Clinical spectrum of ataxia-telangiectasia in adulthood.

OBJECTIVE: To describe the phenotype of adult patients with variant and classic ataxia-telangiectasia (A-T), to raise the degree of clinical suspicion for the diagnosis variant A-T, and to assess a genotype-phenotype relationship for mutations in the ATM gene. METHODS: Retrospective analysis of the clinical characteristics and course of disease in 13 adult patients with variant A-T of 9 families and 6 unrelated adults with classic A-T and mutation analysis of the ATM gene and measurements of ATM protein expression and kinase activity. RESULTS: Patients with variant A-T were only correctly diagnosed in adulthood. They often presented with extrapyramidal symptoms in childhood, whereas cerebellar ataxia appeared later. Four patients with variant A-T developed a malignancy. Patients with classic and variant A-T had elevated serum alpha-fetoprotein levels and chromosome 7/14 rearrangements. The mildest variant A-T phenotype was associated with missense mutations in the ATM gene that resulted in expression of some residual ATM protein with kinase activity. Two splicing mutations, c.331 + 5G>A and c.496 + 5G>A, caused a more severe variant A-T phenotype. The splicing mutation c.331 + 5G>A resulted in less ATM protein and kinase activity than the missense mutations. CONCLUSIONS: Ataxia-telangiectasia (A-T) should be considered in patients with unexplained extrapyramidal symptoms. Early diagnosis is important given the increased risk of malignancies and the higher risk for side effects of subsequent cancer treatment. Measurement of serum alpha-fetoprotein and chromosomal instability precipitates the correct diagnosis. There is a clear genotype-phenotype relation for A-T, since the severity of the phenotype depends on the amount of residual kinase activity as determined by the genotype.

Intrathecal baclofen for dystonia of complex regional pain syndrome.

Dystonia in complex regional pain syndrome (CRPS) responds poorly to treatment. Intrathecal baclofen (ITB) may improve this type of dystonia, but information on its efficacy and safety is limited. A single-blind, placebo-run-in, dose-escalation study was carried out in 42 CRPS patients to evaluate whether dystonia responds to ITB. Thirty-six of the 38 patients, who met the responder criteria received a pump for continuous ITB administration, and were followed up for 12 months to assess long-term efficacy and safety (open-label study). Primary outcome measures were global dystonia severity (both studies) and dystonia-related functional limitations (open-label study). The dose-escalation study showed a dose-effect of baclofen on dystonia severity in 31 patients in doses up to 450 microg/day. One patient did not respond to treatment in the dose-escalation study and three patients dropped out. Thirty-six patients entered the open-label study. Intention-to-treat analysis revealed a substantial improvement in patient and assessor-rated dystonia scores, pain, disability and quality-of-life (Qol) at 12 months. The response in the dose-escalation study did not predict the response to ITB in the open-label study. Eighty-nine adverse events occurred in 26 patients and were related to baclofen (n=19), pump/catheter system defects (n=52), or could not be specified (n=18). The pump was explanted in six patients during the follow-up phase. Dystonia, pain, disability and Qol all improved on ITB and remained efficacious over a period of one year. However, ITB is associated with a high complication rate in this patient group, and methods to improve patient selection and catheter-pump integrity are warranted.

Hyperacusis in patients with complex regional pain syndrome related dystonia.

INTRODUCTION: In complex regional pain syndrome type 1 (CRPS-1), patients may have manifestations of central involvement, including allodynia, hyperalgesia or dystonia. We noted that more severely affected patients may experience hyperacusis, which may also reflect central involvement. The aim of this study was to evaluate the occurrence and characteristics of hyperacusis in patients with CRPS related dystonia. METHODS: The presence of hyperacusis, speech reception thresholds (SRT), pure-tone thresholds (PTT) and uncomfortable loudness (UCL) was evaluated in 40 patients with CRPS related dystonia. RESULTS: PTT and SRT were normal for all patients. 15 patients (38%) reported hyperacusis and this was associated with allodynia/hyperalgesia and with more affected extremities. UCLs of patients with hyperacusis were significantly lower than UCLs of patients without hyperacusis. CONCLUSION: Hyperacusis is common among severely affected patients with CRPS related dystonia and may indicate that the disease spreads beyond those circuits related to sensory-motor processing of extremities.

Changes in cerebrospinal fluid levels of pro-inflammatory cytokines in CRPS.

Complex Regional Pain Syndrome (CRPS) Types I and II are characterized by various combinations of sensory, autonomic and motor abnormalities. Pain disproportionate to the severity and duration of the inciting event is the most devastating symptom. In animal studies, conditions resulting in exaggerated pain states demonstrate elevated pro-inflammatory cytokines. In addition, pro-inflammatory cytokines have been shown to induce or increase neuropathic and inflammatory pain. Utilizing high sensitivity enzyme linked immunosorbent assay (ELISA), we compared the levels of the pro-inflammatory cytokines interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and Tumor Necrosis Factor-alpha (TNF-alpha) in the cerebrospinal fluid (CSF) of patients afflicted with CRPS to CSF levels found in other patients with and without painful conditions. The results from this study demonstrated significant increases in IL-1beta and IL-6, but not TNF-alpha in the CSF of individuals afflicted with CRPS as compared to controls. CSF cytokine levels in controls with painful conditions did not differ from levels in controls without pain. These increases showed no correlation with the patient's gender or weight. These results are consistent with studies that suggest that the pathogenesis of CRPS is due in part to central neuroimmune activation.

DNA testing for fragile X syndrome: implications for parents and family.

The fragile X syndrome is an X linked, semidominant mental retardation disorder caused by the amplification of a CGG repeat in the 5' UTR of the FMR1 gene. Nineteen fragile X families in which the mutated FMR1 gene segregated were evaluated. The implications of the diagnosis for the parents and family were studied through pedigree information, interviews, and questionnaires. Information about the heredity of fragile X syndrome was only disseminated by family members to a third (124/366) of the relatives with an a priori risk of being a carrier of the fragile X syndrome. Twenty-six percent (94/366) of the relatives were tested. Transmission of information among first degree relatives seemed satisfactory but dropped off sharply with increasing distance of the genetic relationship, leaving 66% uninformed. This is particularly disadvantageous in an X linked disease. Of those subjects tested, 42% (39/94) had a premutation and 18% (17/94) had a full mutation. On average, in each family one new fragile X patient and two new carriers were found. When people have the task of transmitting genetic information to their relatives, they usually feel responsible and capable; however, reduced acquaintance and contact with more distant relative severely reduces the effectiveness of such transfer of information in fragile X families.

Patients with combined hypercholesterolemia-hypertriglyceridemia show an increased monocyte-endothelial cell adhesion in vitro: triglyceride level as a major determinant.

Hypercholesterolemia (HC) is one of the primary risk factors for atherosclerosis. Patients with familial hypercholesterolemia (FH) or combined hypercholesterolemia-hypertriglycerinemia (CHH) are at risk to develop premature atherosclerosis. Animal models have revealed that diet-induced HC in vivo leads to an increased adhesion of monocytes to the endothelium of the vessel wall. Changes in the monocytes, endothelial cells, or serum components may lead to the increased monocyte adhesion that results in atherosclerotic plaque formation. In the present study, we investigated the binding of the monocyte in an in vitro system. Incubation of freshly isolated monocytes from CHH patients with cultured human umbilical vein endothelial cells (HUVEC) gave a significant 60% increase in monocyte adhesion when compared with monocytes from healthy subjects. No such increase was observed using monocytes from nontreated FH patients. These data suggest that CHH results in in vivo alterations of the monocytes that lead to an increased in vitro adhesion to HUVEC, and that an increased level of plasma triglycerides is the major determinant, since HC alone does not induce this alteration.

Isolation of human and porcine monocytes and lymphocytes by three parameter flow sorting.

Monocytes and lymphocytes were separated from total human blood cells by Ficoll-paque gradient centrifugation (at 600 g) followed by two parameter fluorescence activated cell sorting (forward [FLS] and perpendicular light scatter [PLS]). For human blood cells this technique gives good separation and high purity of the monocytes (more than 85%). For porcine blood cells we modified the Ficoll-paque gradient centrifugation-step by centrifuging at a lower speed (250 g). Since two parameter flow cytometry of porcine leukocytes (FLS and PLS) gave poor resolution we added endogenous non-specific esterase activity as a third parameter using fluorescein diacetate (FDA) as a fluorogenic substrate. The sorted fractions were cytocentrifuged and purity was checked with hematoxylin and/or peroxidase staining. Moreover, monoclonal antibodies against monocyte cell surface antigens were used to evaluate the purity of the sorted fractions. Three parameter sorting (PLS, FLS and fluorescence) yields good purification of porcine monocytes (86 +/- 1% pure) and lymphocytes (81 +/- 2% pure). There was a substantial adhesion of porcine monocytes (326 +/- 25/mm2) and lymphocytes (146 +/- 21/mm2) to monolayers of porcine aorta endothelial cells (PAEC).