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See detailPhenotypical characterization of alpha-galactosidase A gene mutations identified in a large Fabry disease screening program in stroke in the young.
De Brabander, Isabel; Yperzeele, Laetitia; Ceuterick-De Groote, Chantal et al

in Clinical Neurology & Neurosurgery (2013), 115(7),

OBJECTIVE: In the Belgian Fabry Study (BeFaS), the prevalence of Fabry disease was assessed in 1000 young patients presenting with stroke, unexplained white matter lesions or vertebrobasilar ... [more ▼]

OBJECTIVE: In the Belgian Fabry Study (BeFaS), the prevalence of Fabry disease was assessed in 1000 young patients presenting with stroke, unexplained white matter lesions or vertebrobasilar dolichoectasia. The results of the BeFaS suggested that Fabry disease may play a role in up to 1% of young patients presenting with cerebrovascular disease. However, the clinical relevance was unclear in all cases. We report on detailed phenotyping in subjects identified with alpha-galactosidase A (alpha-Gal A) enzyme deficiency or GLA mutations identified in the BeFaS (n=10), and on the results of family screening in this population. METHODS: Family screening was performed to identify additional mutation carriers. Biochemical and/or clinical evaluation of all subjects (BeFaS index patients and relatives carrying a GLA mutation) was performed. RESULTS: Genetic family screening revealed 18 additional GLA mutation carriers. Bloodspot alpha-Gal A enzyme activity was normal in all GLA mutation carriers, even in 2 males with the p.A143T mutation. Plasma Gb3 and lyso-Gb3 levels were normal in all subjects. Elevated Gb3 in urine was detected in 2 subjects. Some classic clinical signs of Fabry disease, like angiokeratoma or cornea verticillata, could not be detected in our population. Cardiac symptoms of Fabry disease were found in 6 out of 10 p.A143T carriers. No signs of cerebrovascular disease were found in the relatives with a GLA mutation. CONCLUSIONS: We could not identify mutations causing the classical clinical phenotype of Fabry disease in our cerebrovascular disease population. Enzyme activity analysis in bloodspots and plasma may fail to identify late-onset variants of Fabry disease. We recommend genetic testing when an atypical, late-onset variant of Fabry disease is suspected in a male cerebrovascular disease patient. However, this may lead to the identification of non-disease causing or controversial genetic variants. [less ▲]

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See detailDetection and Quantification of Efficiency and Quality of Gait Impairment in Multiple Sclerosis through Foot Path Analysis
PHAN BA, Remy ULg; Pierard, Sébastien ULg; MOONEN, Gustave ULg et al

Poster (2012, October 11)

Introduction: Walking speed is generally considered as the best outcome measure in trials for people with multiple sclerosis (pMS). We recently designed a device based on range laser scanner capable to ... [more ▼]

Introduction: Walking speed is generally considered as the best outcome measure in trials for people with multiple sclerosis (pMS). We recently designed a device based on range laser scanner capable to track feet paths of walking subjects. Our purpose was to explore gait descriptors of pMS and compare them with those of healthy volunteers (HV). Methods: Fourty-four pMS (considered as moderatly or highly disabled according to a cut-off EDSS value of 3.0) and 28 HV performed 4 walking tasks along 2 trajectories in 3 walking modes. Twenty-six gait descriptors crudely dichotomized in « efficiency» and « quality » of gait were compared in the 2 populations using unpaired t-tests. Results: (i) apart from an older age in pMS, the two populations were comparable, (ii) efficiency of gait descriptors including walking speed distinguished HV from pMS, and pMS with moderate from pMS with high disability, (iii) quality of gait descriptors were also significantly altered in pMS, including in walking tasks where their walking speed was comparable to that of HV. Conclusions: RLS technology can distinguish pMS from HV according to (i) more efficiency of gait descriptors than the sole walking speed and (ii) quality of gait descriptors, including in subjects with a « normal » walking speed. [less ▲]

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See detailThe earlier the smaller the better for natalizumab-associated PML: in MRI vigilance veritas ?
PHAN BA, Remy ULg; Belachew, Shibeshih ULg; Outteryck, Olivier et al

in Neurology (2012), 79

Natalizumab-associated progressive multifocal leukoencephalopathy (N-PML) in multiple sclerosis (MS) is due to CNS infection by the opportunistic JC virus (JCV). As of december 2011, 193 confirmed cases ... [more ▼]

Natalizumab-associated progressive multifocal leukoencephalopathy (N-PML) in multiple sclerosis (MS) is due to CNS infection by the opportunistic JC virus (JCV). As of december 2011, 193 confirmed cases of N-PML have been observed, giving rise to an overall risk of approximately 0,202%. N-PML pathogenesis remains partially elusive although risk factors have now been clearly delineated. In patients with prior JCV infection detected by serum anti-JCV antibodies, duration of therapy and prior use of immunosuppressants (IS) increase the risk of N-PML. The clinical outcome of MS patients who developed N-PML was highly variable, ranging from asymptomatic case to varying degrees of neurological disability or even death. It was also observed in real life setting that the earlier N-PML was diagnosed and treated, the better was the clinical outcome. Clinical vigilance is now considered as the established cornerstone of PML risk-management algorithm. Here we present early MRI features of 4 out of 8 N-PML cases, which were observed in Wallonia-Brussels and Northern France in more than 4 years of post-marketing utilization of natalizumab for both regions. We are not aware of the specific context and outcome of the 4 other N-PML cases, which were diagnosed and treated in other centers. The reported cases emphasize that (i) N-PML can have a long presymptomatic course while still being clearly detectable with MR imaging, (ii) N-PML can have a benign outcome provided it is diagnosed and treated early, (iii) a clinically symptomatic N-PML may be a further advanced infection with a poorer prognosis, and (iv) periodic brain MR scans, particularly in high risk situations, are likely to provide earlier detection of N-PML and better outcomes. [less ▲]

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See detailMotor fatigue measurement by distance-induced slow down of walking speed in multiple sclerosis
PHAN BA, Remy ULg; CALAY, Philippe ULg; GRODENT, Patrick ULg et al

in PLoS ONE (2012), 7(4), 34744

Background: Motor fatigue and ambulation impairment are prominent clinical features of people with multiple sclerosis (pMS). We hypothesized that a multimodal and comparative assessment of walking speed ... [more ▼]

Background: Motor fatigue and ambulation impairment are prominent clinical features of people with multiple sclerosis (pMS). We hypothesized that a multimodal and comparative assessment of walking speed on short and long distance would allow a better delineation and quantification of gait fatigability in pMS. Objectives: To compare 4 walking paradigms: the timed 25-foot walk (T25FW), a corrected version of the T25FW with dynamic start (T25FW+), the timed 100-meter walk (T100MW) and the timed 500-meter walk (T500MW). Methods: Thirty controls and 81 pMS performed the 4 walking tests in a single study visit. Results: The 4 walking tests were performed with a slower WS in pMS compared to controls even in subgroups with minimal disability. The finishing speed of the last 100-meter of the T500MW was the slowest measurable WS whereas the T25FW+ provided the fastest measurable WS. The ratio between such slowest and fastest WS (Deceleration Index, DI) was significantly lower only in pMS with EDSS 4.0-6.0, a pyramidal or cerebellar functional system score reaching 3 or a maximum reported walking distance !4000m. Conclusion: The motor fatigue which triggers gait deceleration over a sustained effort in pMS can be measured by the WS ratio between performances on a very short distance and the finishing pace on a longer more demanding task. The absolute walking speed is abnormal early in MS whatever the distance of effort when patients are unaware of ambulation impairment. In contrast, the DI-measured ambulation fatigability appears to take place later in the disease course. [less ▲]

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See detailImmune Reconstitution Inflammatory Syndrome in Natalizumab-Associated PML
Phan-Ba, Rémy ULg; LOMMERS, Emilie ULg; Moonen, Gustave ULg et al

in Neurology (2012), 78(1), 73

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See detailMultimodal evaluation of gait and stride dynamics in relapsing and progressive forms of multiple sclerosis
Belachew, Shibeshih ULg; Pierard, Sébastien ULg; PHAN BA, Remy ULg et al

in Proceedings of the Belgian Royal Academies of Medicine (2012), 1

Ambulation measures are being increasingly recognized as highly relevant to the quantification of multiple sclerosis (MS) severity and response to treatment. Feet paths are highly informative for gait ... [more ▼]

Ambulation measures are being increasingly recognized as highly relevant to the quantification of multiple sclerosis (MS) severity and response to treatment. Feet paths are highly informative for gait analysis and we have recently designed a new system, which captures the position of the feet in real time. We use several range laser scanners (RLS) to analyze a horizontal slice of the scene in which each foot is considered as a point, and the vertical movements are ignored. Neat ambulation measures may be easily extracted such as walking speed, distance between feet over time, swing phase duration, and gait asymmetry in specific settings of walking recommendations. Our RLS platform is much cheaper than existing sensor-based and motion capture systems and may be more convenient for the development of multicentric clinical trials settings since patients can be easily and rapidly assessed without tags or sensors in the hallway of an outpatient clinic. We use 4 BEA LZR-i100 RLS arranged in a corridor of at least 10m long and 4m width, devoid of obstacle. The scanned plane is chosen to be located at 15 cm above the floor, which is right above the tibio-tarsal joint of the ankle in a barefoot configuration for adult individuals in stance phase. We expect further studies to validate and empower the meaning of non-intrusive RLS-derived gait measures that should pave the ground for major improvements in the way we will assess the efficacy of disease-modifying treatments (DMTs), physical therapy and symptomatic interventions on walking impairment, ataxia and fatigability in MS. RLS-derived gait measures may also reveal to be crucial in the near future for the development of treatments that would specifically target progressive forms of MS. [less ▲]

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See detailA corrected version of the Timed-25 Foot Walk Test with a dynamic start to capture the maximum ambulation speed in multiple sclerosis patients
Phan-Ba, Rémy ULg; CALAY, Philippe ULg; GRODENT, Patrick ULg et al

in NeuroRehabilitation (2012), 30(4), 261-266

Background : No clinical test is currently available and validated to measure the maximum walking speed (WS) of multiple sclerosis (MS) patients. Since the Timed 25-Foot Walk Test (T25FW) is performed ... [more ▼]

Background : No clinical test is currently available and validated to measure the maximum walking speed (WS) of multiple sclerosis (MS) patients. Since the Timed 25-Foot Walk Test (T25FW) is performed with a static start, it takes a significant proportion of the distance for MS patients to reach their maximum pace. Objectives : In order to capture the maximum WS and to quantify the relative impact of the accelerating phase during the first meters, we compared the classical T25FW with a modified version (T25FW+) allowing a dynamic start after a 3 meters run-up. Methods : Sixty-four MS patients and 30 healthy subjects performed successively the T25FW and the T25FW+. Results : The T25FW+ was performed faster than the T25FW for the vast majority of MS and healthy subjects. In the MS population, the mean relative gain of speed due to the dynamic start on T25FW+ was independent from the EDSS and from the level of ambulation impairment. Compared to healthy subjects, the relative difference between dynamic versus static start was more important in the MS population even in patients devoid of apparent gait impairment according to the T25FW. Conclusion : The T25FW+ allows a more accurate measurement of the maximum WS of MS patients, which is a prerequisite to reliably evaluate deceleration over longer distance tests. Indirect arguments suggest that the time to reach the maximum WS may be partially influenced by the cognitive impairment status. The maximum WS and the capacity of MS patients to accelerate on a specific distance may be independently regulated and assessed separately in clinical trials and rehabilitation programs. [less ▲]

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See detailVitamin D tweets light to genes in multiple sclerosis
LOMMERS, Emilie ULg; Lecrompe, Laurence ULg; Moonen, Gustave ULg et al

in Revue Médicale de Liège (2012), 67(5-6), 359-365

The relationship between sunlight exposure and the incidence of multiple sclerosis and the understanding of immunomodulatory effects of vitamin D triggered, in recent years, a broad range of ... [more ▼]

The relationship between sunlight exposure and the incidence of multiple sclerosis and the understanding of immunomodulatory effects of vitamin D triggered, in recent years, a broad range of investigations. Immunological studies performed in vitro and in vivo have demonstrated how tolerogenic vitamin D can be. Epidemiological studies confirmed an increased incidence of multiple sclerosis in vitamin D deficient subjects and signs of increased disease activity in such MS patients. Although small-scale observational studies have suggested a beneficial impact of vitamin D supplementation on the incidence and severity of multiple sclerosis, large scale clinical trials remain warranted to confirm these preliminary results. [less ▲]

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See detailMRI preclinical detection and asymptomatic course of a progressive multifocal leucoencephalopathy (PML) under natalizumab therapy.
Phan-Ba, Rémy ULg; LOMMERS, Emilie ULg; TSHIBANDA, Luaba ULg et al

in Journal of Neurology, Neurosurgery & Psychiatry (2012), 83

Early detection of progressive multifocal leucoencephalopathy (PML) in the setting of natalizumab therapy currently is performed by rapid evaluation of new symptoms occurring in treated patients. The role ... [more ▼]

Early detection of progressive multifocal leucoencephalopathy (PML) in the setting of natalizumab therapy currently is performed by rapid evaluation of new symptoms occurring in treated patients. The role of MR scanning has not been investigated but holds promise since MR detection is highly sensitive for PML lesions. The authors report a case of presymptomatic PML of the posterior fossa detected by MR scans. Immediate suspension of natalizumab and plasma exchanges resulted in a rapid decline of natalizumab serum concentration. Intravenous steroids started together with plasma exchanges followed by an oral tapering course were used to minimise the immune reconstitution inflammatory syndrome. No symptoms (beyond mild headache) developed, and the repeat PCR for JC Virus (JCV) DNA detection performed 10 weeks later was negative. This case suggests that: (1) periodic brain MR scans may detect signs of presymptomatic PML in MS patients treated with natalizumab, (2) corticosteroid management of inflammatory reaction may contribute to optimal control of the immune reconstitution inflammatory syndrome routinely seen with natalizumab-associated PML and (3) early radiological detection of PML can have an excellent outcome even in a clinically critical region and despite prior immunosuppressant exposure. The potential benefit of regular MR scanning just using the T2/FLAIR modalities could be further investigated in order to detect early natalizumab-associated PML, leading to benign outcomes. [less ▲]

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See detailA new low-cost and non-intrusive feet tracker
Pierard, Sébastien ULg; PHAN BA, Remy ULg; Van Droogenbroeck, Marc ULg et al

in Workshop on Circuits, Systems and Signal Processing (ProRISC) (2011, November)

Capturing gait is useful for many applications, including video-surveillance and medical purposes. The most common sensors used to capture gait suffer from significant drawbacks. We have therefore ... [more ▼]

Capturing gait is useful for many applications, including video-surveillance and medical purposes. The most common sensors used to capture gait suffer from significant drawbacks. We have therefore designed a new low-cost and nonintrusive system to capture gait. Our system is able to track the feet on the horizontal plane in both the stance and the swing phases by combining measures of several range laser scanners. The number of sensors can be adjusted according to the target application specifications. The first issue addressed in this work is the calibration: we have to know the precise location of the sensors in a plane, and their orientations. The second issue addressed is how to calculate feet coordinates from the distance profiles given by the sensors. Our method has proven to be robust and precise to measure gait abnormalities in various medical conditions, especially neurological diseases (with a focus on multiple sclerosis). [less ▲]

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See detailPrimary central nervous system lymphoma in a patient treated with Natalizumab.
Phan-Ba, Rémy ULg; Bisig, Bettina ULg; Deprez, Manuel ULg et al

in Annals of Neurology (2011), 69(6), 1060-1

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See detailRadiation-induced malignant peripheral nerve sheat tumors – a report of 2 cases
PHAN BA, Remy ULg; BELACHEW, Shibeshih ULg; JEDIDI, Zayd ULg et al

Poster (2011, May)

We discuss the case of two patients who developped delayed malignant peripheral nerve sheath tumor (MPNST) following radiotherapy. Case report: the first patient is a sixty year-old woman with a 2 years ... [more ▼]

We discuss the case of two patients who developped delayed malignant peripheral nerve sheath tumor (MPNST) following radiotherapy. Case report: the first patient is a sixty year-old woman with a 2 years history of right cervicobrachial pain and weakness. The neurological examination depicted severe weakness, atrophy and loss of sensation in the right C5 and C6 territories. A subclavicular hardened and enlarged lymph node was noted. Her past medical history was notable for a Hodgkin’s disease (HD) treated with radiation therapy (>40Gy) 35 years earlier. Brachial plexus MRI revealed a tumoral mass arising from the right brachial plexus. Biopsy of the subclavicular mass revealed a poorly differentiated malignant tumour consisting of spindle cells showing moderate polymorphism and a high mitotic index. Immunohistochemistry showed positivity for the S-100 protein, the CD56 and for the epithelial membrane antigen (EMA) and a diagnosis of MPNST of the brachial plexus was proposed. The second case is a 36 year-old man referred for a history of right sciatic neuralgia that appeared 3 years earlier. The medical history of the patient was notable for a right seminoma, treated by orchidectomy and prophylactic radiotherapy (24 Gy) 5 years earlier. The neurologic examination revealed right L5 and S1 radicular territories involvement, and the CT of the pelvis demonstrated a nodular mass at the level of the greater sciatic foramen. A surgical biopsy was performed and the neuropathological findings were consistent with a diagnosis of low-grade MPSNT. Discussion: MPNSTs are rare tumors accounting for 3 to 10% of all tissues sarcomas. Half of the cases described are sporadic, while the other half tend to appear in patients suffering from tumor prone conditions, such as neurofibromatosis type 1. Although secondary neoplasms are known complications of radiotherapy, descriptions of peripheral nerve sheath tumors (PNST) are scarce. The exact pathophysiology of radiation-induced PNSTs remains unclear but vascular alterations, direct damages to axon or Schwann cell and nerve compression by soft tissue fibrosis are thought to play a role. Although surgical removal sometimes followed by chemotherapy is the mainstay of MPNSTs, they usually carry a poor prognosis. Our 2 cases emphasize that the possibility of radiation-induced MPNST has to be kept in mind when investigating a localized neuropathy in a previously irradiated area. [less ▲]

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See detailComparison of the Timed 25-Foot and the 100-Meter Walk as Performance Measures in Multiple Sclerosis
Phan-Ba, Rémy ULg; Pace, Amy; CALAY, Philippe ULg et al

in Neurorehabilitation and neural repair (2011), 25(7), 672-9

BACKGROUND: Ambulation impairment is a major component of physical disability in multiple sclerosis (MS) and a major target of rehabilitation programs. Outcome measures commonly used to evaluate walking ... [more ▼]

BACKGROUND: Ambulation impairment is a major component of physical disability in multiple sclerosis (MS) and a major target of rehabilitation programs. Outcome measures commonly used to evaluate walking capacities suffer from several limitations. OBJECTIVES: To define and validate a new test that would overcome the limitations of current gait evaluations in MS and ultimately better correlate with the maximum walking distance (MWD). METHODS: The authors developed the Timed 100-Meter Walk Test (T100MW), which was compared with the Timed 25-Foot Walk Test (T25FW). For the T100MW, the subject is invited to walk 100 m as fast as he/she can. In MS patients and healthy control volunteers, the authors measured the test-retest and interrater intraclass correlation coefficient. Spearman rank correlations were obtained between the T25FW, the T100MW, the Expanded Disability Status Scale (EDSS), and the MWD. The coefficient of variation, Bland-Altman plots, the coefficient of determination, and the area under the receiver operator characteristic curve were measured. The mean walking speed (MWS) was compared between the 2 tests. RESULTS: A total of 141 MS patients and 104 healthy control volunteers were assessed. Minor differences favoring the T100MW over the T25FW were observed. Interestingly, the authors demonstrated a paradoxically higher MWS on a long (T100MW) rather than on a short distance walk test (T25FW). CONCLUSION: The T25FW and T100MW displayed subtle differences of reproducibility, variability, and correlation with MWD favoring the T100MW. The maximum walking speed of MS patients may be poorly estimated by the T25FW since MS patients were shown to walk faster over a longer distance. [less ▲]

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See detailCdk6-dependent regulation of g(1) length controls adult neurogenesis.
Beukelaers, Pierre; Vandenbosch, Renaud ULg; Caron, Nicolas ULg et al

in Stem Cells (2011), 29(4), 713-24

The presence of neurogenic precursors in the adult mammalian brain is now widely accepted, but the mechanisms coupling their proliferation with the onset of neuronal differentiation remain unknown. Here ... [more ▼]

The presence of neurogenic precursors in the adult mammalian brain is now widely accepted, but the mechanisms coupling their proliferation with the onset of neuronal differentiation remain unknown. Here, we unravel the major contribution of the G(1) regulator cyclin-dependent kinase 6 (Cdk6) to adult neurogenesis. We found that Cdk6 was essential for cell proliferation within the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles. Specifically, Cdk6 deficiency prevents the expansion of neuronally committed precursors by lengthening G(1) phase duration, reducing concomitantly the production of newborn neurons. Altogether, our data support G(1) length as an essential regulator of the switch between proliferation and neuronal differentiation in the adult brain and Cdk6 as one intrinsic key molecular regulator of this process. STEM Cells 2011;29:713-724. [less ▲]

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See detailNatalizumab to kill two birds with one stone: A case of celiac disease and multiple sclerosis.
Phan-Ba, Rémy ULg; LAMBINET, Nadine ULg; Louis, Edouard ULg et al

in Inflammatory Bowel Diseases (2011), 17(6), 62-63

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See detailNatalizumab induces a rapid improvement of disability status and ambulation after failure of previous therapy in relapsing-remitting multiple sclerosis.
Belachew, Shibeshih ULg; Phan-Ba, Rémy ULg; Bartholome, Emmanuel et al

in European Journal of Neurology (2010), 18(2), 240-245

Background: Natalizumab (Tysabri) is a monoclonal antibody that was recently approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). Our primary objective was to analyse the efficacy ... [more ▼]

Background: Natalizumab (Tysabri) is a monoclonal antibody that was recently approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). Our primary objective was to analyse the efficacy of natalizumab on disability status and ambulation after switching patients with RRMS from other disease-modifying treatments (DMTs). Methods: A retrospective, observational study was carried out. All patients (n = 45) initiated natalizumab after experiencing at least 1 relapse in the previous year under interferon-beta (IFNB) or glatiramer acetate (GA) treatments. The patients also had at least 1 gadolinium-enhancing (Gd+) lesion on their baseline brain MRI. Expanded Disability Status Scale (EDSS) scores, and performance on the Timed 25-Foot Walk Test and on the Timed 100-Metre Walk Test were prospectively collected every 4 weeks during 44 weeks of natalizumab treatment. Brain MRI scans were performed after 20 and 44 weeks of treatment. Results: Sixty-two per cent of patients showed no clinical and no radiological signs of disease activity, and 29% showed a rapid and confirmed EDSS improvement over 44 weeks of natalizumab therapy. Patients with improvement on the EDSS showed similar levels of baseline EDSS and active T1 lesions, but had a significantly higher number of relapses, and 92% of them had experienced relapse-mediated sustained EDSS worsening in the previous year. A clinically meaningful improvement in ambulation speed was observed in approximately 30% of patients. Conclusions: These results indicate that natalizumab silences disease activity and rapidly improves disability status and walking performance, possibly through delayed relapse recovery in patients with RRMS who had shown a high level of disease activity under other DMTs. [less ▲]

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See detailOligodendrocyte development and myelinogenesis are not impaired by high concentrations of phenylalanine or its metabolites.
Schoemans, Renaud; Aigrot, Marie-Stephane; Wu, Chaohong et al

in Journal of Inherited Metabolic Disease (2010), 33(2), 113-20

Phenylketonuria (PKU) is a metabolic genetic disease characterized by deficient phenylalanine hydroxylase (PAH) enzymatic activity. Brain hypomyelination has been reported in untreated patients, but its ... [more ▼]

Phenylketonuria (PKU) is a metabolic genetic disease characterized by deficient phenylalanine hydroxylase (PAH) enzymatic activity. Brain hypomyelination has been reported in untreated patients, but its mechanism remains unclear. We therefore investigated the influence of phenylalanine (Phe), phenylpyruvate (PP), and phenylacetate (PA) on oligodendrocytes. We first showed in a mouse model of PKU that the number of oligodendrocytes is not different in corpus callosum sections from adult mutants or from control brains. Then, using enriched oligodendroglial cultures, we detected no cytotoxic effect of high concentrations of Phe, PP, or PA. Finally, we analyzed the impact of Phe, PP, and PA on the myelination process in myelinating cocultures using both an in vitro index of myelination, based on activation of the myelin basic protein (MBP) promoter, and the direct quantification of myelin sheaths by both optical measurement and a bioinformatics method. None of these parameters was affected by the increased levels of Phe or its derivatives. Taken together, our data demonstrate that high levels of Phe, such as in PKU, are unlikely to directly induce brain hypomyelination, suggesting involvement of alternative mechanisms in this myelination defect. [less ▲]

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See detailBelgian Fabry study: prevalence of Fabry disease in a cohort of 1000 young patients with cerebrovascular disease.
Brouns, Raf; Thijs, Vincent; Eyskens, Francois et al

in Stroke (2010), 41(5), 863-8

BACKGROUND AND PURPOSE: Data on the prevalence of Fabry disease in patients with central nervous system pathology are limited and controversial. In this study, we assessed the prevalence of Fabry disease ... [more ▼]

BACKGROUND AND PURPOSE: Data on the prevalence of Fabry disease in patients with central nervous system pathology are limited and controversial. In this study, we assessed the prevalence of Fabry disease in young patients presenting with cerebrovascular disease in Belgium. METHODS: In this national, prospective, multicenter study, we screened for Fabry disease in 1000 patients presenting with ischemic stroke, transient ischemic attack, or intracranial hemorrhage; unexplained white matter lesions; or vertebrobasilar dolichoectasia. In male patients, we measured alpha-galactosidase A (alpha-GAL A) activity in dried blood spots. Female patients were screened for mutations by exonic DNA sequencing of the alpha-GAL A gene. RESULTS: alpha-GAL A activity was deficient in 19 men (3.5%), although all had normal alpha-GAL A gene sequences. Enzymatic deficiency was confirmed on repeat assessment in 2 male patients (0.4%). We identified missense mutations in 8 unrelated female patients (1.8%): Asp313Tyr (n=5), Ala143Thr (n=2), and Ser126Gly (n=1). The pathogenicity of the 2 former missense mutations is controversial. Ser126Gly is a novel mutation that can be linked to late-onset Fabry disease. CONCLUSIONS: alpha-GAL A deficiency may play a role in up to 1% of young patients presenting with cerebrovascular disease. These findings suggest that atypical variants of Fabry disease with late-onset cerebrovascular disease exist, although the clinical relevance is unclear in all cases. [less ▲]

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See detailNatalizumab induced freedom from disease activity after failure to previous therapy in relapsing remitting multiple sclerosis.
Belachew, Shibeshih ULg; Bartholome E.; DELVAUX, Valérie ULg et al

Conference (2009, June)

Objectives: To analyze the efficacy of natalizumab after switching relapsing-remitting multiple sclerosis (RRMS) patients from other disease modifying treaments (DMTs). Background: Natalizumab (Tysabri ... [more ▼]

Objectives: To analyze the efficacy of natalizumab after switching relapsing-remitting multiple sclerosis (RRMS) patients from other disease modifying treaments (DMTs). Background: Natalizumab (Tysabri) is a monoclonal antibody directed against VLA4 that was recently approved for the treatment of RRMS. Due to safety concerns, the use should be restricted to highly active patients and/or patients with insufficient response to other DMTs. The pivotal trials were not designed to examine the effect of natalizumab as an escalation monotherapy. Methods: Prospective, open label, observational study. All patients initiating natalizumab had experienced at least 1 relapse in the previous year under DMTs and had at least 1 Gd-enhancing lesion on their brain MRI. Previous treatment with interferon-beta (IFN-beta) or glatiramer acetate (GA) were stopped at least one week and azathioprine or mitoxantrone at least 3 months before switching. The minimum therapy duration with natalizumab was 6 months for all patients. 21 RRMS patients were included in this analysis. The mean age of the patients was 25,5 yo with mean disease duration of 6,8 years. All patients were under IFN-beta (17) or GA (4) during at least the previous year before starting natalizumab therapy. Four patients had also received azathioprine and 1 patient mitoxantrone. Results: The mean relapse rate in the previous year was 2.15 (1-4), the mean EDSS at baseline was 3.3 (1,0-6.0), the mean number of Gd+ lesions at baseline 2,58 (1-6). Under tysabri treatment the annualized relapse rate dropped to 0,20. Eleven patients improved their EDSS (0,5 to 1,5 steps down), others remained stable at 6 months. The mean number of Gd+ T1 lesions dropped to 0,23 and the mean number of new T2 lesions was 0.25 on the control MRI at 6 months. 55% of patients were free from disease activity, i.e. had no relapses, no EDSS progression, no new T2 lesion and no Gd+ T1 lesions after 6 months of Tysabri. 5 patients experienced minor adverse events (1 zona, 2 flu-like symptoms, 1 gastroenteritis, 1 allergic reaction). Conclusion: Natalizumab was well tolerated and safe as escalation therapy when previous DMTs had failed to control disease progression in this group of highly active RRMS patients. These results suggest comparable efficacy to the phase III AFFIRM trial of natalizumab when the drug is used in a context of breakthrough disease. Although data from preliminary analyses are promising, long term investigations are warranted. [less ▲]

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