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]

Bačić Baronica, Koraljka and Mlinac, Kristina and Ozretić, David and Vladić, Anton and Kalanj Bognar, Svjetlana (2011) 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]. Collegium Antropologicum, 35 (S. 1). pp. 11-16. ISSN 0350-6134

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Abstract

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.

Abstract in Croatian

Arilsulfataza A (ASA) je lizosomski enzim uključen u razgradnju cerebrozid-sulfata, glavnog lipidnog sastojka oligodendrocitnih membrana. Opisani su brojni polimorfizmi u genu za arilsulfatazu A koji imaju za posljedicu različite razine nedostatne aktivnosti enzima. Tako se kod metakromatske leukodistrofije (MLD) razvija progresivna demijelinizacija, a za ASA-pseudodeficijenciju (ASA-PD) pretpostavlja se da je povezana sa složenom patogenezom multiple skleroze (MS). Ovaj rad ukazuje na korisnost analize korelacije genotipa i fenotipa u procjeni težine i progresije bolesti. Prisutnost dviju najčešćih mutacija povezanih s ASA-PD ispitivana je metodom analize duljine restrikcijskih fragmenata u 56 pacijenata s dijagnozom relapsno-remitirajućeg oblika multiple skleroze. U pacijenata za koje je utvrđeno da su nositelji ASA-PD mutacija, određena je aktivnost arilsulfataze A u leukocitnim homogenatima spektrofotometrijskom metodom. Utvrđivanje razlika stupnja invalidnosti i/ili progresije bolesti u pacijenata sa ili bez ASA-PD mutacija temeljeno je na procjeni stupnja invalidnosti primjenom EDSS (Expanded disability status scale) i MSSS (Multiple sclerosis severity score) zbroja. Korelacija genotipa i progresije bolesti analizirana je statistički Kruskal-Wallis-ovim testom. Pacijenti s višim MSSS vrijednostima za koje je utvrđeno da ujedno imaju obje ASA-PD mutacije dodatno su pregledani konvencionalnim tehnikama magnetske rezonancije (MR). Prisutnost jedne ili obje ASA-PD mutacije utvrđena je u 13 pacijenata. U ovih je pacijenata nađena i niža aktivnost arilsulfataze A. Također je u 9 pacijenata zabilježena blaga invalidnost (EDSS=0–4,0), 1 je pacijent imao umjereni stupanj invalidnosti (EDSS=4,5–5,5), a 3 pacijenata tešku invalidnost (EDSS>ili=6,0). Samo 3 pacijenta nositelja mutacija imali su MSSS vrijednost nižu od 5,000, dok su MSSS vrijednosti ostalih nositelja mutacija bile u rasponu od 5,267 do 9,453. Usporedba nalaza MR-e između pacijenta nositelja mutacija i pacijenta bez mutacija, usklađenih po spolu, dobi i duljini trajanja bolesti, pokazala je da je ukupan broj lezija kao i broj hipointenzivnih lezija na T1-snimkama veći u pacijenta koji je nositelj ASA-PD mutacija. Rezultati analize korelacije genotipa i fenotipa ukazuju da utvrđeni polimorfizmi u genu za arilsulfatazu A mogu utjecati na težinu kliničke slike multiple skleroze, procjenjenu pomoću EDSS, MSSS i MR nalaza. MSSS zbroj dokazan je kao bolji pokazatelj progresije bolesti i trebao bi se češće koristiti u kliničkoj praksi naročito za usporedbu progresije bolesti među različitim skupinama bolesnika te za prepoznavanje faktora koji mogu utjecati na progresiju bolesti poput prisutnosti genskih polimorfizama.

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