Early clinical signs and imaging findings in Gerstmann-Sträussler-Scheinker syndrome (Pro102Leu).

OBJECTIVE: To determine the clinical and radiologic features of Gerstmann-Sträussler-Scheinker syndrome caused by Pro102Leu mutation in PRNP (GSS102). METHODS: The authors report 11 patients (nine families) with clinically and radiologically diagnosed GSS102. RESULTS: All patients showed mild gait disturbance, dysesthesia and hyporeflexia of the lower legs, and truncal ataxia, and 9 of 11 patients showed proximal leg muscle weakness during the early stage of the disease. Dementia was not a main symptom during the early stage. Brain MRI and EEG abnormalities were not prominent initially. SPECT (N-isopropyl-p-[(123)I]iodoamphetamine) analyzed by the three-dimensional stereotactic surface projection (SSP) method detected abnormalities in five patients early during the course of the illness. SPECT findings showed diffusely decreased cerebral blood flow, demonstrated by a mosaic pattern, with the lowest perfusion noted in the occipital lobes. In contrast, blood flow to the cerebellum was preserved. These studies suggested sites of pathology in GSS102, with the main lesions probably located in the cerebrum and the spinal cord (posterior horn and spinocerebellar tract) instead of the cerebellum. CONCLUSIONS: Key features for early diagnosis of Gerstmann-Sträussler-Scheinker syndrome caused by Pro102Leu mutation in PRNP (GSS102) are truncal ataxia, dysesthesia and hyporeflexia of the lower legs, and mild dysarthria. Normal cerebellar MRI and abnormal cerebral SPECT findings are characters of early GSS102.

Clonal expansion within CD4+ and CD8+ T cell subsets in human T lymphotropic virus type I-infected individuals.

To investigate the diversity of the T cell repertoire involved in human T lymphotropic virus type I (HTLV-I) infections, peripheral blood T cell subsets were analyzed by using a PCR-based assay that permits determination of complementarity-determining region 3 (CDR3) length variation in TCR Vbeta transcripts. In two of four asymptomatic HTLV-I carriers and in four of five patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), mono- or oligoclonal expansions were detected in the CD4+ T cell subset. In one patient with adult T cell leukemia, a specific clone bearing Vbeta7 was detected in the CD4+ T cell subset. In contrast, clonal expansion was not observed in the CD4 T cell subsets of three individuals with asymptomatic HTLV-II infection or in our previous studies of a large number of uninfected individuals. Oligoclonal expansions in the CD8+ T cell subset were detected in all subjects, including the patient with adult T cell leukemia. No differences in the number of expanded clones were noted between asymptomatic carriers and in patients with HAM/TSP and there was no obvious restriction in the TCR V region usage. Direct sequencing revealed no significant bias in the CDR3 motifs utilized by the predominant clones. This report is the first direct demonstration of clonal expansions within fractionated T cell subsets (CD4+ and CD8+) in HTLV-I infections and suggests that 1) clonal expansion of CD4+ T lymphocytes likely occurs as a direct result of infection and 2) polyclonal CD8+ T cell expansion occurs frequently and independently of disease association.

Alteration of cytokine levels by fosfomycin and prednisolone in spontaneous proliferation of cultured lymphocytes from patients with HTLV-I-associated myelopathy (HAM/TSP).

Fosfomycin has recently been reported as an antibiotic with immunomodulatory activities. To evaluate the possibility of clinical administration of fosfomycin in patients with human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), the effects of this agent on the HTLV-I-induced in vitro phenomenon were studied. The influence of fosfomycin on in vitro spontaneous proliferation (SP) of peripheral blood mononuclear cells (PBMCs) from four patients with HAM/TSP was measured by thymidine incorporation into the cells, and the concentration of several cytokines in the culture supernatants was examined in three HAM/TSP patients. Enzyme-linked immunosorbent assays (ELISAs) were employed to detect the concentrations of interleukin-4 (IL-4), IL-6, IL-10, interferon-gamma (IFN-gamma), transforming growth factor-beta1 (TGF-beta1), and macrophage inflammatory protein-1alpha (MIP-1alpha). The data were compared to the changes by prednisolone which is known to regulate the HTLV-I-associated in vitro phenomenon and to have a therapeutic benefit in patients with HAM/TSP. Production of IL-6, IFN-gamma and MIP-1alpha from the spontaneously proliferating cells were demonstrated. Fosfomycin could not suppress the HTLV-I-associated SP, but had the properties to decrease the levels of TGF-beta1 and MIP-1alpha. It was also demonstrated that the concentrations of IFN-gamma and MIP-1alpha in the cultures in the presence of prednisolone were apparently decreased, suggesting a possible involvement of these cytokines in the pathogenesis of HAM/TSP. These findings support the hypothesis that fosfomycin may have immunomodulatory potentials in HTLV-I-related cellular interactions in a different manner from ordinary immunomodulatory agents.

In vitro virus propagation and high cellular responsiveness to the infected cells in patients with HTLV-I-associated myelopathy (HAM/TSP).

The reasons for the development of HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in certain infected individuals remain poorly understood, but the susceptibility should involve both viral factors and host conditions. To assess simultaneously both virus-induced activation of infected cells and the cellular response to virus producing cells, an analysis of fractionated peripheral blood lymphocytes obtained from patients with HAM/TSP (n = 15) were compared with those of asymptomatic HTLV-I carriers (n = 9) in an age-matched manner. The in vitro propagation of HTLV-I infection was evaluated as the spontaneous thymidine incorporation into CD4+ cells, and proliferative response of CD8+ cells against cultured and irradiated autologous CD4+ cells was employed to analyze the HTLV-I-induced cellular response. The comparative analysis using these two parameters demonstrated that HAM/TSP patients were characterized by the concomitance of a high inducibility of HTLV-I propagation and a high cellular responsiveness against HTLV-I as compared with asymptomatic HTLV-I carriers, suggesting the involvement of both of these factors in disease susceptibility. In addition, the coupled evaluation of these two in vitro phenomena may offer a better diagnostic hallmark for HTLV-I seropositive myelopathy cases with other known cause of myelopathy.

Immunological abnormality in patients with lysinuric protein intolerance.

Lysinuric protein intolerance (LPI) is a rare hereditary disorder manifesting hyperammonemia induced by low levels of basic amino acids, these low levels being due to the impaired transport of these acids in the intestinal mucosa and the renal tubules. Low serum arginine levels and probably the consequently low in vivo levels of nitric oxide (NO), which against acts as a physiological and immunological mediator/modulator, are thought to influence the immunological status in patients with LPI. Accordingly, this study was conducted to. We found that patients with LPI had leukocytopenia, high serum IgG levels, a high ratio of CD44B4-positive lymphocytes (helper inducer) to CD42H4-positive lymphocytes (suppressor inducer), low levels of leukocyte phagocytic, cytotoxic, and natural killer cell activity, and increased spontaneous proliferation of lymphocytes. These results were probably the consequence of persistent low NO levels in vivo.

An autoaggressive process against bystander tissues in HTLV-I-infected individuals: a possible pathomechanism of HAM/TSP.

Human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a well-defined clinico-pathological entity in which the virus infection and the host immune responses are involved in the pathomechanism. It is generally agreed that the virus infection precedes the development of HAM/TSP and the infection is persistent during the course of disease. However, what plays the key role for the development of HAM/TSP remains to be elucidated. In this article, we emphasise the importance of the unique nature of HTLV-I-infected cells, which may have a potential ability to produce viral antigens outside of the blood flow, and we also review a variety of evidences supporting the following proposal. In our hypothesis, the supply of infected T cells from blood flow to central nervous system (CNS) is primary for the development of CNS lesions. Both anatomically determined hemodynamic conditions and adhesion molecule-mediated interactions between circulating infected T cells and endothelial cells may contribute to the localization of the main lesions. Following an induction of the HTLV-I antigens on the surface of infected T cells in CNS compartment, expansion of the responses of immunocompetent T cells against the viral proteins may result in CNS tissue damage which may be mediated by released cytokines. This is the first attempt to implicate a bystander damage mechanism in a human disease as an essential pathomechanism.

Limited sequence divergence of HTLV-I of Indian HAM/TSP patients from a prototype Japanese isolate.

Nucleotide sequences of two HTLV-I proviruses isolated from Indian patients with HAM/TSP were analyzed. The sequence data of the env, pX, and LTR regions showed 98-99% homologies with the prototype HTLV-I, ATK-1, isolated from a Japanese ATL patient, indicating that HTLV-I isolates in India and Japan are similar, with minor variations. However, certain small sequences of noncoding regions in the pX and LTR showed differences of 6.1 and 7.2%, respectively, thus the conclusion could vary depending on the regions and length of the sequences used for comparison.

Elevated levels of interleukin-6 in serum and cerebrospinal fluid of HTLV-I-associated myelopathy/tropical spastic paraparesis.

A significant elevation of interleukin-6 (IL-6) level was observed both in serum (mean 0.455 +/- 0.251) and in cerebrospinal fluid (CSF) (mean 0.043 +/- 0.016) obtained from 13 patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) when compared to that of either asymptomatic carriers (mean 0.181 +/- 0.074 and 0.021 +/- 0.015, respectively) or controls (mean 0.208 +/- 0.119 and 0.021 +/- 0.015, respectively). The differences were statistically significant between HAM/TSP and asymptomatic carrier for serum (P less than 0.05) or CSF (P less than 0.01). The correlation indexes between serum IL-6 and anti-HTLV-I antibody titers in serum and CSF were 0.61 (P less than 0.06) and 0.67 (P less than 0.05), respectively. Both the cell count and protein level in CSF correlated with CSF IL-6 activity at 0.68 (P less than 0.01) and 0.56 (P less than 0.05), respectively. The results demonstrate that IL-6 may contribute to the production of anti-HTLV-I antibody, and signs of slight inflammation are present in the central nervous system in HAM/TSP.