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A Werner's syndrome patient with spastic paraparesis and polyneuropathy had slowing of central and peripheral nerve conduction. Sural nerve biopsy revealed a significantly higher frequency of demyelination and remyelination and a loss of myelinated fibers. These data suggest that the central and peripheral nervous systems are affected in Werner's syndrome.
Lymphoid cell lines derived from the peripheral blood of French West Indian patients with HTLV-I sero-positive Tropical Spastic Paraparesis and HTLV-I isolates were characterized. While patients' peripheral blood lymphocytes did not express detectable HTLV-I antigens when uncultured, they did so after short-term culture. Established cell lines were of T-cell lineage: CD2+, CD3+, CD4+, CD7+, WT31+ with activated T-cell markers CD25+, DR+ and a clonal rearrangement of the beta and gamma genes of the T-cell receptor. HTLV-I antigens were detected in cell lines by indirect immunofluorescence, Western blot and radio-immunoprecipitation assays. After 4 months in culture, low levels of Mg2+ dependent reverse transcriptase activity were detected and electron microscopy revealed numerous type-C retroviral particles similar to HTLV-I virions. Western blot and radio-immunoprecipitation analysis of purified viruses revealed gp46, p24, p19 and Pr53gag proteins similar to those detected in HUT 102 and MT2 cell lines. Deep analysis of env-coded precursor of one TSP versus ATL isolates revealed minor differences in their molecular weights. Southern blot analysis using 32P HTLV-I env gene as a probe showed the presence of HTLV-I proviral fragments clonally integrated into the genome of the cell lines. Our data suggest that HTLV-I isolated from Tropical Spastic Paraparesis does not differ significantly from the leukemogenic prototypes. Does HTLV-I induce either acute lymphoproliferative diseases or chronic neuromyelopathies depending upon as yet unknown co-factors? This question remains to be determined.
A 35 year old woman presented with two episodes of spastic paraparesis, occurring in the third trimester of two consecutive pregnancies. The neurological symptoms seemed to be caused by an intramedullary cyst in the thoracic spinal cord. The cyst was subtotally removed and histopathologically diagnosed as enterogenous cyst. Other congenital abnormalities were absent. The peculiar timing of the clinical manifestation of an intramedullary cyst has not been described before. An unequivocal explanation for this phenomenon is missing, but several factors related to pregnancy that may play a part are discussed.
Progressive myelopathy is a rare neurological complication of chronic liver disease with portal hypertension and there is no special diagnostic tool for hepatic myelopathy. Neuropathological studies of the patients with hepatic myelopathy have demonstrated demyelination of the lateral corticospinal tracts with various degree of axonal loss. Transcranial magnetic stimulation (TMS) is widely utilized as an indicator of changes in excitability and conductivity of the motor pathways. TMS studies are also used for the diagnosis of hereditary spastic paraparesis in the literature. In this study, we described two patients who presented with spastic paraparesis; TMS studies suggested that they had myelopathy and diagnosed as hepatic myelopathy when all the other possible diagnoses were ruled out.
BACKGROUND: Human T cell lymphotropic virus type 1 (HTLV-1)-associated infective dermatitis (IDH) is a chronic and recurrent eczema occurring during childhood and adolescence. HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic myelopathy of adulthood, presenting with slowly progressive spastic paraparesis and sphincter dysfunction with mild sensory involvement. There are few reports describing an association between IDH and HAM/TSP. The objective of this study was to evaluate the occurrence of HAM/TSP in patients with IDH and in seropositive members of their families and to determine the blood levels of antibodies against HTLV-1 in patients with HAM/TSP. METHODS: Twenty patients with IDH and their seropositive mothers and siblings underwent clinical, neurological, and laboratory evaluations. The diagnosis of HAM/TSP was made in accordance with the World Health Organization criteria. RESULTS: Nine individuals had HAM/TSP (6 of the patients with IDH, 2 mothers, and 1 seropositive brother). In 3 families, > 1 individual had HAM/TSP. The serum antibody titers of the patients with HAM/TSP varied from 1 : 3.125 to 1 : 78.125. CONCLUSIONS: A strong association was observed between IDH and HAM/TSP. The familial clustering of both diseases suggests a genetic background. Serological screening for HTLV-1 in children with symptoms of myelopathy is essential in areas where HTLV-1 is endemic.
A 57 year old woman living independently in the community presented with four years of progressive spastic paraparesis and dementia. An extensive evaluation for the usual causes of these difficulties was unrevealing, but her serum phenylalanine concentration was markedly elevated and genetic analysis demonstrated mutations in the phenylalanine hydroxylase gene consistent with classic phenylketonuria. A protein restricted diet was associated with improvement in her condition. Although untreated phenylketonuria is typically associated with severe neurological dysfunction beginning in early childhood, this case shows that disability may be delayed until adulthood.
Human T-lymphotropic virus type I (HTLV-I)-associated tropical spastic paraparesis in Martinique has been identified in 54 patients, 49 women and 5 men. This myelopathy represents an endemic problem on this island and the earliest documented case dates from 1952. A blood transfusion history was obtained in 7 of the 54 patients (13%). There was a preponderance of cases from the northern Atlantic coast of Martinique, the most humid region on the island. The prevalence in this region reached 49.5 per 100,000, compared with the global prevalence of 11.9 cases per 100,000 for the island. An immune-mediated mechanism may be important in the pathogenesis of HTLV-I-associated tropical spastic paraparesis.
Ten possible cases of tropical spastic paraparesis (TSP) in Northeastern Brazil (Ceará) are presented. They show the typical symptoms and signs of TSP consisting of weakness of the lower limbs, spastic gait, hyperreflexia, bladder dysfunction and variable signs of posterior columns impairment. The laboratory examinations excluded other compressive, infective, degenerative or demyelinating lesions of their spinal cord. Our patients age ranged from 21 to 59 years, all were of black origin and all were of lower social class. There was a slight preponderance of females. An etiological implication of a retrovirus (HTLV-I) has been shown for TSP, but for lack of technical conditions we could not determine it in our patients, and that stands as our subsequent step in those and further cases.
Hereditary spastic paraparesis (HSP) comprises a clinically and genetically heterogeneous group of disorders characterized by progressive spasticity and hyperreflexia of the lower limbs. The past few years have witnessed an exponential increase in knowledge of this disease and we can now list 19 loci mapped on the human genome and eight genes cloned. However, this wider knowledge of the molecular basis of HSP has had limited impact on clinical practice: the use of antispastic drugs and regular physiotherapy still remain crucial in the therapeutic management of patients. Nonetheless, the identification of new genes mutated in HSP furthers comprehension of the pathomechanisms involved and helps in genetic counseling, especially of asymptomatic individuals who request molecular analyses.
We report a case of progressive spastic paraparesis in a 45-year-old man with total portal-systemic shunting, which developed spontaneously due to congenital hepatic fibrosis. Cellular functions of the liver, except for an elevated blood ammonia level, were within normal limits, as is usual in congenital hepatic fibrosis. This case shows that spastic paraparesis following portal-systemic shunting may occur without liver failure.
This study was designed to investigate the prevalence and determinants of the association of restless legs syndrome (RLS) and hereditary spastic paraparesis (HSP). Therefore, 132 patients with HSP were evaluated concerning the symptoms of RLS by a standardized questionnaire. RLS was supposed when patients met all of the established four essential criteria of RLS defined by the International RLS Study Group. In addition, we studied the relationship between RLS and age at HSP symptom onset and evaluated the severity of RLS symptoms. Out of 59 responses, RLS was found in 27 HSP patients (15 male, 12 female) so that RLS was more frequent in the total HSP group (20.5%; 27/132) than in previous population-based studies (about 11%). In all 27 patients, the diagnosis of RLS was established based on an additional personal interview. The probability to develop RLS did not increase with higher age. Age at onset of HSP symptoms in the HSP group with RLS (27.7 +/- 12.6 years) and the HSP group without RLS (37.0 +/- 16.9 years) differed significantly (p = 0.04). Most of the patients with RLS showed a moderate and severe grade on the RLS severity score. Only 8 patients had previously been diagnosed to have RLS and were on medication. The data of this screening for RLS provided evidence that patients with HSP are particularly susceptible to develop RLS. Consequently, special emphasis should be put on the diagnosis criteria of RLS in HSP patients.
OBJECTIVE: To identify the frequency and characterize the phenotype of paraplegin mutations in the hereditary spastic paraparesis (HSP) population in the northeast of England. BACKGROUND: HSP is a disorder that shows both clinical and genetic heterogeneity. To date, 13 loci have been associated with an HSP phenotype, with the causative gene having been identified in four of these. Two autosomal genes have been identified, paraplegin and spastin, and two X-linked genes have been identified, L1CAM (cell adhesion molecule) and proteolipid protein. METHODS: Thirty HSP pedigrees from the northeast of England were analyzed for mutation in each of the 17 exons of the paraplegin gene. RESULTS: A single family with a paraplegin mutation was identified in which the paraplegin mutation co-segregates with an HSP phenotype in an apparent dominant manner. The authors also describe frequent polymorphism in the paraplegin gene in both the HSP and control populations. CONCLUSION: Mutations in the paraplegin gene are not a common cause of HSP in the northeast of England. The phenotype of the paraplegin-related HSP family described had several striking features including amyotrophy, raised creatine kinase, sensorimotor peripheral neuropathy, and oxidative phosphorylation defect on muscle biopsy.
A case of HTLV-1 associated tropical spastic paraparesis is described in a Belgian nun who had been working as a midwife in Central Africa. Occupational exposure was the only risk factor identified. Among 2,482 Belgian expatriates in tropical countries, 92% of whom had resided in sub-Saharan Africa for an average of 15.5 years, only one Belgian-born man was found seropositive for HTLV-1. He was married to an African woman and living in Central Africa for 23 years. The risk of HTLV-1 infection is low in Belgian expatriates and on its own does not support generalised anti-HTLV screening in autochthonous Belgian blood donors.
HTLV-I causes T-cell leukemia and tropical spastic paraparesis (TSP) in a minority of infected people, whereas the majority remain healthy. The virus differs little in sequence between isolates but has been shown to have a quasispecies structure. Using the Nei and Gojobori algorithm, we have shown that the proportion of nonsynonymous to synonymous changes in HTLV-I proviral tax gene sequences from healthy seropositive subjects (Dn/Ds = 0.9 to 1.3) is significantly higher than those from TSP patients (Dn/Ds = 0.3 to 0.6). Here we show that the distinction between healthy seropositives and TSP patients can only be seen with proviral tax sequences, but not with cDNA, the amino-terminal or carboxy-terminal half of tax, or the rex gene. The Dn/Ds ratio of proviral tax sequences was used to analyze two TSP patients with atypical features and to investigate the influence of cytotoxic T cells (CTL) on the viral quasispecies.
All 17 patients with tropical spastic paraparesis (TSP) in a series seen in the United Kingdom have antibodies to the human T cell leukemia virus type 1 (HTLV-1). Cultured peripheral blood lymphocytes from these patients formed multinucleated giant cells and reacted with sera and monoclonal antibodies to HTLV-1 in a manner identical to adult T cell leukemia-lymphoma (ATLL) patient lymphocytes. Western blot analysis failed to reveal any marked difference in the antigens recognized by sera from TSP and ATLL patients. The sera from TSP patients, their asymptomatic relatives and ATLL patients were titrated using the following assays: enzyme-linked immunosorbent assays (ELISA), particle agglutination, antibody-dependent cell-mediated cytotoxicity, and pseudotype neutralization. There were significantly stronger serologic responses in the TSP patients than in their relatives or ATLL patients. High antibody titers in the presence of replicating virus often reflect the antigen load; however, these data are also consistent with the suggestion that neurologic damage in TSP may be immunologically mediated.
HTLV-1-associated myelopathy/tropical spastic paraparesis (TSP/HAM) is a chronic CNS disease characterized by axomyelinic degeneration of the long axons of corticospinal tracts. Levels of NGF, NT-3, NT-4/5, BDNF, GDNF, CNTF, and FGF-2 were measured in the cerebrospinal fluid (CSF) of 21 TSP/HAM patients and 20 controls. NGF, BDNF, and FGF-2 levels were also determined in 19 patients with HIV motor cognitive motor syndrome, and in 21 subjects diagnosed with Creutzfeldt Jakob disease (CJD). No significant differences were detected in the concentrations of NGF, BDNF, NT-3, NT-4/5, GDNF, and CNTF in the CSF between TSP/HAM patients and controls. FGF-2 was significantly lower in the CSF of the three groups of patients compared with controls; the HIV group exhibited the lowest values. HIV patients differed from TSP/HAM in their significantly higher levels of NGF and lower levels of BDNF and FGF-2, whereas CJD patients differed only in their higher levels of NGF. Immunohistochemical studies were done of trophic factors (NGF and FGF-2) and neurotrophin receptors (trkA and p75) in spinal cord and motor cortical areas from anatomopathological cases of TSP/HAM. Results indicated that NGF is expressed in motoneurons and oligodendrocytes of the posterior column of the spinal cord. FGF-2 was detected in motoneurons and spinal cord vessels. p75 receptor was detected in cortical neurons. The absence of a significant change in the trophic factor levels in TSP/HAM may be attributed to a selective axonal lesion in a slow process.
The tropical spastic paraparesis (TSP) is a chronic myelopathy, predominant in the tropics, recently known to be of retroviral origin (HTLV-I). This paper aims at delineating the clinico-etiological evolution of this entity. The historical analysis of it showed that the TSP has had, along decades, many different denominations and the discovery of the retroviral origin for some of them has stimulated new paths of research and epidemiological interest in the tropics and Brazil.
Seven members of a family with an X-linked spastic paraparesis syndrome were analyzed by MR imaging and stimulated echo, solvent-suppressed proton nuclear magnetic resonance spectroscopy. The MR scans of three symptomatic males and two asymptomatic females demonstrated abnormal signal in the supratentorial white matter. Each of these patients had a proton spectroscopic examination of a 2 X 2 X 2 cm voxel localized to the abnormal white matter of the centrum semiovale. The spectra demonstrated depression of N-acetyl aspartate/creatine, N-acetyl aspartate/choline, and creatine/choline ratios compared with normal control subjects. Additionally, these patients had abnormal elevations of amino acid resonances in the 2.1-3.0 ppm range. In a patient with symmetric white matter signal intensity abnormalities, an asymmetric spectroscopic study correlated with asymmetric symptoms. One asymptomatic family member with a normal MR study had abnormal metabolite ratio measurements. She was referred for further evaluation, since the proton spectrum suggested she may possess the affected gene. If the findings in this study are duplicated in other cases of hereditary dysmyelinating syndromes, we believe the integrated MR/proton nuclear magnetic resonance spectroscopy examination will be of benefit in evaluating and counseling families with familial dysmyelinating disorders.