worldwide, this biomarker will likely prove useful in HTLV-1 endemic areas across the globe.
| S-EPMC7980450 | biostudies-literature
Project description:BACKGROUND:As human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare chronic neurological disease, large scale studies to collect continuous clinical data have been difficult to conduct. Therefore, the incidence of comorbidities and drug utilization data remain unknown. When conducting trials to develop new drugs in rare disease such as HAM/TSP, historical control data obtained from registry studies would be useful, as cohorts in rare disease tend to be small. Long-term follow-up of patients with a chronic disease can also be challenging. In this study, we addressed the following two goals using registry data on patients (n = 486) enrolled in the Japanese HAM/TSP patient registry "HAM-net" from 2012 to 2016: 1) to clarify the epidemiological information of HAM/TSP such as the incidence of comorbidities and drug utilization and 2) to provide the real-world data on changes in lower limb motor dysfunction. RESULTS:In HAM-net-registered patients, common comorbidities were fractures, herpes zoster, and uveitis, with incidences of 55.5, 10.4, and 6.5, respectively, per 1000 person-years. Every year, oral steroid treatment was administered in 48.2-50.7% of the HAM-net-registered patients and interferon-α treatment was used in 2.6-3.5% of patients. The median dose of oral prednisolone was low at 5.0 mg/day. The incidence of fractures and herpes zoster tended to be higher in the steroid-treated group than in the untreated group (fractures: 61.0 vs. 48.3, herpes zoster: 12.7 vs. 8.8, per 1000 person-years). The analysis of chronological change in Osame motor disability score (OMDS) indicated that the mean change in OMDS was + 0.20 [95% confidence intervals (CI): 0.14-0.25] per year in the one-year observation group (n = 346) and + 0.57 (95% CI: 0.42-0.73) over four years in the four-year observation group (n = 148). Significant deterioration of OMDS was noted in all subgroups with varying steroid use status. CONCLUSIONS:This study revealed the incidence of comorbidities and drug utilization data in patients with HAM/TSP using registry data. Furthermore, this study provided real-world data on chronological changes in lower limb motor dysfunction in patients with HAM/TSP, indicating the utility of these data as historical controls.
| S-EPMC6802124 | biostudies-literature
Project description:BackgroundAlthough human T-lymphotropic virus type 1 (HTLV-1) infection is a prerequisite for the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), specific provirus mutations in HAM/TSP have not yet been reported. In this study, we examined whether HAM/TSP patients had the disease-specific genomic variants of HTLV-1 by analyzing entire sequences of HTLV-1 proviruses in these patients, including familial cases. In addition, we investigated the genetic variants of host restriction factors conferring antiretroviral activity to determine which mutations may be related to resistance or susceptibility to HAM/TSP.ResultsThe subjects included 30 patients with familial HAM/TSP (f-HAM/TSP), 92 patients with sporadic HAM/TSP (s-HAM/TSP), and 89 asymptomatic HTLV-1 carriers (ACs). In all 211 samples, 37 samples (18%) were classified into transcontinental subtype and 174 samples (82%) were classified as Japanese subtype. Among three groups, the percentage of transcontinental subtype in f-HAM/TSP, s-HAM/TSP and ACs was 33, 23 and 7%, respectively. The frequency of transcontinental subtype was significantly higher in both f-HAM/TSP (p < 0.001) and s-HAM/TSP (p < 0.001) than in ACs. Fifty mutations in HTLV-1 sequences were significantly more frequent in HAM/TSP patients than in ACs, however, they were common only in transcontinental subtype. Among these mutations, ten common mutations causing amino acid changes in the HTLV-1 sequences were specific to the transcontinental subtype. We examined host restriction factors, and detected a rare variant in TRIM5α in HAM/TSP patients. The patients with TRIM5α 136Q showed lower proviral loads (PVLs) than those with 136R (354 vs. 654 copies/104 PBMC, p = 0.003). The patients with the 304L variant of TRIM5α had significantly higher PVLs than those with 304H (1669 vs. 595 copies/104 PBMC, p = 0.025). We could not find any HAM/TSP-specific mutations of host restriction factors.ConclusionsTranscontinental subtype is susceptible to HAM/TSP, especially in familial cases. Ten common mutations causing amino acid changes in the HTLV-1 gene were specific to the transcontinental subtype. TRIM5α polymorphisms were associated with PVLs, indicating that TRIM5α could be implicated in HTLV-1 replication.
| S-EPMC5395872 | biostudies-literature
Project description:Human T-cell leukemia virus type 1 (HTLV-1) causes incurable adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Patients with HAM/TSP have increased levels of HTLV-1-infected cells compared with asymptomatic HTLV-1 carriers. However, the roles played by cellular genes in HTLV-1-infected CD4+ T cells await discovery. We combined microarray data and pathway analysis, and found that the ABL1 tyrosine kinase gene is a critical gene in HAM/TSP. ABL1 is a known survival factor for T- and B-lymphocytes. ABL1 is also part of the fused gene (BCR-ABL) known to be responsible for chronic myelogenous leukemia (CML), and tyrosine kinase inhibitors (TKI), including imatinib, nilotinib, and dasatinib, are in safe clinical use for treating CML. To evaluate whether ABL1 is indeed critical for the pathogenesis of HAM/TSP, we investigated the effect of ABL1 inhibitors on HTLV-1-infected cells. We developed a propidium monoazide-HTLV-1 viability quantitative PCR assay, which distinguishes DNA from live cells and DNA from dead cells. Using this method, we were able to measure the HTLV-1 proviral load (PVL) in live cells alone when peripheral blood mononuclear cells (PBMCs) from HAM/TSP cases were treated with TKI. Treating the PBMCs with nilotinib or dasatinib produced significant reductions in the PVL (21.0% and 17.5%, respectively) in live cells. Furthermore, a retrospective survey based on our clinical records found a rare case of HAM/TSP, where the patient also suffered from CML. The patient showed an 84.2% PVL reduction after CML treatment with imatinib. We conclude that inhibiting the ABL1 tyrosine kinase specifically reduced the PVL in PBMCs from patients with HAM/TSP, suggesting that ABL1 is a significant gene for the survival of HTLV-1-infected cells and that TKI may be a potential therapeutic agent for HAM/TSP.
2020-05-26 | GSE132666 | GEO
Project description:BackgroundHuman T-lymphotropic virus type 1 (HTLV-1) -associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare chronic neuroinflammatory disease. Since the disease course of HAM/TSP varies among patients, there is a dire need for biomarkers capable of predicting the rate of disease progression. However, there have been no studies to date that have compared the prognostic values of multiple potential biomarkers for HAM/TSP.Methodology/principal findingsPeripheral blood and cerebrospinal fluid (CSF) samples from HAM/TSP patients and HTLV-1-infected control subjects were obtained and tested retrospectively for several potential biomarkers, including chemokines and other cytokines, and nine optimal candidates were selected based on receiver operating characteristic (ROC) analysis. Next, we evaluated the relationship between these candidates and the rate of disease progression in HAM/TSP patients, beginning with a first cohort of 30 patients (Training Set) and proceeding to a second cohort of 23 patients (Test Set). We defined "deteriorating HAM/TSP" as distinctly worsening function (≥3 grades on Osame's Motor Disability Score (OMDS)) over four years and "stable HAM/TSP" as unchanged or only slightly worsened function (1 grade on OMDS) over four years, and we compared the levels of the candidate biomarkers in patients divided into these two groups. The CSF levels of chemokine (C-X-C motif) ligand 10 (CXCL10), CXCL9, and neopterin were well-correlated with disease progression, better even than HTLV-1 proviral load in PBMCs. Importantly, these results were validated using the Test Set.Conclusions/significanceAs the CSF levels of CXCL10, CXCL9, and neopterin were the most strongly correlated with rate of disease progression, they represent the most viable candidates for HAM/TSP prognostic biomarkers. The identification of effective prognostic biomarkers could lead to earlier detection of high-risk patients, more patient-specific treatment options, and more productive clinical trials.
| S-EPMC3794911 | biostudies-literature
Project description:BackgroundUrinary dysfunction is one of the main features of human T-cell leukemia virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). However, a comprehensive assessment of the severity is difficult because a standardized assessment measure is unavailable. Therefore, this study aimed to develop a novel symptom score for the assessment of urinary dysfunction in HAM/TSP. We interviewed 449 patients with HAM/TSP using four internationally validated questionnaires for assessment of urinary symptoms (27 question items in total): the International Prostate Symptom Score; the International Consultation on Incontinence Questionnaire-Short Form; the Overactive Bladder Symptom Score; and the Nocturia Quality-of-Life questionnaire. We developed a symptom score based on the data of 322 patients who did not use urinary catheters by selecting question items from questionnaires focused on descriptive statistics, correlation analysis, and exploratory factor analysis. The score distribution, reliability, and validity of the developed score were evaluated.ResultsFirst, 16 questions related to quality of life, situations, or subjective assessment were omitted from the 27 questions. Exploratory factor analysis revealed that the remaining 11 questions pertained to three factors: frequent urination, urinary incontinence, and voiding symptoms. Three questions, which had similar questions with larger factor loading, were deleted. Finally, we selected eight question items for inclusion in the novel score. The score distribution exhibited no ceiling or floor effect. The Cronbach's alpha (0.737) demonstrated reliable internal consistency. The new score comprised two subscales with acceptable factorial validity (inter-factor correlation coefficient, 0.322): storage symptoms (frequent urination plus urinary incontinence) and voiding symptoms. The correlation between each item and the subscales suggested acceptable construct validity.ConclusionsWe developed a novel score, the HAM/TSP-Bladder Dysfunction Symptom Score, and demonstrated its reliability and validity. The applicability of this score to patients using catheters should be examined in future research.
| S-EPMC7333329 | biostudies-literature
Project description:Patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) become progressively impaired, with chronic pain, immobility and bladder, bowel and sexual dysfunction. Tested antiretroviral therapies have not been effective and most patients are offered a short course of corticosteroids or interferon-?, physiotherapy and symptomatic management. Pathogenesis studies implicate activated T-lymphocytes and cytokines in tissue damage. We therefore tested the hypothesis that inhibition of T-cell activation with ciclosporin A would be safe and clinically beneficial in patients with early and/or clinically progressing HAM/TSP.Open label, proof of concept, pilot study of 48 weeks therapy with the calcineurin antagonist, ciclosporin A (CsA), in seven patients with 'early' (<two years) or 'progressive' (>50% deterioration in timed walk during the preceding three months) HAM/TSP. Primary outcomes were incidence of clinical failure at 48 weeks and time to clinical failure.All patients completed 72 weeks study participation and five showed objective evidence of clinical improvement after 3 months treatment with CsA. Two patients exhibited clinical failure over 6.4 person-years of follow-up to week 48. One patient had a >2 point deterioration in IPEC (Insituto de Pesquisa Clinica Evandro Chagas) disability score at weeks 8 and 12, and then stopped treatment. The other stopped treatment at week 4 because of headache and tremor and deterioration in timed walk, which occurred at week 45. Overall pain, mobility, spasticity and bladder function improved by 48 weeks. Two patients recommenced CsA during follow-up due to relapse.These data provide initial evidence that treatment with CsA is safe and may partially reverse the clinical deterioration seen in patients with early/progressive HAM/TSP. This trial supports further investigation of this agent's safety and effectiveness in larger, randomised controlled studies in carefully selected patients with disease progression.
| S-EPMC3373656 | biostudies-literature