Institute of Psychiatry and Neurology
Recent publications
Purpose Wilson's disease (WD) is an inherited disorder involving copper accumulation in the liver and brain. An important mechanism responsible for hepatocyte injury in WD is mitochondria destruction, although damage may also be caused by oxidative stress and lipid peroxidation. Patients/methods The study included 54 treated patients with WD without liver cirrhosis and 10 healthy controls. All patients had liver biopsy and immunohistochemical analysis of liver samples was performed using targeted staining for markers of mitochondrial injury (thioredoxin-2 [TRX2], cytochrome c oxidases subunit 2 [COX2], and cytochrome c oxidases complex IV subunit 4 isoform 1 [COX4-1]), of oxidative stress (peroxiredoxin-1 [PRDX1] and 8-hydroxyguanosine [8-OHdG]), and of lipid peroxidation (4-hydroxynonenal [4-HNE]). Results Expression, measured as mean strengths of intensity (SI) of immunohistochemical reactions per 5 fields of view, was significantly lower in patients with WD compared to controls for COX2 (2.9 vs 8.3), 8-OHdG (0.05 vs 3.8), TRX2 (4.9 vs 10.1), and PRDX1 (4.6 vs 10.1) (all P < 10⁻⁵). COX4-1 expression was undetected in patients with WD but detected in control specimens (8.1) (P < 10⁻⁵). 4-HNE was overexpressed in patients with WD compared to controls (10.1 vs 9.1; P < 0.07). Conclusions Negligible COX4-1 and low COX2 expression in liver specimens may serve as markers of inner mitochondrial membrane injury in treated patients with WD and early stages of liver fibrosis.
Studies of patients with schizophrenia and offenders with severe mental disorders decision-making performance have produced mixed findings. In addition, most earlier studies have assessed decision-making skills in offenders or people with mental disorders, separately, thus neglecting the possible additional contribution of a mental disorder on choice patterns in people who offend. This study aimed to fill this gap by comparing risk-taking in patients with schizophrenia spectrum disorders (SSD), with and without a history of serious violent offending assessing whether, and to what extent, risk-taking represents a significant predictor of group membership, controlling for their executive skills, as well as for socio-demographic and clinical characteristics. Overall, 115 patients with a primary diagnosis of SSD were recruited: 74 were forensic patients with a lifetime history of severe interpersonal violence and 41 were patients with SSD without such a history. No significant group differences were observed on psychopathological symptoms severity. Forensic generally displayed lower scores than non-forensic patients in all cognitive subtests of the Brief Assessment of Cognition in Schizophrenia (except for the “token motor” and the “digit sequencing” tasks) and on all the six dimensions of the Cambridge Gambling Task, except for “Deliberation time”, in which forensic scored higher than non-forensic patients. “Deliberation time” was also positively, although weakly correlated with “poor impulse control”. Identifying those facets of impaired decision-making mostly predicting offenders' behaviour among individuals with mental disorder might inform risk assessment and be targeted in treatment and rehabilitation protocols.
Information on personality development (and its linguistic predictors) in the aftermath of a critical life event among depressive patients is relatively limited. The study’s aim was to verify two hypotheses: (1) Participants with depression will use concrete rather than abstract language to describe their most recent critical life event and its psychological consequences and (2) The more abstract the language used, the higher the level of personality development. 16 Cognitive Behavioral Therapy patients suffering from depression participated in the study (M = 34 years old; SD = 4.02). Their level of personality development was assessed qualitatively by two independent coders. The coding system was based on the Positive Disintegration Theory (Dąbrowski 1964). We used typology from the Linguistic Category Model (Semin and Fiedler 1991) to analyse the level of abstractness vs. concreteness. Depressed patients were classified as either abstract language speakers or concrete language speakers. There were equal numbers of both types of speakers. Moreover participants consistently used one type of language, regardless of whether they were describing the critical life event itself or its psychological consequences. As expected, using higher levels of language abstractness when speaking correlated with possessing higher levels of personality development. Our findings provide practitioners with useful knowledge on the benefits of using abstract language to improve supportive strategies when dealing with people in crisis and modify the psychotherapeutic protocols used to treat depression.
The efficacy of a ketogenic diet (KD) in controlling seizure has been shown in many experimental and clinical studies, however, its mechanism of action still needs further clarification. The major goal of the present study was to investigate the influence of the commercially available KD and caloric restriction (CR) on the hippocampal afterdischarge (AD) threshold in rats, and concomitant biochemical changes, specifically concerning the kynurenine pathway, in plasma and the hippocampus. As expected, the rats on the KD showed higher AD threshold accompanied by increased plasma β-hydroxybutyrate level compared to the control group and the CR rats. This group presented also lowered tryptophan and elevated kynurenic acid levels in plasma with similar changes in the hippocampus. Moreover, the KD rats showed decreased levels of branched chain amino acids (BCAA) and aromatic amino acids (AAA) in plasma and the hippocampus. No regular biochemical changes were observed in the CR group. Our results are analogous to those detected after single administrations of fatty acids and valproic acid in our previous studies, specifically to an increase in the kynurenine pathway activity and changes in peripheral and central BCAA and AAA levels. This suggests that the anticonvulsant effect of the KD may be at least partially associated with those observed biochemical alternations.
Introduction: Complex regional pain syndrome (CRPS) is a debilitating disease with limited available treatment options. Spinal cord stimulation (SCS) is a universal option that promises to improve quality of life by reducing intractable neuropathic pain. The aim of this study was to describe the effectiveness and safety of SCS as a treatment for CRPS patients. Clinical rationale for the study: SCS as an invasive method has relatively recently been introduced to CRPS therapy. We hypothesised that by assessing the effectiveness and safety of SCS, we could justify its early use in the treatment of this debilitating condition. Material and methods: CRPS is a multifactorial and disabling disorder with complex aetiopathogenesis. The primary goals of CRPS treatment include pain relief, functional restoration, and psychological stabilisation. Early intervention is needed to achieve these objectives. In this study, we performed a retrospective evaluation of clinical outcomes in seven patients with severe, intractable CRPS treated by SCS. All patients underwent implantation of a non-rechargeable prime advanced MRI implantable pulse generator (IPG) (Medtronic, Minneapolis, MN, USA) between December 2017 and December 2020 using identical surgical and intraprocedural techniques. Results: From a total of 21 patients treated with SCS over the three years in question, seven (33%) were diagnosed with severe CRPS. The duration of chronic pain ranged between two and 12 years. In six cases (86%), an electrode was implanted in the thoracic segment. Good (partial pain reduction) or very good (complete pain relief) treatment results were observed in five patients (72%). In two cases (28%), two revision surgeries were performed for wound debridement. These hardware-related complications were primarily related to erosions located over implanted IPG's. Conclusions and clinical implications: SCS is the best alternative for patients with CRPS. It should be used immediately after the failure of conservative treatment. Despite the relatively high complication rate in our series, it is the best choice for pain reduction management in this select group of patients.
Background Recent discoveries show that high-intensity interval training (HIIT) can bring many positive effects such as decreases in fat tissue, lower blood sugar levels, improved learning and memory, and lower risk of cardiac disease. Parkinson’s disease (PD) is a neurodegenerative disorder characterized by loss of the dopaminergic neurons, accompanied by chronic inflammation and neuroinflammation. Previous research shows that interval training can bring a beneficial effect on the inflammation and neuroplasticity in PD. Objectives The objective of this study was to investigate the effect of 12 weeks of HIIT on the inflammation levels and antioxidant capacity in the serum of PD patients. Methods Twenty-eight people diagnosed with PD were enrolled in this study. Fifteen PD patients performed 12 weeks of HIIT on a cycloergometer. Thirteen non-exercised PD patients constitute the control group. Concentrations of inflammation markers and antioxidants’ capacity in the serum were measured at 3 sampling points (a week before, a week after, and 3 months after the HIIT). Results Twelve weeks of HIIT decreases the level of TNF-α ( p = 0.034) and increases the level of IL-10 ( p = 0.024). Those changes were accompanied by a decreased level of neutrophils ( p = 0.03), neutrophil/lymphocyte ratio ( p = 0.048) and neutrophil/monocyte ratio ( p = 0.0049) with increases in superoxide dismutase levels ( p = 0.04). Conclusions Twelve weeks of HIIT can decrease systemic inflammation in PD patients and improve the antioxidant capacity in their serum, which can slow down the progression of the disease.
Introduction: The expansion of a hexanucleotide GGGGCC repeat (G4C2) in the C9orf72 locus is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In addition, C9orf72 expansion has also been detected in patients with a clinical manifestation of Parkinson's Disease (PD), Alzheimer's Disease (AD), Huntington's Disease (HD), and ataxic disorders. Material and methods: A total of 1,387 patients with clinically suspected ALS, HD or spinal and bulbar muscular atrophy (SBMA) were enrolled, and the prevalence of C9orf72 expansions was estimated. Results: The hexanucleotide expansion accounted for 3.7% of the ALS patients, 0.2% of the HD suspected patients with excluded HTT mutation, and 1.3% of the suspected SBMA patients with excluded mutation in AR gene. Conclusions: This is the first report revealing the presence of C9orf72 expansion in patients with a suspected SBMA diagnosis. Consequently, we advise testing for C9orf72 expansion in patients presenting with the SBMA phenotype and a genetically unsolved diagnosis.
Patient‐reported helpfulness of treatment is an important indicator of quality in patient‐centered care. We examined its pathways and predictors among respondents to household surveys who reported ever receiving treatment for major depression, generalized anxiety disorder, social phobia, specific phobia, post‐traumatic stress disorder, bipolar disorder, or alcohol use disorder. Data came from 30 community epidemiological surveys – 17 in high‐income countries (HICs) and 13 in low‐ and middle‐income countries (LMICs) – carried out as part of the World Health Organization (WHO)’s World Mental Health (WMH) Surveys. Respondents were asked whether treatment of each disorder was ever helpful and, if so, the number of professionals seen before receiving helpful treatment. Across all surveys and diagnostic categories, 26.1% of patients (N=10,035) reported being helped by the very first professional they saw. Persisting to a second professional after a first unhelpful treatment brought the cumulative probability of receiving helpful treatment to 51.2%. If patients persisted with up through eight professionals, the cumulative probability rose to 90.6%. However, only an estimated 22.8% of patients would have persisted in seeing these many professionals after repeatedly receiving treatments they considered not helpful. Although the proportion of individuals with disorders who sought treatment was higher and they were more persistent in HICs than LMICs, proportional helpfulness among treated cases was no different between HICs and LMICs. A wide range of predictors of perceived treatment helpfulness were found, some of them consistent across diagnostic categories and others unique to specific disorders. These results provide novel information about patient evaluations of treatment across diagnoses and countries varying in income level, and suggest that a critical issue in improving the quality of care for mental disorders should be fostering persistence in professional help‐seeking if earlier treatments are not helpful.
Background and purpose: The association of dyslipidemia with stroke has been inconsistent, which may be due to differing associations within etiological stroke subtypes. We sought to determine the association of lipoproteins and apolipoproteins within stroke subtypes. Methods: Standardized incident case-control STROKE study in 32 countries. Cases were patients with acute hospitalized first stroke, and matched by age, sex and site to controls. Concentrations of total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (apoA1), and apoB were measured. Non-HDL-C was calculated. We estimated multivariable odds ratio (OR) and population attributable risk percentage (PAR%). Outcome measures were all stroke, ischemic stroke (and subtypes), and intracerebral hemorrhage (ICH). Results: Our analysis included 11,898 matched case-control pairs; 77.3% with ischemic stroke and 22.7% with ICH. Increasing apoB (OR, 1.10; 95% confidence interval [CI], 1.06 to 1.14 per standard deviation [SD]) and LDL-C (OR, 1.06; 95% CI, 1.02 to 1.10 per SD) were associated with an increase in risk of ischemic stroke, but a reduced risk of ICH. Increased apoB was significantly associated with large vessel stroke (PAR 13.4%; 95% CI, 5.6 to 28.4) and stroke of undetermined cause. Higher HDL-C (OR, 0.75; 95% CI, 0.72 to 0.78 per SD) and apoA1 (OR, 0.63; 95% CI, 0.61 to 0.66 per SD) were associated with ischemic stroke (and subtypes). While increasing HDL-C was associated with an increased risk of ICH (OR, 1.20; 95% CI, 1.14 to 1.27 per SD), apoA1 was associated with a reduced risk (OR, 0.80; 95% CI, 0.75 to 0.85 per SD). ApoB/A1 (OR, 1.38; 95% CI, 1.32 to 1.44 per SD) had a stronger magnitude of association than the ratio of LDL-C/HDL-C (OR, 1.26; 95% CI, 1.21 to 1.31 per SD) with ischemic stroke (P<0.0001). Conclusions: The pattern and magnitude of association of lipoproteins and apolipoproteins with stroke varies by etiological stroke subtype. While the directions of association for LDL, HDL, and apoB were opposing for ischemic stroke and ICH, apoA1 was associated with a reduction in both ischemic stroke and ICH. The ratio of apoB/A1 was the best lipid predictor of ischemic stroke risk.
Background Morbid obesity (MO) has been steadily increasing in the last few years. Pharmacotherapy and bariatric surgeries remain the main treatment modalities for MO, although in the long-term they may lose their effectiveness. Other treatment approaches are urgently needed and deep brain stimulation (DBS) is a promising therapy. Disturbed energy homeostasis caused by intake of highly palatable and caloric foods may induce hedonic eating. The brain nuclei responsible for energy homeostasis and hedonia are the hypothalamic nuclei and nucleus accumbens. These brain structures constitute the stereotactic targets approached with DBS to treat MO. Material and Methods We have performed a literature search of all available clinical applications of DBS for MO in humans. We were able to identify three case series reports and additional six case reports involving 16 patients. The selected stereotactic targets included lateral hypothalamus in eight patients, ventromedial hypothalamus in two patients, and nucleus accumbens in six patients. Results In general, the safety profile of DBS in refractory MO patients was good. Clinical improvement regarding the mean body mass index could be observed in obese patients. Conclusions MO is a demanding condition. Since in some cases standardized treatment is ineffective, new therapies should be implemented. DBS is a promising therapy that might be used in patients suffering from MO, however, more studies incorporating more individuals and with a longer follow-up are needed to obtain more reliable results concerning its effectiveness and safety profile.
Hereditary ataxias (HA) are a rare group of heterogeneous disorders. Here, we present the results of molecular testing of a group of ataxia patients using a custom-designed next-generation sequencing (NGS) panel. Due to the genetic and clinical overlapping of hereditary ataxias and spastic paraplegias (HSP), the panel encompasses together HA and HSP genes. The NGS libraries, comprising coding sequences for 152 genes, were performed using KAPA HyperPlus and HyperCap Target Enrichment Kit, sequenced on the MiSeq instrument. The results were analyzed using the BaseSpace Variant Interpreter and Integrative Genomics Viewer. All pathogenic and likely pathogenic variants were confirmed using Sanger sequencing. A total of 29 patients with hereditary ataxias were enrolled in the NGS testing, and 16 patients had a confirmed molecular diagnosis with diagnostic accuracy rate of 55.2%. Pathogenic or likely pathogenic mutations were identified in 10 different genes: POLG (PEOA1, n = 3; SCAE, n = 2), CACNA1A (EA2, n = 2), SACS (ARSACS, n = 2), SLC33A1 (SPG42, n = 2), STUB1 (SCA48, n = 1), SPTBN2 (SCA5, n = 1), TGM6 (SCA35, n = 1), SETX (AOA2, n = 1), ANO10 (SCAR10, n = 1), and SPAST (SPG4, n = 1). We demonstrated that an approach based on the targeted use of the NGS panel can be highly effective and a useful tool in the molecular diagnosis of ataxia patients. Furthermore, we highlight the fact that a sequencing panel targeting both ataxias and HSP genes increases the diagnostic success level.
Multiple sclerosis (MS) is a central nervous system chronic neuroinflammatory disease followed by neurodegeneration. The diagnosis is based on clinical presentation, cerebrospinal fluid testing and magnetic resonance imagining. There is still a lack of a diagnostic blood-based biomarker for MS. Due to the cost and difficulty of diagnosis, new and more easily accessible methods are being sought. New biomarkers should also allow for early diagnosis. Additionally, the treatment of MS should lead to the personalization of the therapy. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) as well as their target genes participate in pathophysiology processes in MS. Although the detailed mechanism of action of non-coding RNAs (ncRNAs, including miRNAs and lncRNAs) on neuroinflammation in MS has not been fully explained, several studies were conducted aiming to analyse their impact in MS. In this article, we review up-to-date knowledge on the latest research concerning the ncRNAs in MS and evaluate their role in neuroinflammation. We also point out the most promising ncRNAs which may be promising in MS as diagnostic and prognostic biomarkers.
Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The National Centre for Research and Development, Poland Introduction Bipolar radiofrequency ablation (BFRA) emerged as a viable technique of radiofrequency ablation where the standard unipolar approach (RFA) failed. A number of studies describing BRFA were published recently suggesting high effectiveness and acceptable safety of this technology for ablation of ventricular tachycardia in structural heart disease (SHD VT), premature ventricular contractions (PVC) or atrial flutter (AFL). Purpose We performed a systematic review with meta-analysis of available evidence to assess contemporary evidence on the effectiveness and safety of bipolar ablation of heart arrhythmia. Methods We systematically searched MEDLINE, EMBASE, and CENTRAL databases from inception to 27 August 2022 for prospective and retrospective studies with or without a control group. We also contacted BRFA experts to obtain information on the most up-to-date studies or conference presentations. Case studies and papers describing technical aspects of BRFA rather than clinical outcomes were excluded. Study quality was assessed using the Newcastle–Ottawa Scale. Results Out of 1919 records we included 12 studies: one good quality case-control study and 11 low-quality case series without a control group. Studies described 120 patients who received BFRA: mean age 61.9±10.3 years, 81% males, mean ejection fraction 43.2±12.4, SHD 62.6%, ICD/CRT-D 52.2%. Almost all patients were qualified to BRFA due to failure of at least one unipolar RFA. Follow-up period differed between studies and ranged between 1-2 years in most cases. The overall acute effectiveness of BRFA was 88.2% (95%CI 82.5-93.8), I2=6.7%. The overall effectiveness of a first BRFA at the end of the follow-up period was 55% (95%CI 46.2-63.7), I2=7.2%. There was a need for a re-ablation in 21.2% patients (95%CI 11.2-31.2), I2=64%. A subgroup analysis for SHD VT, PVC and AFL yielded similar results. There were 16 serious complications including one surgical intervention and no acute deaths; five patients died during the follow-up, mainly due to heart failure progression. Conclusions Bipolar radiofrequency ablation may be an effective and safe procedure in selected patients who failed at least one unipolar radiofrequency ablation but the quality of the supporting evidence is generally low.
Objectives To analyse additional structural and genetic anomalies in fetuses with acrania/exencephaly/anencephaly sequence (AEAS). Methods A retrospective analysis of 139 fetuses with AEAS diagnosed between 2006 and 2020 in a single tertiary referral ultrasound department. Results The median gestational age at diagnosis decreased from 15 weeks in 2006 to 13 weeks in 2020 (− 0.21 per each year; p = 0.009). In 103 fetuses, the defects were limited to the neural tube (NTD) (74.1%), in 36 fetuses (25.9%), there were additional structural non-NTD anomalies. The most common were ventral body wall defects present in 17.8% (23/139), followed by anomalies of the limbs (7.2%; 10/139), face (6.5%; 9/139) and heart (6.5%; 9/139). Genetic anomalies were diagnosed in 7 of the 74 conclusive results (9.5%; 7/74; trisomy 18, n = 5; triploidy, n = 1; duplication of Xq, n = 1). In univariate logistic regression models, male sex, limb anomalies and ventral body wall defects significantly increased the risk of genetic anomalies (OR 12.3; p = 0.024; OR 16.5; p = 0.002 and OR 10.4; p = 0.009, respectively). Conclusions A significant number of fetuses with AEAS have additional structural non-NTD anomalies, which are mostly consistent with limb body wall complex. Genetic abnormalities are diagnosed in almost 10% of affected fetuses and trisomy 18 is the most common aberration. Factors that significantly increased the odds of genetic anomalies in fetuses with AEAS comprise male sex, limb anomalies and ventral body wall defects.
Provision of mental health care in Poland has long been characterised by an overreliance on psychiatric hospitals and the underdevelopment of community care. The introduction of the first National Mental Health Protection Programme for 2011–2015, with the explicit goal to base provision of mental care on the community mental health centres, failed to achieve any tangible results. The ensuing critique led to the launch of the second National Mental Health Protection Programme for 2017–2022 and the establishment, from mid-2018 onwards, of 41 (33 in operation) mental health centres across Poland. These will be piloted until the end of 2022 but have already shown positive results in terms of access to non-stationary care and a small fall in hospitalisations. They have also performed well during the COVID-19 pandemic, allowing for a quick reorganization of care and continued provision of mental health services. Some of the key innovations of the new model include the introduction of recovery assistants (a new profession) and mental health coordinators (a new role); liaison with social assistance services; and a shift to budget financing. The key obstacles to the national rollout of mental health centres are the low financing of mental health care in Poland, which is among the lowest in Europe, and acute workforce shortages.
The metabolic disorder Wilson’s disease (WD) is caused by copper accumulation in the tissues due to a biallelic pathogenic mutation of the gene ATP7B, encoding intracellular copper transporter ATPase-7B. As copper is a redox active metal; aberrations in its homeostasis may create favourable conditions for superoxide-yielding redox cycling and oxidative damage to the cells. We tried to characterise antioxidant defence in WD patients and to evaluate whether it is related to liver function. The blood glutathione concentration, the activity of manganese-SOD (MnSOD), catalase (Cat), glutathione peroxidase, and glutathione S-transferase glutathione (GST), and serum antioxidant potential (AOP-450) were measured in WD treatment-naive patients and healthy controls and correlated with clinical data. The blood glutathione concentration, the activity of MnSOD, Cat, glutathione peroxidase, and GST and AOP-450 are signifcantly decreased in WD patients. There was a positive correlation of AOP-450 with AST. Moreover, the Cat and GST activity as well as AOP-450 strongly correlated with parameters of synthetic liver function. MnSOD activity correlated positively with ALT and AST.The blood glutathione concentration, the activity of MnSOD, Cat, glutathione peroxidase, and GST and AOP-450 are signifcantly decreased in WD patients. There was a positive correlation of AOP-450 with AST. Moreover, the Cat and GST activity as well as AOP-450 strongly correlated with parameters of synthetic liver function. MnSOD activity correlated positively with ALT and AST. Liver injury in course of WD is linked with decreased antioxidant capacity.
Purpose Both depression and loneliness have been recognized as major public health issues, yet investigation into their role among young and middle-aged, professionally active persons is still required. The aim of the present study was to evaluate whether depression and loneliness may independently predict inefficiency at work among professionally active adults. Methods This is a cross-sectional study on a representative, nationwide sample. 1795 questionnaires were gathered from among professionally active adults from Poland from 1 to 31 July 2018 with a direct pen-and-paper interview. The sample was chosen by means of the stratified random method. The survey included a Patient Health Questionnaire (PHQ-9) to measure depression and questions, devised by the authors, relating to loneliness and inefficiency at work. Regression models were constructed with depression and loneliness as predictors of inefficiency at work, unadjusted and adjusted for selected sociodemographic, health- and work-related factors. Results In the unadjusted models, both depression and loneliness were independently associated with an increase of work inefficiency and absence from work, with effect sizes being higher for loneliness than for depression. After accounting for the control variables (i.e., sociodemographic, work- and health-related factors), the PHQ-9 score, but not the loneliness score, was associated with an increased probability of frequent thoughts about changing or leaving a job. Conclusion Depression and loneliness independently predicted occupational functioning and differentially affect its various aspects. Counteracting depression and loneliness among employees should be regarded as a public health priority.
Introduction: The X and Y chromosomes are responsible for the determination and differentiation of the gonads, and their numerical and structural abnormalities may cause the abnormal development of secondary sex characteristics. The presence of abnormalities concerning X chromosome can also contribute to many genetically heterogeneous diseases associated with cognitive impairment and intellectual disability. Purpose: This study shows the effect of aberrations of the maternal X chromosome on the abnormal development of the child. Patients and methods: Ten women aged 26 to 40 years were consulted in genetic counselling clinic and subsequently subjected to cytogenetic and molecular tests due to abnormal psychomotor development of their children, in whom structural aberrations of the X chromosome had been detected. Results: Two women were diagnosed with changes in karyotype: 46,X,der(X)t(X;Y)(p22.3;q11.2) in one and 46,X,inv(X)(p21.2q13). Five women were diagnosed with microduplications in the short arm of the X chromosome; dupXp22.31 in one, and in four women dupXp22.33. The remaining three women were diagnosed with duplication in the long arm of the X chromosome; dupXq25 in one and dupXq26.3 in two women. Conclusion: Genetic analysis of the X chromosome, based on cytogenetic and molecular methods of the highest available resolution, is extremely important in women with reproductive failure. These methods allow establishing accurately the breakpoints and rearrangements in chromosomes, and assessment of the copy number variation (CNV) can explain phenotypic variability with apparently similar aberrations. A more precise characterization of the alterations is necessary for the correct genetic diagnosis, as well as determination of the carrier status and genetic risk in family members.
Purpose: Narcolepsy type-1 (NT1) is a rare chronic neurological sleep disorder with excessive daytime sleepiness (EDS) as usual first and cataplexy as pathognomonic symptom. Shortening the NT1 diagnostic delay is the key to reduce disease burden and related low quality of life. Here we investigated the changes of diagnostic delay over the diagnostic years (1990-2018) and the factors associated with the delay in Europe. Patients and methods: We analyzed 580 NT1 patients (male: 325, female: 255) from 12 European countries using the European Narcolepsy Network database. We combined machine learning and linear mixed-effect regression to identify factors associated with the delay. Results: The mean age at EDS onset and diagnosis of our patients was 20.9±11.8 (mean ± standard deviation) and 30.5±14.9 years old, respectively. Their mean and median diagnostic delay was 9.7±11.5 and 5.3 (interquartile range: 1.7-13.2 years) years, respectively. We did not find significant differences in the diagnostic delay over years in either the whole dataset or in individual countries, although the delay showed significant differences in various countries. The number of patients with short (≤2-year) and long (≥13-year) diagnostic delay equally increased over decades, suggesting that subgroups of NT1 patients with variable disease progression may co-exist. Younger age at cataplexy onset, longer interval between EDS and cataplexy onsets, lower cataplexy frequency, shorter duration of irresistible daytime sleep, lower daytime REM sleep propensity, and being female are associated with longer diagnostic delay. Conclusion: Our findings contrast the results of previous studies reporting shorter delay over time which is confounded by calendar year, because they characterized the changes in diagnostic delay over the symptom onset year. Our study indicates that new strategies such as increasing media attention/awareness and developing new biomarkers are needed to better detect EDS, cataplexy, and changes of nocturnal sleep in narcolepsy, in order to shorten the diagnostic interval.
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207 members
Lukasz Wieczorek
  • Department of Studies on Alcoholism and Drug Dependence
Tomasz Litwin
  • Second Department of Neurology
Jan Bembenek
  • Department of Clinical Neurophysiology
Tadeusz Mendel
  • Second Department of Neurology
Agnieszka Ługowska
  • Department of Genetics
Sobieskiego 9, 02-957, Warsaw, Poland