Arylsulfatase a Gene Polymorphisms in Relapsing Remitting Multiple Sclerosis: Genotype-Phenotype Correlation and Estimation of Disease Progression

Arylsulfatase A (ASA) is a lysosomal enzyme involved in catabolism of cerebroside-sulfate, major lipid constituent of oligodendrocyte membranes. Various polymorphisms in ASA gene have been described, leading to different levels of enzyme deficiency. Progressive demyelination occurs in metachromatic leukodystrophy (MLD), while the condition of ASA-pseudodeficiency (ASA-PD) is suggested to contribute to complex pathogenesis of multiple sclerosis (MS). This work presents usefulness of genotype-phenotype correlation in estimation of disease severity and progression. The presence of two most common mutations associated with ASA-PD was analyzed in 56 patients with diagnosis of relapsing-remitting multiple sclerosis, by polymerase chain reaction restriction fragment length polymorphism method. In MS patients confirmed as ASA-PD mutations carriers, arylsulfatase activity was determined in leukocyte homogenates by spectrophotometry. To determine whether there is a difference between disability level and/or disease progression in patients with or without mutations we have estimated disability level using Expanded disability status scale (EDSS) and disease progression using Multiple sclerosis severity score (MSSS). Correlation of genotypes and disease progression was statistically analyzed by Kruskal-Wallis test. Patients showing higher MSSS score and found to be carriers of both analyzed ASA-PD mutations were additionally examined using conventional magnetic resonance (MR) techniques. The presence of either one or both mutations was determined in 13 patients. Lower ASA activities were observed in allMS patients carrying the mutations. Nine of the mutations carriers had mild disability (EDSS=0–4.0), 1 had moderate disability (EDSS=4.5–5.5), and 3 had severe disability (EDSS6.0). On the other hand, only 3 MS patients who were mutation carriers showed MSSS values lower than 5.000 while in other MS patients-mutation carriers the MSSS values ranged from 5.267 to 9.453. Comparison of MR findings between MS patients, mutations carrier vs. non-carrier, matched for sex, age and disease duration, showed that the total number of lesions and the number of hypointense lesions on T1-weighted images was greater in MS patient carrying the ASA-PD mutations. Our results on genotype-phenotype correlation analysis indicate a possible contribution of detected arylsulfatase A gene polymorphisms to the clinical severity of multiple sclerosis, estimated by EDSS, MSSS and MR findings. The MSSS proved to be more appropriate indicator of disease progression and should be more frequently used in clinical practice especially for comparison of disease progression in different groups of patients and identification of factors that may influence disease progression such as the presence of gene polymorphisms

Arylsulfatase a Gene Polymorphisms in Relapsing Remitting Multiple Sclerosis: Genotype-Phenotype Correlation and Estimation of Disease Progression

Arylsulfatase A (ASA) is a lysosomal enzyme involved in catabolism of cerebroside-sulfate, major lipid constituent of oligodendrocyte membranes. Various polymorphisms in ASA gene have been described, leading to different levels of enzyme deficiency. Progressive demyelination occurs in metachromatic leukodystrophy (MLD), while the condition of ASA-pseudodeficiency (ASA-PD) is suggested to contribute to complex pathogenesis of multiple sclerosis (MS). This work presents usefulness of genotype-phenotype correlation in estimation of disease severity and progression. The presence of two most common mutations associated with ASA-PD was analyzed in 56 patients with diagnosis of relapsing-remitting multiple sclerosis, by polymerase chain reaction restriction fragment length polymorphism method. In MS patients confirmed as ASA-PD mutations carriers, arylsulfatase activity was determined in leukocyte homogenates by spectrophotometry. To determine whether there is a difference between disability level and/or disease progression in patients with or without mutations we have estimated disability level using Expanded disability status scale (EDSS) and disease progression using Multiple sclerosis severity score (MSSS). Correlation of genotypes and disease progression was statistically analyzed by Kruskal-Wallis test. Patients showing higher MSSS score and found to be carriers of both analyzed ASA-PD mutations were additionally examined using conventional magnetic resonance (MR) techniques. The presence of either one or both mutations was determined in 13 patients. Lower ASA activities were observed in allMS patients carrying the mutations. Nine of the mutations carriers had mild disability (EDSS=0–4.0), 1 had moderate disability (EDSS=4.5–5.5), and 3 had severe disability (EDSS6.0). On the other hand, only 3 MS patients who were mutation carriers showed MSSS values lower than 5.000 while in other MS patients-mutation carriers the MSSS values ranged from 5.267 to 9.453. Comparison of MR findings between MS patients, mutations carrier vs. non-carrier, matched for sex, age and disease duration, showed that the total number of lesions and the number of hypointense lesions on T1-weighted images was greater in MS patient carrying the ASA-PD mutations. Our results on genotype-phenotype correlation analysis indicate a possible contribution of detected arylsulfatase A gene polymorphisms to the clinical severity of multiple sclerosis, estimated by EDSS, MSSS and MR findings. The MSSS proved to be more appropriate indicator of disease progression and should be more frequently used in clinical practice especially for comparison of disease progression in different groups of patients and identification of factors that may influence disease progression such as the presence of gene polymorphisms

UPDATE ON GUIDELINES FOR PHARMACOLOGICAL TREATMENT OF MULTIPLE SCLEROSIS BY THE CROATIAN SOCIETY FOR NEUROVASCULAR DISORDERS OF THE CROATIAN MEDICAL ASSOCIATION AND CROATIAN SOCIETY OF NEUROIMMUNOLOGY AND NEUROGENETICS

Multipla skleroza (MS) je bolest središnjeg živčanog sustava koja se prezentira brojnim simptomima iz različitih funkcijskih cjelina toga sustava. Kako se posljednjih godina povećao broj dostupnih lijekova, ukazuje se potreba trajne provjere saznanja o dijagnostici i liječenju ove bolesti putem medicine temeljene na dokazima. Time se nameće i potreba kontinuiranog obnavljanja nacionalnih i međunarodnih smjernica, u našem slučaju, na razini regionalnih smjernica Europskog odbora za liječenje i istraživanje multiple skleroze (engl. ECTRIMS, European Committee of Treatment and Research in Multiple Sclerosis) i Europske neurološke akademije (engl. EAN, European Academy of Neurology) s ciljem omogućavanja najbolje medicinske terapije za svakog bolesnika, koja je temeljena na individualiziranom pristupu. Temelji novih smjernica su nedavno ažurirane EAN-ove preporuke za razvoj smjernica, koje su rezultat iscrpnog istraživanja literature do prosinca 2016. godine. S obzirom na rizik od sistemske pogreške, kvaliteta dokaza za svaki ishod bila je stupnjevana u četiri kategorije kako slijedi: vrlo visoka, visoka, niska i vrlo niska. S obzirom na kvalitetu dokaza te omjera rizika i dobrobiti preporukama je pridružena snažna i slaba jačina. Pozornost istraživanja bila je usmjerena na nekoliko najvažnijih pitanja, koja su obuhvaćala uspješnost liječenja, odgovor na primijenjenu terapiju, strategiju za prepoznavanje odgovarajućeg odgovora i sigurnost, te terapijsku strategiju liječenja multiple skleroze u trudnoći. Smjernicama su obuhvaćeni svi lijekovi koji modifi ciraju tijek bolesti, a koji su odobreni od strane Europske agencije za lijekove (engl. EMA, European Medicine Agency). U posebne skupine raspoređeni su bolesnici s klinički izoliranim sindromom koji ne ispunjavaju dijagnostičke kriterije za klinički defi nitivnu MS, dok su bolesnici s dokazanom MS podijeljeni s obzirom na različite kliničke podtipove MS-a sukladno važećim dijagnostičkim smjernicama.Multiple sclerosis (MS) affects the central nervous system (CNS) and presents by numerous symptoms from different CNS functional systems. As the number of available treatments has increased in recent years, the need has emerged for continuous evaluation on MS diagnosis and treatment based on evidence-based medicine. This implies the need for continuous renewal of national and international guidelines, in our case, based on the regional guidelines of the European Committee for Treatment and Research in Multiple Sclerosis and European Academy of Neurology (EAN) with the aim of providing the best medical therapy for each patient, based on an individualized approach. These new guidelines are based on the recently updated EAN recommendations that have been derived as the result of exhaustive literature research as of December 2016. Given the risk of system error, the quality of evidence for each outcome has been subdivided into four categories, as follows: very high, high, low and very low. Given the quality of evidence and the risk and benefit ratio, the recommendations are accompanied by strong and weak strength. The research was focused on several key issues, including treatment effectiveness, response to therapy applied, strategy for recognizing appropriate response and safety, and therapeutic strategy for MS treatment during pregnancy. The guidelines cover all medicines that modify the course of the disease and are approved by the European Medicines Agency. Patients with clinically isolated syndrome that do not meet diagnostic criteria for clinically definitive MS have been assigned to special groups while patients with proven MS are divided into different clinical subtypes of MS in accordance with valid diagnostic guidelines

UPDATE ON GUIDELINES FOR PHARMACOLOGICAL TREATMENT OF MULTIPLE SCLEROSIS BY THE CROATIAN SOCIETY FOR NEUROVASCULAR DISORDERS OF THE CROATIAN MEDICAL ASSOCIATION AND CROATIAN SOCIETY OF NEUROIMMUNOLOGY AND NEUROGENETICS

Multipla skleroza (MS) je bolest središnjeg živčanog sustava koja se prezentira brojnim simptomima iz različitih funkcijskih cjelina toga sustava. Kako se posljednjih godina povećao broj dostupnih lijekova, ukazuje se potreba trajne provjere saznanja o dijagnostici i liječenju ove bolesti putem medicine temeljene na dokazima. Time se nameće i potreba kontinuiranog obnavljanja nacionalnih i međunarodnih smjernica, u našem slučaju, na razini regionalnih smjernica Europskog odbora za liječenje i istraživanje multiple skleroze (engl. ECTRIMS, European Committee of Treatment and Research in Multiple Sclerosis) i Europske neurološke akademije (engl. EAN, European Academy of Neurology) s ciljem omogućavanja najbolje medicinske terapije za svakog bolesnika, koja je temeljena na individualiziranom pristupu. Temelji novih smjernica su nedavno ažurirane EAN-ove preporuke za razvoj smjernica, koje su rezultat iscrpnog istraživanja literature do prosinca 2016. godine. S obzirom na rizik od sistemske pogreške, kvaliteta dokaza za svaki ishod bila je stupnjevana u četiri kategorije kako slijedi: vrlo visoka, visoka, niska i vrlo niska. S obzirom na kvalitetu dokaza te omjera rizika i dobrobiti preporukama je pridružena snažna i slaba jačina. Pozornost istraživanja bila je usmjerena na nekoliko najvažnijih pitanja, koja su obuhvaćala uspješnost liječenja, odgovor na primijenjenu terapiju, strategiju za prepoznavanje odgovarajućeg odgovora i sigurnost, te terapijsku strategiju liječenja multiple skleroze u trudnoći. Smjernicama su obuhvaćeni svi lijekovi koji modifi ciraju tijek bolesti, a koji su odobreni od strane Europske agencije za lijekove (engl. EMA, European Medicine Agency). U posebne skupine raspoređeni su bolesnici s klinički izoliranim sindromom koji ne ispunjavaju dijagnostičke kriterije za klinički defi nitivnu MS, dok su bolesnici s dokazanom MS podijeljeni s obzirom na različite kliničke podtipove MS-a sukladno važećim dijagnostičkim smjernicama.Multiple sclerosis (MS) affects the central nervous system (CNS) and presents by numerous symptoms from different CNS functional systems. As the number of available treatments has increased in recent years, the need has emerged for continuous evaluation on MS diagnosis and treatment based on evidence-based medicine. This implies the need for continuous renewal of national and international guidelines, in our case, based on the regional guidelines of the European Committee for Treatment and Research in Multiple Sclerosis and European Academy of Neurology (EAN) with the aim of providing the best medical therapy for each patient, based on an individualized approach. These new guidelines are based on the recently updated EAN recommendations that have been derived as the result of exhaustive literature research as of December 2016. Given the risk of system error, the quality of evidence for each outcome has been subdivided into four categories, as follows: very high, high, low and very low. Given the quality of evidence and the risk and benefit ratio, the recommendations are accompanied by strong and weak strength. The research was focused on several key issues, including treatment effectiveness, response to therapy applied, strategy for recognizing appropriate response and safety, and therapeutic strategy for MS treatment during pregnancy. The guidelines cover all medicines that modify the course of the disease and are approved by the European Medicines Agency. Patients with clinically isolated syndrome that do not meet diagnostic criteria for clinically definitive MS have been assigned to special groups while patients with proven MS are divided into different clinical subtypes of MS in accordance with valid diagnostic guidelines

Arylsulfatase a gene polymorphisms in relapsing remitting multiple sclerosis: genotype-phenotype correlation and estimation of disease progression [Polimorfizmi u genu za arilsulfatazu A i relapsno-remitirajuća multipla skleroza: koleracija genotipa i fenotipa u svrhu procjene progresije bolesti]

Arylsulfatase A (ASA) is a lysosomal enzyme involved in catabolism of cerebroside-sulfate, major lipid constituent of oligodendrocyte membranes. Various polymorphisms in ASA gene have been described, leading to different levels of enzyme deficiency. Progressive demyelination occurs in metachromatic leukodystrophy (MLD), while the condition of ASA-pseudodeficiency (ASA-PD) is suggested to contribute to complex pathogenesis of multiple sclerosis (MS). This work presents usefulness of genotype-phenotype correlation in estimation of disease severity and progression. The presence of two most common mutations associated with ASA-PD was analyzed in 56 patients with diagnosis of relapsing-remitting multiple sclerosis, by polymerase chain reaction restriction fragment length polymorphism method. In MS patients confirmed as ASA-PD mutations carriers, arylsulfatase activity was determined in leukocyte homogenates by spectrophotometry. To determine whether there is a difference between disability level and/or disease progression in patients with or without mutations we have estimated disability level using Expanded disability status scale (EDSS) and disease progression using Multiple sclerosis severity score (MSSS). Correlation of genotypes and disease progression was statistically analyzed by Kruskal-Wallis test. Patients showing higher MSSS score and found to be carriers of both analyzed ASA-PD mutations were additionally examined using conventional magnetic resonance (MR) techniques. The presence of either one or both mutations was determined in 13 patients. Lower ASA activities were observed in allMS patients carrying the mutations. Nine of the mutations carriers had mild disability (EDSS=0–4.0), 1 had moderate disability (EDSS=4.5–5.5), and 3 had severe disability (EDSS>or=6.0). On the other hand, only 3 MS patients who were mutation carriers showed MSSS values lower than 5.000 while in other MS patients-mutation carriers the MSSS values ranged from 5.267 to 9.453. Comparison of MR findings between MS patients, mutations carrier vs. non-carrier, matched for sex, age and disease duration, showed that the total number of lesions and the number of hypointense lesions on T1-weighted images was greater in MS patient carrying the ASA-PD mutations. Our results on genotype-phenotype correlation analysis indicate a possible contribution of detected arylsulfatase A gene polymorphisms to the clinical severity of multiple sclerosis, estimated by EDSS, MSSS and MR findings. The MSSS proved to be more appropriate indicator of disease progression and should be more frequently used in clinical practice especially for comparison of disease progression in different groups of patients and identification of factors that may influence disease progression such as the presence of gene polymorphisms

Progression of multiple sclerosis is associated with gender differences in glutathione S-transferase P1 detoxification pathway

The impact of glutathione S-transferases (GSTs) detoxification pathway on complex pathogenesis and heterogeneity of clinical findings in multiple sclerosis (MS), particularly the exact correlation between indicators of clinical severity and different GST genotypes, has not yet been fully elucidated. The aim of the study was to assess the relationship between disability level in multiple sclerosis (estimated by Kurtzke Expanded Disability Status Scale), disease progression (estimated by Multiple Sclerosis Severity Score), the level of brain atrophy and lesion load (determined by MRI) and detoxification status (analyzing glutathione S-transferase P1, GSTP1, genotype profile), in a group of 58 MS patients and 68 age/gendermatched controls. The results present the first evidence on significantly higher frequency of GSTP1 C341T polymorphism (C-T transition) in healthy subjects compared to MS patients, suggesting it may act as a moderating factor in developing MS clinical phenotype. Gender-dependent distribution of the C341T polymorphism was found in both MS patients and controls, with higher frequency of C-T transition in females. In addition, preliminary data showed higher proportion of male MS patients with higher median MSSS scores, as well as lower brain atrophy level and lesion load in MS patients carrying the C341T mutation. Observed gender difference in distribution of the C341T polymorphism in MS patients, as well as in disease progression, suggests that GSTP1 detoxification pathway occurs in a gender-dependent manner and could therefore add to clinical severity in male MS patients

Dynamics of distribution of (3)H-inulin between the cerebrospinal fluid compartments

Since the distribution of substances between various cerebrospinal fluid (CSF) compartments is poorly understood, we studied (3)H-inulin distribution, over time, after its injection into cisterna magna (CM) or lateral ventricle (LV) or cisterna corporis callosi (CCC) in dogs. After the injection into CM (3)H-inulin was well distributed to cisterna basalis (CB), lumbar (LSS) and cortical (CSS) subarachnoid spaces and less distributed to LV. When injected in LV (3)H-inulin was well distributed to all CSF compartments. However, after injection into CCC (3)H-inulin was mostly localized in CCC and adjacent CSS, while its concentrations were much lower in CM and CB and very low in LSS and LV. Concentrations of (3)H-inulin in venous plasma of superior sagittal sinus and arterial plasma were very low and did not differ significantly, while its concentration in urine was very high. In (3)H-inulin distribution it seems that two simultaneous processes are relevant: a) the pulsation of CSF with to-and-fro displacement of CSF and its mixing, carrying (3)H-inulin in all directions, and b) the passage of (3)H-inulin from CSF into nervous parenchyma and its rapid distribution to a huge surface area of capillaries by vessels pulsations. (3)H-inulin then slowly diffuses across capillary walls into the bloodstream to be eliminated in the urine

Lack of CD4+ T cell percent decrease in alemtuzumab-treated multiple sclerosis patients with persistent relapses

Alemtuzumab, a highly effective treatment for relapsing remitting multiple sclerosis (RRMS), induces lymphopenia especially of CD4+ T cells. Here, we report the atypical CD4+ T population behaviour of two patients with persistent disease activity despite repeated alemtuzumab treatments. Whereas lymphocytes count decreased and fluctuated accordingly to alemtuzumab administration, their CD4+ cell percentage was not or just mildly affected and was slightly below the lowest normal limit already before alemtuzumab. These cases anticipate further studies aimed to investigate whether the evaluation of the CD4+ cell percentage could represent a helpful tool to address the individual clinical response to alemtuzumab

Long-Term Effects of Alemtuzumab on CD4+ Lymphocytes in Multiple Sclerosis Patients: A 72-Month Follow-Up

Introduction: Alemtuzumab is highly effective in the treatment of patients with relapsing multiple sclerosis (PwRMS) and selectively targets the CD52 antigen, with a consequent profound lymphopenia, particularly of CD4+ T lymphocytes. However, the immunological basis of its long-term efficacy has not been clearly elucidated. ----- Methods: We followed up 29 alemtuzumab-treated RMS patients over a period of 72 months and studied the immunological reconstitution of their CD4+ T cell subsets by means of phenotypic and functional analysis and through mRNA-related molecule expression, comparing them to healthy subject (HS) values (rate 2:1). ----- Results: In patients receiving only two-course alemtuzumab, the percentage of CD4+ lymphocytes decreased and returned to basal levels only at month 48. Immune reconstitution of the CD4+ subsets was characterized by a significant increase (p < 0.001) in Treg cell percentage at month 24, when compared to baseline, and was accompanied by restoration of the Treg suppressor function that increased within a range from 2- to 6.5-fold compared to baseline and that persisted through to the end of the follow-up. Furthermore, a significant decrease in self-reactive myelin basic protein-specific Th17 (p < 0.0001) and Th1 (p < 0.05) cells reaching HS values was observed starting from month 12. There was a change in mRNA of cytokines, chemokines, and transcriptional factors related to Th17, Th1, and Treg cell subset changes, consequently suggesting a shift toward immunoregulation and a reduction of T cell recruitment to the central nervous system. ----- Conclusions: These data provide further insight into the mechanism that could contribute to the long-term 6-year persistence of the clinical effect of alemtuzumab on RMS disease activity

Update on guidelines for pharmacological treatment of multiple sclerosis by the croatian society for neurovascular disorders of the Croatian medical association and Croatian society of neuroimmunology and neurogenetics

Multipla skleroza (MS) je bolest središnjeg živčanog sustava koja se prezentira brojnim simptomima iz različitih funkcijskih cjelina toga sustava. Kako se posljednjih godina povećao broj dostupnih lijekova, ukazuje se potreba trajne provjere saznanja o dijagnostici i liječenju ove bolesti putem medicine temeljene na dokazima. Time se nameće i potreba kontinuiranog obnavljanja nacionalnih i međunarodnih smjernica, u našem slučaju, na razini regionalnih smjernica Europskog odbora za liječenje i istraživanje multiple skleroze (engl. ECTRIMS, European Committee of Treatment and Research in Multiple Sclerosis) i Europske neurološke akademije (engl. EAN, European Academy of Neurology) s ciljem omogućavanja najbolje medicinske terapije za svakog bolesnika, koja je temeljena na individualiziranom pristupu. Temelji novih smjernica su nedavno ažurirane EAN-ove preporuke za razvoj smjernica, koje su rezultat iscrpnog istraživanja literature do prosinca 2016. godine. S obzirom na rizik od sistemske pogreške, kvaliteta dokaza za svaki ishod bila je stupnjevana u četiri kategorije kako slijedi: vrlo visoka, visoka, niska i vrlo niska. S obzirom na kvalitetu dokaza te omjera rizika i dobrobiti preporukama je pridružena snažna i slaba jačina. Pozornost istraživanja bila je usmjerena na nekoliko najvažnijih pitanja, koja su obuhvaćala uspješnost liječenja, odgovor na primijenjenu terapiju, strategiju za prepoznavanje odgovarajućeg odgovora i sigurnost, te terapijsku strategiju liječenja multiple skleroze u trudnoći. Smjernicama su obuhvaćeni svi lijekovi koji modifi ciraju tijek bolesti, a koji su odobreni od strane Europske agencije za lijekove (engl. EMA, European Medicine Agency). U posebne skupine raspoređeni su bolesnici s klinički izoliranim sindromom koji ne ispunjavaju dijagnostičke kriterije za klinički defi nitivnu MS, dok su bolesnici s dokazanom MS podijeljeni s obzirom na različite kliničke podtipove MS-a sukladno važećim dijagnostičkim smjernicam