Browsing by Author "Gailīte, Linda"
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Item Allelic variants of breast cancer susceptibility genes PALB2 and RECQL in the Latvian population(2019) Hilz, Philip; Heinrihsone, Reičela; Paetzold, Lukas Alexander; Qi, QI; Trofimovičs, Genadijs; Gailīte, Linda; Irmejs, Arvīds; Gardovskis, Jānis; Miklaševičs, Edvīns; Daneberga, Zanda; Onkoloģijas institūts; Department of Surgery; Scientific Laboratory of Molecular GeneticsItem The association of FMR1 gene (CGG)n variation with idiopathic female infertility(2021) Grasmane, Adele; Rots, Dmitrijs; Vītiņa, Zane; Magomedova, Valerija; Gailīte, Linda; Rīga Stradiņš UniversityIntroduction: The FMR1 gene plays an important role in brain development and in the regulation of ovarian function. The FMR1 gene contains CGG repeat variation and the expansion of the repeats is associated with various phenotypes e.g. fragile X syndrome, premature ovarian failure, etc. Repeats ranging < 55 CGG are considered normal, however recent studies suggest that high-normal (35-54 CGG) and low-normal ([removed] 0.05). In addition, the analysis of low-normal allele and genotype frequencies did not present a difference between primary, secondary infertility and the control group (p > 0.05). Conclusions: In our study, the FMR1 gene high-normal alleles were associated with secondary infertility. However, to address the controversies related to the role of FMR1 genes in the development of diminished ovarian reserve, further studies on the subject are required.Item Clinical Phenotyping and Biomarkers in Spinal and Bulbar Muscular Atrophy(2021-01-20) Millere, Elīna; Rots, Dmitrijs; Glāzere, Ieva; Tauriņa, Gita; Kurjāne, Nataļja; Priedīte, Viktorija; Gailīte, Linda; Blennov, Kaj; Zetterberg, Henrik; Ķēniņa, Viktorija; Department of Doctoral Studies; Scientific Laboratory of Molecular Genetics; Department of Biology and MicrobiologyBackground: Spinal and bulbar muscular atrophy (SBMA) or Kennedy disease [OMIM: 313200] is a rare X-linked neuromuscular disease. Patients commonly present with muscle cramps, tremors, leg weakness, dysarthria and dysphagia. Methods: We deeply phenotyped and evaluated the possible extent of affected systems in all patients with SBMA in Latvia (n = 5). In addition, neurophysiological studies and blood analyses were used to perform a molecular diagnosis and evaluate biochemical values. We analyzed neurofilament light (NfL) as a possible biomarker. Results: Neurological examination revealed typical SBMA clinical manifestations; all patients had small or large nerve fiber neuropathy. Three of five patients had increased neurofilament light levels. Conclusion: The study confirms the systemic involvement in patients suffering from SBMA. Increased NfL concentration was associated with either peripheral neuropathy or decreased body mass index. The complex phenotype of the disease should be kept in mind, as it could help to diagnose patients with SBMA.Item Clinical Variability of Charcot-Marie-Tooth Disease and its Association with Neurofilament and Genetic Type of Disease. Summary of the Doctoral Thesis(Rīga Stradiņš University, 2023) Kalniņa, Elīna; Gailīte, Linda; Ķēniņa, ViktorijaCharcot-Marie-Tooth (CMT) disease is a slowly-progressing, clinically and genetically very heterogeneous disease. There are disease causing variants associated with CMT in almost 100 different genes, which may have very different phenotypes between subtypes and within a single subtype. Until now no specific treatment for the disease is currently available. The lack of specific disease progression biomarkers limits the execution of clinical trials, however, different biomarkers have been studied. One of the most promising is neurofilament light chain (NfL) that has been suggested as a potential biomarker for peripheral nervous system disorders, although previously more studied in central nervous system disorders. Aim of this study was to determine and describe the association between clinical variability of CMT disease and the neurofilament light chain concentration as well as the genetic type of CMT. In this study the genetic type of disease and NfL concentration association to the clinical heterogenity has been evaluated. The study included 101 CMT patients, aged 5 to 81 year old as well as a control group (n = 60), aged 5 to 62 year old. Genetic testing included peripheral myelin protein 22 (PMP22) gene copy number detection and exome sequencing (ES). In the clinical evaluation CMT disease-specific severity scales was used as well as aditional neuropathic and musculosceletal pain, anxiety level, and memory / cognitive abilitiy testing was done. Neurophysiological analysis included evaluation of nerve condution study data. Blood plasma NfL concentrations were measured using the single-molecule array (Simoa) NfL assay. After determining the PMP22 copy number variations, the CMT diagnosis was confirmed in 45.8 % of cases, while after ES – in 77.8 % cases. Most common confirmed genetic type was CMT1A, caused by PMP22 duplication, followed by CMTX1, caused by GJB1 gene disease causing variant. Evaluation of disease severity indicated high clinical variability between genetic groups as well as within one genetic type group. At least mild anxiety level was present in fifth (20.7 %) of patients, twice as much (41.0 %) patients reported pain – these patients had significantly more common at least low levels of anxiety. The time from the onset of the first symptoms to the CMT diagnosis was more than 13 years. The NfL concentration was significantly higher in the CMT disease patient group than in the controls (p < 0.001). Of the CMT disease patients, those with type CMTX1 had a higher NfL level than those in the two other analysed subgroups (p = 0.0498). The NfL concentration had a significant, but weak correlation with the disease severity score (rs = 0.25, p = 0.012). Receiver operating characteristic (ROC) analysis showed that an NfL concentration of 8.9 pg/ml could be used to discriminate CMT disease patients from controls. The study raises awerness of the CMT clinical and genetic profile in the Latvian population, as well as confirms the high clinical heterogenity of the disease. The time spend from first symptoms to confirm diagnosis should be improved by the initial testing of PMP22 duplication / deletion followed by ES. Genetic type was not associated with clinical severity, however CMTX1 patients tended to have more severe phenotype compared to other CMT types, especially in males. The data confirms that plasma NfL levels in patients with CMT are significantly higher than in controls, in addition, plasma NfL levels are significantly, albeit weak, reflecting the disease severity of CMT. In the future, NfL may be used, either individually or collaboratively, as a biomarker in the clinical context of suspected CMT disease.Item COVID-19 Vaccination Coverage and Factors Influencing Vaccine Hesitancy among Patients with Inborn Errors of Immunity in Latvia: A Mixed-Methods Study(2023-10-25) Lucāne, Zane; Kursīte, Mirdza; Šablinskis, Kristaps; Gailīte, Linda; Kurjāne, Nataļja; Department of Biology and Microbiology; Department of Public Health and Epidemiology; Department of Internal Diseases; Scientific Laboratory of Molecular GeneticsBackground: The European Society for Immunodeficiencies recommends that all patients with inborn errors of immunity (IEI) without contraindications should receive SARS-CoV-2 vaccination. The aim of this study was to investigate the reasons that discourage IEI patients from receiving the recommended vaccination and to assess vaccination coverage among IEI patients in Latvia. Methods: In this multicenter mixed-methods study, the vaccination status of all patients with IEI within two tertiary centers in Latvia was reviewed using electronic health records. Semi-structured interviews were conducted with 16 IEI patients who did not undergo vaccination, and a thematic analysis was performed. Results: A total of 341 patients (49.3% female; median age 19.7 years (IQR:17)) were included in the quantitative part. The proportion of fully vaccinated individuals aged ≥ 12 years was 66.8%–70.9% with patients with selective IgA deficiency and 58.8% with other IEI (χ² = 14.12, p < 0.001). The proportion of fully vaccinated individuals aged 5–11 years was 11.1%. Age was associated with vaccination status: younger patients were found to have a significantly lower likelihood of receiving vaccination (U = 8585, p < 0.001). The five main themes identified were as follows: (1) fear and uncertainty; (2) risk and benefit assessment: COVID-19 vaccine—is it worth it? (3) external influences: the dark horse of the decision-making—people around us; (4) individuals against the system; and (5) beliefs about vaccination and COVID-19. Under-representation of certain IEI groups and recall bias are possible limitations of this study. Conclusions: While most reasons for hesitancy were similar to those previously described in the general population, disease-specific concerns were also identified.Item Cytokine Response Following SARS-CoV-2 Antigen Stimulation in Patients with Predominantly Antibody Deficiencies(2023-05-10) Lucāne, Zane; Šlisere, Baiba; Gersone, Gita; Papirte, Sindija; Gailīte, Linda; Tretjakovs, Pēteris; Kurjāne, Nataļja; Department of Biology and Microbiology; Department of Internal Diseases; Department of Human Physiology and Biochemistry; Scientific Laboratory of Molecular GeneticsPredominantly antibody deficiencies (PADs) are inborn disorders characterized by immune dysregulation and increased susceptibility to infections. Response to vaccination, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), may be impaired in these patients, and studies on responsiveness correlates, including cytokine signatures to antigen stimulation, are sparse. In this study, we aimed to describe the spike-specific cytokine response following whole-blood stimulation with SARS-CoV-2 spike peptides in patients with PAD (n = 16 with common variable immunodeficiency and n = 15 with selective IgA deficiency) and its relationship with the occurrence of coronavirus disease 2019 (COVID-19) during up to 10-month follow-up period. Spike-induced antibody and cytokine production was measured using ELISA (anti-spike IgG, IFN-γ) and xMAP technology (interleukin-1β (IL-1β), IL-4, IL-6, IL-10, IL-15, IL-17A, IL-21, TNF-α, TGF-β1). No difference was found in the production of cytokines between patients with PAD and controls. Anti-spike IgG and cytokine levels did not predict contraction of COVID-19. The only cytokine that distinguished between vaccinated and naturally infected unvaccinated PAD patients was IFN-γ (median 0.64 (IQR = 1.08) in vaccinated vs. 0.10 (IQR = 0.28) in unvaccinated). This study describes the spike-specific cytokine response to SARS-CoV-2 antigens, which is not predictive of contracting COVID-19 during the follow-up.Item Hereditary or acquired? Comprehensive genetic testing assists in stratifying angioedema patients(2024-03-30) Rozevska, Marija; Kaņepa, Adīne; Puriņa, Signe; Gailīte, Linda; Nartiša, Inga; Farkas, Henriette; Rots, Dmitrijs; Kurjāne, Nataļja; Rīga Stradiņš UniversityHereditary angioedema (HAE) poses diagnostic challenges due to its episodic, non-specific symptoms and overlapping conditions. This study focuses on the genetic basis of HAE, particularly focusing on unresolved cases and those with normal C1-inhibitor levels (nC1-INH HAE). This study reveals that conventional testing identified pathogenic variants in only 10 patients (n = 32), emphasizing the necessity for an integrative approach using genome, exome, and transcriptome sequencing. Despite extensive genetic analyses, the diagnostic yield for nC1-INH HAE remains low in our study, the pathogenic variant for nC1-INH HAE was identified in only 1 patient (n = 21). Investigation into candidate genes yielded no pathogenic variants, prompting a re-evaluation of patients’ diagnoses. This study advocates for a nuanced approach to genetic testing, recognizing its limitations and emphasizing the need for continuous clinical assessment. The complex genetic landscape of nC1-INH HAE necessitates further research for a more comprehensive understanding. In conclusion, this study contributes valuable insights into the genetic intricacies of HAE, highlighting the challenges in diagnosis and the evolving nature of the disease. The findings underscore the importance of advanced sequencing techniques and an integrated diagnostic strategy in unravelling the complexities of HAE, particularly in nС1-INH HAE cases.Item A higher polygenic risk score is associated with a higher recurrence rate of atrial fibrillation in direct current cardioversion-treated patients(2021) Vogel, Simon; Rudaka, Irina; Rots, Dmitrijs; Isakova, Jekaterīna; Kalējs, Oskars; Vīksne, Kristīne; Gailīte, Linda; Scientific Laboratory of Molecular GeneticsItem The Impact of IL1B rs1143634 and DEFB1 rs11362 Variants on Periodontitis Risk in Phenylketonuria and Type 1 Diabetes Mellitus Patients in a Latvian Population(2024) Emulina, Darta Elizabete; Ābola, Iveta; Brinkmane, Anda; Isakovs, Aleksejs; Skadiņš, Ingus; Moisejevs, Georgijs; Gailīte, Linda; Auzenbaha, Madara; Scientific Laboratory of Molecular Genetics; Department of Conservative Dentistry and Oral Health; Department of Biology and MicrobiologyObjectives: Periodontitis is a multifactorial disease that affects approximately 11% of the global population. The objective of this study was to examine whether, among individuals with phenylketonuria and type 1 diabetes mellitus, those with the IL1B rs1143634 and/or DEFB1 rs11362 genetic variants exhibit a higher periodontitis risk compared to healthy controls. Materials and Methods: In all, 43 phenylketonuria patients (aged 12–53), 28 type 1 diabetes mellitus patients (aged 11–40), and 63 healthy controls (aged 12–53) were included. The evaluation of periodontitis risk was conducted using the Silness–Löe plaque index, the Greene–Vermillion index, and an assessment for the necessity of calculus removal. Genetic variants rs1143634 and rs11362 were genotyped from salivary samples using restriction length polymorphism analysis. Results: The DEFB1 rs11362 variant was associated with higher Silness–Löe and Greene–Vermillion index scores in phenylketonuria patients (p = 0.011 and p = 0.043, respectively). The IL1B rs1143634 variant was associated with lower calculus removal necessity in type 1 diabetes mellitus patients (p = 0.030). Clinical examination showed the worst oral hygiene index scores for PKU patients. PKU patients also reported the least consistent tooth brushing and flossing habits. Conclusions: Genetic associations between DEFB1 rs11362 and IL1B rs1143634 variants and oral hygiene indices were observed in the PKU and T1DM groups, suggesting that genetic factors may contribute to periodontal health differences in these populations. Further research with a larger sample size is needed to confirm these findings and develop targeted oral health interventions.Item Management of Pregnancy with Cervical Shortening: Real-Life Clinical Challenges(2023-03-26) Kornete, Anna; Voložonoka, Ludmila; Zolovs, Maksims; Rota, Adele; Kempa, Inga; Gailīte, Linda; Rezeberga, Dace; Miskova, Anna; Department of Obstetrics and Gynaecology; Scientific Laboratory of Molecular Genetics; Statistics UnitBackground and Objectives: Preterm birth is the leading cause of neonatal mortality worldwide and may be responsible for lifelong morbidities in the survivors. Cervical shortening is one of the common pathways to preterm birth associated with its own diagnostic and management challenges. The preventive modalities that have been tested include progesterone supplementation and cervical cerclage and pessaries. The study aimed to assess the management strategies and outcomes in a group of patients with a short cervix during pregnancy or cervical insufficiency. Materials and Methods: Seventy patients from the Riga Maternity Hospital in Riga, Latvia, were included in the prospective longitudinal cohort study between 2017 and 2021. Patients were treated with progesterone, cerclage, and/or pessaries. The signs of intra-amniotic infection/inflammation were assessed, and antibacterial therapy was given when the signs were positive. Results: The rates of PTB were 43.6% (n = 17), 45.5% (n = 5), 61.1% (n = 11), and 50.0% (n = 1) in progesterone only, cerclage, pessary, and cerclage plus pesssary groups, respectively. The progesterone therapy was associated with a reduced preterm birth risk (x2(1) = 6.937, p = 0.008)), whereas positive signs of intra-amniotic infection/inflammation significantly predicted the risk of preterm birth (p = 0.005, OR = 3.82, 95% [CI 1.31–11.11]). Conclusions: A short cervix and bulging membranes, both indicators of intra-amniotic infection/inflammation, are the key risk factors in preterm birth risk predictions. Progesterone supplementation should remain at the forefront of preterm birth prevention. Among patients with a short cervix and especially complex anamnesis, the preterm rates remain high. The successful management of patients with cervical shortening lies between the consensus-based approach for screening, follow-up, and treatment on the one side and personalising medical therapy on the other.Item Newborn Screening for Spinal Muscular atrophy : first results of a Pilot Study in Latvia(2021) Kreile, Madara; Isakova, Jekaterina; Isakovs, Aleksejs; Konika, Maija; Mičule, Ieva; Diriks, Mikus; Gailīte, Linda; Scientific Laboratory of Molecular GeneticsItem Oral health care knowledge among Phenylketonuria patients in the Latvian population(2024-12) Ābola, Iveta; Intlere, Nikola Anna; Brinkmane, Anda; Laktina, Sabine; Zariņa, Agnese; Vasilevska, Lauma; Skadiņš, Ingus; Moisejevs, Georgijs; Gailīte, Linda; Auzenbaha, Madara; Department of Conservative Dentistry and Oral Health; Scientific Laboratory of Molecular Genetics; Department of Biology and MicrobiologyBACKGROUND: Phenylketonuria (PKU) is an autosomal recessive inherited disorder of phenylalanine (Phe) metabolism that results from a deficiency of phenylalanine hydroxylase (PAH). Patients with PKU rely on amino acid mixtures and low-protein diets, which often exhibit an acidic nature and pose various challenges to oral health. The objective of the study was to evaluate oral care habits of PKU patients in Latvia and the impact of the recommendations developed on improving oral care. MATERIALS AND METHODS: In this study, during a one-month interval before and after the implementation of oral hygiene recommendations, questionnaires were distributed to all patients with PKU diagnosed in Latvia, with a response rate of 78 % (79 of 101). RESULTS: The group older and 18 years of age showed a poorer understanding of oral care even after receiving recommendations, 82 % brushing their teeth twice a day (92 % in the group <18 years of age), continuing 57 % rinsing their mouth after using amino acid formula (75 % in the younger group). Significant improvements were observed only in the respondent group younger than 18 years of age - including increases in toothbrushing twice a day by 25 % ( p = 0.001), dental flossing by 23 % ( p = 0.001), mouth rinsing after amino acid-based formula by 13 % ( p = 0.020). CONCLUSION: This study concludes that PKU patients older and 18 years of age have a poor understanding of maintaining oral hygiene and the use of the necessary supplements to improve it. Activities are needed in the future that would regularly remind and motivate PKU patients to take care of their oral health.Item Performance comparison of two whole genome amplification techniques in frame of multifactor preimplantation genetic testing(2018-08-01) Volozonoka, Ludmila; Perminov, Dmitry; Korņejeva, Liene; Alkšere, Baiba; Novikova, Natālija; Pīmane, Evija Jokste; Blumberga, Arita; Kempa, Inga; Miskova, Anna; Gailīte, Linda; Fodina, Violeta; Scientific Laboratory of Molecular Genetics; Department of Obstetrics and GynaecologyPurpose: To compare multiple displacement amplification and OmniPlex whole genome amplification technique performance during array comparative genome hybridization (aCGH), Sanger sequencing, SNaPshot and fragment size analysis downstream applications in frame of multifactor embryo preimplantation genetic testing. Methods: Preclinical workup included linked short tandem repeat (STR) marker selection and primer design for loci of interest. It was followed by a family haplotyping, after which an in vitro fertilization preimplantation genetic testing (IVF-PGT) cycle was carried out. A total of 62 embryos were retrieved from nine couples with a confirmed single gene disorder being transmitted in their family with various inheritance traits—autosomal dominant (genes—ACTA2, HTT, KRT14), autosomal recessive (genes—ALOX12B, TPP1, GLB1) and X-linked (genes—MTM1, DMD). Whole genome amplification (WGA) for the day 5 embryo trophectoderm single biopsies was carried out by multiple displacement amplification (MDA) or polymerase chain reaction (PCR)-based technology OmniPlex and was used for direct (Sanger sequencing, fragment size analysis, SNaPshot) and indirect mutation assessment (STR marker haplotyping), and embryo aneuploidy testing by array comparative genome hybridization (aCGH). Results: Family haplotyping revealed informative/semi-informative microsatellite markers for all clinical cases for all types of inheritance. Indirect testing gave a persuasive conclusion for all embryos assessed, which was confirmed through direct testing. The overall allele dropout (ADO) rate was higher for PCR-based WGA, and MDA shows a better genomic recovery scale. Five euploid embryos were subjected to elective single embryo transfer (eSET), which resulted in four clinical pregnancies and birth of two healthy children, which proved free of disease causative variants running in the family postnataly. Conclusions: A developed multifactor PGT protocol can be adapted and applied to virtually any genetic condition and is capable of improving single gene disorder preimplantation genetic testing in a patient-tailored manner thus increasing pregnancy rates, saving costs and increasing patient reliability.Item Phenotypic variability and diagnostic characteristics in inherited peripheral neuropathy in Latvia(2022) Millere, Elīna; Kupats, Einārs; Mičule, Ieva; Gailīte, Linda; Ķēniņa, Viktorija; Department of Paediatrics; Scientific Laboratory of Molecular Genetics; Department of Doctoral Studies; Department of Biology and MicrobiologyInherited peripheral neuropathies (IPN) are a clinically and genetically heterogeneous group of disorders. The most common IPN is Charcot-Marie-Tooth (CMT) disease. Here we describe IPN clinical variability and diagnostic characteristics in the Latvian population. A total of 101 patients were enrolled in the study. Genetic testing consisted of PMP22 copy number analysis and whole-exome sequencing (WES). Clinical assessment comprised CMT Neuropathy Score version 2 (CMTNSv2), CMT Examination Score, pain, anxiety and memory/cognitive ability testing. The diagnostic yields for PMP22 copy number detection and WES were 45.8% and 77.8%, respectively. Disease severity assessment indicated high clinical heterogeneity, with CMTNSv2 scores ranging between 0 and 33. More than one-third of patients reported pain, and it was found to be significantly more common in patients with at least a mild anxiety level. From the initial development of symptoms, on average, it took more than 13 years for a diagnosis of IPN to be confirmed. This study updates the IPN genetic and clinical profile of the Latvian population and demonstrates the presence of a high level of heterogeneity. The time to diagnosis for IPN patients needs to be improved by employing multiplex ligation-dependent probe amplification initially followed by WES.Item Policistisko olnīcu sindroms pusaudzēm – starppaaudžu, ģenētiskie, dzīves kvalitātes un negausīgas ēšanas aspekti. Promocijas darba kopsavilkums(Rīgas Stradiņa universitāte, 2022) Līdaka, Lāsma; Lazdāne, Gunta; Gailīte, LindaPolicistisko olnīcu sindroms (PCOS) ir visbiežākā endokrinopātija sievietēm, kas skar 4,8 % līdz 18,6 % reproduktīvā vecuma pārstāvju. 10–19 gadu vecumā PCOS sastopams 3,39–8,03 % pusaudžu. Diagnozes apstiprināšana pusaudžu vecumā ir sarežģīta, jo PCOS izpausmes līdzinās normālām pubertātes pazīmēm (piemēram, neregulārs menstruālais cikls, akne u. c.). 2018. gadā ir izdotas jaunas uz pierādījumiem balstītas vadlīnijas, kurās akcentēti diagnostiskie kritēriji tieši pusaudzēm – menstruāciju traucējumi un hiperandrogēnisms. Šīs vadlīnijas rekomendē arī atsevišķi izdalīt riska grupas pacientes – pusaudzes, kurām vēl nav apstiprināti abi diagnostiskie PCOS kritēriji un kuras jāturpina novērot. Šo slimību svarīgi diagnosticēt iespējami agrīni, lai savlaicīgi uzsāktu dzīvesveida korekcijas un, iespējams, arī ārstēšanu.PCOS ilgtermiņā palielina neauglības un 2. tipa cukura diabēta, sirds un asinsvadu sistēmas slimību, insulīna rezistenci (IR) un metaboliskā sindroma attīstības risku. Palielināta ķermeņa masa, kas sastopama 40–70 % pusaudžu ar PCOS, ievērojami palielina risku vēlākām hroniskām, neinfekciozām slimībām un uztur PCOS simptomātiku. PCOS un ar to saistītie simptomi samazina ar veselību saistīto dzīves kvalitāti (AVSDZK). Pacientēm ar PCOS biežāk sastopama negausīga ēšana. Visefektīvākā terapijas taktika ir dzīvesveida pārmaiņas, tādēļ īpaši svarīgi ir atpazīt pacientes ar paaugstinātu PCOS attīstības risku, agrīni noskaidrot viņu diagnozi un piedāvāt ārstēšanu, kas visvairāk atbilst konkrētās personas vajadzībām un uzlabo dzīves kvalitāti.Promocijas darba mērķis ir izpētīt starppaaudžu, ģenētiskos, dzīves kvalitātes un negausīgas ēšanas aspektus pusaudzēm ar PCOS.Pētījumam ir vairākas sadaļas. Lai novērtētu starppaaudžu saiti, I sadaļā tika iekļautas 57 pusaudzes ar PCOS un viņu mātes. Šajā sadaļā tika pētīta pacienšu ar PCOS un viņu māšu klīnisko pazīmju saistība. II sadaļā papildus PCOS pacientēm iekļautas arī veselas pusaudzes un riska grupas pacientes. Biežāko hipotalāma-hipofīzes-olnīcu (HHO) ass darbībā iesaistīto olbaltumvielu kodējošo gēnu (FSHR, ESR2, LHCGR, GNRHR) variāciju loma PCOS attīstībā un saistībā ar PCOS klīnisko ainu tika pētīta, iekļaujot 63 pusaudzes ar PCOS diagnozi, 67 veselas kontroles grupas pārstāves un 22 riska grupas pacientes. CYP21A2 gēna variāciju loma PCOS attīstībā un klīniskajā fenotipā tika noteikta 55 PCOS pacientēm, 49 kontroles grupas pārstāvēm un 23 riska grupas pacientēm. Savukārt AVSDZK komponenti, negausīga ēšana un faktori, kas ietekmē kopējo AVSDZK, tika analizēti 63 PCOS pacientēm un 66 kontroles grupas pārstāvēm.Pētījuma rezultātos tika konstatēts, ka pusaudzēm ar PCOS saistītos klīniskos simptomus nav iespējams prognozēt, balstoties uz viņu māšu PCOS simptomiem. Netika pierādīta dzimumhormonu darbībā iesaistīto olbaltumvielu kodējošo gēnu variāciju loma PCOS attīstībā, tomēr tika konstatēts, ka atsevišķu gēnu variāciju (ESR2 rs4986938 un LHCGR rs2293275) retāk sastopamo alēļu nesējām homozigotiskā stāvoklī bija augstāks kopējā testosterona līmenis asinīs nekā pacientēm, kuras nebija šo alēļu nesējas. Būtiskākie komponenti, kas ietekmēja AVSDZK pusaudzēm ar PCOS, bija PCOS diagnoze pati par sevi, negausīgas ēšanas izteiktības pakāpe un ķermeņa masas indeksa procentile. Vienlaikus visvairāk AVSDZK ietekmēja raizes par ķermeņa apmatojumu un ķermeņa masu. Netika konstatētas atšķirības negausīgas ēšanas biežumā starp PCOS pacientēm un kontroles grupas pārstāvēm.Veicot šo pētījumu, netika atklāta saistība starp māšu PCOS diagnozi vai ar to saistītajiem simptomiem un pusaudžu ar PCOS fenotipu. Konstatēta atsevišķu alēļu saistība ar PCOS klīnisko ainu. Labāk izprasti AVSDZK komponenti, kurus visvairāk ietekmē PCOS un kuriem jāpievērš īpaša uzmanība klīniskajā praksē. Nepieciešami turpmāki pētījumi lielākā izlasē, kā arī longitudināli dati par šo dalībnieku kopu, kas sniegtu precīzāku ieskatu par slimības attīstību vēlākā vecumā.Item Policistisko olnīcu sindroms pusaudzēm – starppaaudžu, ģenētiskie, dzīves kvalitātes un negausīgas ēšanas aspekti. Promocijas darbs(Rīgas Stradiņa universitāte, 2022) Līdaka, Lāsma; Lazdāne, Gunta; Gailīte, LindaPolicistisko olnīcu sindroms (PCOS) ir visbiežākā endokrinopātija sievietēm, kas skar 4,8 % līdz 18,6 % reproduktīvā vecuma pārstāvju. 10–19 gadu vecumā PCOS sastopams 3,39–8,03 % pusaudžu. Diagnozes apstiprināšana pusaudžu vecumā ir sarežģīta, jo PCOS izpausmes līdzinās normālām pubertātes pazīmēm (piemēram, neregulārs menstruālais cikls, akne u. c.). 2018. gadā ir izdotas jaunas uz pierādījumiem balstītas vadlīnijas, kurās akcentēti diagnostiskie kritēriji tieši pusaudzēm – menstruāciju traucējumi un hiperandrogēnisms. Šīs vadlīnijas rekomendē arī atsevišķi izdalīt riska grupas pacientes – pusaudzes, kurām vēl nav apstiprināti abi diagnostiskie PCOS kritēriji un kuras jāturpina novērot. Šo slimību svarīgi diagnosticēt iespējami agrīni, lai savlaicīgi uzsāktu dzīvesveida korekcijas un, iespējams, arī ārstēšanu.PCOS ilgtermiņā palielina neauglības un 2. tipa cukura diabēta, sirds un asinsvadu sistēmas slimību, insulīna rezistenci (IR) un metaboliskā sindroma attīstības risku. Palielināta ķermeņa masa, kas sastopama 40–70 % pusaudžu ar PCOS, ievērojami palielina risku vēlākām hroniskām, neinfekciozām slimībām un uztur PCOS simptomātiku. PCOS un ar to saistītie simptomi samazina ar veselību saistīto dzīves kvalitāti (AVSDZK). Pacientēm ar PCOS biežāk sastopama negausīga ēšana. Visefektīvākā terapijas taktika ir dzīvesveida pārmaiņas, tādēļ īpaši svarīgi ir atpazīt pacientes ar paaugstinātu PCOS attīstības risku, agrīni noskaidrot viņu diagnozi un piedāvāt ārstēšanu, kas visvairāk atbilst konkrētās personas vajadzībām un uzlabo dzīves kvalitāti.Promocijas darba mērķis ir izpētīt starppaaudžu, ģenētiskos, dzīves kvalitātes un negausīgas ēšanas aspektus pusaudzēm ar PCOS.Pētījumam ir vairākas sadaļas. Lai novērtētu starppaaudžu saiti, I sadaļā tika iekļautas 57 pusaudzes ar PCOS un viņu mātes. Šajā sadaļā tika pētīta pacienšu ar PCOS un viņu māšu klīnisko pazīmju saistība. II sadaļā papildus PCOS pacientēm iekļautas arī veselas pusaudzes un riska grupas pacientes. Biežāko hipotalāma-hipofīzes-olnīcu (HHO) ass darbībā iesaistīto olbaltumvielu kodējošo gēnu (FSHR, ESR2, LHCGR, GNRHR) variāciju loma PCOS attīstībā un saistībā ar PCOS klīnisko ainu tika pētīta, iekļaujot 63 pusaudzes ar PCOS diagnozi, 67 veselas kontroles grupas pārstāves un 22 riska grupas pacientes. CYP21A2 gēna variāciju loma PCOS attīstībā un klīniskajā fenotipā tika noteikta 55 PCOS pacientēm, 49 kontroles grupas pārstāvēm un 23 riska grupas pacientēm. Savukārt AVSDZK komponenti, negausīga ēšana un faktori, kas ietekmē kopējo AVSDZK, tika analizēti 63 PCOS pacientēm un 66 kontroles grupas pārstāvēm.Pētījuma rezultātos tika konstatēts, ka pusaudzēm ar PCOS saistītos klīniskos simptomus nav iespējams prognozēt, balstoties uz viņu māšu PCOS simptomiem. Netika pierādīta dzimumhormonu darbībā iesaistīto olbaltumvielu kodējošo gēnu variāciju loma PCOS attīstībā, tomēr tika konstatēts, ka atsevišķu gēnu variāciju (ESR2 rs4986938 un LHCGR rs2293275) retāk sastopamo alēļu nesējām homozigotiskā stāvoklī bija augstāks kopējā testosterona līmenis asinīs nekā pacientēm, kuras nebija šo alēļu nesējas. Būtiskākie komponenti, kas ietekmēja AVSDZK pusaudzēm ar PCOS, bija PCOS diagnoze pati par sevi, negausīgas ēšanas izteiktības pakāpe un ķermeņa masas indeksa procentile. Vienlaikus visvairāk AVSDZK ietekmēja raizes par ķermeņa apmatojumu un ķermeņa masu. Netika konstatētas atšķirības negausīgas ēšanas biežumā starp PCOS pacientēm un kontroles grupas pārstāvēm.Veicot šo pētījumu, netika atklāta saistība starp māšu PCOS diagnozi vai ar to saistītajiem simptomiem un pusaudžu ar PCOS fenotipu. Konstatēta atsevišķu alēļu saistība ar PCOS klīnisko ainu. Labāk izprasti AVSDZK komponenti, kurus visvairāk ietekmē PCOS un kuriem jāpievērš īpaša uzmanība klīniskajā praksē. Nepieciešami turpmāki pētījumi lielākā izlasē, kā arī longitudināli dati par šo dalībnieku kopu, kas sniegtu precīzāku ieskatu par slimības attīstību vēlākā vecumā.Item Polycystic Ovarian Syndrome in Adolescents – Intergenerational, Genetic, Quality of Life and Binge Eating Aspects. Summary of the Doctoral Thesis(Rīga Stradiņš University, 2022) Līdaka, Lāsma; Lazdāne, Gunta; Gailīte, LindaPolycystic ovary syndrome (PCOS) is the most common endocrinopathy in women, affecting 4.8 % to 18.6 % of women of reproductive age. Between 10 and 19 years of age, PCOS occurs in 3.39 % to 8.03 % of adolescents. Confirmation of diagnosis in adolescent age is difficult because manifestations of PCOS are similar to normal puberty signs (e. g., irregular menstrual cycle, acne, etc.). New evidence-based guidelines have been issued in 2018 highlighting the diagnostic criteria for establishing PCOS diagnosis in adolescents. These guidelines also recommend a separate identification of risk group patients – adolescent patients for whom both diagnostic PCOS criteria have not yet been confirmed and who should continue to be monitored. It is important to diagnose this disease as early as possible in order to initiate lifestyle adjustments and possibly also begin treatment in a timely manner.In the long term, PCOS increases the risk of developing infertility and type 2 diabetes, cardiovascular disease, insulin resistance and metabolic syndrome. Increased body weight occurring in 40–70 % of adolescents with PCOS significantly increases the risk of chronic non-communicable diseases at a later stage, and maintains PCOS symptoms. PCOS and associated symptoms reduce health-related quality of life (HRQOL). Binge eating is more common in patients with PCOS. The most effective tactics of therapy are lifestyle changes, so it is particularly important to recognise patients at increased risk of developing PCOS, to diagnose them early and to offer treatment that is most relevant to the needs of the individual and improves their quality of life.The aim of the doctoral thesis is to explore intergenerational, genetic, quality of life and binge eating aspects in teenagers with PCOS.The study contains several sections. To evaluate the intergenerational bond, 57 teenagers with PCOS and their mothers were included in Section I. The section studies the relationship between patients with PCOS and their mothers. In addition to PCOS patients, Section II also includes healthy adolescent patients and patients at risk. The role of the most common variation of protein-coding genes involved in the activity of the Hypothalamic-Pituitary-Ovarian axis (FSHR, ESR2, LHCGR, GNRHR) in PCOS development and in the PCOS clinical presentation was studied by including 63 adolescents with a diagnosis of PCOS, 67 healthy control patients and 22 patients at risk. The role of CYP21A2 gene variations in PCOS development and clinical phenotype was established in 55 PCOS patients, 49 control patients and 23 patients at risk. Additionally, components of HRQOL, binge eating and factors affecting the total HRQOL were analysed in 63 PCOS patients and 66 control patients. The study concluded that it was not possible to predict clinical symptoms associated with PCOS in adolescents based on PCOS symptoms in their mothers. The role of protein-coding gene variations that are involved in the functioning of sex hormones was also not found, in regard to PCOS development. However, it was found that the homozygous minor allele carriers within variations of specific genes (ESR2 rs4986938 and LHCGR rs2293275) had a higher total testosterone level in blood than patients who were not carriers of these alleles. The most important components that affected HRQOL in adolescents with PCOS were the diagnosis of PCOS as such, the degree of binge eating, and the percentile of the body mass index. At the same time, HRQOL was most affected by concerns about body hair and body weight. There was no difference in the frequency of binge eating between PCOS patients and adolescent control group patients.In this study, no link was found between the diagnosis of PCOS or associated symptoms in mothers and the phenotype of adolescents with PCOS. Individual alleles have been associated with the clinical presentation of PCOS. There is a better understanding of the components of HRQOL that affect PCOS the most and require particular attention in clinical practice. Further research with a larger sample-size is needed. Furthermore, longitudinal data on the population studied in this project would provide a more accurate insight into the development of the disease at a later age.Item Role of Single Nucleotide Variants in FSHR, GNRHR, ESR2 and LHCGR Genes in Adolescents with Polycystic Ovary Syndrome(2021-12-11) Lidaka, Lasma; Beķere, Laine; Rota, Adele; Isakova, Jekaterina; Lazdāne, Gunta; Ķīvīte-Urtāne, Anda; Dzīvīte-Krišāne, Iveta; Kempa, Inga; Dobele, Zane; Gailīte, Linda; Department of Obstetrics and Gynaecology; Scientific Laboratory of Molecular Genetics; Institute of Public HealthBackground: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women, affecting up to 16.6% of reproductive-age women. PCOS symptoms in adolescents comprise oligomenorrhoea/amenorrhoea and biochemical and/or clinical hyperandrogenism. Long-term health risks of PCOS patients include infertility, metabolic syndrome, type 2 diabetes and cardiovascular disease. Genetic factors have been proven to play a role in development of the syndrome and its symptoms. Objective: To investigate single nucleotide variants (SNVs) in the GNRHR, ESR2, LHCGR and FSHR genes in adolescent patients with PCOS and their association with PCOS symptoms. Methods: We conducted a cross-sectional study comprising of 152 adolescents: 63 patients with PCOS, 22 patients at risk of developing PCOS and 67 healthy controls. Participants were recruited from out-patients attending a gynaecologist at the Children’s Clinical University Hospital, Riga, Latvia, between January 2017 and December 2020. Genomic DNA was extracted from whole blood, and SNVs in the GNRHR, ESR2, LHCGR and FSHR genes were genotyped. The distributions of SNV genotypes were compared among the three groups and genotype-phenotype associations within the PCOS group were evaluated. Results: No statistically significant differences were found in the distributions of genotypes for GNRHR (rs104893837), ESR2 (rs4986938), LHCGR (rs2293275) and FSHR (rs6166, rs6165, rs2349415) among PCOS patients, risk patients and healthy controls. Within the PCOS group, ESR2 rs4986938 minor allele homozygous patients had a significantly higher level of total testosterone than major allele homozygous patients and heterozygous patients. A significantly higher total testosterone level was also observed in PCOS patients carrying the LHCGR rs2293275 minor allele compared with major allele homozygous patients. Conclusions: The SNVs ESR2 rs4986938 and LHCGR rs2293275 play a role in the phenotypic characteristics of PCOS. To fully uncover their influence on the development of PCOS and its symptoms, further studies of larger cohorts and a follow up of this study sample through to adulthood are required. Furthermore, studies of adolescent PCOS patients conducted prior to the latest European Society of Human Reproduction and Embryology (ESHRE) criteria (2018) should be re-evaluated as the study groups might include risk patients according to these updated criteria, thereby potentially significantly impacting the published results.Item Šarko-Marī-Tūta slimības klīnisko izpausmju dažādība un tās saistība ar neirofilamentu un ģenētisko tipu. Promocijas darba kopsavilkums(Rīgas Stradiņa universitāte, 2023) Kalniņa, Elīna; Gailīte, Linda; Ķēniņa, ViktorijaŠarko-Marī-Tūta (ŠMT) slimība ir lēni progresējoša, klīniski un ģenētiski ļoti heterogēna slimība. Ar ŠMT saistīti slimību izraisošie varianti gandrīz 100 dažādos gēnos, kas var izpausties ar ļoti atšķirīgu fenotipu starp ģenētiskajiem tipiem un arī viena tipa ietvaros. Šobrīd ŠMT slimībai specifiska ārstēšana nav zināma un pieejama. Slimības progresēšanas un smaguma biomarķieru trūkums ierobežo klīniskos pētījumus terapijas efektivitātes izvērtēšanā, tomēr vairāki potenciāli biomarķieri ir pētīti. Viens no daudzsološākajiem ir neirofilamenta vieglās ķēdes (NfL), dati norāda par tā biomarķiera potenciālu perifēro nervu sistēmas slimību gadījumā, līdz šim plašāk tas ir pētīts centrālās nervu sistēmas slimību gadījumā. Darba mērķis ir noteikt un aprakstīt NfL koncentrācijas un ģenētiskā slimības tipa saistību ar ŠMT klīnisko izpausmju dažādību. Darba ietvaros vērtēta ŠMT slimības ģenētiskā tipa un NfL koncentrācijas saistība ar slimības klīnisko izpausmju dažādību. Pētījumā piedalījās 101 ŠMT pacients no piecu līdz 81 gada vecumam, kā arī kontroles grupa (n = 60) NfL līmeņa noteikšanai – no pieciem līdz 62 gadiem. Ģenētiskā testēšana iekļāva perifērā mielīna proteīna (PMP22) gēna kopiju skaita noteikšanu un eksoma sekvencēšanu (ES). Klīniskā izvērtēšanā izmantoja ŠMT slimībai specifiskas smaguma skalas, kā arī papildus veikta muskuloskeletālu un neiropātisku sāpju, trauksmes līmeņa un atmiņas / kognitīvo spēju testēšana. Neirofizioloģisks raksturojums iekļāva neirogrāfijas izmeklējuma datu analīzi. Asins plazmas NfL koncentrācija tika noteikta, izmantojot vienas molekulas testu (Simoa). Rezultāti liecināja, ka pēc PMP22 kopiju skaita noteikšanas diagnozi apstiprināja 45,8 % gadījumu, savukārt pēc ES – 77,8 %. Biežākais ģenētiskais slimības tips bija ŠMT1A, kuru izraisa PMP22 gēna duplikācija, otrs biežākais – ŠMTX1, kuru izraisa GJB1 gēna slimību izraisošs vairants. Slimības smaguma izvērtēšana norādīja augstu klīnisko dažādību starp ģenētiskajiem tipiem, kā arī viena ģenētiskā tipa ietvaros. Vismaz zems trauksmes līmenis bija piektdaļai pacientu (20,7 %), divas reizes vairāk pacientu bija sāpes (41,0 %). Pacientu grupā ar sāpēm nozīmīgi vairāk atklāja vismaz zemu trauksmes līmeni. Laiks no pirmo simptomu parādīšanās līdz diagnozes noteikšanai bija vairāk nekā 13 gadi. NfL koncentrācija bija ievērojami augstāka ŠMT pacientu grupā nekā kontroles grupā (p < 0,001). ŠMTX1 pacientiem bija augstāks NfL līmenis nekā divās citās analizētajās apakšgrupās (p = 0,0498). NfL koncentrācijai bija nozīmīga, bet vāja korelācija ar slimības smaguma rādītāju (rs = 0,25, p = 0,012). Uztvērēja operatora līknes (ROC, angliski receiver operator curve) datu analīze parādīja, ka 8,9 pg/ml NfL koncentrāciju var izmantot, lai izšķirtu ŠMT slimības pacientus no kontroles grupas. Pētījums aktualizē ŠMT klīnisko un ģenētisko profilu Latvijas populācijā, kā arī apliecina augstu slimības klīnisko dažādību. Ilgumu no pirmo simptomu parādīšanās līdz diagnozes noteikšanai var uzlabot, sākotnēji nosakot ŠMT1A tipu (testējot PMP22 gēna duplikāciju / delēciju) un turpinot ar ES, lai pārbaudītu pārējos ŠMT tipus. Lai gan netika pierādīta ģenētiskā tipa saistība ar slimības klīnisko smagumu, tomēr ŠMTX1 pacientiem bija tendence uz smagāku klīnisko ainu salīdzinājumā ar citiem ŠMT tipiem, īpaši vīriešu grupā. Dati apstiprina, ka plazmas NfL koncentrācija ŠMT slimības pacientiem ir nozīmīgi augstāka nekā kontroles grupā, papildus konstatēts, ka NfL koncentrācija plazmā būtiski, kaut arī vāji, korelē ar ŠMT slimības smagumu. Nākotnē NfL varētu tikt izmantots individuāli vai kombinējot ar citiem rādījumiem kā biomarķieris ŠMT slimības klīniskajā kontekstā.Item Šarko-Marī-Tūta slimības klīnisko izpausmju dažādība un tās saistība ar neirofilamentu un ģenētisko tipu. Promocijas darbs(Rīgas Stradiņa universitāte, 2023) Kalniņa, Elīna; Gailīte, Linda; Ķēniņa, ViktorijaŠarko-Marī-Tūta (ŠMT) slimība ir lēni progresējoša, klīniski un ģenētiski ļoti heterogēna slimība. Ar ŠMT saistīti slimību izraisošie varianti gandrīz 100 dažādos gēnos, kas var izpausties ar ļoti atšķirīgu fenotipu starp ģenētiskajiem tipiem un arī viena tipa ietvaros. Šobrīd ŠMT slimībai specifiska ārstēšana nav zināma un pieejama. Slimības progresēšanas un smaguma biomarķieru trūkums ierobežo klīniskos pētījumus terapijas efektivitātes izvērtēšanā, tomēr vairāki potenciāli biomarķieri ir pētīti. Viens no daudzsološākajiem ir neirofilamenta vieglās ķēdes (NfL), dati norāda par tā biomarķiera potenciālu perifēro nervu sistēmas slimību gadījumā, līdz šim plašāk tas ir pētīts centrālās nervu sistēmas slimību gadījumā. Darba mērķis ir noteikt un aprakstīt NfL koncentrācijas un ģenētiskā slimības tipa saistību ar ŠMT klīnisko izpausmju dažādību. Darba ietvaros vērtēta ŠMT slimības ģenētiskā tipa un NfL koncentrācijas saistība ar slimības klīnisko izpausmju dažādību. Pētījumā piedalījās 101 ŠMT pacients no piecu līdz 81 gada vecumam, kā arī kontroles grupa (n = 60) NfL līmeņa noteikšanai – no pieciem līdz 62 gadiem. Ģenētiskā testēšana iekļāva perifērā mielīna proteīna (PMP22) gēna kopiju skaita noteikšanu un eksoma sekvencēšanu (ES). Klīniskā izvērtēšanā izmantoja ŠMT slimībai specifiskas smaguma skalas, kā arī papildus veikta muskuloskeletālu un neiropātisku sāpju, trauksmes līmeņa un atmiņas / kognitīvo spēju testēšana. Neirofizioloģisks raksturojums iekļāva neirogrāfijas izmeklējuma datu analīzi. Asins plazmas NfL koncentrācija tika noteikta, izmantojot vienas molekulas testu (Simoa). Rezultāti liecināja, ka pēc PMP22 kopiju skaita noteikšanas diagnozi apstiprināja 45,8 % gadījumu, savukārt pēc ES – 77,8 %. Biežākais ģenētiskais slimības tips bija ŠMT1A, kuru izraisa PMP22 gēna duplikācija, otrs biežākais – ŠMTX1, kuru izraisa GJB1 gēna slimību izraisošs vairants. Slimības smaguma izvērtēšana norādīja augstu klīnisko dažādību starp ģenētiskajiem tipiem, kā arī viena ģenētiskā tipa ietvaros. Vismaz zems trauksmes līmenis bija piektdaļai pacientu (20,7 %), divas reizes vairāk pacientu bija sāpes (41,0 %). Pacientu grupā ar sāpēm nozīmīgi vairāk atklāja vismaz zemu trauksmes līmeni. Laiks no pirmo simptomu parādīšanās līdz diagnozes noteikšanai bija vairāk nekā 13 gadi. NfL koncentrācija bija ievērojami augstāka ŠMT pacientu grupā nekā kontroles grupā (p < 0,001). ŠMTX1 pacientiem bija augstāks NfL līmenis nekā divās citās analizētajās apakšgrupās (p = 0,0498). NfL koncentrācijai bija nozīmīga, bet vāja korelācija ar slimības smaguma rādītāju (rs = 0,25, p = 0,012). Uztvērēja operatora līknes (ROC, angliski receiver operator curve) datu analīze parādīja, ka 8,9 pg/ml NfL koncentrāciju var izmantot, lai izšķirtu ŠMT slimības pacientus no kontroles grupas. Pētījums aktualizē ŠMT klīnisko un ģenētisko profilu Latvijas populācijā, kā arī apliecina augstu slimības klīnisko dažādību. Ilgumu no pirmo simptomu parādīšanās līdz diagnozes noteikšanai var uzlabot, sākotnēji nosakot ŠMT1A tipu (testējot PMP22 gēna duplikāciju / delēciju) un turpinot ar ES, lai pārbaudītu pārējos ŠMT tipus. Lai gan netika pierādīta ģenētiskā tipa saistība ar slimības klīnisko smagumu, tomēr ŠMTX1 pacientiem bija tendence uz smagāku klīnisko ainu salīdzinājumā ar citiem ŠMT tipiem, īpaši vīriešu grupā. Dati apstiprina, ka plazmas NfL koncentrācija ŠMT slimības pacientiem ir nozīmīgi augstāka nekā kontroles grupā, papildus konstatēts, ka NfL koncentrācija plazmā būtiski, kaut arī vāji, korelē ar ŠMT slimības smagumu. Nākotnē NfL varētu tikt izmantots individuāli vai kombinējot ar citiem rādījumiem kā biomarķieris ŠMT slimības klīniskajā kontekstā.